key: cord- -fhm abxp authors: wang, hao; duan, qianglin; wang, lemin; gong, zhu; liang, aibin; wang, qiang; song, haoming; yang, fan; song, yanli title: analysis on the pathogenesis of symptomatic pulmonary embolism with human genomics date: - - journal: int j med sci doi: . /ijms. sha: doc_id: cord_uid: fhm abxp background: in the present study, the whole human genome oligo microarray was employed to investigate the gene expression profile in symptomatic pulmonary embolism (pe). methods: twenty patients with pe and age and gender matched patients without pe as controls were enrolled into the present study in the same period. the diagnosis of pe was based on the clinical manifestations and findings on imaging examinations. acute arterial and/or venous thrombosis was excluded in controls. the whole human genome oligo microarray was employed for detection. statistical analysis was performed with t test following analysis of very small samples of repeated measurements and gene ontology (go) analysis. results: genomic data showed no damage to vascular endothelial cells in pe patients. genomic data only found increased mrna expression of a small amount of coagulation factors in pe patients. in the pe group, anticoagulant proteins, fibrinolytic system and proteins related to platelet functions only played partial roles in the pathogenesis of pe. in addition, the mrna expressions of a fraction of adhesion molecules were markedly up-regulated. gene ontology analysis showed the genes with down-regulated expressions mainly explain the compromised t cell immunity. symptomatic vte patients have compromised t cell immunity. conclusion: the damage to vascular endothelial cells is not necessary in the pathogenesis of vte, and only a fraction of factors involved in the shared coagulation cascade are activated. genomic results may provide a new clue for clinical diagnosis, treatment and prevention of vte. thrombus which may result in pulmonary embolism (pe) mostly comes from deep venous thrombosis (dvt). altogether, both pe and dvt are named venous thromboembolism (vte). because of the high incidence of misdiagnosis, morbidity and mortality, vte has become one of the essential medical problems around world ( , ) . after 's, clinical report of incidence of pe are sharply increased yearly in china ( ) . after 's, clinical reports of pe are sharply increased yearly in china ( ) . in other asia ivyspring international publisher regions, such as japan, thailand, singapore, taiwan, the number of reported pe cases is also increasing ( ) ( ) ( ) ( ) ( ) . there are nearly , new pe cases in usa every year ( ) , , new cases in canada, , - , cases in europe including france, italy, spain, britain, germany, and , cases in australia every year ( ). according to the statistical data, provided by an epidemiological surveillance in us, pe is the third leading cause of death ( , ) , only lags behind malignancy and myocardial infarction. virchow's classical triad of abnormalities including blood stasis, hypercoagulability and vessel damage has been regarded as the authentic theory for explaining pathogenesis of vte since 's century ( ) , however, the triad does not fit all clinical profiles. in , egeberg et al ( ) firstly introduced the concept of thrombophilia based on discovering a family with an autosomal dominant inheritance disease whose members manifested with repeatedly onset of dvt due to depletion of antithrombin iii. since then, many reports have considered that genetic gene mutation was one of the major factors in the pathogenesis of vte ( ) , but there has been a lack of sufficient genetic etiology evidence in many clinical pe patients. in recent years, some scholars have suggested that dvt-pe is a heterogeneous polygenic and multifactor disease involving the interaction of hereditary factors and environment with many risk factors such as trauma, surgery, advanced age, malignancy, pregnancy, heart failure, stasis, oral contraceptive, and so on ( ) . in and , accp proposed risk stratifications in patients receiving surgery, and different strategies should be performed for patients with different risks to prevent the occurrence of vte ( , ) . however, the annual number of vte cases is increasing over year actually. generally, the traditional concept can merely be verified merely in few patients with vte, the pathogenesis of majority of other patients is still to be elucidated. gene chip analysis provides the advanced tool for the study of gene function ( ) ( ) ( ) . it can be a reliable approach for the study of differential gene expression between healthy people and patients and for the elucidation of molecular etiology of vte. twenty patients enrolled in pe group were those who admitted in hospital during , with males and females, averaged (± ) years of age( - years old). all patients were diagnosed as pe in accordance with at least of following criteria. )selective pulmonary arteriography showed filling defect or blockage; ) pulmonary ventilation perfusion scanning exhibited single or multiple blood flow perfusion defect with normal or abnormal ventilation, mismatched ratio of ventilation/perfusion; ) other clinical characteristics including typical manifestation of pe, arterial blood gas analysis, d-dimer test, ultrasoundcardiogram (ucg) and chest computerized tomography (ct) supported the diagnosis and excluded other cardiac and pulmonary disorders. twenty patients with ischemic heart disease admitted at same period, excluding pe, dvt and other congenital bleeding and thrombosis diseases with comparative clinical presentation ( males, females, - years old with mean age ± ) were enrolled in control group. the study protocol was approved by local ethics committee and informed consent was obtained from all patients in accordance with the declaration of helsinki. total rna isolation ml of peripheral blood samples anti-coagulated with edta were drawn from patients suspected with pe immediately after admitting to the hospital and from those patients without pe, respectively. mononuclear cells were obtained through density gradient centrifugation with ficoll solution and remaining red blood cells were destroyed with erythrocyte lysis buffer (qiagen, hilden, germany). total mononuclear cell rna was extracted with trizol(invitrogen, carlsbad, usa) and purified with qiagen rneasy column (qiagen, hilden, germany) according to the manufacturer's instructions. isolated total rna was testified and quantified by means of nanodrop nd- spectrophotometer (nanodrop technology, cambrige, uk). rna samples of patients with confirmed diagnosis of pe and controls were labeled using indirect labeling method. briefly, μg of total rna was reverse transcribed. the cdna then undergoes second strand synthesis and clean-up to become a template for in vitro transcription (ivt) with t rna polymerase. during ivt, the modified nucleotide, -( -aminoallyl)-utp (aautp) was incorporate into the cdna. after that, fluorescent cy was chemically coupled to aautp which contains a reactive primary amino group on the c position of uracil. the dye incorporation rate was assessed with a nanodrop nd- spectrophotometer and was found to be between . and . pmol/μl. hybridization was carried out using the agilent oligonucleotide microarray in situ hybridization plus kit (p/n - ), fol-lowing the manufacturer's instructions. briefly, ng of cy labeled sample cdna was subjected to fragmentation ( min at °c) and then hybridization on k human whole-genome -mer oligo-chips (g f, agilent technologies) in a rotary oven ( rpm, °c, h). slides were disassembled and washed in solutions i and ii according to the manufacturer's instructions. significant differential gene expression analysis random variance model (rvm) corrected t-test was used for the differential gene expression screening due to the small number of patients ( cases each group) was far less than the amount of genes and low freedom degree of gene expression signal. p< . is criterion of significantly different genes. gene ontology organizes gene function into hierarchical categories based on biological process, molecular function and cellular component ( ) ( ) ( ) . fisher's exact test was applied for over representation of selected genes in go biological categories. in order to assess the significance of a particular category by random chance, false discovery rate (fdr) was estimated for all of categories. after , re-samplings, fdr was defined as fdr= -nk/t, where nk refers to the subtracted number which was from fisher's test p-values minus ϰ test p-values in random samples. we specified the threshold of significant go as p-value< . , fdr< . and enrichment parameters. enrichment represents the degree of gene expression significance. the equation of enrichment is as following re=(nf/n)/(nf/n) where nf is the number of significant genes within the particular category, n is the total number of genes within the same category, nf is the number of significant genes in the entire microarray, n is the number of all genes tested. similar to go analysis, fisher's exact test was employed for the study of over-representation of selected genes. according to the traditional theory, the pathogenesis of vte is associated with abnormalities in blood flow, vessel integrity and blood components. therefore, we compared gene expressions of these vte related factors in patients with pe and without pe. among the expressions of coagulation factor genes, only gene expressions of factor Ⅶ and fibcd were significantly elevated in patients with pe compared with patients without pe. as for genes of other coagulant factors, the expression value of patients with pe was either not significantly different or less than those patients without pe in comparison. there was no significant difference between two groups of patients in gene expression of anticoagulant proteins. and so was in gene expression of fibrinolytic factors except plasminogen urokinase receptor (plaur, fig. ). l-selectin, itgal and icam- are the adhesion molecules originated from different family, mainly distributed on the surface of lymphocytes. icam- is the ligand of itgal which is member of integrin family. significantly elevated mrna expression of these adhesion molecules in pe group indicate activated adhesion function of white blood cells. however, mrna expression of p-selectin (mainly distributed on the surface of ecs and platelets) and e-selection (mainly distributed on the surface of activated ecs) are not elevated in pe group which indicate venous endothelial cells are not impaired in patients with pe (fig. ) . in expression of platelet aggregation related genes, only genes (gp and pafah b ) were significantly elevated in the patients with pe. compared to patients without pe, the expressions of in genes of platelet adhesion function were significantly increased in patients with pe. as for genes of platelet releasing, the expression of one gene was significantly up and down regulated between groups of patients, respectively (fig. ). to identify the gene categories with differential expression in patients with or without pe, gene ontology analysis was carried out on the experiment data. the union of all differential expression genes resulted from data analysis are genes in patients with pe compared to patients without pe. among them, genes are up-regulated and are down-regulated. the main gene ontology categories impacted by these genes involve the up-regulation of functioning categories against down-regulation categories. up-regulated genes are those genes whose functions are associated with transformation, phosphorylation, cell survival and cell conjugation, et al. while the function of down-regulated genes are relevant to the function of plasma membrane and activity of receptors, especially to the lymphocyte receptor complex and immunological synapse (fig. ) . gene ontology analysis exhibited compromised t cell mediated immune function, and t test indicated associated genes were significantly down-regulated in patients with pe than in control groups. two genes with down-regulated expressions are closely related to the t cell mediated immunity according to go analysis (with high value of enrichment). these results reveal that t cell mediated immunity has been declined markedly in pe patients. the declined t cell receptor complex displayed as significanlly diminished mrna expression of cd g, cd d, cd , zap- , t cell granzyme a and b, which will result in loss of functions of cytotoxic t cells. additionally, the high mrna expression of l-selectin, itgal and icam- in pe patients revealed the elevated adhesion of vascular endothelial cells, white blood cells and platelets which indicated that the adhesion molecules play an important role in the pathogenesis of vte. the functions of platelets are characterized by aggregation, adhesion and release response ( ) . our results showed the mrna expressions of / adhesion molecules were markedly up-regulated in pe patients, which suggests the adhesion of platelets plays an important role in the pathogenesis of pe. in , we reported the proportions of cd +t cells and cd +t cells were markedly reduced and cd /cd significantly increased in a series of cteph patients, which suggests the compromised t cell immunity in cteph patients and imbalance between cd +t cells and cd +t cells ( ) . in addition, we also found that the number of cd +t cells and cd +t cells was dramatically reduced in a series of acute pe patients and cytological findings also supported the results from genomics studies on pe patients ( ) . the occurrence of pe is related to the deficient or compromised t cell mediated immunity. this deficiency of t cell immunity may occur under the following conditions: ) viral infection; ) malignant tumors; ) medication with immunosuppresants; ) malnutrition. in the present study, most of subjects were old patients and malnutrition was not clinically obvious. moreover, malignant tumors were not found in these patients and medication with immunosuppressants was absent. thus, the compromised t cell immunity might be possibly related to viral infection. in , we reported a patient who died of sars developed vte in multiple organs, which implies the viral infection induced systemic vte and there is correlation between viral infection and occurrence and vte ( ) . comparisons between pe patients and controls revealed the mrna expressions of only a few proteins in the coagulation system, anti-coagulation system and fibrinolysis system were markedly up-regulated and only factors or receptors in the shared coagulation cascade were activated, which was inconsistent with traditional theory that coagulation factors are comprehensively activated. we reported in our previous study that the main component of thrombus in acute venous thrombosis was fibrinogen and albumin and cytoskeletal proteins accounted for only a minor fraction of the thrombus ( ) . the thrombus composed of fibrinogen is unstable, which makes the delayed thrombolysis feasible and also explain the therapeutic effectiveness of transcatheter thrombolysis not long after ape. findings support that the formation of thrombus in vte is not due to the comprehensive activation of coagulation factors as in traditional theory. in the present study, we apply the unitarian theory to explain the pathogenesis of symptomatic vte: the occurrence of symptomatic vte is closely related to the compromised immune function as well as the viral infection. this also explains why vte is frequently found in patients with advanced age, trauma, surgery, malignant tumors, heart failure, immobilization, pregnancy and other risk factors. our findings provide new knowledge on the etiology and pathophysiology of vte and novel clue for the clinical diagnosis, treatment and prevention of vte. prevention and treatment of venous thromboembolism. international 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confusion of wide thrombolytic time window for acute pulmonary embolism: mass spectrographic analysis for thrombus proteins this study was supported by " th five year" national science and technology supporting program ( bai b ). the authors have declared that no competing interest exists. key: cord- -fpzk k authors: patti, giuseppe; lio, veronica; cavallari, ilaria; gragnano, felice; riva, letizia; calabrò, paolo; di pasquale, giuseppe; pengo, vittorio; rubboli, andrea title: questions and answers on practical thrombotic issues in sars-cov- infection: a guidance document from the italian working group on atherosclerosis, thrombosis and vascular biology date: - - journal: am j cardiovasc drugs doi: . /s - - - sha: doc_id: cord_uid: fpzk k in patients with coronavirus disease (covid- ), the prevalence of pre-existing cardiovascular diseases is elevated. moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. thus, the identification of optimal antithrombotic strategies in terms of the risk–benefit ratio and outcome improvement in this setting is crucial. however, debated issues on antithrombotic therapies in patients with covid- are multiple and relevant. in this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus (sars-cov- ) infection based on the scientific evidence gathered during the pandemic. since december , when the first cases of interstitial pneumonia were identified in the province of wuhan, china, the infection due to severe acute respiratory syndrome coronavirus (sars-cov- ) has rapidly involved a large part of the population worldwide, reaching the global pandemic level. national health systems had to implement public health responses to protect their populations and limit viral diffusion. in patients with coronavirus disease (covid- ) , the high prevalence of cardiovascular comorbidities [ ] and the increased incidence of thrombotic events, sustained by multiple factors (fig. ) , made complex and, at the same time, crucial the optimization of antithrombotic treatments. moreover, guideline recommendations in this setting should be followed, taking into account peculiar features related to the pandemic, in particular, the modalities of transmission and the high contagiousness of sars-cov- , with the related need for use of appropriate personal protective equipment and the design of specific in-hospital diagnostic and therapeutic protocols. in this guidance document, we provide ten questions and answers on issues related to risk stratification and antithrombotic treatments in patients at risk of/with sars-cov- infection based on the scientific evidence gathered during the pandemic. in patients on oral anticoagulant therapy (oac) who are at risk of contagion or have mild covid- and are treated at home, anticoagulation should be individualized according to the patient's characteristics, clinical indication for oac [atrial fibrillation (af), venous thromboembolism (vte), prosthetic heart valve], severity of infection, and therapies used for the viral infection. the duration of oac for preventing af-related thromboembolism is generally lifelong, based on the patient's cha ds -vasc score (> for males and > for females) [ ] . patients with vte usually receive oac for - months after the event, but treatment is frequently prolonged in the presence of relapsing episodes or a high risk of recurrence (i.e., idiopathic thromboembolism, cancer, antiphospholipid syndrome, and severe congenital thrombophilias) [ ] . patients with mechanical valve prostheses are given oac for their lifetime, whereas oac duration is limited to months post-implantation in the case of a biological prosthesis. during the pandemic, lockdown measures reducing interindividual contacts were applied in several countries to contain viral diffusion; thus, the indication was to stay home to keep safe, which was especially addressed to patients with more advanced age or comorbidities. this should be specifically applied to patients with af or vte, who are often older and have a higher prevalence of previous cardiovascular diseases or cancer. moreover, health systems worldwide dealt with an emergency never seen before and had to limit elective, non-urgent, ambulatory visits. therefore, in this context, the management of patients receiving vitamin k antagonist anticoagulants (vkas) for af or vte was even more problematic. for these patients, it became difficult to access the centers for international normalized ratio (inr) control, especially if more frequent monitoring was needed because of unstable inr values (which is not uncommon). moreover, during the outbreak, public centers for inr control had a reduced number of staff members due to the redistribution of care workers for the emergency and re-addressed or limited the outpatient flow to contain the viral diffusion as much as possible. finally, general practitioners were not able to immediately assist patients on vkas in need of inr adjustments, as they were also fully involved in the management of covid- patients. accordingly, in patients at risk for sars-cov- infection on vkas and who have substantial "stability" in their inr [ ] . switching from vkas to direct oral anticoagulants (doacs) must be considered [ ] . in patients with mild covid- treated at home who are on vkas, the use of portable coagulometer devices should be implemented [ ] . moreover, switching from vkas to doacs has a clear indication. in fact, the duration of home isolation can be longer than weeks; inr values are generally unstable during acute infection or illness; and paracetamol decreases the synthesis of vitamin k-dependent clotting factors [ ] , and therefore there is a major interaction between vkas and this drug largely utilized for covid- -related fever (fig. ). treatment approaches in patients with covid- include a combination of several drugs with virtually synergistic effects acting at different steps of the pathogenetic mechanisms of the disease [ ] . scientific evidence in this regard is currently limited but in continuous and rapid evolution [ ] . in the first period of the sars-cov- pandemic, a widespread practice pattern was to treat with hydroxychloroquine both patients with mild covid- kept at home and those with more severe disease requiring hospitalization. notably, most recent data shifted the therapeutic paradigm from the initial enthusiasm to a rise of skepticism and uncertainty when more in-depth analyses of the use of hydroxychloroquine emerged [ ] [ ] [ ] . in particular, the world health organization prematurely stopped the hydroxychloroquine arm of the solidarity trial (nct ), where no survival benefit had been observed in patients hospitalized for covid- . however, no significant interaction has been described between hydroxychloroquine and any antithrombotic agent (fig. ). the protease inhibitors lopinavir and atazanavir (either drug given in association with ritonavir or cobicistat) [ ] [ ] [ ] [ ] have been largely utilized; however, accumulating data from recently published randomized studies and an interim analysis of the previously mentioned solidarity trial, showed no reduction in mortality with the use of lopinavir/ritonavir in covid- [ ] . furthermore, the nucleotide analog remdesivir [ ] [ ] [ ] (developed for the treatment of ebola and marburg virus infections) showed favorable results in hospitalized patients with sars-cov- infection [ ] . a less robust clinical benefit has been demonstrated with the nucleotide analog ribavirin [ ] , as well as with azithromycin [ ] , a macrolide often administered for covid- in combination with hydroxychloroquine. in particular, the effects of the drug combination azithromycin plus hydroxychloroquine are controversial, given the limited evidence, the significant biases of available studies, and the pending results of randomized studies [ ] . interferon-β, currently authorized for the treatment of multiple sclerosis, was used in the treatment of middle east respiratory syndrome coronavirus (mers-cov) infections with some positive preclinical results [ ] ; on this basis, it has been now included in anti-sars-cov- experimental protocols. finally, due to recent encouraging clinical results, the use of glucocorticoids, mainly dexamethasone [ ] , and/ or tocilizumab [ ] (an interleukin- inhibitor) in patients with severe covid- has increased. in asymptomatic or pauci-symptomatic patients with sars-cov- infection maintained at home, during the initial phases of the outbreak, treatment with hydroxychloroquine (with or without azithromycin) was generally performed, although the diffusion of this approach was greatly different across different countries. there is no significant interaction between all agents used in covid- and low-molecular weight heparins (lmwhs) or fondaparinux (fig. ) [ ] . ribavirin and lopinavir/ritonavir decrease the anticoagulant effects of vkas, especially of warfarin, by interfering with cytochrome p a (cyp a ). azithromycin significantly increases the anticoagulant action of warfarin; thus, co-administration should be avoided or at least inr monitoring must be intensified. furthermore, azithromycin enhances the anticoagulant effects of unfractionated heparin (ufh) (fig. ) . doacs, except dabigatran, are metabolized by cyp a . all doacs are substrates of intestinal p-glycoprotein. in specific cases of uncertainty about possible drug interference, although not routinely recommended, a measurement of doac concentration could be considered. macrolides inhibit the action of intestinal p-glycoprotein, resulting in a potential increase in the blood levels of doacs and increased hemorrhagic risk. to date, no clinically relevant interference has been reported for dabigatran, rivaroxaban, or apixaban and azithromycin. there are no data on the interaction between azithromycin and edoxaban. accordingly, the labeling of this agent does not recommend reducing the edoxaban dose in the case of coadministration. however, such interaction has to be considered plausible, similarly to what occurs for edoxaban with clarithromycin or erythromycin [ ] . indeed, in the randomized vte-cancer study [ ] , where edoxaban was compared to dalteparin in patients with cancer and vte, the concomitant use of azithromycin required reduction of the doac dose (fig. ) . some antiviral agents used for covid- (lopinavir/ ritonavir, atazanavir) are competitors of intestinal p-glycoprotein and inhibit cyp a [ ] . these agents significantly increase the bleeding risk of doacs, due to an elevation in blood concentrations [ ] . thus, an absolute contraindication for co-administering the aforementioned antiviral substances with doacs must be indicated (fig. ) . although dabigatran is not metabolized by cyp a , this drug is a substrate of intestinal p-glycoprotein; therefore, the concomitant use of those antiviral agents and dabigatran should be reasonably prohibited. accordingly, in covid- patients on doacs with an established indication for lopinavir/ritonavir or atazanavir, doacs will be temporarily stopped and replaced with lmwh over the short term [ ] . no significant interaction between doacs and ribavirin is described. no significant interference has been reported between vkas or doacs and interferon-ß or tocilizumab (fig. ) . however, the use of this monoclonal antibody has been associated with hepatotoxicity [ ] . thus, close monitoring of liver function and coagulation indices is mandatory if tocilizumab is given in patients on anticoagulant treatment. furthermore, as tocilizumab may cause an increase in the expression of cyp a , its co-administration can lead to a slight decrease in blood levels of anti-xa agents (especially apixaban and rivaroxaban); therefore, close functional monitoring of coagulation parameters is indicated [ ] . therapy with non-steroidal anti-inflammatory drugs (nsaids) was hypothesized to be a potential risk factor for a more serious clinical presentation of covid- , but these data have not been confirmed in the most recent series [ ] . aspirin at the "antiplatelet" daily dose of - mg has limited anti-inflammatory effects. given its significant cardiovascular benefits, in patients on chronic therapy with aspirin for secondary prevention who are hospitalized or are maintained at home for covid- , this agent must be continued (table ) , consistent with the recent recommendations by mccullough and colleagues [ ] . aspirin treatment for primary cardiovascular prevention should also be continued, unless contraindications have occurred during in-hospital stay (acute liver failure, severe renal failure, severe thrombocytopenia, documented drug interactions, planned invasive procedures). in patients hospitalized for covid- , dual antiplatelet therapy (aspirin plus oral p y receptor inhibitor) must be continued in those who have recently undergone percutaneous coronary intervention (pci) (within ≤ months), unless hemorrhagic events are reported [ ] . regarding p y receptor inhibitors, lopinavir/ritonavir and atazanavir reduce the antiplatelet effect of clopidogrel and prasugrel (the latter not significantly), while they increase blood concentrations of ticagrelor (fig. ) [ ] . thus, in this setting, the co-administration of aspirin plus prasugrel should be preferred. indeed, the most recent evidence has indicated no clinical benefit of lopinavir/ ritonavir, and the use of such antiviral drugs has progressively declined over the pandemic course [ ] . however, in patients with covid- who are candidates for lopinavir/ritonavir or atazanavir treatment and are on aspirin plus clopidogrel for a recent (≤ months) pci after chronic coronary syndrome, clopidogrel is continued, with blood cell count and ischemic event monitoring (table ). in patients with covid- who are candidates for lopinavir/ ritonavir or atazanavir and are on aspirin plus clopidogrel/ ticagrelor for a recent (≤ months) pci after acute coronary syndrome (acs), the replacement of clopidogrel/ ticagrelor with prasugrel is indicated. if prasugrel is contraindicated, therapy with clopidogrel/ticagrelor is continued, with blood cell count and ischemic/bleeding event monitoring. there is no significant interference between clopidogrel/ticagrelor/prasugrel and the other agents used in covid- . aspirin therapy for primary cardiovascular prevention should be continued, unless contraindications have arisen or there is need for venous thromboprophylaxis antiplatelet therapy for secondary cardiovascular prevention must be continued, considering possible drug interactions dual antiplatelet therapy in patients who have undergone pci within ≤ months must be continued unless hemorrhagic events are reported in patients on aspirin plus clopidogrel/ticagrelor who have undergone a recent pci (≤ months) for acs requiring treatment with lopinavir/ ritonavir or atazanavir, switching from clopidogrel/ticagrelor to prasugrel is indicated. if prasugrel is contraindicated, therapy with clopidogrel/ticagrelor is continued, monitoring blood cell count and ischemic/bleeding events in patients on aspirin plus clopidogrel who have undergone a recent pci (≤ months) for stable coronary syndrome requiring treatment with lopinavir/ritonavir or atazanavir, clopidogrel is continued, monitoring blood cell count and ischemic events no significant interaction between clopidogrel/prasugrel/ticagrelor and the other agents used for covid- are present if indication for oac is adequate and no contraindication exists, short-term switching from oac to lmwh is reasonable finally, in patients on chronic oac, if the indication for oac is adequate and no contraindication exists, short-term switching from oac to lmwh is reasonable (table ). thromboprophylaxis is not recommended in asymptomatic patients in whom a nasopharyngeal swab tested positive for molecular detection of sars-cov- rna. in patients with mild covid- maintained at home, thromboprophylaxis is indicated only if multiple risk factors for vte and a low bleeding risk exist (table ) [ , ] . in patients with more severe covid- , the release of pro-inflammatory mediators, platelet activation, oxidative stress, endothelial dysfunction [ ] , prolonged immobilization, hypoxia, circulatory stasis, the use of mechanical ventilation, liver dysfunction, central venous catheters, and nutritional deficit increase the risk of vte (fig. ) . thus, these patients should be stratified upon hospitalization based on the clinical pattern and on the risk of thrombotic and bleeding complications. however, it is worth pointing out that this stratification is a dynamic process requiring a periodical reassessment according to clinical course and laboratory tests. patients admitted to the intensive care unit (icu), regardless of the need for mechanical ventilation, and those with acute respiratory insufficiency must be considered at high thromboembolic risk; thus, they require thromboprophylaxis [ , ] . in patients with mild-tomoderate respiratory symptoms, with or without evidence of interstitial pneumonia, stratification based on the risk of vte assessed using the padua prediction score [ ] or the improve vte score [ ] is recommended (fig. ) . a padua score of ≥ identifies patients with an elevated risk of vte; an improve score of - indicates an intermediate risk, whereas a value of ≥ indicates a high risk. following this stratification, thromboprophylaxis is not indicated in patients with a padua score of < or an improve score of * if pharmacological prophylaxys is contraindicated, it is possible to perform mechanical thromboprophylaxys by intermittent mechanical elasto-compression ** due to recent reports showing in covid- a pro-thrombotic milieu and high rates of venous thromboembolism, the use of higherthan-prophylactic doses of enoxaparin (e.g. iu bid) has been recently encouraged *** in patients at high thrombotic risk (padua score ≥ or improve score ≥ ) and low bleeding risk, consider thromboprophylaxys up to days after discharge padua score ≥ or improve score ≥ padua score < or improve score the choice of agent for thromboprophylaxis should take into account renal function. in patients with creatinine clearance < ml/min, ufh [ international units (iu) twice a day (bid) subcutaneously] can be used, whereas in those with creatinine clearance - ml/min, tinzaparin or dalteparin represents an option [ ] . notably, measurement of plasma anti-xa activity is recommended in patients with renal failure, adjusting the dosage to maintain levels of . - . u anti-xa/ml. in patients with creatinine clearance > ml/min, enoxaparin is the first choice for thromboprophylaxis, with nadroparin or fondaparinux alternatively. regarding the dosage of thromboprophylaxis drugs, there is an extensive debate. the world health organization expressed an orientation in favor of using a daily prophylactic dose of lmwh. a general indication is to give enoxaparin at a daily dose of iu (increased up to iu in obese patients) or nadroparin [ ] . notably, available data on the clinical benefit of thromboprophylaxis in patients with covid- were initially based mainly on a single analysis of approximately patients included in a retrospective study. here, prophylaxis was associated with lower mortality only in patients having criteria for sepsis-induced coagulopathy or with d-dimer values sixfold higher than the reference limit [ ] . furthermore, data from a large united states cohort suggested that systemic anticoagulation (including oral, subcutaneous, or intravenous forms) may be associated with higher survival among patients hospitalized with covid- [ ] . notably, in agreement with recent reports showing in such patients a pro-thrombotic milieu [ ] and high rates of venous thromboembolic complications, the use of intermediate doses of enoxaparin (e.g., iu bid) for thromboprophylaxis has been recently encouraged, as prophylactic doses were considered insufficient for this aim [ ] . however, specific studies are urgently needed to establish the optimal approach to thromboprophylaxis with lmwh in this setting, but, in the absence of robust evidence supporting higher dosing regimens, if thromboprophylaxis is indicated, it appears reasonable to utilize lmwh at prophylactic dosages. there are no specific data on the extension of thromboprophylaxis beyond hospitalization in patients with covid- ; it is advisable to proceed individually and consider this extension up to a maximum of days after discharge only in patients with a high vte risk and a low risk of bleeding [ ] . the diagnosis of pulmonary embolism (pe) in patients with sars-cov- infection must be based on the integration of clinical, laboratory, and instrumental data ( table ) . d-dimer testing has a central role as a diagnostic marker for vte; monitoring can allow an early diagnosis, but at the same time, it may be non-specific, if not contextualized. indeed, over % of patients admitted for covid- present elevated d-dimer values (in most cases < . mcg/ml), even without thrombotic complications [ ] . thus, in line with the diagnostic algorithms provided by pre-existing guidelines [ ] , d-dimer must be measured only in the presence of a clinical suspicion of vte. conversely, in the absence of concomitant clinical worsening, high levels of d-dimer should not guide diagnostic and therapeutic processes. pe is suspected if increased values of d-dimer are associated with clinical symptoms/signs of deep venous thrombosis (dvt), worsening hypoxemia disproportionate to the degree of respiratory involvement, and/or acute right ventricular dysfunction. in patients with a worsening clinical status, especially in those without anticoagulant treatment, a diagnosis of vte must always be suspected in patients with suspected vte, the diagnostic and therapeutic workup must integrate clinical data, laboratory findings, and imaging test results measurement of d-dimer for diagnosing vte must be performed only if a clinical suspect exists vascular/cardiac ultrasound imaging for diagnosing vte should precede radiological imaging patients undergoing a ct scan for worsening respiratory status should receive angio-ct sequences to exclude pe the use of lmwh for treating a vte episode is preferred. ufh should be limited to patients with crcl < ml/min an invasive "catheter"-based therapy for pe is indicated in selected cases with contraindication to anticoagulant drugs, recurrent events despite adequate anticoagulation, or when systemic fibrinolysis cannot be performed for the risk stratification of patients with vte, monitoring of the following parameters is useful: troponin, bnp, d-dimer, blood cell count, fibrinogen, prothrombin time, activated partial thromboplastin time, and degradation products of fibrin after the initial approach, doacs may represent an option for in-hospital treatment of a vte episode in patients with clinical stability and decreasing inflammation after a vte episode, doacs should represent the therapy of choice at discharge the use of imaging techniques in diagnosing a vte episode is complex, because of the risk of viral transmission to other patients and to healthcare workers, and must be regulated by specific in-hospital protocols aimed at limiting such risk. each imaging test must be subsequent to an integrated evaluation of clinical and laboratory data. notably, vascular or cardiac ultrasound examination usually anticipates radiological imaging and requires appropriate personal protective equipment and specific methods for sanitizing the instruments. in view of the high rates of dvt in icu patients, an extensive use of vascular ultrasound is advisable to assess broadly the diagnosis of dvt. due to the higher risk of pe, patients with covid- undergoing a lung computed tomography (ct) scan for worsening respiratory function should receive angio-ct sequences to optimize the diagnostic process [ ] . in patients with acute respiratory distress syndrome (ards) and suspected pe, performing radiological tests is difficult because of patient's prone position and unstable clinical conditions. here, echocardiographic evidence of deterioration of the right ventricular function or (more rarely) of transit thrombus represents a relevant finding justifying further diagnostic steps and on this basis the initiation of specific treatments. prognostic stratification of patients with covid- is important and may guide treatment modalities. a higher inflammatory status (as identified by increased c-reactive protein levels or neutrophil/lymphocyte ratio) has been correlated with a poorer outcome, including lower survival [ ] . the measurement of troponin and brain natriuretic peptide (bnp) is also useful, as an increase in these parameters indicates acute myocardial damage and hemodynamic overload [ , , ] . various abnormalities in the hemostatic parameters were associated with a higher risk of cardiovascular complications, mechanical ventilation, and mortality, in particular, thrombocytopenia (especially < , × /l) and elevation of d-dimer (> µg/ml), fibrinogen (> g/l), or degradation products of fibrin. recent studies suggested a relationship between severity in the clinical course of covid- and spontaneous prothrombin time prolongation (> s) or activated partial thromboplastin time prolongation (> s) [ , , ] . accordingly, all the aforementioned hemostatic markers should be routinely monitored in these patients, with the aim to obtain a more accurate prognostic stratification. in covid- patients with vte, the indications for treatment are based on pre-existing guidelines and should be integrated with specific assessments related to the sars-cov- infection [ ] . as described above, the choice of the therapeutic regimen must also take into account considerations regarding the severity of clinical presentation, co-existence of renal disease, liver dysfunction and/or thrombocytopenia, and possible drug interactions with antiviral drugs [ ] . the use of parenteral anticoagulants represents the best initial option, due to the greater manageability and the lower risk of drug interference (table ). lmwh at anticoagulant dosages (i.e., subcutaneous enoxaparin mg/kg bid or nadroparin iu/kg bid) should be preferred over ufh, which exposes healthcare workers to an increased risk of contagion, due to frequent blood samplings for dose adjustment. ufh should be used only in patients with creatinine clearance < ml/min. an invasive catheter-based therapy for pe (locoregional thrombolytic therapy or embolectomy) is indicated in selected cases with contraindication to anticoagulant drugs, in those who experience recurrent events despite adequate anticoagulation, or when systemic fibrinolysis cannot be performed. after the initial approach with lmwh, doacs may represent an option for in-hospital treatment of a vte episode only in patients with clinical stability and decreasing inflammation (table ) . unless contraindicated, doacs should be preferred over vkas, given they are easier to manage during the in-hospital stay and transition to the subsequent home regimen. however, as mentioned above, the choice of the oac drug must consider possible interactions with anti-sars-cov- drugs [ , ] . in patients with covid- , the onset or recurrence of af is favored by fever, hypoxia, and adrenergic activation due to respiratory failure [ , ] . here, anticoagulant treatment for preventing thromboembolic events must be guided by the cha ds -vasc score rather than the characteristics of the arrhythmic episodes (i.e., duration of the episodes, number of relapses). it is reasonable to initiate anticoagulation with lmwh and then switch to oac during the hospitalization course, preferentially with a doac, taking into account possible drug interference. hospitalizations for acs have apparently declined during the pandemic [ ] . however, it was observed that - % of patients hospitalized for covid- have a history of cardiovascular disease [ ] . as demonstrated in other viral inflammatory syndromes [ ] , an acs due to coronary thrombosis can derive from destabilization of pre-existing lesions, as a result of the cytokine storm. given the paucity of specific data, the pharmacological and interventional management of patients with covid- and acs should follow the pre-existing guidelines [ ] , using specific inhospital protocols and appropriate measures for preventing the contagion infecting healthcare workers [ ] . as previously indicated, in this setting, antiplatelet strategies play a crucial role. aspirin can be used without specific additional concerns. in patients with covid- and acs on lopinavir/ ritonavir or atazanavir treatment, the co-administration of aspirin and prasugrel after pci should be preferred. if prasugrel is contraindicated, the use of clopidogrel or ticagrelor can be considered, possibly with testing of their antiplatelet efficacy [ ] . the metabolism of cangrelor is independent of liver function. no drug interaction is expected between this agent and all drugs used in covid- . notably, in patients with covid- , a high incidence of acs, with "st-elevation myocardial infarction (stemi)like" presentation and without coronary lesions, has been reported [ ] . in particular, recent data showed that approximately % of patients with covid- and stemi did not present culprit lesions at coronary angiography [ ] . possible pathogenetic mechanisms of this finding are acute myocarditis, type myocardial infarction (due to mismatch between oxygen demand and supply), or "takotsubo-like" myocardiopathy [ ] . thus, in patients with confirmed (or suspected) sars-cov- infection and "stemi-like" presentation, fibrinolytic therapy should be considered only in selected cases, when coronary angiography and a possible percutaneous revascularization cannot be performed promptly and safely. regarding arterial thrombosis in non-coronary vessels, a recent observational investigation reported a . % incidence of ischemic stroke among consecutive patients hospitalized for covid- [ ] . moreover, there is evidence that patients with sars-cov- infection may have a more severe stroke presentation than non-infected patients [ ] . finally, cases of ischemic stroke associated with bilateral acute lower limbs ischemia in the context of antiphospholipid syndrome have been described [ ] . disseminated intravascular coagulation (dic) represents a possible complication in all patients admitted to the icu with critical infectious diseases. in patients with covid- , a severe clinical course was associated with dic in > % of cases [ ] . serial evaluation of platelet count, prothrombin time, d-dimer, and fibrinogen plays an important role in diagnosing dic and monitoring its coagulation abnormalities (table ) [ ] . the management of these patients includes the identification and treatment of the triggering causes and, in line with international recommendations, the initiation of specific treatments based on platelet transfusion, coagulation factors (fresh concentrated plasma), and fibrinogen (cryo-precipitate) in the presence of bleeding complications or, more rarely, on anticoagulant therapy with heparin, if a thromboembolic pattern is prevalent. in patients with dic, treatment prothrombin time, platelet count, d-dimer, degradation products of fibrin, fibrinogen diagnostic score prolongation of prothrombin time: ≤ s = points; > -≤ s = point; > s = points platelets: ≥ × /l = points; < × /l = point; < × /l = points d-dimer, degradation products of fibrin: normal = points; moderately increased = points; markedly increased = points fibrinogen: > g/l = points; ≤ g/l = point isth score calculation ≥ points: compatible with dic < points: non-suggestive for dic with antiplatelet drugs should be limited to those with recent coronary stent implantation. with regard to patients on dual antiplatelet therapy, such treatment is continued if the platelet count is ≥ , × /l, whereas if the platelet count is , - , × /l, an antiplatelet agent is stopped, and if the platelet count is < , × /l, both antiplatelet drugs are withdrawn. however, the management of these patients must be individualized, balancing thrombotic and hemorrhagic risks. prevalence and impact of cardiovascular metabolic diseases on covid- in china esc guidelines for the management of atrial fibrillation developed in collaboration with eacts antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis feasibility and safety of a week inr follow-up protocol over years in an anticoagulation clinic: a single-arm prospective cohort study validation of the international normalized ratio (inr) in a new point-of-care system designed for home monitoring of oral anticoagulation therapy comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials impact of a new method of warfarin management on patient satisfaction interaction between paracetamol and warfarin in patients: a double-blind, placebocontrolled, randomized study european society of cardiology. esc guidance for the diagnosis and management of cv disease during the covid- pandemic. bruxelles: european society of cardiology efficacy of various treatment modalities for ncov- : a systematic review and metaanalysis swinging the pendulum: lessons learned from public discourse concerning hydroxychloroquine and covid- screening of an fda-approved compound library identifies four small-molecule inhibitors of middle east respiratory syndrome coronavirus replication in cell culture treatment with lopinavir/ ritonavir or interferon-β b improves outcome of merscov infection in a 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hospitalized patients with covid- -preliminary report tocilizumab treatment in covid- : a single center experience antithrombotic treatments in patients with sars-cov- infection: from current evidence to reasonable recommendations-a position paper from the italian working group on atherosclerosis, thrombosis and vascular biology edoxaban for the treatment of cancer-associated venous thromboembolism direct oral anticoagulant plasma levels' striking increase in severe covid- respiratory syndrome patients treated with antiviral agents: the cremona experience hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions covid- and treatment with nsaids and corticosteroids: should we be limiting their use in the clinical setting? pathophysiological basis and rationale for early outpatient treatment of sars-cov- (covid- ) infection systematic review of the efficacy and safety of antiretroviral drugs against sars, mers or covid- : initial assessment current overview 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factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the pulmonary embolism in patients with covid- : time to change the paradigm of computed tomography laboratory abnormalities in patients with covid- infection early detection of elevated cardiac biomarkers to optimise risk stratification in patients with covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia covid- and cardiovascular disease case-fatality rate and characteristics of patients dying in relation to covid- in italy reduced rate of hospital admissions for acs during covid- outbreak in northern italy cardiovascular manifestations and treatment considerations in covid- acute myocardial infarction after laboratory-confirmed influenza infection esc/ eacts guidelines on myocardial revascularization position paper anmco: organizzazione della rete per il trattamento dei pazienti con sindrome coronarica acuta durante emergenza pandemica covid- cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease (covid- ) pandemic association of cardiac injury with mortality in hospitalized patients with covid- in wuhan st-elevation myocardial infarction in patients with covid- : clinical and angiographic outcomes thrombosis in hospitalized patients with covid- in a new york city health system early brain imaging shows increased severity of acute ischemic strokes with large vessel occlusion in covid- patients coagulopathy and antiphospholipid antibodies in patients with covid- guidelines for the diagnosis and management of disseminated intravascular coagulation key: cord- - a vz h authors: aggarwal, mukul; dass, jasmita; mahapatra, manoranjan title: hemostatic abnormalities in covid- : an update date: - - journal: indian j hematol blood transfus doi: . /s - - - sha: doc_id: cord_uid: a vz h covid- has emerged as a pandemic with lung being the primarily afflicted organ. deranged hemostasis has been observed in patients with covid- with scales tipped towards a prothrombotic state. the pathogenesis differs from disseminated intravascular coagulation with a primary pulmonary localization. this is referred to as pulmonary intravascular coagulopathy with strong component of thrombo-inflammation. this is reflected in the lab tests with an increase in d-dimer which correlates with severity and outcomes of disease. common coagulation tests such as prothrombin time, activated partial thromboplastin time are only mildly prolonged while most patients have normal to increased fibrinogen and marginal thrombocytopenia. overall, the patients have an increase in venous and arterial thrombotic events especially in icu patients. routine thromboprophylaxis with low molecular weight heparin is recommended in all hospitalized patients to reduce the incidence of thrombosis. bleeding is uncommon and treated with blood products transfusion. this review shall discuss the hemostatic abnormalities in covid- patients and their impact on prognosis. in addition, strategy of thromboprophylaxis and various academic society guidelines are discussed in detail. introduction covid- , the novel coronavirus infection started from wuhan, china in december . the outbreak was declared a public health emergency of international concern on january and later a pandemic on march , by world health organization (who) [ ] . it is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ). this virus belongs to the b-coronavirus family and is partially like the srs-cov and mers-cov coronaviruses which have caused previous epidemics in china and middle east respectively [ ] . the management of the disease is challenging as the virus is highly infectious and there is a large burden of asymptomatic patients, absence of proven antiviral drugs, and limited understanding of potential benefits from antiviral antibodies [ ] . severe acute respiratory distress syndrome (ards), in addition progression to multi-organ dysfunction syndrome has been recognized as cause of death in most of the patients. ards is common amongst patients needing hospitalization, which comprise around % of all infected patients [ ] . the exact mechanism of pulmonary complications and ards of covid- has not been elucidated but there is a clear component of thrombo-inflammation and cytokine storm [ , ] . irrespective of the cause of sepsis, coagulopathy is consistently associated with poor prognosis [ ] and this has been postulated for covid- as well. multiorgan dysfunction is likely in coagulopathy in patients with sepsis and leads to increased mortality. multiple reports have reported the presence of deranged parameters of coagulation in patients of in this review, we will discuss the various pathophysiological mechanisms leading to covid- associated coagulopathy (cac), derangement in laboratory parameters, incidence, and risk factors of venous thromboembolism (vte) and prevention and treatment of cac. pulmonary intravascular coagulation, its histopathological evidence and contribution of cytokine storm covid- patients have been shown to have high levels of d-dimer [ , ] but unlike patients of sepsis, they only have a mild prolongation of prothrombin time (pt), activated partial thromboplastin time (aptt), mild thrombocytopenia [ , ] . the first histopathology report was incidental in two lung cancer patients with unsuspected covid- . lung histopathology revealed only early findings seen in covid- including alveolar damage with proteinaceous alveolar exudates and edema, vascular congestion, and focal fibrin deposition with pneumocyte hyperplasia [ ] . these findings suggested that pulmonary coagulopathy starts early in the disease itself. mortality has been reported right from the beginning but the autopsy data from covid- patients has lagged. till date, very few studies on histopathological findings are available [ ] [ ] [ ] [ ] [ ] . autopsy data suggests that there is exudative diffuse alveolar damage with severe capillary congestion. in addition, the frequent findings include edema, alveolar hemorrhage, pulmonary embolism and microthrombi in the alveolar capillaries [ ] . these findings were aptly described by mcgonagle as pulmonary intravascular coagulation (pic) with the suggestion that it arises due to macrophage activation syndrome (mas)-like intrapulmonary inflammation that causes vessel wall damage [ ] . this pic is mediated by a thrombo-inflammation. sars-cov infects the type ii pneumocytes via angiotensin converting enzyme (ace- ) receptors eliciting a phenomenon culminating in pic (fig. ) . due to the widespread presence of ace- receptor in the lung, there is a damage to large surface area of the alveoli leading to hypoxemia. in addition, there is extensive vascular damage due to juxtaposition of type ii pneumocytes to the vessels. the infection also causes a massive cytokine storm. there is increased expression of tissue factor on endothelium and inflammatory cells including neutrophils and macrophages. there is extensive endothelial injury and dysfunction partly due to cytokines such as interleukin (il)- , il- and tumour necrosis factora as well as an intra-pulmonary mas-like inflammation. these phenomena ultimately lead to intrapulmonary activation of coagulation cascade. inflammatory reaction also caused a reduced level of plasminogen activator inhibitor- (pai- ) causing increased level of plasmin. there is both a component of intrapulmonary thrombosis, microhemorrhages and hyperfibrinolysis. plasmin and other proteases can also cleave a furin site in the s protein of sars-cov leading to increased virulence of the virus. thrombosis observed is primarily intra-pulmonary but can progress to systemic thrombosis in a subset of patients. the combination of thrombosis and inflammation cause a positive feedback loop exacerbated by local hypoxia [ ] . magro et al. [ ] examined skin and lung tissues from patients. according to them, the pattern of covid- pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural, luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. no viral cytopathic changes were observed and the diffuse alveolar damage (dad) with hyaline membranes, inflammation, and type ii pneumocyte hyperplasia, the hallmarks of classic ards were not prominent. significant deposits of terminal complement components c b- (membrane attack complex), c d, and mannose binding lectin (mbl)-associated serine protease (masp), in the microvasculature were seen consistent with sustained, systemic activation of the alternative and lectin-based complement pathways. purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of c b- and c d. there was co-localization of covid- spike glycoproteins with c d and c b- in the interalveolar septa and the cutaneous microvasculature [ ] . histological similarities were observed between covid and sars - . localized pulmonary hemorrhage, pulmonary edema, desquamation with hyaline membrane formation and an interstitial mononuclear inflammatory infiltrate were seen. localized pulmonary arteriolar thrombosis was seen with sars but not with covid- [ ] . wichmann and colleagues described autopsy findings in covid- patients revealing deep venous thrombosis (dvt) in of unsuspected patients ( %). pulmonary embolism (pe) was the direct cause of death in patients. histologically, dad was seen in patients. in all patients, sars-cov- rna was detected in lungs at high concentrations; viremia in of and of patients demonstrated high viral rna titers in the liver, kidney, or heart [ ] . immunohistochemistry done on lung specimens revealed thickened alveolar capillaries with edema and fibrin thrombi. there were cd and von willebrand factor (vwf) positive resident pulmonary megakaryocytes in alveolar capillaries that exhibited nuclear hyperchromasia and atypia [ ] . overall covid- is associated with a hypercoagulable state with dic setting in only in late cases. coagulation anomalies and clinical features observed in covid- associated coagulopathy are different from dic (fig. ) . dic can complicate the course of disease with reported incidence of . % in non-survivors when compared to only . % survivors [ ] . while dic predominantly presents with generalized derangement of coagulation and bleeding manifestations, cac has specific alterations in these coagulation parameters that differ from dic and clinical bleeding is uncommon. thrombocytopenia has been observed in * - % of hospitalized patients with covid- but is usually not severe [ , , ] . pc of \ /l is seen in only % covid- patients [ ] . covid- patients have a higher indian j hematol blood transfus platelet count than non-covid patients [ ] . this is unlike sepsis where thrombocytopenia is an indicator of mortality due to sepsis [ ] . thrombocytopenia at threshold of x /l was observed more frequently in covid- non-survivors [ , ] . this thrombocytopenia is multi-factorial in etiology including cytokine storm, possible direct cytopathic effect on marrow, immune mediated clearance of platelets due to formation of anti-platelet antibodies and lung injury causing platelet activation and consumption and lastly alteration of pulmonary capillary bed causing reduced lung megakaryocyte fragmentation and platelet production [ ] . initial studies reported mild prolongation of pt in patients with severe disease requiring icu admission and mortality [ , , ] . it is important to remember that these mild prolongations may be missed if pt is expressed as pt ratio or pt% rather than in seconds [ ] , as probably happened in studies when data was reported in these formats [ , ] . aptt values did not correlate with severity of disease in most studies. most consistent data reported was for d-dimer [ , , , , ] . elevated d-dimer value at admission is a predictor for both severity of covid- [ , , ] and mortality [ , , ] . various cut-offs have been determined to predict a higher risk of death in covid- [ , ] and for venous thromboembolism (vte) [ ] . the role of d-dimer to predict disease outcome was subsequently confirmed in a meta-analysis [ ] . it is important to note that since d-dimer elevations in these hospitalized patients are not accurate predictor of subsequent vte. the sensitivity, specificity and negative predictive value of elevated d-dimer at levels of c . lg/ ml that predicted vte were %, . % and . % respectively [ ] . it is important to note that all the coagulation tests have been performed on different equipments using proprietary reagents and hence, cut-offs generated will have to be validated at each center. table discusses the role of d-dimer and table reflects the other routine coagulation parameters in covid- patients. fibrinogen is generally normal or elevated [ , ] in these patients with a reduction in values reported only late in the course of disease when dic sets in some patients [ ] . the levels of antithrombin (at) have been found to be marginally reduced in covid- patients compared to controls [ ] . at values decline in non-survivors by day when compared to survivors [ ] . factor viii, vwf and vwf ristocetin cofactor activity (vwf-rcof) were evaluated in patients and were increased at levels of u/ dl( - ), u/dl( - ) and u/ dl( - ) respectively indicating possible endothelial dysfunction due to sepsis. in the same patient subset, at and free protein s levels were marginally decreased while protein c was increased [ ] . limited studies on viscoelastic testing have shown a procoagulant profile rather than acute dic in patients with covid- (table ) [ , , ] . this hypercoagulability may be attributed to endothelial dysfunction, elevated circulating platelet microparticles, neutrophil extracellular traps (nets) and elevated inflammatory cytokines [ ] . the impact of thromboprophylaxis to normalize the hypercoagulable state seen using the viscoelastic tests has largely not been documented. only one of the studies that utilized the quantra Ò hemostasis analyser where increasing thromboprophylaxis led to a reduction in the increased values of clot strength (cs), platelet contribution to clot strength and fibrinogen contribution to clot strength (fcs) [ ] . however, only data from less than patients in total has been reported in patients using various forms of viscoelastic testing [ , , ] . it remains to be seen whether doing viscoelastic testing at baseline at the time of testing can identify patients who might go on to develop severe disease or thrombosis. the role of viscoelastic testing on management of thromboprophylaxis in covid- patients should be studied further. a report of three critical cases from china with apl antibodies was published by zhang et al. all the patients had a comorbid condition that predisposed them to severe disease and developed cerebral infarcts. anticardiolipin (acl) iga antibodies and anti-b glycoprotein-i iga and igg antibodies were reported in all patients but were negative for lupus anticoagulant (la) [ ] . it was interesting that in this case report, iga antibody testing was performed for both acl and anti-b glycoprotein-i antibodies which are not a part of the diagnostic criteria for antiphospholipid syndrome [ ] while the data on acl igg and igm and anti-b glycoprotein-i igm antibodies is not reported. a series from france on covid- patients reported % positivity for la while acl and anti-b glycoprotein-i (igg/igm) were seen in %. three patients were positive for both la and one of the antiphospholipid antibodies tested [ ] . this study has however, not reported data on thrombosis. in addition, it has not been mentioned whether drvvt and la sensitive ptt were performed before starting anticoagulant prophylaxis or not. should be suspected if there is acute worsening of hypoxemia, blood pressure or tachycardia, and/or oxygen requirement and ventilatory settings are disproportionate to the severity of pneumonia on chest imaging. even the diagnosis of dvt is difficult as the focus of care is on the respiratory system while the patients are in the icu and the signs of dvt in the extremities may be missed. in addition, great amount of hospital resource is utilized in shifting these sicker patients to radiology units for carrying out computed tomography pulmonary angiogram (ctpa) and doppler ultrasound (usg) with associated risk of exposure and aerosolization the major contributory factors to thrombosis, in addition to those described above in pathology and prothrombotic state include icu stay, central lines, cvvh, ecmo, limited mobility, comorbidities etc. in most studies published evaluating symptomatic or asymptomatic vte, overwhelmingly patients were from icu and most of them were on prophylactic doses of lmwh (table ). some studies have also included general ward patients, while some have screened for vte in asymptomatic patients. as a result, incidence of symptomatic vte is variable across studies. llitjos et al. showed that incidence of thrombosis was lower if therapeutic doses of anticoagulation was used as prophylaxis ( % vs % respectively, p = . ) [ ] . the -day mortality of heparin users were lower than nonusers in covid- group with d-dimer [ . lg/ml ( . % vs . %, p = . ) [ ] . this suggests that even therapeutic anticoagulation is insufficient in some of these patients in the face of cac. the incidence of thrombosis varies from . - % in hospitalized patients to as high as % in icu patients. details are given in table . various risk factors identified from different studies are age and coagulopathy defined as prolonged pt [ s or aptt [ s [ ] ; duration of hospital stay (incidence at day , and being %, % and % respectively), icu versus wards ( % vs . %), higher white blood cell count, higher neutrophil-lymphocyte ratio and a higher d-dimer level [ ] ; icu versus general ward ( . % vs . %) [ ] ; d-dimer levels [ ng/ml for asymptomatic dvt [ ] . not surprisingly, vte has been associated with a higher risk of mortality with a hazard ratio (hr) of . ( % ci . - . ) [ ] . helms et al. [ ] compared non-covid- ards patients with covid- ards patients and confirmed that latter developed more thrombotic complications, mainly pe ( . vs . %, p \ . ) and deranged coagulation parameters. griffin et al. [ ] described three patients of arterial thromboembolisms (stroke and popliteal arterial occlusion) in patients with covid- , treated with tpa, and/or antiplatelet therapy. anecdotal reports of arterial thrombosis have also been published [ , ] . in this section, we shall discuss about treatment strategies related to coagulopathy only. considering the high incidence of thromboembolic phenomenon, it is prudent to put all patients admitted to icu/hdu on thromboprophylaxis. vte risk assessment tools like padua prediction model have not been rigorously evaluated in covid- patients. most recent isth guidelines continue to recommend thromboprophylaxis for all hospitalized patients instead of individualized risk assessment tools. the randomized trials are underway, but some of the key published studies available are discussed in table . tang and colleagues reported one of the first studies to show benefit of anticoagulation in covid- patients [ ] . even though day mortality was similar between those on heparin and those without heparin ( . % vs . %, p = . ), sub-group analysis showed that heparin was able to lower mortality in patients with sepsis-induced coagulopathy (sic) score c ( . % vs . %, p = . ) or d-dimer [ sixfold of upper limit of normal ( . % vs . %, p = . ). testa et al. [ ] showed [ times higher c-trough levels of direct acting oral anticoagulants (doac), given simultaneously with antivirals. wang et al. [ ] showed definite but transient improvement without bleeding in ventilatory parameters (pao /fio ) after treatment with short course of tpa (alteplase) in ards due to covid- . liu et al. [ ] suggested potential benefit of adding dipyridamole. they suggested that dipyridamole can benefit patients by reducing viral replication, suppressing hypercoagulability, and enhancing immune recovery. relating the pathogenesis to thrombotic microangiopathy, diurno et al. [ ] showed improved outcome with eculizumab, monoclonal antibody against c compliment used in cases of paroxysmal nocturnal hemoglobinuria. choice of anticoagulant is heparin or lmwh during hospital stay. limited data is available for use of doacs or warfarin. heparin could decrease the inflammatory response by blocking thrombin formation. also, it may possess anti-viral properties by acting on sars-cov- surface receptor binding proteins and inhibiting viral attachment [ ] . however, major issues with heparin are low antithrombin and high fibrinogen seen in cac, both known to incur heparin resistance [ ] . this suggests that prophylactic doses of lmwh or ufh could be less efficacious in severe cac [ ] . shifting from prophylaxis to therapeutic doses in the absence of proven vte, although common but is still not based on evidence. it may be considered in patients who are suspected thrombosis but not able to undergo imaging and those on ecmo. testa et al. [ ] suggested to stop doac and shift to heparins due to high drug levels of doacs when given with antivirals or immunosuppressive therapy. besides, there are issues of compromised absorption of oral medicine, concurrent renal dysfunction, and difficulty in measuring efficacy in sick icu patients. they may be considered after discharge, for a total duration of weeks of thromboprophylaxis. several academic societies have come up with guidance for managing cac. however, they have refrained from providing level of evidence with their recommendations as direct evidence is still lacking and data is evolving. international society for thrombosis and hemostasis (isth) came with interim guidelines in march on recognition and management of coagulopathy in covid- based on isth dic score [ ] . similarly, american society of hematology (ash) mentions about management of cac on its website [ ] . a comparative analysis of these is shown in table . both guidelines mention about therapeutic lmwh in all hospitalized patients, unless contraindicated by pc or fibrinogen or active bleeding. vte prophylaxis should be modified in obese or very thin patients and those with renal dysfunction. patients with obesity should be considered for % rise in thromboprophylaxis dosage. abnormal pt or aptt are not contraindications for pharmacological thromboprophylaxis. mechanical thromboprophylaxis is recommended when pharmacological thromboprophylaxis is contraindicated. therapeutic anticoagulation is not required unless vte or atrial fibrillation is documented. most of the guidelines are based on the premise that coagulopathy is a risk factor to multi-organ failure in patients with sepsis, so inhibiting thrombin generation is beneficial in reducing mortality [ ] . current guidelines recommend lmwh as preferred agent during hospitalization and doac for post discharge therapy for patients with proven thrombosis. at least three months of treatment is required for these patients [ ] . principles of blood transfusion are similar to septic coagulopathy with minor differences between guidelines issued by ash and isth. institution of blood component therapy is not recommended purely based on abnormal laboratory findings without the clinical indication of bleeding or requirement of invasive procedure or in those patients at a high risk of bleeding complications [ , , ] . american college of cardiology also advocates a similar policy with respect to thromboprophylaxis in hospitalized patients with covid- and advised for careful assessment for incident thrombotic events. the duration of thromboprophylaxis is weeks like other medical conditions [ ] . regarding therapeutic doses of anticoagulation for prophylaxis, british thoracic society (bts) advocates risk stratification based on following factors [ ] : • location of patient's care (e.g. critical care). • disease severity (e.g. need for cpap, high oxygen requirements (e.g. pao /fio b kpa ( mmhg)), sic score c ). they also advocate shifting to lmwh if patients were previously on oral anticoagulants during hospital stay. after discharge, thromboprophylaxis should be considered for high risk vte patients who were hospitalized. bts suggest doac for thromboprophylaxis for upto weeks. however, the recommended duration of post discharge prophylaxis ( weeks, weeks, or weeks) and choice of agent (whether lmwh or doac) are still uncertain. recently published chest guidelines on cac provide similar recommendations. they recommend standard dose lmwh as most preferred agent followed by ufh then doac for acutely ill and critical hospitalized patients with covid- . these guidelines recommend against antiplatelet for thromboprophylaxis and intermediate or full dose of lmwh. extended thromboprophylaxis should be considered only for patients who are at low risk of bleeding. mechanical prophylaxis is recommended only for those with contraindication to anticoagulants. for patients who develop vte, these guidelines suggest initial lmwh (preferred) or ufh followed by continuation of same or shift to dabigatran or warfarin analogues. thrombolytic therapy is recommended only for acute confirmed pe who show clinical deterioration. for non-hospitalized covid patients who develop vte, doac are preferred over lmwh for ease of administration and convenience to patients. warfarin analogues can also be used for these patients after lmwh overlap. overall duration of anticoagulation treatment should be at least three months [ ] . covid- associated coagulopathy is associated with high risk of morbidity and mortality and is a cause of concern especially in hospitalized patients. it is multifactorial in nature and manifests with deranged d-dimer, high fibrinogen and is different from dic with respect to a low occurrence of thrombocytopenia, lack of severe thrombocytopenia, accompanied by only a mild prolongation of prothrombin time and activated partial thromboplastin time. it is important to remember that prothrombin time in these patients should be analyzed in seconds rather than as a ratio or percentage. both venous and arterial thrombosis appear to be increased especially in sick patients and many of the thromboses may be subclinical in nature. diagnosing indian j hematol blood transfus pulmonary embolism in patients in icu is challenging and high index of suspicion is warranted. available evidence and guidelines recommend prophylactic anticoagulation with lmwh for all hospitalized patients. anticoagulant and antiplatelet possibly improve by additional mechanisms (antiviral activity, improving thrombo-inflammation etc.) also in treatment of covid- patients. most of the available data is not based on randomized controlled trials, which have started recruitment only recently and are expected to guide us further into management of cac. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- covid- : towards understanding of pathogenesis clinical features of patients infected with novel coronavirus in wuhan covid- : consider cytokine storm syndromes and immunosuppression cytokine storm and sepsis disease pathogenesis the coagulopathy of acute sepsis abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical characteristics of coronavirus disease in china pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases pathological findings of covid- associated with acute respiratory distress syndrome autopsy findings and venous thromboembolism in patients with covid- : a prospective cohort study vander heide rs ( ) 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in patients with covid- high incidence of venous thromboembolic events in anticoagulated severe covid- patients venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in incidence of asymptomatic deep vein thrombosis in patients with covid- pneumonia and elevated d-dimer levels high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study arterial thromboembolic complications in covid- in low risk patients despite prophylaxis anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy direct oral anticoagulant plasma levels' striking increase in severe covid- respiratory syndrome patients treated with antiviral agents: the cremona experience tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series therapeutic effects of dipyridamole on covid- patients with coagulation dysfunction eculizumab treatment in patients with covid- : preliminary results from real life asl napoli nord experience the coronavirus (sars-cov- ) surface protein (spike) s receptor binding domain undergoes conformational change upon heparin binding postinjury hyperfibrinogenemia compromises efficacy of heparin-based venous thromboembolism prophylaxis isth interim guidance on recognition and management of coagulopathy in covid- : a comment isth interim guidance on recognition and management of coagulopathy in covid- diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation subcommittee on perioperative, critical care thrombosis, haemostasis of the scientific, standardization committee of the international society on thrombosis, haemostasis? ( ) scientific and standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with covid- guidance for diagnosis and treatment of dic from harmonization of the recommendations from three guidelines. the scientific standardization committee on dic of the international society on thrombosis haemostasis covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy and follow up bts guidance on venous thromboembolic disease in patients with covid- ) prevention, diagnosis, and treatment of vte in patients with covid- : chest guideline and expert panel report conflict of interest the authors declare that they have no conflict of interests. key: cord- - vajpo authors: doyle, andrew j.; thomas, will; retter, andrew; besser, martin; macdonald, stephen; breen, karen a.; desborough, michael j.r.; hunt, beverley j. title: updated hospital associated venous thromboembolism outcomes with -days follow-up after hospitalisation for severe covid- in two uk critical care units date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: vajpo nan hospitalisation with covid- infection has been associated with an increased incidence of thrombosis, particularly in the critical care setting. our two centres have previously described the early in-patient incidence of venous thromboembolism (vte) at the peak of the covid- outbreak in the united kingdom , . the cohort from cambridge showed patients out of a total of who developed vte with a median follow-up of days whereas london showed patients of had vte with a median follow-up of days. the risk of hospital-associated vte (hat) for patients has been shown to extend from admission to days following discharge with an early peak within the first weeks of this period . however, it has not yet been established whether the risk of vte following covid- pneumonia also persists to days. we conducted an observational study of our previous cohorts with a minimum of days follow-up from their critical care admission at our centres. our methods have previously been described and approval was obtained from the research and development departments at both trusts , . the composite endpoint was image-proven pulmonary embolism (pe) and deep vein thrombosis (dvt) including catheter-associated thrombi. the index date was admission to critical and censorship data was th july . we assessed the d-dimer levels at the time of imaging in those with and without thrombosis, which we and others have previous shown to be significantly higher in those developing vte . cumulative incidence was adjusted for the competing risk of death but not for hospital discharge although the majority of patients had been discharged in this study . in total, patients with covid- infection confirmed by polymerase chain reaction on nasopharyngeal swab or bronchoalveolar lavage were included. both centres performed j o u r n a l p r e -p r o o f journal pre-proof vte risk assessments using the department of health tool . our guidance for thromboprophylaxis was based originally on nice guidance for medical patients using dalteparin that was prescribed according to weight and renal function unless contraindicated in all patients. post-discharge (i.e. extended thromboprophylaxis) was not used. the demographics of these patients are described fully in the previous articles. to summarise, there was predominance of males in both cohorts ( % cambridge and % london), high rates of mechanical ventilation use ( % and %) and the mean ages was and years, respectively. the median number of days of follow-up was (range - days) for those who were alive at review. the median duration of critical care admission was . days (range - days). at the censorship date, / patients had died ( %), / patients ( %) remained in critical care, / ( %) were in-patients but had been discharged from critical care, / ( %) were transferred to their local hospitals and / ( %) were alive and discharged from hospital. / ( %) of the patients discharged alive at follow-up had a hospital discharge duration of ≥ days. / ( %) patients developed vte events. the estimated cumulative incidence of vte over a minimum of days following critical care admission was . % shown in figure (a) ( % confidence interval . - . ). when segmental/sub-segmental pulmonary embolism was excluded, the cumulative incidence of vte was . % ( % ci . - . %), which is displayed in figure due to the concerns of an extended prothrombotic risk with covid- , particularly in those with severe disease, the use of extended thromboprophylaxis has been considered although there is no clinical trial data yet. in a meta-analysis in medically unwell patients who did not have covid- infection, extended chemical thromboprophylaxis compared to standard duration thromboprophylaxis resulted in no overall change in mortality rates but a % relative risk reduction in vte and a % relative risk increase in major haemorrhage . at present, we feel that this data however cannot be extrapolated to the setting of patients with covid- . the international society on thrombosis and haemostasis (isth) and american college of chest physicians (accp) in their expert-led guidance advocated the use of low molecular weight heparin during hospitalisation with covid- infection and isth advocated consideration of using extended thromboprophylaxis while accp did not , . thrombotic complications of patients admitted to intensive care with covid- at a teaching hospital in the united kingdom image-proven thromboembolism in patients with severe covid- in a tertiary critical care unit in the united kingdom fatal venous thromboembolism associated with hospital admission: a cohort study to assess the impact of a national risk assessment target beware overestimation of thrombosis in icu: mortality is not the only competing risk! incidence of thrombotic complications in critically ill icu patients with covid- incidence of venous thromboembolism in hospitalized patients with covid- high incidence of venous thromboembolic events in anticoagulated severe covid- patients post-discharge venous thromboembolism following hospital admission with covid- extended vs. standard-duration thromboprophylaxis in acutely ill medical patients: a systematic review and meta-analysis subcommittee on perioperative, critical care thrombosis, haemostasis of the scientific, standardization committee of the international society on thrombosis, haemostasis. scientific and standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with covid- prevention, diagnosis, and treatment of vte in patients with coronavirus disease : chest guideline and expert panel report key: cord- - pjfawk authors: melazzini, federica; colaneri, marta; fumoso, federica; freddi, giulia; lenti, marco vincenzo; pieri, teresa chiara; piloni, davide; noris, patrizia; pieresca, carla; preti, paola stefania; russo, mariaconcetta; corsico, angelo; tavazzi, guido; baldanti, fausto; triarico, antonio; mojoli, francesco; bruno, raffaele; di sabatino, antonio title: venous thromboembolism and covid- : a single center experience from an academic tertiary referral hospital of northern italy date: - - journal: intern emerg med doi: . /s - - - sha: doc_id: cord_uid: pjfawk preliminary evidence supports the notion that covid- patients may have an increased susceptibility to develop venous thromboembolism (vte). however, the magnitude of this association still needs to be defined. furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. on this basis, we conducted a retrospective, observational study on consecutive covid- patients admitted to an academic tertiary referral hospital in northern italy between march th and april th, . records of covid- patients with a definite vte event were reviewed for demographic information, co-morbidities, risk factors for vte, laboratory tests, and anticoagulation treatment. twenty-five cases among covid- patients developed vte ( . %), all of them having a padua score > , although being under standard anticoagulation prophylaxis since hospital admission. in the vte subcohort, we found a significant positive correlation between platelet count (plt) and either c reactive protein (crp) (p < . ) or lactate dehydrogenase (ldh) (p = . ), while a significant inverse correlation was observed between plt and mean platelet volume (p < . ). platelet-to-lymphocyte ratio significantly correlated with crp (p < . ). the majority of vte patients was male and younger compared to non-vte patients (p = . and p = . , respectively). no significant difference was found in d-dimer levels between vte and non vte patients, while significantly higher levels of ldh (p = . ) and il- (p = . ) were observed in vte patients in comparison to non-vte patients. in conclusion, our findings showed a quite high prevalence of vte in covid- patients. raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of vte. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. coronavirus disease (covid- ) is caused by severe acute respiratory syndrome coronavirus (sars-cov- ), which is responsible for acute respiratory distress syndrome the members of san matteo pavia covid- task force are listed in acknowledgements section. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. in a significant proportion of affected patients ( - %) [ , ] . the clinical spectrum of sars-cov- infection appears to be wide, encompassing asymptomatic infection, mild flulike syndrome, and severe viral pneumonia with respiratory failure and superimposed bacterial infections which may be fatal [ ] [ ] [ ] . venous thromboembolism (vte) includes deep vein thrombosis (dvt), pulmonary embolism (pe) and portal vein thrombosis. the association between vte and covid- was described for the first time by zhou et al. [ ] , who identified thrombotic events in . % of a cohort of covid- patients. in previous asian series, thromboembolic events have been reported in roughly one fourth of covid- patients admitted to the intensive care unit, and these findings correlated with a poor prognosis [ ] . a number of pathogenic mechanisms have been hypothesized for vte in covid- patients, including active inflammation, immobilization and intensive care treatments, but the limited evidence available in the literature does not allow to estimate the relative contribution of each of the abovementioned factors [ ] . little is known regarding the risk of vte in non-asian countries, that are known to have a higher incidence of vte in comparison to asian countries [ ] . recent publications reported a high rate of vte and arterial thrombotic events especially in critically ill patients ( - % depending on the analyzed cohort), also in occidental cohorts of covid- subjects [ ] [ ] [ ] [ ] [ ] [ ] . starting from these premises, we here aimed to define vte rates and types, not considering peripheral and central catheter-related thrombosis, among a cohort of covid- patients during their hospital stay at the san matteo hospital foundation (pavia, northern italy). this is a single-center, retrospective, observational study. we extracted data from medical records of all consecutive patients with a diagnosis of covid- admitted to the departments of internal medicine, infectious disease, intensive care, and respiratory disease of the san matteo hospital foundation (pavia, northern italy), between march th and april th, . the enrolment was limited to this time lapse as exhaustive data were available only for patients enrolled during this period. all patients had a confirmed diagnosis of covid- by real time polymerase chain reaction (rt-pcr) in respiratory samples (see supplementary materials). we reviewed records of all covid- patients for demographic information, co-morbidities, risk factors for vte according to the padua prediction score [ ] , laboratory tests and anticoagulation treatment at the time of hospital admission. dvt and pe were diagnosed through ultrasound and ctscan or ct-angiography, respectively. in particular, every patient with clinical suspect of vte or worsening respiratory function, underwent four-points us or ct-scan. the regions tested included: the common femoral vein at the level of inguinal crease, the superficial femoral vein superior to the adductor canal, the popliteal vein in the popliteal fossa and the great saphenous vein. the remaining patients were tested for routine laboratory tests if not daily, at least every - days. symptomatic patients were defined as follows: worsening pao /fio despite optimized therapy, signs and symptoms of dvt (i.e., pain, swelling, warmth), increase of d-dimer. no peripheral and central catheter-related dvts were included in the study. we also examined the correlation between dvt and selected inflammatory markers, including c-reactive protein (crp), interleukin (il)- , mean platelet volume (mpv), neutrophil-to-lymphocyte ratio (nlr), and platelet-to-lymphocyte ratio (plr). the study was performed as a clinical audit using routinely collected clinical data and as such is exempt from the need to require written informed consent. the study was approved by the local ethics committee (san matteo hospital foundation) on march th . the results of this study are reported according to the strengthening the reporting of observational studies in epidemiology (strobe) recommendations [ ] . given the observational nature of the study, sample size was not calculated a priori. continuous variables were expressed as median and range and compared with the mann-whitney u test. categorical variables were described as number (%), and proportions for categorical variables were compared using the fisher exact test. spearman correlation coefficient was calculated for relevant laboratory parameters. when variables were not available for some patients, these were excluded for percentage calculation. a two-sided α of < . was considered statistically significant. statistical analyses were performed using medcalc (belgium, version ). a total of cases of definite covid- patients were included in the registry between march th and april th . demographic characteristics, medical history and laboratory parameters of all patients included in the study are reported in table . the median age of the patients was years (range - ), % of the total were female (median age , range - ), % were male with a median age of (range - ). twenty-five patients turned out to be complicated by vte ( . %), of which had dvt, four had pe, and one among them also had portal vein thrombosis. all patients with vte had a padua score > . we did not identify any incidental diagnosis of vte, because asymptomatic patients did not twenty-two out of the vte cohort patients underwent prophylactic therapy with low molecular weight heparin (lwmh) or calcic heparin. three patients of the vte-group had clinical evidence of lower dvt by the time of hospital admission, hence anticoagulant therapy was immediately started. the median time lapse between hospital admission and vte onset was . days (range - days). the median time lapse between onset of covid- -related symptoms and vte was . days (range - days). dvt was the most frequent event, distributed among upper extremities and lower limb, being upper dvt more prevalent. of note, the prevalence of vte in icu patients was higher in respect to sub intensive/intermediate care patients departments ( % and %, respectively; p = . ). there was a significant correlation between platelet parameters and inflammation. in particular, platelet count directly correlated with either crp (p < . , r s = . ) or ldh (p = . , r s = . ), and it inversely correlated with mpv (p < . , r s = − . ). mpv significantly correlated in an inverse manner with either crp (p < . , r s = − . ) or ldh (p < . , r s = . ). plr significantly correlated directly with crp (p < . , r s = . ). d-dimer correlated directly with plt (p = . , r s = . ), ldh (p = . , r s = . ) and inversely with mpv (p < . , r s = . ) and lymphocyte (p < . , r s = − . ). of note, in the non-vte group a correlation between plr and crp was not observed (p = . , r s = . ) ( table ) . furthermore, % of vte patients were male and the median age at admission was (range - ), while in the non-vte group patients were significantly older (median , range - ), and the male population was less represented. no differences were found between vte and non-vte cohorts in terms of anticoagulant prophylactic therapy. there was no significant difference in d-dimer levels between the vte and non-vte patients (p = . ). ldh was significantly higher in vte-group compared to the non-vte group (median , range - mu/ml). serum levels of il- were significantly increased in vte compared to non-vte patients (p = . ). all the other parameters did not significantly differ between vte and non-vte patients. supplementary table shows characteristics and differences between vte patients admitted to intensive care unit (icu) and vte general ward patients. our findings showed a high prevalence ( . %) of vte in a non-asian cohort of covid- patients, which is higher when compared to the prevalence of vte in patients hospitalized for other causes ( . - . %) [ , ] . surprisingly, this high rate of vte was encountered despite prophylactic anticoagulation therapy in almost all patients. in fact, of all the patients who received thromboprophylaxis, . % developed vte, which is a higher rate compared to the standard of - % of symptomatic vte during enoxaparin prophylaxis. in the subcohort of icu patients, vte rate was . %, which is rather comparable to the literature-reported rate for these critically ill patients ( - %, if vte is screened). indeed, the vte rate in our cohort is lower than that from some other recent reports [ , ] . this might reflect the patients' setting, since a minority of our patients was managed in the icu and underwent chest ct-scan. surprisingly, out of vte patients ( %) presented with upper extremities dvt. of note, of these were icu patients ( %), while the remaining ( %) were general ward patients and all of them received supportive ventilation through c-pap. these findings support the notion that intensive care expose critically ill patients to a higher risk of developing dvt. in fact, critically ill patients are at high risk of vte as they are susceptible to both general risks factors of vte as well as those specific to icu patients, such as sedation, immobilization, and use of vasopressors [ ] . furthermore, peripheral lines and peripherally inserted central catheters (piccs) for intravenous therapy, could have contributed to the thrombotic process, particularly in an inflammatory state like the covid- related one. the relationship between viral pneumonia and predisposition to vte has been well described [ , ] . this phenomenon is the result of interaction between activated leukocytes and cellular adhesion molecules on the vein wall [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . inflammatory mechanisms up-regulate procoagulant factors, down-regulate natural anticoagulants and inhibit fibrinolytic activity [ ] . in particular, as marongiu et al. assert, the massive endothelial damage and activation of coagulation cascade is local [ ] , leading to pulmonary microvessels thrombosis [ ] . therefore, our study supports the notion that vte correlates with an inflammatory burst and inflammatory indexes such as ldh, il- and plr could be useful in stratifying the risk for covid- patients to develop vte manifestations. unfortunately, there is still a gap of knowledge on the certain pathogenesis of vte related to sars-cov- infection, so that we cannot exclude that a part of the pe reported were pulmonary thrombosis and not traditional isolated pe [ , ] . indexes such as mpv and plr have been used as unfavorable predictors in other viral infections [ , ] . the existence of a significant correlation between plr and inflammatory indexes in the vte subcohort seems to support the role of this marker as an unfavorable predictor in covid- patients, in keeping with recent reports [ ] . in contrast with tang et al. [ ] , we did not find any significant difference in d-dimer between the two cohorts and this could be related to the numerical imbalance between vte and non vte patients. our study also showed that, unexpectedly, platelet count was only slightly reduced or normal in most of covid- patients. that could be explained by the inflammatory state too, since thrombopoietin could increase in response to lung inflammation [ ] . hence, inflammatory profile, more than platelet count and coagulation profile, could help us to determine and estimate the severity of covid- . according to recent publications, we believe that enoxaparin and fondaparinux should be preferred instead of calcic heparin because of its anti-inflammatory properties [ ] . moreover, mycroft-west et al. [ ] , showed that lmwh can bind to the sars-cov- surface protein (spike) s receptor binding domain and block the replication of the virus, thus showing potential antiviral effects. if early initiation of prophylactic anticoagulant therapy should be recommended in covid- patients [ ] , how to optimize anticoagulant therapy is still a matter of debate [ ] . it can be assumed that by implementing the dosage of lmwh traditionally considered as prophylactic, if renal function is permissive and in the absence of bleeding diathesis, most vte events could be prevented, but further studies are necessary to confirm this therapeutic strategy. indeed, this study has some limitations, including the small sample size, the numerical imbalance between vte and non-vte cohorts, the lack of follow-up data, and the scarce use of chest ct-scan in the imaging diagnostic protocol of covid- pneumonia at the time of hospital admission. moreover, even if catheter-related dvts were not included in the study, we cannot exclude that blood sampling could partially explain such a high incidence. nevertheless, our study confirmed the high rate of vte in covid- patients, especially in those admitted to the icu. if anticoagulant therapy is then essential in the management of these patients, attention should be paid to the bleeding risk, due to the increased incidence of peptic ulcer disease in covid- patients [ ] . the relationship between vte and inflammation might support the hypothesis that a cytokine burst plays a central role in thrombotic complication in covid- patients. supporting our speculation, recent works have discussed how hyperinflammation and detrimental immunothrombosis might play a central role in covid- pathophysiology. the short median time lapse between hospital admission and vte onset suggests that this phenomenon is not correlated with hospitalization, but rather with covid- per se. since % of vte patients had a padua score greater than , we suggest performing upper and lower 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metastasis old and new applications of nonanticoagulant heparin the coronavirus (sars-cov- ) surface protein (spike) s receptor binding domain undergoes conformational change upon heparin binding the versatile heparin in covid- peptic ulcer disease as a common cause of bleeding in patients with coronavirus disease publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements dr. federica melazzini is grateful to the university of pavia for supporting her research projects. we thank all the specialists, resident physicians, and all healthcare professionals who are currently facing the covid- epidemic at san matteo hospital foundation. we thank dr. lorenzo neill aldegheri for having proofread the manuscript. author contributions all authors significantly participated in the drafting of the manuscript or critical revision of the manuscript for important intellectual content and provided approval of the final submitted version. individual contributions are as follow: ads, fm and mc designed and coordinated the study, interpreted data and wrote the manuscript. fb detected coronavirus in biologic specimens. all the other authors followed up patients, locally collected data, and reviewed the paper for final approval. ads, fm, mvl and fm, reviewed the paper and made final critical revisions for important intellectual contents.funding open access funding provided by università degli studi di pavia within the crui-care agreement.. conflict of interest the authors declare that they have no conflict of interest. the study was performed as a clinical audit using routine collected clinical data. the study was approved by the local ethics committee (san matteo hospital foundation) on march th .human and animal rights statement all procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. the study was performed as a clinical audit using routine collected clinical data in an anonymised format, and as such is exempt from the need to take specific written informed consent.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -ni toh c authors: kermani-alghoraishi, mohammad; ghahramani, rahil title: a review of venous thromboembolism phenomena in covid- patients date: - - journal: curr probl cardiol doi: . /j.cpcardiol. . sha: doc_id: cord_uid: ni toh c with the outbreak of the second peak of covid- in many countries of the world, re-attention to the symptoms and complications of this disease has received much attention. one of the most important known complications of severe acute respiratory syndrome coronavirus (sars-cov- ) is the occurrence of venous thromboembolic (vte) events, especially in critically ill patients and hospitalized in the intensive care unit. the pathology of this event is complex and multifactorial, but the main problem now is the timely diagnosis of these phenomena, which can reduce the mortality and morbidity of patients. deterioration of clinical condition in patients with sars-cov- infection along with increased coagulation markers can increase clinical suspicion of vte events. imaging techniques, especially computed tomography pulmonary angiography, can well solve this puzzle and lead to timely treatment of these patients. in late , a new coronavirus called covid- broke out in wuhan, hubei province, china, rapidly becoming a catastrophic pandemic ( ) . the spread, virulence and pathogenicity of this virus is so high that the world health organization (who) announced a total of , , cases affected and deaths in the th situational report on august , ( ) . the main complication of covid- is severe acute respiratory syndrome coronavirus (sars-cov- ), with fever, dry cough, and shortness of breath being the common primary symptoms ( ) . one of the important pathologies discovered in the course of this disease was an increase in coagulation status. in this regard, the occurrence of numerous venous thromboembolic (vte) events attracted the attention of medical staff, recording various reports and papers. therefore, in this review, the pathogens, epidemiology, diagnosis and therapeutic management of covid- patients with vte disease are discussed. as previously reported, severe viral infections such as influenza and sars-cov- either directly and indirectly cause hypercoagulability conditions and vte events ( ) ( ) ( ) . although the mechanism of vte with covid- infection has not been fully understood yet, it might be related to the endothelial cell damage caused by the virus which induces a hypercoagulant state ( ) . in this way and as the main pathology of covid- , sars-cov- invades host cells through the binding of spike glycoprotein, blocking angiotensin-converting enzyme (ace ) receptor and inhibition of transmembrane protease serine (tmprss ) activity which causes endothelial dysfunction, followed by hypoxia and thrombosis due to increased viscosity and increased signals of coagulation cascade activation ( ) . the above theory could explain pulmonary embolism in covid- patients who are not in critical condition. on the other hand, severe infection and sepsis dysregulate hemostatic pathways and activate coagulation cascade by inducing inflammation status with exceeded cytokines releases along with elevated d-dimer, fibrinogen and fibrinogen degradation products (fdp) ( , ( ) ( ) ( ) . these possible hypotheses are in addition to the clinical condition of patients admitted to the icu with multiple organ failure and loss of consciousness. although the exact mechanism of coagulopathy in patients with covid- is very complex and multifactorial, the triangle of abnormal haemostasis, severe inflammation and endothelial dysfunction is the most logical pathology in vte events ( - ). the incidence of pulmonary embolism has been reported differently in different studies and locations. in a retrospective observational multicenter study in france, out of , patients infected with covid- who had a computed tomography pulmonary angiography (ctpa), only ( . %) had evidence of pulmonary embolism ( ) , while most studies report an incidence of to % ( ) ( ) ( ) . the difference in the report of these studies was related to the type of patients studied. in the french study, patients who had been admitted to the intensive care unit (icu) from the beginning were excluded; in contrast, in other studies, the main target group was critically ill patients admitted to the icu ( ) ( ) ( ) . the prevalence of deep vein thrombosis (dvt) has varied widely in studies, ranging from % to % ( ) ( ) ( ) . this difference is also due to the severity of the disease and the clinical condition of the patients, such that llitjos et al report % cumulative incidence of peripheral vte in patients with severe novel coronavirus pneumonia ( ) . in contrast, screening ultrasound in non-icu ward patients in northern italy showed no evidence of venous thrombosis ( ) . the difference between the prevalence of venous thrombosis and pulmonary embolism indicates the independent pathology of thrombus formation in the lung mentioned above. overall, in a recent full systematic review and meta-analysis, the occurrence of vte was approximately %, while in cumulative incidences it could rise up to % during hospitalization; however, their post-hoc meta-analysis indicated high statistical heterogeneity and risk of publication bias. as an absolute finding, they acknowledged that there was more embolism in patients admitted to the icu ( ). diagnosis of vte disease, especially pulmonary embolism, in patients with sars-cov infections are incredibly difficult and challenging. in most covid- patients, no association was found between traditional major risk factors (age, history of vte disease, malignancy history, smoking and cardiovascular comorbidities including diabetes, hypertension, chronic heart failure and coronary artery disease) and vte diseases ( , ( ) ( ) . male gender and obesity were risk factors directly associated with an increased incidence of pulmonary embolism ( ) ( ) ) . as a noteworthy point in poyiadji et al study, patients who were on satin therapy prior to admission proved to have fewer pulmonary embolisms occurrence ( ) . therefore, using wells and geneva risk scores to predict the occurrence of pulmonary embolism is of low value and difficult ( , ) . as the first para-clinical approach in the diagnostic algorithm of pulmonary embolism, the use of d-dimer in the patients admitted with sars-cov infection is controversial, because this marker has been increased as an acute reaction factor in hospitalized patients in need of respiratory care and loses its predictive value due to its low specificity ( ) . however, in most reports and studies, the increase in d-dimer level is considered as a contributing factor along with clinical evidence, especially the clinical worsening of the patient's condition ( , , and ) . lung ventilation perfusion imaging (vq scans) is also limited in use due to lung tissue involvement and reduced test accuracy, as well as the possibility of contamination of the environment and medical staff. when ctpa is contraindicated and doppler ultrasound of the limbs has no evidence of thrombosis vq scans can be useful. finally, the most accurate modality in the diagnosis of pulmonary embolism, especially in critically ill covid- patient's pulmonary infection, is ctpa ( ). according to european society of radiology and the european society of thoracic imaging advices, ctpa is recommended to rule out pe if supplementary oxygen is needed in covid- lung infected patients when disease extension was limited ( ) . the european society of cardiology also recommends that ctpa may [or should] be considered for sars-cov patients before leaving the radiology department if unenhanced lung ct cannot explain the severity of respiratory failure ( ) . therefore, if we have clinical suspicion of pulmonary embolism, especially in the cases with clinical deterioration and disturbances in coagulation parameters and rising d-dimer, ctpa is recommended as a preferred step in the diagnosis ( , ( ) ( ) . the predominant pattern of pulmonary embolism in covid- patients is both segmental and sub-segmental ( ) ( ) ( ) ) , and treatment should be guided based on risk stratification and extent of lung involvement ( ) . patients in shock state and unstable hemodynamic should receive immediate reperfusion therapy ( ) . in patients with stable hemodynamic or low/intermediate vte risk treatment with unfractionated heparin (ufh), low molecular weight heparin (lmwh) or oral anticoagulant agent including non-vitamin k antagonist oral anticoagulants (noacs) and warfarin is recommended. ufh and lmwh are the most practical anticoagulants at time of admission, basically changing to oral medications at discharge time. noacs use compared to that of warfarin was significant in most patients; however, it is necessary to pay attention to the interaction between these drugs and medication used in covid- treatment, such as levofloxacin, azithromycin and anti-viral drugs including lopinavir/ritonavir or darunavir/ritonavir which increase the bleeding risk by inhibiting cytochrome p a (cyp a ) and/or p-glycoprotein (p-gp) pathways ( , ) . due to the need for close monitoring and the possibility of disease spread, warfarin is recommended only in patients with mechanical prosthetic valve or antiphospholipid syndrome ( ) . the decision on the duration of anticoagulation depends on the existence of provocative factor. therefore, it makes sense to perform anticoagulant therapy for at least months in critically ill patients, especially those admitted to the icu as provoked vte. moreover, it might be reasonable to extend the duration of anticoagulation and vte prophylaxis in covid- infected patients based on the patient's condition and risk factors. finally, according to recent studies, it is recommended that most of the hospitalized covid- patients, especially critically ill patients admitted to icu or cases with high d-dimer level, use pharmacological vte prophylaxis ( , ) . this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. a novel coronavirus outbreak of global health concern world health organization. coronavirus disease (covid- ) pandemic anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza a h n acute respiratory distress syndrome patients h n -induced venous thromboembolic events? results of a single-institution case series diagnosis, treatment, and prevention of novel coronavirus infection in children: experts' consensus statement procoagulant activity of endothelial cells after infection with respiratory viruses covid- and the cardiovascular system 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coronavirus pneumonia pulmonary embolism or pulmonary thrombosis in covid- ? is the recommendation to use high-dose heparin for thromboprophylaxis justified? thrombosis risk associated with covid- infection. a scoping review pulmonary embolism: a complication of covid infection covid- quarantine and acute pulmonary embolism coexistent covid- pneumonia and pulmonary embolism: challenges in identifying dual pathology acute pulmonary embolism in covid- related hypercoagulability diagnosis, prevention, and treatment of thromboembolic complications in covid- : report of the national institute for public health of the netherlands findings of acute pulmonary embolism in covid- patients. société française d'anesthésie et de réanimation diagnostic evaluation of pulmonary embolism during the covid- pandemic covid- patients and the radiology department -advice from the european society of radiology (esr) and the european society of thoracic imaging (esti) the european society for cardiology. esc guidance for the diagnosis and management of cv disease during the covid- pandemic pulmonary thromboembolism as a potential cause of clinical deterioration in covid- patients; a commentary pulmonary embolism in patients with covid- pneumonia incidence of pulmonary embolism in patients with covid- direct oral anticoagulant plasma levels' striking increase in severe covid- respiratory syndrome patients treated with antiviral agents: the cremona experience coagulopathy and plausible benefits of anticoagulation among covid- patients key: cord- -ylajz authors: demirci, ufuk; ozdemir, hande; demirbag-kabayel, derya; umit, elif g.; demir, ahmet muzaffer title: reducing the risk of venous thrombosis during self-isolation and covid- pandemic for patients with cancer: focus on home exercises prescription date: - - journal: clin appl thromb hemost doi: . / sha: doc_id: cord_uid: ylajz nan venous thromboembolism (vte) is a frequent complication of cancer. the incidence of clinically overt vte has been reported to be % with even higher rates in postmortem studies. risk factors of vte in patients with cancer include tumorspecific factors (ie, tissue factor such as microparticles), anatomic factors (ie hepatocellular cancer and venous invasion), patient-specific factors (ie, prior vte, age, obesity, and thrombophilia), and treatment-related factors (ie, high-risk surgery, chemotherapeutical agents). although several studies have attempted to predict the risk of vte in patients with malignancy, khorana score has been favored internationally for its simplicity and strength. during covid- pandemic, absolute home isolation has been recommended for all patients with cancer, which will bring an extra risk for thrombosis, inactivity for old patients. as a general notification, patients should be warned to be active as much as possible since there is an obvious relation between limb immobilization and vte. however, the intensity of the exercise has been demonstrated to be essential, strenuous exercise (ie, h/wk) has been related to increased risk of vte in elderly and obese patients. patients with cancer may perform moderate intensity aerobic exercises, which cause them lightly to perspire, such as brisk walking, dancing, cycling for minutes times per week, with an extra care for negative side effects including shortness of breath, nausea, or dizziness. the most commonly used mechanical methods to prevent the development of deep venous thrombosis and reduce the risk of pulmonary embolism are calf pump exercises. these exercises are safe, feasible even for elderly and bed-dependent patients with cancer. recent studies have demonstrated that active ankle dorsiflexion, plantar flexion, subtalar inversion, and eversion exercises increase venous return in the lower extremity, which suggest that combination of these exercises will be effective to reduce and even prevent the stasis and so forth, vte. likewise, the application of deep breathing exercises along with ankle exercises is suggested to contribute to venous return in the lower extremity. according to the american society of hematology guidelines for management of vte, it is appropriate to use compression stocks in acutely or critically ill patients, who are not appropriate for anticoagulant prophylaxis because of bleeding risk. also, it is convenient for patients who travel long distance and have high risk for vte. however, using of compression stocks in vte prophylaxis is not recommended in outpatients with minor vte risk factors. another important issue is that the necessity of primary thromboprophylaxis should not be neglected, unless there is a contraindication in high-risk selected patients with cancer, considering the khorana score. apixaban, rivaroxaban, or low molecular weight (lmwh) thromboprophylaxis should be initiated in accordance with the current guidance recommendations of the international society on thrombosis and haemostasis and the american society of clinical oncologists. in conclusion, we recommend all caregivers to include a reasonable yet effective prescription of home exercise for all patients with malignancies. ufuk demirci https://orcid.org/ - - - elif g. umit https://orcid.org/ - - - the use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the ssc of the isth venous thromboembolism prophylaxis and treatment in patients with cancer: asco clinical practice guideline update american college of sports medicine resource manual for guidelines for exercise testing and prescription the relationship of foot and ankle movements to venous return in the lower limb guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients key: cord- -ligqoj authors: duan, qianglin; gong, zhu; song, haoming; wang, lemin; yang, fan; lv, wei; song, yanli title: symptomatic venous thromboembolism is a disease related to infection and immune dysfunction date: - - journal: int j med sci doi: . /ijms. sha: doc_id: cord_uid: ligqoj the characteristics of human genomics and cellular immune function between clinically symptomatic venous thromboembolism (vte) and controls were systematically compared to explore the immunologic pathogenesis of vte. microarray assay showed the mrna expressions of genes related to non-specific cellarer immune and cytokines were significantly down-regulated. abnormal expressions of cd +, cd +, cd +, nk marker cd + +, cd and aberrant cd +/cd + ratio were detected in among patients. in pe patients, microarray assay revealed the imbalance in the expressions of genes related to the immune system. the expressions of genes related to non-specific immune cells and cytokines were markedly up-regulated and those associated with cellular immune were dramatically down-regulated. in vte patients, cytological examination indicated the functions of nk cells were significantly compromised, and the antigen recognition and killing function of t cells markedly decreased. the consistence between genomic and cytological examination suggests the symptomatic vte is closely associated with the infection and immune dysfunction. venous thromboembolism (vte) including acute pulmonary embolism (ape), chronic thromboembolic pulmonary hypertension (cteph) and deep venous thrombosis (dvt) is a global disease. the high morbidity, high misdiagnosis rate and high mortality render pe as a worldwide health problem ( ) . in , egeberg et al first described a parentage with inherited antithrombin deficiency, a member of which repeatedly developed dvt. the antithrombin deficiency is an autosomal dominant genetic disease and they first proposed the concept of thrombophilia ( ) . however, evidence on the genetic pathogenesis of vte is rarely identified in a majority of vte patients ( ) . according to the pathogenesis, vte is classified into genetic vte and acquired vte which is frequently found in clinical practice. the symptomatic vte is an entity of hereditary vte and acquired vte. the american college of chest physicians (accp) has recommended the guidelines for the diagnosis and prevention of vte since . a total of issues have been published by the end of ( ) , and the contents have also been continuously renewed. accp proposed that trauma, surgery, old age, malignancies, pregnancy, heart failure and oral administration of contraceptives are the main risk factors of vte and accp also proposed the concept of risk stratification for prophylaxis of vte by which differ-ivyspring international publisher ent managements were used for prevention from vte in different risk patients ( , ) . the incidence of symptomatic vte is not reduced but gradually increased, the reason of which may be related to the unclear pathogenesis of vte ( ) . in , smeeth et al reported the occurrence of vte was associated with infection, and vte was frequently observed within weeks after infection ( ) . in , we reported vte in multiple organs of a patient who died of sars, suggesting viral infection is a cause of systemic vte ( ) . in addition, in , we detected virus-like microorganisms in the lymphocytes of a young pulmonary hypertension patient with increased d-dimer, which morphologically confirmed the attack of t cells by virus, and peripheral decreased cd + and cd + level also indicated virus infection caused significantly compromised function of t cells ( ) . in , we reported the decreased cd + and cd + level with an increased cd + /cd + ratio in a group of cteph patients, suggesting t cellular immune dysfunction and ratio imbalance in cteph patients ( ) . in the present study, the whole human genome microarray and gene ontology (go) analysis were employed to detect the targeting of symptomatic pulmonary embolism (pe). in addition, flow cytometry was performed to investigate the changes in immune cells in vte patients, which aimed to validate the results from genome analysis. based on the findings above, the relationship between immune dysfunction and clinical symptomatic vte was analyzed. the cpr level in part of vte inpatients was determined. genomic study pe inpatients and controls were randomly selected in cardiology department, tongji hospital of tongji university. in the pe group, there were males and females, with a mean age of ± years ( ~ years). there were patients with acute pe and with cteph. the pulmonary artery pressure was - mmhg in cteph patients. in the control group, patients ( males and females) with a mean age of ± years ( ~ years) were enrolled during the same period. no significant difference in age was found between pe patients and control patients (p> . ). malignancies, use of immunosuppresants or autoimmune diseases were excluded in all patients. a total of clinically proven vte patients ( with ape, with dvt and with cteph) aged ± years ( ~ years) were recruited from tongji hospital, including males and females. the immunological parameters of these patients were all compared with the detection intervals of normal population. the diagnostic criteria of acute pe were the same as the above and the diagnosis of dvt was based on the criteria previously reported ( ) . the criteria for cteph developed by american aha were used for the diagnosis of cteph ( ) . in the present study, patients had the mean pulmonary artery systolic pressure of - mmhg. malignancies, use of immunosuppresants or autoimmune diseases were excluded in all patients. all patients were from shanghai, china. the present study was approved by the ethics committee of tongji hospital and informed consent was obtained before study. a total of ml of venous edta anti-coagulated blood was obtained from patients of both groups and mononuclear cells were isolated by density gradient centrifugation. red blood cell lysis buffer (qiagen, hilden, germany) was used to isolate mononuclear cells and total rna was extracted from mononuclear cells with trizol (invitrogen, carlsbad, usa) followed by purification with rneasy column (qiagen). treatment with dnase was performed to avoid the influence by genomic dna. quantification of extracted rna was performed with nanodrop nd- spectrophotometer (nanodrop technology, cambridge, uk). agilent g a whole human genome oligo microarrays were purchased from agilent (usa). a microarray is composed of , spots including genes or transcripts, negative control spots, positive control spots and blank spots. the functions of more than % of genes in the microarray have been known. all patients of both groups were subjected to microarray analysis. indirect approach was applied to mark samples. about μg of total rna was reversely transcribed into double strand cdna. after purification, in vitro amplification was performed with agilent low rna input linear amplification kit (agilent, pal alto, usa) and modified utp [aautp, -( -aminoally )-utp] was used to replace utp. the integrated aautp can interact with cy nhs ester forming fluorescent products which are then used for hybridization. the integration rate of fluorescence can be determined with a nanodropnd- spectrophotometer. then, hybridization mixture was prepared with agilent oligonucleotide microarray in situ hybridization plus kit. about ng of fluorescent products were fragmented at ℃ and hybridization was conducted in human whole-genome -mer oligo-chips (g f, agilent technologies) at ℃ for h at rpm. after hybridization, the chips were washed with agilent gene expression wash buffer according to manufacturer's instructions. original signals were obtained agilent scanner and feature extraction software. the standardization of original signals was carried out with rma standardized method and standardized signal values were used for screening of differentially expressed genes. the spots in the microarray were randomly selected and their expressions were confirmed by rt-pcr. among genes with differential expressions, genes were randomly selected and these genes and house keeping gene (gapdh) were subjected to rt-pcr. the relative expressions were expressed as the expressions of target genes normalized by that of gapdh ( -△△ ct ). melting curve and -△△ ct method were used to compare the difference in the expressions between control group and pe group. results from rt-pcr were consistent with microarray analysis. gene ontology organizes gene function into hierarchical categories based on biological process, molecular function and cellular component. fisher's exact test was applied for over representation of selected genes in go biological categories. in order to assess the significance of a particular category by random chance, false discovery rate (fdr) was estimated for all of categories. after , re-samplings, fdr was defined as fdr= -nk/t, where nk refers to the subtracted number which was from fisher's test in random samples. we specified the threshold of significant go as p-value< . , fdr< . and enrichment parameters. enrichment represents the degree of gene expression significance. the equation of enrichment is as following: re=(nf/n)/(nf/n) ( ) , where nf is the number of significant genes within the particular category, n is the total number of genes within the same category, nf is the number of significant genes in the entire microarray, n is the number of all genes tested. agilent feature extraction software was used to collect original data from microarray followed by analysis with robust multichip average (rma). gene intensity data between pe group and control group were compared with t test after calibration with a stochastic variance model. differentially expressed genes were identified from whole genomes. independent-samples t test was used to compare mrna levels in samples from pe patients and controls. statistical tests were performed using spss . , and p values < . were considered significant. before t test, test for equality of variances was performed, if variances were not equal, t test result would be corrected. sample collection: the fasting venous blood ( ml) was collected in the morning and added to the et tube. flow cytometry was performed to detect the differentiation antigens on immune cells with beckmancoulter epics xl-ii flow cytometer. in patients, the cd + , cd + , cd + , and cd were detected, and the nk cell marker cd + + + was detected in patients. the crp level in vte patients was detected by scintillation turbidimetry. go analysis targets the compromised immune functions of t cells and the decreased expression of immune receptor complex in pe patients. among genes related to the activation and chemotaxis of neutrophils, the mrna expressions of genes were significantly up-regulated in pe group (figure ). in the pe patients, the mrna expression of cd , a mononuclear cell surface antigen, was markedly up-regulated and that of cd , a macrophage activating factor, was also significantly up-regulated. in addition, the mrna expressions related to fc fragment of surface receptors (fcgr a, fcgr b, fcgr c, itgal and scarb ) were largely increased significantly ( figure ). the mrna expressions of c and c remain unchanged. in pe group, the mrna expressions of c b, c , c b as well as their receptors and complement integrins were markedly up-regulated but those of membrane attack complex component c , c , and c were significantly down-regulated when compared with the control group ( figure ). in the pe group, the mrna expressions of ifn regulatory factors, tnf and il- were markedly up-regulated. il- and il- a mrna expressions were significantly down-regulated when compared with control group (figure ). in the pe group, the expression of killer lectin-like receptor (klr) was markedly down-regulated when compared with control group, and the ncr mrna expression was also markedly down-regulated ( figure ). only cd mrna expression was significantly up-regulated in pe group ( figure ). in the pe group, the mrna expressions of t cell mediated cellular immunity, protein kinases related to transmembrane signal transduction (protein tyro-sine kinase-zap ), t cell surface antigens (especially cd ), membrane surface immune receptor complex and t cell granzymes were markedly down-regulated when compared with the control group (figure ) . a total of parameters(cd + , cd + , cd + , cd + /cd + , cd and cd + + + ) were measured in the pe patients, and had abnormalities in one or more parameters: had abnormal cd + expression (decreased in and increased in ) ( figure a ); had aberrant cd + expression (decreased in and increased in ) ( figure b) ; had abnormal cd + expression(decreased in and increased in ) ( figure c ); had aberrant cd + /cd + ratio (decreased in and increased in ) ( figure d ); had abnormal nk cd + + + expression in patients (decreased in and increased in ) ( figure e ) and had aberrant cd expression in patients (decreased in and increased in )( figure f ); the cd + expression was decreased in out of patients( . %), the cd + and cd + + + expressions were decreased in out of patients( . %), and the cd + , cd + + + and cd expressions were decreased in out of patients( . %)( figure g ). in vte patients, patients received crp determination. the crp level in out of patients ( . %) was higher than normal range (figure ). the go analysis of the genomic study targeted the decreased immune function of t cells and immune receptor complex in pe patients, suggesting the occurrence of pe is closely related to the immune dysfunction. statistical analysis revealed the mrna expressions of genes associated with innate immunity and cytokines were markedly up-regulated and those related to the cellular immunity of t cells and nk cells significantly down-regulated. in addition, cytological experiment indicated parameters related to immune function were abnormal in of vte patients. the expressions of cd + and cd + were markedly reduced and the cd + /cd + ratio significantly increased. the number of cd + + + and cd cells was reduced. the results from cytological examination and genome analysis were consistent. among the patients with vte, ( . %) had decreased cd + t cells, had reduced cd + t cells and ( %) had increased cd + /cd + ratio. these findings indicated the ability of t cells to recognize antigen and transmit activation signals was significantly compromised, and the capability of t cells to kill the pathogen infected cells decreased. the compromised t cell immune function is often identified in patients with malignancy, use of immunosuppressant, viral infection or malnutrition ( , ) . in the present study, none of patients had malignancies or were treated with immunosuppressants. therefore, the pathogenesis of vte might be closely related to viral infection or malnutrition. in our report, the syn-thesis and release of virus-like micro-organisms were noted in the lymphocytes under an electron microscope in a young pulmonary hypertension patient with increased d-dimer ( ) . among patients with vte, had decrease of cd + + + nk cells, which suggests the ability of nk cells to kill intracellular pathogens including virus is impaired. cd is only expressed on the b lymphocytes of normal hemopoietic system and the follicular dendritic cells (fdc) of germinal center. the expression of cd is detectable back to progenitor b cells and present during the maturation of b lymphocytes. once the b cells differentiate into plasma cells, the cd expression is absent. cd involves in the flux of ca + in the b lymphocytes, and can regulate the activation and proliferation of b cells ( ) . among vte patients, had decreased cd expression, which suggests the activity and proliferation of b cells are compromised. in of vte patients, the expressions of cd + , cd + , cd + + + and cd were separately or combinedly down-regulated or the cd + /cd + ratio was abnormal. these results imply the occurrence of vte is closely related to the immune function. in the present study, cd + + + t cells and/or cd + t cells were decreased in out of vte patients ( . %). down-regulation of cd + + + , cd + and/or cd was found in out of patients ( . %). these findings indicate the symptomatic vte is associated with the decrease of innate immunity and adaptive immunity in more than / of patients. moreover, vte patients ( . %) had one or more immune dysfunctions. among vte patients, only had normal immune function. two patients were a -year-old male acute pe patient and -year-old female acute pe patient who did not receive genetic testing. the remaining one patient was a -year-old female patient who was diagnosed as cteph and underwent splenectomy years ago. for patients with abnormal immune function on admission, it was difficult to confirm when the immune function became abnormal. however, we found that more than patients with down-regulation of cd + and cd + + + developed symptomatic vte sequentially. among vte patients, more than % of patients had symptoms of respiratory infection or a history of respiratory infection recently. among vte patients, crp was measured in patients and ( . %) had increase of crp, which implies inflammation is related to the occurrence of vte. in response to the invasion of foreign pathogens to human body, instantaneous innate immune response occurs within - hours after infection, and early innate immune response occurs - hours after infection ( , ) . dvt and pe often occurred after - days postoperatively, which coincided with the infection process of innate and adaptive immune function ( ) . during the -year follow up period, vte patients ( %; including those died) were lost to follow up. among patients receiving follow up, all were treated with warfarin for anti-coagulation. in addition, immunological examination and detection of d-dimer were also carried at designed time points. our results showed about % of vte patients receiving follow up did not have increase of d-dimer level any more at . ~ year after warfarin discontinuation when the immunological examination and detection of d-d dimer showed normal. of patients with symptomatic vte, the relationship between vte and immune dysfunction was found in ( . %). nevertheless, patients with immune dysfunction do not develop symptomatic vte in a short time. the compromised or disorganized immune function may be the internal cause of susceptibility to acquired vte, and infection acts as a triggering factor of acquired vte. when the pathogens invade the subjects with immune dysfunction, the pathogens can not be completely removed by the immune system. thus, patients with compromised or disorganized immune function are susceptible to acquired vte. prevention and treatment of venous thromboembolism. international consensus statement (guidelines according to scientific evidence) inherited antithrombin deficiency causing thrombophilia genetic risk factors of venous thrombosis prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis prevention of venous thromboembolism: the seventh accp conference on antithrombotic and thrombolytic therapy prevention of venous thromboembolism: american college of chest physicians evidence-based clinical practice guidelines a -year analysis of venous thromboembolism on the surgical service: the effect of practice guidelines for prophylaxis risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting severe acute respiratory syndrome and venous thromboembolism in multiple organs compromised t-cell immunity and virus-like structure in a patient with pulmonary hypertension cell-mediated immune deficiency or compromise in patients with cteph current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the american academy of family physicians and the american college of physicians accf/aha expert consensus document on pulmonary hypertension: a report of the american college of cardiology foundation task force on expert consensus documents and the american heart association: developed in collaboration with the genome-scale analysis of in vivo spatiotemporal promoter activity in caenorhabditis elegans cd molecules --human cell differentiation molecules immune reconstitution in hiv infection and its relationship to cancer cd is essential for b cell activation by promoting b cell receptor-antigen microcluster formation in response to membrane-bound ligand c-reactive protein and risk of venous thromboembolism in the general population the evolution of inducible defenses: current ideas early development of deep-vein thrombosis following hip fracture surgery: the role of venous wall thickening detected by b-mode ultrasonography this study was supported by " th five year" national science and technology supporting program ( bai b ). the authors have declared that no competing interest exists. key: cord- -tgpsd r authors: haider, maryam b.; abbas, farrukh; hafeez, wasif title: a -year-old woman who presented with diabetic ketoacidosis and covid- pneumonia with multiple pulmonary thromboemboli: a case report date: - - journal: am j case rep doi: . /ajcr. sha: doc_id: cord_uid: tgpsd r patient: female, -year-old final diagnosis: covid provoked thromboembolism symptoms: cough • dyspnea medication:— clinical procedure: — specialty: infectious diseases • general and internal medicine objective: unknown ethiology background: coronavirus disease (covid- ) occurs because of a novel enveloped ribonucleic acid coronavirus called severe acute respiratory distress syndrome coronavirus- (sars-cov- ). one of the major reported complications of covid- includes both arterial and venous thromboembolism (vte). here we describe a case of covid- provoked pulmonary embolism in a young patient already receiving prophylactic treatment for vte. case report: a -year-old female with past medical history of diabetes mellites, hypertension, and asthma presented in the emergency department (ed) with dyspnea requiring liters per minute of oxygen on presentation. her main complaints were cough and vomiting. in the ed, hypoxemia worsened, and she ultimately required endotracheal intubation. labs were suggestive of diabetic ketoacidosis (dka) and showed increase in all inflammatory markers and absolute lymphocytopenia. chest x-ray showed bilateral diffuse patchy airspace opacities. standard dka management was started. she was also started on ceftriaxone, azithromycin, hydroxychloroquine, and subcutaneous heparin ( u every h) for vte prophylaxis. sars-cov reverse transcription-polymerase chain reaction returned positive. ceftriaxone and azithromycin were discontinued the very next day because of low suspicion of bacterial infection while hydroxychloroquine was completed for days. on the third day of admission, the patient self-extubated and was immediately placed on nonrebreather with spo( ) in low s. on the fourth day of admission, d-dimer came back . mg/l, which was elevated from a prior value, so computed tomography angiography of the lungs was done, which disclosed multiple emboli in the lungs. she was started on therapeutic doses of enoxaparin sodium, which was continued through her admission. she was switched to apixaban on discharge. conclusions: the finding of the case suggested that low-molecular-weight heparin prophylaxis may not be sufficient to prevent vte in covid- pneumonia. some of these patients may benefit from receiving prophylactic half doses or full doses of anticoagulants. coronavirus disease (covid- ), which is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), is a novel enveloped ribonucleic acid beta coronavirus believed to have its origin from bats and is thought to have originated in the meat markets of wuhan, china. according to the new data, almost confirmed cases are present worldwide, and it has been declared a pandemic by the world health organization [ ] . so far, multiple complications of covid- have been observed, including both arterial and venous thromboembolism, leading to deep vein thrombosis, pulmonary embolism (pe), and ischemic stroke [ , ] . precise knowledge pertinent to the pathogenesis of such complications as well as covid- have hardly been described [ ] and is being actively discussed by many researchers and clinicians. here, we describe a case of covid- that provoked pe in a young patient already receiving prophylactic treatment of venous thromboembolism (vte). a -year-old nonpregnant female with past medical history of diabetes mellitus, hypertension, and asthma presented in the emergency department (ed) with dyspnea, requiring liters per minute of oxygen on admission. the patient was complaining of cough and had a few episodes of vomiting. in the ed, her respiratory failure with hypoxemia worsened; it was initially managed with nonrebreather but she ultimately required endotracheal intubation. labs were consistent with diabetic ketoacidosis (dka). chest x-ray showed bilateral diffuse patchy airspace opacities, which may represent multifocal or viral pneumonia ( figure ). standard dka management was started. she was also started on ceftriaxone, azithromycin, hydroxychloroquine, and subcutaneous heparin ( u every h) for vte prophylaxis. upon admission she was afebrile with t max . °c, blood pressure / , heart rate , respiratory rate . labs showed c-reactive protein (crp) . mg/l, lactic acid . mmol/l, serum sodium mmol/l, serum potassium . mmol/l, glucose mg/dl, anion gap mmol/l, blood urea nitrogen mg/dl, serum creatinine . mg/dl, lactate dehydrogenase , alanine aminotransferase , aspartate aminotransferase , white blood cells . with absolute lymphocyte count of . , red blood cells . , hemoglobin . mg/dl with mean corpuscular volume . fl, platelet , hematocrit . %, d-dimer . mg/l, fibrinogen > mg/dl. testing for influenza a, b, respiratory syncytial virus, pneumococcus urine antigen, and legionella urine antigen were negative. the sars-cov- was confirmed by real-time reverse transcription-polymerase chain reaction test from nasopharyngeal or oropharyngeal swabs. ceftriaxone and azithromycin were discontinued the very next day because of low suspicion of bacterial infection, whereas hydroxychloroquine was completed for days. on the third day of admission, the patient self-extubated and was immediately placed on nonrebreather with spo in low s. the next day, she remained on the nonrebreather at l/min with spo ranging to %. on the fourth day of admission, d-dimer came back . mg/l, which was elevated from the prior value. a computed tomography (ct) angiography of the lungs (figures , ) was done, which disclosed multiple emboli involving segmental and subsegmental pulmonary arteries in the left lower and upper lobes and the left lower lobe lobar artery and subsegmental emboli in the right upper lobe, and no large central emboli. there was probable associated right heart strain. the spleen was prominent in size and displayed few small hypoattenuation areas peripherally and its inferior region highly likely related to focal infarcts. her pe was suspected to be provoked by covid- . she was placed on enoxaparin sodium mg/kg every h and was discharged on apixaban mg twice daily for at least months of anticoagulant. thrombotic complications are new emerging issues in patients infected with covid- , as very limited data are available on postmortem/autopsy findings of such patients that suggest thrombotic microangiopathy [ ] . it is suspected to be more prevalent in covid- patients, especially those needing admission in the intensive care unit. moreover, the precise pathogenetic mechanism is unknown, but multiple etiologies are being suspected by experts in this field [ , ] . one mechanism of pathogenesis being considered is virus attaching to angiotensin-converting enzyme (ace- ) receptors in pulmonary epithelium and endothelium, leading to proinflammatory cytokine activation, which further activates the coagulation system, such as interleukin , a prominent inducer of tissue factor and hence activates thrombin generation. another perspective involved the coagulation system being evolved as an effector pathway of the immune response. for instance, the end result of inflammation is thrombosis as in behcet's disease or vasculitis, and anticoagulants do not improve the outcome in these states. instead, we treat the inflammatory process. moreover, hypoxia could be induced by transcription factor, which leads to a prothrombotic state (affects tissue factor and plasminogen activator inhibitor- genes). the patient in discussion developed pe despite being on a prophylactic dose of heparin, suggesting that only a prophylactic dose may not be sufficient to prevent vte in covid- patients with higher inflammatory markers. various institutions have implemented their own protocols regarding anticoagulation and testing for vte in covid- . many institutions are giving double the dose than the prophylactic anticoagulation therapy in covid- patients. some institutions are giving full-dose anticoagulants to all covid- patients, especially those with d-dimer levels three to five times higher than normal. it is not known if this is the right strategy, and we will need to look toward randomized controlled trials to seek definitive answers in this situation. the findings of the case suggested that low-molecular-weight heparin prophylaxis may not be sufficient to prevent vte in covid- patients with proinflammatory state. some of these patients may benefit from receiving a prophylactic half dose or full dose of anticoagulant. nevertheless, in the presence of clinical signs or suspicion of vte, compression ultrasound or echocardiography or ct pe should always be performed, irrespective of disease stage. last, d-dimer is not a very specific marker for vte, as it is generally increased in severe covid- pneumonia, but it can still guide testing and anticoagulation strategy in patients with covid- pneumonia on the medical floors as well those in the critical care unit. world health organization (who): coronavirus disease (covid- ) situation reports incidence of thrombotic complications in critically ill icu patients with covid- deep vein thrombosis and pulmonary embolism: two complications of covid- pneumonia? clinical characteristics of deceased patients with coronavirus disease : retrospective study pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans. medrxiv anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy thromboinflammation and the hypercoagulability of covid- a -year-old woman who presented with diabetic ketoacidosis… © key: cord- -at c q authors: porfidia, angelo; pola, roberto title: venous thromboembolism and heparin use in covid- patients: juggling between pragmatic choices, suggestions of medical societies date: - - journal: j thromb thrombolysis doi: . /s - - - sha: doc_id: cord_uid: at c q nan the disease caused by coronavirus sars-cov- , named covid- , has become a global emergency. the virus spreads via respiratory droplets and is mainly responsible for infections of the respiratory airways, with potentially fatal pneumonia [ , ] . although mortality is higher in elderly frail patients presenting with comorbidities, cases of deaths have been reported also in younger age groups [ ] . physicians treating patients with covid- are facing novel and unexpected challenges. one of these is the proper prevention and diagnosis of venous thromboembolism (vte) and, more generally, how to deal with coagulative activation apparently existing in these patients. in this article, we discuss the many doubts currently existing on the use of heparins and the correct prevention and diagnosis of vte in covid- patients, with physicians that juggle between pragmatic choices, different suggestions being released on a daily by hospital and medical societies, and the lack of solid evidence or guidelines. finally, we highlight the need for a call to action by the medical and scientific community. acute infections are associated with a transient increased risk of vte and subjects hospitalized for covid- pneumonia are the prototypical example of acutely ill medical patients at increased risk of vte. indeed, hospitalized covid- patients not only suffer from an acute infection, but also have respiratory failure and are bedridden, or have reduced mobility, due to the need of oxygen supplementation and the isolation imposed by hospital restrictions. the combination of these conditions results in a padua prediction score ≥ , which corresponds to increased risk for vte [ ] . this risk may be higher, in case of cancer, history of previous vte, and age ≥ years [ ] . in addition, abnormal coagulation parameters have been reported in hospitalized patients with severe covid- disease [ , ] and d-dimer levels above > µg/l have been associated with increased risk of death [ ] . it is also known that some patients with severe covid- meet the criteria for disseminated intravascular coagulation (dic) and display laboratory sings of vascular inflammation [ ] . based on this, one would expect that, in the absence of contraindications, proper thromboprophylaxis is given to all hospitalized patients with covid- pneumonia. a retrospective analysis conducted at tongji hospital in wuhan, china, reports that, among patients with severe covid- , only ( %) received heparin treatment (mainly low molecular weight heparin, lmwh) for days or longer. the -day mortality among subjects with sepsis-induced-coagulopathy (sic.) score ≥ , or d-dimer levels > fold of upper normal limit, was higher in non-heparin than in heparin treated patients [ ] . the authors of this retrospective analysis correctly point out that anticoagulation was seldom used in this population because at the time of its hospitalization there was a poor understanding of the disease, and they state that heparin has been increasingly used later during the outbreak of covid- in china. the use of prophylactic-doses of lmwh is now recommended by the international society on thrombosis and haemostasis (isth) for all hospitalized covid- patients, unless they have active bleeding or platelet count < × /l [ ] . likewise, the american society of hematology (ash) states that all hospitalized patients with covid- should receive pharmacologic thromboprophylaxis with lmwh or fondaparinux, unless they are judged to be at increased bleeding risk [ ] . however, there is a strong feeling around the medical community that prophylactic doses of anticoagulation might not be sufficient to contrast the hypercoagulable state displayed by many covid- patients in response to a cytokine storm syndrome. in this scenario, some physicians, underlying the anti-inflammatory role of heparin [ , ] , and even its anti-viral potentials [ , , ] are considering higher dose of anticoagulation in patients that do not have documented vte [ , ] . in any case, it is important to point out that, at the moment, the use of anticoagulation at doses different from those commonly used for thromboprophylaxis is not supported by any published evidence, but only by pragmatic considerations. in particular, the true incidence of vte in covid- patients that receive pharmacological thromboprophylaxis remains uncertain, as we will discussed below, and data showing improved outcomes in patients treated with therapeutic anticoagulation are lacking. in this puzzling situation, physicians around the world are making decisions on a case by case basis and therapeutic regimens are very heterogeneous from hospital to hospital, even within the same country. we are also concerned about the fact that nothing is known about the best strategy to use to prevent vte in the many covid- patients that are treated at home, either before and after hospitalization. one might argue that these subjects are comparable to medical outpatients with minor provoking factors for vte (i.e. immobility, minor injury, illness, or infection) and that international guidelines suggest not to use vte prophylaxis in these cases [ ] . however, guidelines on this topic have very low level of evidence as they have been indirectly extrapolated from data on acutely ill medical inpatients who received extended prophylaxis upon hospital discharge. in addition, we are doubtful that all patients with covid- who are treated at home are comparable to medical outpatients with minor provoking factors for vte, especially when they have clinical signs of respiratory infection, fever, cough, and dyspnea. also, most of these patients are elderly and have reduced mobility, as they are confined in their houses, or even in their bedrooms, in order to avoid spreading the infection to the other family members. they might also have other comorbidities that increase vte risk, such as cancer, previous vte, heart failure, and venous insufficiency. therefore, it is reasonable to hypothesize that at least some of these outpatients would benefit from pharmacological thromboprophylaxis. to support this concept, it is worth mentioning the report published by danzi and coll., which describes the case of a -year-old woman who was hospitalized in cremona, italy, after days of fever and a recent onset of dyspnea at home and was diagnosed with severe covid- -positive bilateral pneumonia and concomitant acute pe two days after hospital admission [ ] . it is also worth mentioning the case of a -year-old man, who, according to the news in the media, died because of pe days after been discharged from a hospital in trento, italy, where he had been treated for a confirmed case of covid- pneumonia [ ]. of note, both the woman in cremona and the young man in trento had no strong predisposing risk factors for vte, which suggests that the criteria that we classically use to estimate the risk for vte in outpatients may not apply well to subjects with covid- , who might instead have infection per se as precipitant factor for acute vte, and reduced mobility due to the current restriction rules that have been adopted by many countries to reduce the diffusion of sars-cov- infection as contributing factor, even when people are not in the hospital. this issue is critical and has been taken into consideration in a recent position paper from the italian society on thrombosis and haemostasis (siset), in which it is suggested to maintain thromboprophylaxis at home for - days after hospital discharge or in the pre-hospital phase, at least in subjects with pre-existing or persisting vte risk factors [ ] . at the moment, very little is known on the exact incidence of vte among hospitalized patients with covid- pneumonia. this is due to the fact that diagnostic exams cannot be easily performed in these patients, since they must remain in isolation, there is a risk of virus aerosolization, sometimes a lack of proper protective personal equipment, or patients are too unstable. the consequence is that for now there are only two studies published on this issue, both performed on patients assisted in intensive care units (icu). the first study has been carried out in the netherlands and reports a remarkable % incidence of vte (including both dvt and pe), confirmed by either computed tomography pulmonary angiography (ctpa) and/or venous ultrasonography of the legs, on a total of evaluated patients [ ] . the second study has been carried out in china and reports a % incidence of dvt, assessed by venous ultrasonography of the legs, on a total of evaluated patients [ ] . it is very important to point out that in the dutch study all patients were receiving at least standard doses of anticoagulant thromboprophylaxis, while in the chinese study no preventive anticoagulant was administered to patients. in addition to these studies, there are two 'preprints' -which are preliminary reports that have not undergone peer review -and case reports. one of these preprints reports cases of deep vein thrombosis (dvt) among covid- patients consecutively admitted to a hospital in china, with a prevalence of . % [ ] . the authors of this study highlight that of these dvts were found in critically ill patients, suggesting that the incidence of vte may be higher in subjects with severe covid- . another preprint reports that, among patients with covid- pneumonia, underwent ctpa and were found to have pe [ ] . regarding case reports, there is the one published by danzi and coll, which we have mentioned above [ ] , and another one published by xie and coll., which describes the cases of two patients who, after presenting with fever, cough, and dyspnea due to covid- pneumonia, displayed respiratory deterioration associated with increased serum d-dimer level and were diagnosed with acute pe by ctpa [ ] . taken together, these findings support the concept that vte might complicate the clinical course of covid- pneumonia. indeed, it is well established that acute pe is a cause of clinical deterioration in viral pneumonias [ , ] and we do not see why covid- pneumonia should make an exception. however, we have evidence from our clinical practice that the diagnostic algorithm that international guidelines recommend for patients with suspected pe, which consists in the execution of ctpa in subjects with high clinical probability of pe independently on d-dimer levels, and in subjects with low or intermediate clinical probability of pe in case of positive d-dimer test [ ] , is used very rarely in subjects with covid- pneumonia. this is probably due to the fact that the value of the clinical prediction rules that have been developed to estimate the probability of pe, such as the geneva score [ ] , is uncertain in subjects with covid- pneumonia. nonetheless, we wonder whether such approach might have resulted in missing cases of pe around the world. not to mention the fact that many covid- patients stay at home with fever and respiratory symptoms for several days before being hospitalized, as in the case of the -year-old woman described by danzi and coll., [ ] and thus might have vte already at the moment of hospital admission. it is for these reasons that some hospitals are considering to carry out a systematic screening of deep vein thrombosis (dvt) by means of an ultrasonography of the legs among all hospitalized covid- -positive patients. however, a cost-effectiveness analysis of such systematic approach has not been done. we wonder whether ultrasound screening might be more effective if limited to patients with elevated d-dimer levels and/or clinical signs of the disease, as assessed by probability scores (i.e. wells score). in any case, a screening based only on ultrasound of the legs would not identify 'isolated' pe (i.e. pe without dvt of the legs). there are many open questions on the correct diagnosis and management of vte during the covid- pandemic. some are the following: what is the prevalence of vte among patients hospitalized for covid- outside of the icu? is there a need for a dedicated scoring system to estimate the risk of vte among patients with covid- ? what is the optimal dose of anticoagulation to prevent vte in covid- patients? should patients treated at home receive pharmacological thromboprophylaxis? should we screen covid- patients for dvt at the moment of hospital admission, or during hospitalization? when should we consider performing ctpa to rule out pe in patients with covid- pneumonia? we call for a sustained research effort to investigate the issues identified here and reduce the burden of vte and its consequences in patients with covid- . we are aware that randomized clinical trials show the best scientific evidence, but in this moment of emergency and uncertainty, we solicit the medical community to share data and create dedicated registries. world health organization. who director-general's opening remarks at the media briefing on covid- - clinical features of covid- in elderly patients a comparison with young and middle-aged patients a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia hematologic parameters in patients with covid- infection clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy isth interim guidance on recognition and management of coagulopathy in covid- covid- and vte/anticoagulation: frequently asked questions more than an anticoagulant: do heparins have direct anti-inflammatory effects? the anti-inflammatory effects of heparin and related compounds herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry heparin prevents zika virus induced-cytopathic effects in human neural progenitor cells coronaviridae and sars-associated coronavirus strain hsr covid- and haemostasis: a position paper from italian society on thrombosis and haemostasis (siset) the versatile heparin in covid- american society of hematology guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients acute pulmonary embolism and covid- pneumonia: a random association? incidence of thrombotic complications in critically ill icu patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia risk assessment of venous thromboembolism and bleeding in covid- patients findings of acute pulmonary embolism in covid- patients zhang s ( ) covid- complicated by acute pulmonary embolism similarities between community-acquired pneumonia and pulmonary embolism acute thrombotic vascular events complicating influenza-associated pneumonia esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the a. porfidia, r. pola key: cord- -zo n wf authors: vadukul, prakash; sharma, deepak s; vincent, paul title: massive pulmonary embolism following recovery from covid- infection: inflammation, thrombosis and the role of extended thromboprophylaxis date: - - journal: bmj case rep doi: . /bcr- - sha: doc_id: cord_uid: zo n wf covid- is the infectious disease caused by a recently discovered sars-cov- . following an initial outbreak in december in wuhan, china, the virus has spread globally culminating in the who declaring a pandemic on march . we present the case of a patient with an initial presentation of covid- pneumonitis requiring mechanical ventilation for nearly weeks and total admission time of weeks. she was given prophylactic dose anticoagulation according to hospital protocol during this time. following a week at home, she was readmitted with acute massive pulmonary embolism with severe respiratory and cardiac failure, representing the first such case in the literature. our understanding of covid- continues to evolve as the disease remains a global public health emergency. a plethora of research has been conducted to investigate the disease process and the optimal treatment modalities but there still remain many unknowns. infection with sars-cov- is often asymptomatic but leads to deregulated immune responses with multiorgan failure and critical illness in a minority of patients. this case examines aspects of covid- emphasising the increased thrombogenicity seen during infection and the potential need for extended anticoagulation following recovery particularly in those patients with severe illness and pre-existing risk factors. a -year-old woman with a background of obesity and undiagnosed type diabetes mellitus was admitted to intensive care with breathlessness preceded by a week-long viral prodrome. admission chest radiography revealed diffuse bilateral infiltrates (figure ) associated with severe type respiratory failure (pao /fio ratio mm hg prior to mechanical ventilation). after a -hour trial of continuous positive airway pressure, she deteriorated with tiredness, increased work of breathing and fluctuating conscious level. a confirmatory nasopharyngeal swab detected sars-cov- rna. following endotracheal intubation and mechanical ventilation, she underwent intensive care treatment for weeks including airway pressure release ventilation, multiple sessions of prone positioning, antimicrobial therapy for secondary bacterial infection and continuous renal replacement therapy for days. she gradually improved and after days was successfully liberated from respiratory support without requirement of reintubation or tracheostomy. her condition continued to improve with rigorous physiotherapy and after step-down to the ward, she was successfully discharged home after a total -week inpatient stay. during her hospitalisation she received consistent doses of prophylactic low molecular weight heparin (lmwh) adjusted to her weight ( kg, body mass index (bmi) ) according to standard hospital protocol for venous thromboembolism (vte) prophylaxis. initially mg of enoxaparin was administered subcutaneously once daily, increased to mg two times per day after days to reflect updated local anticoagulation protocols for those seriously affected by the disease. she was stepped down to ward from the intensive care unit and later at the time of discharge to home she was given insulin and antihypertensive medication to take away. lmwh was discontinued in keeping with standard hospital protocol predating any specific covid- guidance. one week later at : hours, she was brought to the emergency department by ambulance with severe breathlessness. she reported days of rightsided chest pain with progressive dyspnoea culminating in syncope prior to presentation to the emergency department. on arrival the patient was conscious but unable to complete sentences. initial examination demonstrated a diaphoretic and agitated patient with unremarkable chest auscultation. the respiratory rate was /min and oxygen saturations were % on l via a non-rebreathe device with a partial pressure arterial oxygen of . kpa. her systolic blood pressure was mm hg with a heart rate of beats/minute and cold peripheries. although alert she was confused and unable to give a clear history. she was apyrexial with unremarkable abdominal and lower limb examinations. electrocardiography demonstrated a sinus tachycardia and right heart strain suggested by subtle s-waves in lead i associated with q-waves and subtle t-wave inversion in lead iii. findings that shed new light on the possible pathogenesis of a disease or an adverse effect urgent ct pulmonary angiography (ctpa) was undertaken after initial management revealing bilateral pulmonary emboli with saddle component and right heart strain. bedside echocardiography after subsequent admission to intensive care revealed a dilated, impaired right ventricle and a 'd-shaped' left ventricle with pronounced left-ward septal deviation, more pronounced during systole indicative of pressure overload. during the initial presentation d-dimer levels were . fibrinogen equivalent units (feu) mcg/ml (normal range in our institution . - . feu mcg/ml). d-dimer levels at the time of her second admission were . feu mcg/ml. the clinical instability and refractory hypoxia warranted emergency rapid sequence induction and endotracheal intubation with intermittent boluses ( - μg) of epinephrine required to support her increasingly labile blood pressure. despite intubation, hypoxia persisted even after maximal oxygen delivery (fio . ), recruitment manoeuvres and optimisation of ventilation and patient position. urgent ct was arranged while thrombolysis was considered. other considerations during the initial patient assessment included secondary bacterial infection, atypical pnuemonia, cardiogenic pulmonary oedema and pulmonary embolism (pe). with the overall lack of clarity over the cause of her presentation and the uncertain nature of covid- with its unknown potential for relapse, confirmatory imaging was sought to confirm the diagnosis. with persistent severe hypoxia and hypotension, an urgent decision regarding administration of thrombolysis was required. intensive care personnel reviewed the images (figures and ) immediately after performance of the scan. we were able to accurately identify pulmonary emboli (subsequently confirmed on formal reporting an hour later), and this enabled immediate initiation of intravenous thrombolysis with tissue plasminogen activator ( mg bolus of alteplase with subsequent mg infusion over min as per our trust protocol) within minutes of completion of ctpa, while still within the scanning room. she was admitted to intensive care to continue ventilation and inotropic support. overnight she was sedated, ventilated and required an epinephrine infusion (maximum dose μg/min) to maintain an adequate mean arterial blood pressure. she made a rapid recovery. an initial fio of . was required for hours following endotracheal intubation likely due to significant shunt and deadspace ventilation with the large volume bilateral pe. however following thrombolysis there was a brisk improvement in her clinical condition with no requirement for vasopressors or inotropes at hours post presentation and an fio requirement of . . she was successfully liberated from mechanical ventilation hours later with no immediate neurological sequelae. after step-down to the ward long-term anticoagulation therapy was initiated after multidisciplinary discussion followed by discharge after days. risk factors for thrombosis are numerous but are generally considered to contribute by three key mechanisms (virchow's triad); endothelial injury, reduced flow/stasis and hypercoagulable state. although there are many unknowns with regard to this novel disease, increasing experience suggests that patients with severe covid- infection have elements of all three. following initial discharge our patient was also noted to have reduced mobility and difficulty exercising with easy fatigability. allied to her obesity, a risk factor for vte, this illustrates a picture of thromboembolic risk. pulmonary emboli has been reported frequently in covid- and are often noted in patients with covid- without other standard risk factors, suggesting that it is an independent risk factor for vte. data from early french experiences revealed pe prevalence of % in patients with severe covid- infection. requirement for mechanical ventilation was also strongly linked to the presence of pe on imaging. there is no current evidence to define the incidence of pe following recovery. at readmission this patient had little evidence of persistent infection with resolution of the majority of ground glass changes seen in prior imaging or other symptoms such as cough or fever. the duration of the prothrombotic state associated with covid- and therefore the optimal management strategy is unclear. this case report aims to review the current literature regarding thromboprophylaxis in patients with covid- and highlights the potential for patient readmission after critical illness. with regard to the emergent management of pe, guidelines recommend thrombolysis where there is persistent haemodynamic compromise, evidence demonstrating survival benefit and improved long-term outcomes. thrombolysis without cardiovascular compromise is controversial. furthermore refractory hypoxia is not considered a typical indication for thrombolysis which is not without risk; reported rates of intracerebral haemorrhage of . %. however case reports and studies do suggest patients with profound respiratory failure may benefit from clot lysis. it is worthwhile to note that while we administered thrombolysis for hypotension, there was marked improvement in gas exchange to go with stabilised blood pressure. sars-cov- is a single-stranded rna coronavirus. common symptoms include fatigue, fever, headache, dyspnoea and myalgia. although advanced age and comorbidity (eg, hypertension, diabetes mellitus) are risk factors for developing serious illness, young and otherwise healthy patients can become critically unwell. data from populations affected by the covid- demonstrate abnormal activation of the clotting cascade. markers such as d-dimer concentration are associated with deleterious patient trajectory and increased incidence of mortality. while covid- is typically associated with pneumonia, a multisystem inflammatory disorder and deregulated coagulation are at play leading to poor outcomes in those worst affected. many pathways have been postulated to explain these extreme derangements in clotting. a syndrome of hyperinflammation is seen in those worst affected and it appears that parts of this cascade are responsible for coagulopathy. it is widely accepted that the general endpoint of the inflammatory process is thrombosis. thus immune system activation and subsequent inflammatory processes are intrinsically linked to clotting. common laboratory investigation abnormalities include a lymphopaenia, elevated c-reactive protein, ferritin, interleukin- (il- , an inflammatory cytokine) and dramatically elevated d-dimers. coagulation tests commonly reveal a prolongation of the prothrombin time and international normalised ratio alongside shortened activated partial thromboplastin times and ratios. studies have implicated elevated expression of il- as a potential cause of endothelial dysfunction leading to thrombosis, reinforced further by research implicating il- as a contributor to thrombotic risk in inflammatory conditions such as psoriasis. initial data suggest that patients with complicated covid- infection have nearly three times the concentration of il- compared with those exhibiting less severe disease. this highlights the importance of ongoing work examining the efficacy of il- inhibitors as an immunomodulatory therapy. obesity in isolation is a risk factor for vte. the increased risk for vte is thought to be in part a result of the background chronic inflammatory state found in obese patients. hypertrophic adipose tissues lend to the over production of inflammatory cytokines such as tnf-a, interferon-g and il- . these cytokines induce an inflammatory state the endpoint of which is an increase in procoagulant factors, increased tissue factor expression and augmented platelet activation. patients with severe covid- infection are at risk of mortality and this risk is compounded by the presence of comorbidity including cardiovascular disease, diabetes mellitus and chronic obstructive pulmonary disease. obesity is additionally recognised as lending to poor outcomes in covid- . it appears possible that the obesity-related inflammation exacerbated by covid- mediated effects could lead to excess thrombosis in this group partly explaining the poorer outcomes seen in obese patients. thromboprophylaxis can take many forms, however a study by tang et al demonstrated a clear survival benefit in patients with covid- receiving lmwh as part of their treatment. severe covid- with either high d-dimers or high likelihood of sepsis-induced coagulopathy were shown to have improved rates of mortality when treated with lmwh at prophylactic doses. appropriate use of lmwh may therefore have a central role to play in managing the sick population with covid- . although classically considered an anticoagulant, heparin does have secondary properties which may have utility in the treatment of covid- . its effects may have a role in disruption of clot production as well as ameliorating the inflammatory effects of thrombin. heparin has been shown to have direct antiinflammatory properties including the antagonism of cytokines and sequestration of acute phase proteins. the international society for thrombosis and haemostasis suggests that prophylactic treatment with lmwh is prudent in all patients with covid- , particularly with severe disease or findings that shed new light on the possible pathogenesis of a disease or an adverse effect extreme derangements in clotting parameters. regular monitoring of clotting parameters during admission with severe disease was also strongly recommended. the american college of cardiology suggests implementing extended courses of thromboprophylaxis in patients with covid- with other risks factors for vte for example, reduced mobility, pre-existing comorbidity or malignancy. d-dimer levels, greater than two times the upper limit of normal at point of discharge, have also been suggested as a guide for the initiation of prolonged anticoagulation treatment. the british society of haematology advocates the use of lmwhs in the management of covid- . hospital-acquired vte is defined as any thrombotic event occurring within days of hospital admission even after discharge. compared with other populations, patients with covid- appear to have higher incidences of vte particularly with deranged clotting markers, critical care admission or reduced mobility. reports from france and the netherlands revealed a high burden of thrombotic complications (primarily pe) despite routine prophylactic lmwh. there were strong recommendations towards the use of vte prophylaxis for all patients requiring intensive care management and a low threshold for more aggressive anticoagulation strategies given the development of thrombotic complications in approximately one third of patients in intensive care despite prophylactic anticoagulation. emerging antithrombotic guidance highlights the potential benefits of extended thromboprophylaxis beyond hospital admission. several risk factors were identified including the presence of a d-dimer level twice the upper limit of normal at the time of potential discharge. suggested regimens described courses of up to days for adequate protection. other identified risk factors included patients over years old, those with a past history of vte, active malignancy, reduced mobility, bmis> and recent stay in critical care. these recommendations have subsequently been reflected in local guidelines produced shortly after our case. contributors pav and dss helped in conception or design of the work. prv performed data collection. prv and dss helped in drafting the article. pav, prv and dss performed critical revision and provided final approval of the version to be published. the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. competing interests none declared. provenance and peer review not commissioned; externally peer reviewed. this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid- pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. deepak s sharma http:// orcid. org/ - - - learning points ► the case presented illustrates the wide reaching and prolonged sequelae of critical illness following covid- with complications occurring despite recovery from the acute phase of the illness. ► reduced mobility, easy fatigability and weakness in recovered patients are also likely to contribute to morbidity and mortality. ► given the still uncertain nature of covid- and its long-term effects on patients, there will be much to learn in the coming weeks and months regarding subsequent management of patients after the acute phase of the disease. ► further work may better characterise the thrombotic risks and identify appropriate management strategies. the role of thromboprophylaxis for mild cases of covid- in patients with significant risk factors remains unclear. these patients may be advised to self-isolate with resulting reduced levels of physical activity. ► it is also uncertain how long the proinflammatory/ prothrombotic state associated with covid- persists for after apparent resolution of the disease with regard to physical symptoms for example, oxygen requirement, fever. there are few recommendations for extended thromboprophylaxis but this case supports subsequent early guidance, which suggests it is beneficial in at-risk populations. we would advocate the use of a structured approach on a patient-to-patient basis, balancing thrombotic and bleeding risks. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- mechanisms of thrombosis in obesity acute pulmonary embolism and covid- pneumonia: a random association? acute pulmonary embolism associated with covid- pneumonia detected with pulmonary ct angiography scientific and standardization committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with covid- esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the respiratory failure as an indication for thrombolysis in pulmonary embolism? thrombolysis in pulmonary embolism: are we under-using it? covid- infection: origin, transmission, and characteristics of human coronaviruses are patients with hypertension and diabetes mellitus at increased risk for covid- infection? abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china facing covid- in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation blood coagulation in immunothrombosis-at the frontline of intravascular immunity coagulation abnormalities and thrombosis in patients with covid- interleukin and haemostasis interleukin regulates psoriasiform inflammationassociated thrombosis interleukin- in covid- : a systematic review and metaanalysis sars-cov- and covid- : is interleukin- (il- ) the 'culprit lesion' of ards onset? what is there besides tocilizumab? sgp fc features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy the versatile heparin in covid- more than an anticoagulant: do heparins have direct anti-inflammatory effects? isth interim guidance on recognition and management of coagulopathy in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: jacc state-of-the-art review high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study incidence of thrombotic complications in critically ill icu patients with covid- emergence of institutional antithrombotic protocols for coronavirus key: cord- - bp xyo authors: spyropoulos, alex c.; ageno, walter; albers, gregory w.; elliott, c. gregory; halperin, jonathan l.; hiatt, william r.; maynard, gregory a.; steg, p. gabriel; weitz, jeffrey i.; lu, wentao; spiro, theodore e.; barnathan, elliot s.; raskob, gary. e. title: post-discharge prophylaxis with rivaroxaban reduces fatal and major thromboembolic events in medically ill patients date: - - journal: j am coll cardiol doi: . /j.jacc. . . sha: doc_id: cord_uid: bp xyo background: hospitalized acutely ill medical patients are at risk for fatal and major thromboembolic events. whether use of extended-duration primary thromboprophylaxis can prevent such events is unknown. objectives: the purpose of this study was to evaluate whether extended-duration rivaroxaban reduces the risk of venous and arterial fatal and major thromboembolic events without significantly increasing major bleeding in acutely ill medical patients after discharge. methods: mariner (a study of rivaroxaban [jnj- ] on the venous thromboembolic risk in post-hospital discharge patients) studied acutely ill medical patients with additional risk factors for venous thromboembolism (vte). medically ill patients with a baseline creatinine clearance ≥ ml/min were randomized in a double-blind fashion to rivaroxaban mg or placebo daily at hospital discharge for days. exploratory efficacy analyses were performed with the intent-to-treat population including all data through day . time-to-event curves were calculated using the kaplan-meier method. a blinded independent committee adjudicated all clinical events. results: in total, , patients were assigned to rivaroxaban and , patients to placebo. the mean age was . years, . % were men, mean baseline creatinine clearance was . ml/min, and mean duration of hospitalization was . days. the pre-specified composite efficacy endpoint (symptomatic vte, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death) occurred in . % and . % of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: . ; % confidence interval: . to . ; p = . ), whereas major bleeding occurred in . % and . % of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: . ; % confidence interval: . to . ; p = . ). conclusions: extended-duration rivaroxaban in hospitalized medically ill patients resulted in a % reduction in fatal and major thromboembolic events without a significant increase in major bleeding. (a study of rivaroxaban [jnj- ] on the venous thromboembolic risk in post-hospital discharge patients [mariner]; nct ) a large proportion of the approximately million acute medically ill patients each year in the united states are at risk for venous thromboembolism (vte) ( ) . hospitalization is considered the single most important risk factor for developing these events ( ) , and the risk of vte continues beyond hospitalization, especially within the first weeks after discharge ( ) . although the relationship between vte and atherothrombosis/ arterial thromboembolism has been known for some time due to the shared mechanisms of inflammation, hypercoagulability, and endothelial injury inherent to both disease processes and due to common patient-level risk factors, such as obesity, dyslipidemia, and tobacco use ( , ) , it has only recently been appreciated that medically ill patients are also at increased risk of arterial thromboembolic events in the post-hospital discharge period ( , ) . retrospective data also reveal that extended duration of a prophylactic dose of a direct oral anticoagulant in medically ill patients may reduce the risk of fatal and major arterial thromboembolism by % to % ( , ) . although the trial did not demonstrate a reduction in the primary endpoint of symptomatic vte and vte-related death, key secondary efficacy endpoints revealed a % reduction in symptomatic vte and a % reduction in symptomatic vte and all-cause mortality. the lower . mg dose of rivaroxaban used in patients with moderate renal insufficiency was found to be ineffective ( ) a meta-analysis of arterial thrombosis (including mi and ischemic stroke) of older studies involving w , medically ill inpatients receiving heparinbased prophylaxis did not find a reduction of these events compared with control subjects (odds ratio: on-treatment includes all data from randomization to days after the last dose of the study drug (inclusive). subjects who do not have events are censored on the minimum of last visit before or on death, or last dose þ days. ci ¼ confidence interval; hr ¼ hazard ratio. spyropoulos et al. ( ) . in the large population of at-risk medically ill patients each year, this strategy would have the potential to prevent , fatal and major thromboembolic events annually at the cost of one-fourth to one-half that number of major or fatal bleeds ( ) . study limitations. limitations of this study include its exploratory nature, because the mariner study failed to meet its primary efficacy endpoint. we cannot exclude potential under-reporting of arterial thromboembolic events as the trial was powered to assess the risk of vte, although this is unlikely because a standardized case report form was used with careful study oversight of outcomes and central adjudication of all of these events. in addition, the composite endpoint was driven primarily by a reduction in symptomatic vte and ischemic stroke. although event rates may be considered low (< . %), the time-to-event curves suggest that events continued to accumulate after the study period of that rivaroxaban continues to reduce these events over a longer period of time. our study also excluded subjects with moderate renal insufficiency because the reduced dose chosen ( . mg) was deemed inadequate. however, a recent study has demonstrated efficacy in this population with mg daily of rivaroxaban with a favorable benefit risk profile ( ) . as approximately % of our study population had baseline aspirin use, an important antithrombotic synergy between prophylactic dose rivaroxaban and antiplatelet therapy cannot be excluded, and there are mechanistic implications of such a synergistic antithrombotic strategy that may lead to reductions in cv outcomes ( , ) . our analysis suggests that in at-risk medically ill patients who are discharged from the hospital, extended-duration rivaroxaban at the mg daily dose leads to a significant risk reduction in a composite of fatal and major thromboembolic eventsincluding symptomatic vte, mi, nonhemorrhagic stroke, and cv death-without a significant increase in major bleeding, compared with placebo. these data suggest that in properly selected patients at risk for vte and at low risk for bleeding, that extendedduration rivaroxaban at mg has a favorable benefit risk profile. venous thromboembolic events in hospitalised medical patients publications and reports of the surgeon general. in: the surgeon general's call to action to prevent deep vein thrombosis and pulmonary embolism duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients venous thromboembolism and atherothrombosis: an integrated approach. circulation an association between atherosclerosis and venous thrombosis extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an apex trial substudy (acute medically ill venous thromboembolism prevention with extended duration betrixaban) for the apex investigators. comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an apex trial substudy rivaroxaban for thromboprophylaxis after hospitalization for medical illness thromboprophylaxis with rivaroxaban in acutely ill medical patients with renal impairment: insights from the magellan and mariner trials cardiovascular risk factors and venous thromboembolism: a meta-analysis thromboprophylaxis by rivaroxaban, aspirin, both, or placebo after hospitalization for medical illness for the compass investigators. rivaroxaban with or without aspirin in stable cardiovascular disease influence of model-predicted rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations improved benefit risk profile of rivaroxaban in a subpopulation of the magellan study key: cord- -pc ybxw authors: singhania, namrata; bansal, saurabh; nimmatoori, divya p.; ejaz, abutaleb a.; mccullough, peter a.; singhania, girish title: current overview on hypercoagulability in covid- date: - - journal: am j cardiovasc drugs doi: . /s - - -z sha: doc_id: cord_uid: pc ybxw the coronavirus disease (covid- ) pandemic, caused by severe acute respiratory syndrome coronavirus (sars-cov- ), has brought many unique pathologies, such as coagulopathy, prompting a desperate need for effective management. covid- -associated coagulopathy (cac) can cause various thromboembolic complications, especially in critically ill patients. the pathogenesis is likely due to endothelial injury, immobilization, and an increase in circulating prothrombotic factors. data on treatment are limited, although prophylactic anticoagulation is advised in all hospitalized patients. herein, we have comprehensively reviewed the current literature available on cac and highlight the pathogenesis, clinical features, and management of cac. a novel coronavirus was first identified in late in wuhan, china, and rapidly spread throughout the world, causing a pandemic [ ] . the virus was identified as severe acute respiratory syndrome coronavirus (sars-cov- ), and the world health organization designated the disease as coronavirus disease . the most common symptoms are respiratory, but gastrointestinal, neurological, and other atypical symptoms can also be seen, although these symptoms are rare [ ] . recent studies showed several coagulation abnormalities in patients with covid- , raising questions about appropriate management to prevent or treat thrombosis; this state has been termed covid- -associated coagulopathy (cac) [ ] . the international society on thrombosis and hemostasis (isth), the american society of hematology (ash), and the american college of cardiology (acc) have posted interim guidance on this topic. herein, we provide a clinical overview on the pathogenesis, clinical features, and management of hypercoagulability in individuals with covid- . the pathogenesis of hypercoagulability in covid- is illdefined. figure summarizes the proposed pathogenesis of hypercoagulability in covid- ; all three components of virchow's triad appear to be involved, including endothelial injury, stasis, and hypercoagulable state. endothelial injury is evident from the direct invasion of endothelial cells by sars-cov- [ ] ; endothelial cells have a high number of angiotensin-converting enzyme (ace- ) receptors. sars-cov- enters the cell through the ace- receptor [ ] . in the study by varga et al., viral elements were found inside the endothelial cells, suggesting direct invasion [ ] . increased angiogenesis was also seen in these patients [ ] . increased cytokines are released, such as interleukin (il)- , and various acute-phase reactants in covid- can lead to endothelial injury [ ] . reports also suggest activation of alternate and lectin complement pathways (c b- [membrane attack complex], c d, and mannose-binding proteinassociated serine protease [masp ]), leading to further endothelial cell injury [ ] . the use of intravascular catheters can cause direct endothelial cell injury. stasis is due to immobilization in all hospitalized patients, especially those who are critically ill. a hypercoagulable state is seen due to several coagulation abnormalities from elevated circulating prothrombotic factors such as elevated von willebrand factor (vwf), factor viii, d-dimer, fibrinogen, neutrophil extracellular traps, prothrombotic microparticles, and anionic phospholipids [ ] . elevated levels of d-dimer have been observed to correlate with illness severity and -day mortality [ ] . fibrinogen levels were also significantly (p = . ) associated with il- levels at baseline, according to a logarithmic regression [ ] . upon autopsy, most patients showed macro-and microvascular thrombosis [ ] . gross examination of the lungs fig. pathogenesis of coagulopathy in covid- . endothelial injury (endotheliitis) is caused by direct invasion of endothelial cells by the sars-cov- virus via ace- receptors, release of inflammatory cytokines such as il- , acute-phase reactants, complement activation, and direct injury from intravascular catheters. stasis is due to immobilization in all hospitalized patients. the hypercoagulable state is due to elevated circulating prothrombotic factors such as elevated vwf activity, factor viii, d-dimer, fibrinogen, neutrophil extracellular traps, prothrombotic microparticles, and anionic phospholipids. teg findings showed shortened r (increased early thrombin burst), shortened k (increased fibrin generation), increased ma (greater clot strength), and reduced ly (reduced fibrinolysis). ace- angiotensin-converting enzyme , c d complement d, c b- complement b- , covid- coronavirus disease , il interleukin, k clot formation time, ly clot lysis at min, ma maximum amplitude, mac membrane attack complex, masp mannose-binding proteinassociated serine protease , r reaction time, sars-cov- severe acute respiratory syndrome coronavirus , teg thromboelastography, vwf von willebrand factor showed small and firm thrombi in peripheral parenchyma [ ] . the pathological hallmark of covid- is diffuse, small-vessel platelet-fibrin thrombi and intravascular megakaryocytes in all major organs, including the heart, lungs, kidneys, liver, and mesenteric fat [ ] . microscopic findings demonstrated pauci-inflammatory capillary injury, capillary congestion with luminal fibrin deposition, and angiogenesis [ , ] . the density of intussusceptive angiogenic features (mean ± standard error [se]) . ± . features per field) was significantly higher in the lungs from patients with covid- than from patients with influenza ( . ± . ) or from uninfected controls ( . ± . ) [p < . for both comparisons] [ ] . the degree of intussusceptive angiogenesis correlated significantly with the duration of hospitalization (p < . ). endotheliitis is visible by electron microscopy in the endothelium of the heart, lung, small bowel, and kidneys [ ] . autopsy of the kidneys showed diffuse tubular injury, interstitial edema, and fibrin thrombi in the glomerular capillaries [ ] . routine laboratory testing was performed in critically ill covid- patients and identified several abnormalities, including normal or slightly prolonged prothrombin time (pt) and activated partial thromboplastin time (aptt), normal or increased platelet count, and increased d-dimer and fibrinogen levels [ ] . further testing also showed increased factor viii activity and vwf antigens. thromboelastography (teg) showed a shortened reaction time (r), consistent with an increased early thrombin burst, in % of patients; shortened clot formation time (k), consistent with increased fibrin generation, in % of patients; increased maximum amplitude (ma), consistent with greater clot strength, in % of patients; and reduced clot lysis at min (ly ), consistent with reduced fibrinolysis, in % of patients [ ] . similarly, in another viscoelastic test, increased platelet and fibrinogen contribution to clot strength was found [ ] . in patients with severe disease and a positive lupus anticoagulant test, thrombocytopenia and marked prolongation of pt and aptt can be seen [ ] . although disseminated intravascular coagulation (dic) has been rarely reported in severely ill patients with covid- , there are several features that distinguish cac from dic ( table ). the major clinical finding in cac is thrombosis, whereas in acute decompensated dic, bleeding is the predominant feature. pathological bleeding is not a commonly observed feature of covid- . furthermore, covid- has a few findings similar to dic, including a marked increase in d-dimer levels and, in some cases, mild thrombocytopenia [ ] . however, other coagulation parameters such as fibrinogen and factor viii activity are high in cac, while acute decompensated dic is associated with low fibrinogen, which suggests that consumption of clotting factors is less likely in cac. regardless of the above similarities or differences, the basic principle of management in both cac and dic is treatment of the underlying condition. venous thromboembolism (pulmonary embolism [pe] and/ or deep vein thrombosis [dvt]) is common in patients with covid- , even when prophylactic anticoagulation is used, and can be seen in up to two-thirds of patients in the intensive care unit (icu). a search of the pubmed database using the key words 'hypercoagulability' and 'covid- ' found studies with a patient population of or more. details of the studies, including type, country, number of patients enrolled, mean age, sex, comorbidities, use of anticoagulation, incidence of thromboembolism, and other relevant laboratory findings are listed in table . two of studies were autopsy studies. older age, male sex, obesity, smoking and other chronic medical comorbidities, especially cardiovascular disease, hypertension, chronic bronchitis, active cancer, and diabetes mellitus were associated with a higher risk of thromboembolism. in a post-mortem examination of patients with covid- , alveolar and glomerular microthrombi were seen in % and . % of individuals, respectively, while in another post-mortem study of patients, dvt was seen in % of patients with % mortality due to a massive pe [ , ] . extremely high values of d-dimer (> , ng/ml; normal value < ng/ml) were found in % of patients. in a series of patients (all patients receiving prophylactic anticoagulation) with severe covid- and in the icu, vte was reported in % [ ] ; the study was associated with a % mortality rate. age (adjusted hazard ratio [ahr] . /year, % confidence interval [ci] - %) and coagulopathy (prolongation of pt > s or aptt > s; ahr . , % ci . - . ) were found to be independent predictors of thrombosis. in another series of icu patients, patients had clinically relevant thrombotic complications (mostly pe) [ ] . clotting of the extracorporeal circuit was seen in of patients receiving continuous renal replacement therapy (rrt), and of patients undergoing extracorporeal membrane oxygenation (ecmo). all patients received anticoagulation (prophylactic dose, %; therapeutic dose, %). that study also compared patients with covid- -associated acute respiratory distress syndrome (ards) with a matched cohort of non-covid- ards patients and found the rate of pe was higher in covid- patients [ . % vs. . %; odds ratio (or) . , % ci . - . ; p < . ]. more than % of patients had elevated d-dimer and fibrinogen levels, with a considerable increase in vwf activity, vwf antigen, and factor viii. the study also reported a positive lupus anticoagulant test in . % of patients. similarly, a series of icu patients reported pe in . %. by comparison, in two matched cohorts (one from the same time interval in the previous year and one from concurrent patients with influenza rather than covid- ) . % [absolute risk (ar) . %, % ci . - . %] and . % (ar . %, % ci . - . %) of patients, respectively, reported pe [ ] . the study also showed elevated d-dimer, plasma factor viii and vwf antigen levels associated with higher pe risk. in one study of icu patients, vte was associated with higher mortality (ahr . , % ci . - . [ ] . the cumulative incidence of vte was higher in the icu than on the wards. another study that performed screening leg ultrasounds in patients with covid- in the icu who were all receiving either prophylactic-dose anticoagulation ( %) or therapeutic-dose anticoagulation ( %), found vte in ( %) patients, with a % mortality rate [ ] . the majority of the above data were from icu patients, however the data are limited in non-icu patients. two studies ( and non-icu patients, respectively) found an incidence of vte in the range of . - %, in spite of the majority of patients receiving anticoagulation [ , ] . although vte is more commonly seen with covid- , there have been a few cases of arterial events such as ischemic stroke and acute limb ischemia. in one report, five covid- patients younger than years of age were identified with acute ischemic stroke due to large vessel occlusion during a -week period, compared with an average of . patients every weeks over the previous months [ ] . the cumulative incidence rate of acute ischemic stroke was found to be between and . % in icu patients [ , ] and approximately % in non-icu patients [ ] . a report evaluated data from patients ( % male; mean age years) with covid- who developed acute limb ischemia at a single institution over a -month period and found that the incidence of acute limb ischemia was significantly higher compared with the previous year ( . % in vs. . % in ; p < . ) [ ] . surgical revascularization was performed in patients, of whom ( %) were successful. re-intervention was not required in those who received postoperative heparin. the study was associated with a % mortality rate, which was significantly higher in older patients ( ± years vs. ± years; p = . ). the use of postoperative heparin infusion was significantly associated with improvement in survival ( % vs. . %; p = . ). another series reported on two young and healthy patients ( and years of age, respectively) [ ] . both patients had very high d-dimer levels and were receiving prophylactic-dose anticoagulation at the time of the event. there are a few reports on st elevation myocardial infarction (stemi) and mesenteric ischemia [ , ] . all patients admitted to the hospital with covid- should get a complete blood count (cbc), and pt, aptt, fibrinogen, and d-dimer levels should be checked. d-dimer levels have shown to be directly proportional to the severity of the disease. high d-dimer and fibrinogen levels, normal or mildly prolonged pt and aptt, mild thrombocytopenia or thrombocytosis, or normal platelet count are typically seen. the values of these typical tests were also found to correlate with -day mortality based on multivariate analysis of patients in a retrospective study [ ] . pt (or . , % ci . - . ) and d-dimer (or . , % ci . - . ) levels correlated positively, while platelet count (or . , % ci . - . ) correlated negatively, with -day [ ] . few studies have evaluated d-dimer levels at various cut-off values to predict vte in patients with covid- [ ] . cui et al. showed that if a cut-off value of . µg/ml was used to predict vte, the sensitivity was . %, the specificity was . %, and the negative predictive value was . % [ ] . according to ash, a normal d-dimer may be enough to rule out pe in most stable covid- patients with low to moderate pretest probability, as calculated using the wells score [ ] . although yao et al. did not specifically study the correlation between various d-dimer levels and vte, they showed that d-dimer at a cut-off value of . µg/ml was present in more than % of patients with covid- , and an increase in d-dimer levels correlated significantly with disease severity [ ] . as many covid- patients may present with high levels of d-dimer due to inflammation, it is difficult to rule out vte based on d-dimer alone in patients with high pretest probability [ ] . additional testing, including ultrasonography of the extremities and computed tomography angiography (cta) of the chest are recommended and should be used readily depending on clinical presentation, due to the high risk of vte associated with this disease. a ventilation-perfusion (vq) scan is recommended in patients with contraindications to cta, such as those with poor renal function. an echocardiogram may be considered in some patients, especially those in whom cta cannot be performed and in whom a vq scan has limited value due bilateral infiltrates. an echocardiogram may show right heart strain and a dilated/hypokinetic right ventricle. additional work-up is recommended in those patients with unexplained hypotension, tachycardia, worsening respiratory status, or other risk factors for thrombosis. patients with atypical findings such as severe thrombocytopenia and/or markedly prolonged pt/ aptt require further investigation. if thrombotic microangiopathy is suspected, serum lactate dehydrogenase, haptoglobin, adamts activity, and peripheral blood smear are recommended. antiphospholipid antibody testing is not routinely recommended as it can be transiently present in viral infections. the management of hypercoagulability in covid- can be challenging due to limited data. although all hospitalized patients are at higher risk for thrombosis, icu patients are at the highest risk (incidence . % in non-icu patients vs. % in icu patients) [ ] . it is recommended to start prophylactic-dose anticoagulation with low molecular weight heparin (lmwh) in all acutely ill hospitalized patients unless contraindicated [ ] . many experts suggest initiating intermediate-dose (lmwh - mg subcutaneously twice daily) or full-dose anticoagulation in critically ill individuals with covid- due to the high percentage of patients with vte despite receiving prophylactic anticoagulation [ , [ ] [ ] [ ] . due to the lack of high-quality studies favoring such interventions, and the risks of bleeding associated with antithrombotic therapies, some medical societies have deferred from adopting these recommendations in universal guidelines [ ] . in addition, data are lacking comparing different doses of anticoagulation (prophylactic or therapeutic) in patients with covid- . most institutions have made their own criteria to manage coagulopathy in these patients. it is advised to balance the risks of thrombosis with bleeding while making decisions regarding antithrombotic therapy. the isth has also issued interim guidelines to manage coagulopathy in covid- [ ] . in a pre-proof retrospective study of patients hospitalized with covid- , patients who received anticoagulation ( patients, %) had an in-hospital mortality rate of . % and a median survival of days, compared with . % and a median survival of days in those who did not receive anticoagulation [ ] . a significantly higher number of patients required mechanical ventilation in those who did not receive anticoagulation compared with those who did ( . % vs. . %, p < . ). the in-hospital mortality rate was . % and a median survival of days in a subgroup of intubated patients who received anticoagulation compared with a mortality rate of . % and a median survival of days in those who were intubated but did not receive anticoagulation. in a multivariate proportional hazard model, a longer duration of anticoagulation was associated with a reduced risk of mortality (ahr . /day, % ci . - . ; p < . ). of a total of patients who received anticoagulation, had bleeding events (not statistically significant); of those patients, had bleeding events after starting anticoagulation. the above study had multiple limitations, such as its retrospective observational nature, unknown reasons for not starting prophylactic anticoagulation in % of patients, unobserved confounding factors, and a lack of metrics to classify patients based on severity. another retrospective study of patients ( patients received anticoagulation for > days) with severe covid- (defined as a respiratory rate of ≥ breaths/min, arterial oxygen saturation ≤ % at rest, and pao /fio ≤ mmhg), -day mortality benefit was found in patients who received heparin and had either a high sepsis-induced coagulopathy score ( % with heparin vs. . % without; p = . ) or a high d-dimer of more than sixfold the upper limit of normal ( . % vs. . %; p = . ) [ ] . this mortality benefit was not significant in the cohort as a whole. the recommended prophylactic dose of lmwh for patients with creatinine clearance (crcl) > ml/min is mg once daily, and mg once daily for crcl - ml/ min. for patients with a body mass index > kg/m , it is recommended to increase the dose by %. unfractionated heparin should be considered in patients with crcl < ml/ min or receiving rrt, or in those where an invasive procedure is anticipated, such as a cesarean section. other medications, such as dalteparin ( units once daily), nadroparin ( - units once daily), and tinzaparin ( units once daily), are alternatives in other parts of the world. therapeutic-dose (full-dose) anticoagulation (e.g. lmwh mg/ kg every h) is appropriate in patients with documented vte, similar to those individuals without covid- , and in a few cases of suspected vte where confirmatory testing is not feasible and the patient developed unexplained respiratory failure with stable chest radiograph, along with elevated d-dimer and/or fibrinogen levels. more than % of the studies summarized in table showed d-dimer levels being positively correlated with risk for vte or illness severity. d-dimer levels were in the range of - , ng/ml (normal range < ng/ml) [ ] . full-dose anticoagulation is appropriate for individuals with recurrent clotting of intravascular access devices (arterial lines, central venous catheters) or extracorporeal circuits, such as continuous rrt or ecmo, despite prophylactic-dose anticoagulation. alternative therapy should be considered in patients with contraindications for heparin, such as heparin-induced thrombocytopenia or active or recent bleeding. tissue plasminogen activator can be used in cases of arterial thrombosis, such as acute limb ischemia, acute stemi, acute ischemic stroke, and massive bilateral pe associated with hemodynamic instability. surgical consultation is recommended in patients with acute mesenteric ischemia. in patients with severe acute kidney injury, initiating rrt is recommended. patients with covid- and documented vte need at least months of anticoagulation post-discharge from the hospital, with appropriate follow-up. a few patients who are at high risk, such as those with immobilization due to recent surgery and trauma, may need post-discharge prophylaxis even without documented vte. rivaroxaban mg daily for - days is considered a reasonable alternative as outpatient prophylaxis in such high-risk patients [ ] . vte is common is critically ill patients with covid- . work-up includes routine testing with cbc, pt, aptt, fibrinogen, and d-dimer. these tests also correlate with disease severity and mortality. it is recommended to start at least prophylactic-dose anticoagulation in all patients with covid- admitted to the hospital, especially those in the icu unless contraindicated. if vte is suspected, confirmatory testing should be obtained to justify full-dose anticoagulation. some experts support intermediate-or full-dose anticoagulation, even in individuals with covid- who do not have documented vte, but data on appropriate dosing are limited. in cases of suspected vte where standard confirmatory testing cannot be obtained, full-dose anticoagulation can be considered in patients with unexplained respiratory failure with stable chest radiograph, along with elevated d-dimer and/or fibrinogen levels. close monitoring for clinical signs of thrombosis or bleeding is recommended in all patients. physicians are advised to use their clinical judgment to balance the risks and benefits associated with anticoagulation. several therapies for covid- are under investigation, some of which may impact thrombotic risk. participation in clinical trials is encouraged to improve our understanding of pathogenesis and management of coagulopathy in covid- . further trials on anticoagulation doses in patients with covid- are warranted. funding no external funding was used in the preparation of this manuscript. conflict of interest namrata singhania, saurabh bansal, divya p. nimmatoori, abutaleb a. ejaz, peter a. mccullough, and girish singhania declare they have no potential conflicts of interest that might be relevant to the contents of this manuscript. ethics approval not applicable. availability of data and materials not applicable. author contributions ns wrote the manuscript and reviewed the literature. sb, dpn, aae, pam, and gs reviewed the literature and critically revised the manuscript. all authors had access to the data and had a role in writing and reviewing the manuscript. clinical characteristics of coronavirus disease in china an atypical presentation of novel coronavirus disease (covid- ) 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recognition and management of coagulopathy in covid- association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with covid- covid- and vte/anticoagulation: frequently asked questions venous thrombosis among critically ill patients with coronavirus disease (covid- ) key: cord- - ym h t authors: cui, songping; chen, shuo; li, xiunan; liu, shi; wang, feng title: prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: ym h t background: three months ago, severe acute respiratory syndrome coronavirus (sars‐cov‐ ) broke out in wuhan, china, and spread rapidly around the world. severe novel coronavirus pneumonia (ncp) patients have abnormal blood coagulation function, but their venous thromboembolism (vte) prevalence is still rarely mentioned. objectives: to determine the incidence of vte in patients with severe ncp. methods: in this study, severe ncp patients in the intensive care unit (icu) of union hospital (wuhan, china) were enrolled. the results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed. results: the incidence of vte in these patients was % ( / ), of which patients with vte events died. the vte group was different from the non‐vte group in age, lymphocyte counts, activated partial thromboplastin time (aptt), d‐dimer, etc. if . µg/ml was used as the d‐dimer cut‐off value to predicting vte, the sensitivity was . %, the specificity was . %, and the negative predictive value (npv) was . %. conclusions: the incidence of vte in patients with severe ncp is % ( / ), which may be related to poor prognosis. the significant increase of d‐dimer in severe ncp patients is a good index for identifying high‐risk groups of vte. severe acute respiratory syndrome coronavirus (sars-cov- ) is a new type of respiratory transmitted virus. by mid-march , it had sickened more than people and killed more than in china, triggering a global pandemic. a number of studies have shown that coagulation dysfunction exists in patients with severe novel coronavirus pneumonia (ncp), [ ] [ ] [ ] [ ] which is clearly correlated with poor prognosis. the conventional coagulation parameters of intensive care unit (icu) patients were significantly higher than those of non-icu patients. however, the prevalence of venous thromboembolism (vte) in icu patients with severe ncp is unknown. therefore, the purpose of this study was to explore the incidence of vte in such patients and to investigate the differences between vte patients and non-vte patients. data are presented as means ± standard deviation (sd) or number (percentage) where appropriate. t test or mann-whitney u test were used to analyze the differences between the two groups. p < . was defined as statistically significant. statistical analysis was conducted using spss software version . (ibm). a total of patients with severe ncp were enrolled in this study, with the mean age of . years (range, - years), including females ( %). thirty-three ( %) patients had chronic medical illness, including hypertension, diabetes, and coronary heart disease; ( %) patients had a history of smoking. as of march, ( %) patients had been discharged from hospital, ( %) had died, and the rest ( ; %) remained hospitalized (table ) . a total of ( %) patients with severe ncp developed lower extremity venous thrombosis, of which patients died. the vte group had older age ( . ± . versus . ± . years, p < . ), lower lymphocyte counts ( . ± . versus . ± . × /l, p < . ), longer aptt ( . ± . versus . ± . seconds, p = . ), and higher d-dimer ( . ± . versus . ± . µg/ml, p < . ). moreover, the d-dimer of the two groups was not within the normal range (table ) . table shows the sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv) of different d-dimer levels in predicting vte in patients with severe ncp. if . µg/ml was used as the cut-off value for d-dimer to predict vte, the sensitivity, specificity, ppv, and npv were . %, . %, . %, and . %, respectively (table ) . in this study, the decrease of lymphocytes was common in patients with ncp, especially in patients with vte. other studies have also observed that infection with sars-cov- leads to lymphocytopenia. , , in the analysis of lymphocyte subset, t cells were more susceptible to sars-cov- , because t cell count was almost half of the lower reference limit, and the severe ncp patients were more likely to be hampered. moreover, abnormal expression of t cell associated mrna can lead to vte. this meant that older patients with more underlying diseases were more likely to develop immune dysfunction and have a higher risk of vte because of their poor immunity. inflammatory cytokines can promote the activation of blood coagulation in many ways, and then promote the occurrence of vte. [ ] [ ] [ ] sepsis is also a common cause of disseminated intravascular coagulation (dic) and the incidence of dic in dead ncp patients was . %. this suggests that abnormal blood coagulation and thrombosis are associated with poor prognosis in patients with ncp. elevated d-dimer level is a sign of excessive coagulation activation and hyperfibrinolysis. therefore, d-dimer is often used to detect active thrombus with high sensitivity but low specificity. but, if . µg/ml was used as the cut-off value, the sensitivity, specificity, and npv were . %, . %, and . %, respectively. after receiving anticoagulant therapy, the level of d-dimer decreased gradually, which means that d-dimer can not only predict thrombosis but also monitor the effectiveness of anticoagulants. there are several limitations in our report. first, this is a retrospective, single-center, small sample study. the results may be biased and need to be confirmed by a large sample study. second, some patients are still being treated in hospital, and the clinical outcome may change. despite that, our study described the incidence of vte in patients with severe ncp and demonstrated the application of d-dimer in vte prediction. we hope that these results will contribute to the prevention, diagnosis, and treatment of vte. thanks to all the patients involved in the study. the authors declare that they have no conflicts of interest. xl and sl collected the clinical data. spc and sc processed statistical data. spc and sc drafted and revised the manuscript. fw designed and guided the study. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia prominent changes in blood coagulation of patients with sars-cov- infection epub ahead of print -ncov) in suspected human cases. interim guidance the fifth revised trial version of the novel coronavirus pneumonia diagnosis and treatment guidance novel coronavirus-infected pneumonia in wuhan dysregulation of immune response in patients with covid- in wuhan. china symptomatic venous thromboembolism is a disease related to infection and immune dysfunction plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome mers-cov infection in humans is associated with a pro-inflammatory th and th cytokine profile interactions between coagulation and inflammation bidirectional relation between inflammation and coagulation crosstalk between inflammation and coagulation: the lessons of sepsis present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a perspective from japan diagnostic performance of d-dimer in predicting venous thromboembolism and acute aortic dissection prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia normal range vte (n = ) non-vte (n = ) key: cord- -fqptz v authors: porfidia, angelo; pola, roberto title: venous thromboembolism in covid‐ patients date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: fqptz v we read with interest the study published by tang and coll.( ) in a recent issue of the journal of thrombosis and haemostasis. in this retrospective analysis, conducted at the tongji hospital of wuhan, china, it is reported that heparin treatment reduces mortality in subjects affected by severe covid‐ who have “sepsis‐induced coagulopathy”. the definition of severe covid‐ was the presence of at least one of following: respiratory rate ≥ breaths /min; arterial oxygen saturation ≤ % at rest; pao /fio ≤ mmhg. the authors of this study also reported that, among subjects not treated with heparin, mortality raised according with d‐dimer levels. of note, patients that received heparin in this study were mostly treated with enoxaparin, at the thromboprophylactic dose of ‐ mg/day, for at least days. we read with interest the study published by tang and coll. in a recent issue of the journal of thrombosis and haemostasis. in this retrospective analysis, conducted at the tongji hospital of wuhan, china, it is reported that heparin treatment reduces mortality in subjects affected by severe covid- who have "sepsis-induced coagulopathy". the definition of severe covid- was the presence of at least one of following: respiratory rate ≥ breaths /min; arterial oxygen saturation ≤ % at rest; pao /fio ≤ mmhg. the authors of this study also reported that, among subjects not treated with heparin, mortality raised according with d-dimer levels. of note, patients that received heparin in this study were mostly treated with enoxaparin, at the thromboprophylactic dose of - mg/day, for at least days. we are surprised that only . % of the population analyzed by tang and coll. ( patients on a total of ) received anticoagulant therapy for the prevention of venous thromboembolism (vte). indeed, patients hospitalized for covid- , and in particular those with a "severe" disease, are by definition at increased risk for vte. considering that these patients had respiratory failure, were likely bedridden for oxygen supplementation, and had an acute respiratory infection, their padua score was necessarily ≥ , without even taking into account the possibility that some of them could have cancer, history of previous vte, and age > years. based on this, it is possible to hypothesize that, among the patients that did not receive heparin (or were treated for less than days), some developed pulmonary embolism (ep), which could have contributed to mortality in this group. such hypothesis is strengthened by the fact that mortality correlates with d-dimer levels among heparin non-users, although we are aware that high d-dimer levels may be due to many factors in covid- patients and do not necessarily depend on the presence of vte. it would be helpful to know whether heparin users and non-users differed in terms of padua score. also, it would interesting if the authors could retrospectively reanalyze their study population to determine how many patients were screened for vte by ultrasonography of the legs this article is protected by copyright. all rights reserved anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy a riskassessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score and/or ct scan pulmonary angiography, and assess whether vte was more frequent among subjects who did not receive thromboprophylaxis with heparin, compared to heparin-treated individuals. the authors declare no conflicts of interest in association with this study. angelo porfidia and roberto pola equally contributed to this article. both authors discussed, commented, and finally approved the manuscript. key: cord- -etibcspx authors: wright, franklin l.; vogler, thomas o.; moore, ernest e.; moore, hunter b.; wohlauer, max v.; urban, shane; nydam, trevor l.; moore, peter k.; mcintyre, robert c. title: fibrinolysis shutdown correlates to thromboembolic events in severe covid- infection date: - - journal: j am coll surg doi: . /j.jamcollsurg. . . sha: doc_id: cord_uid: etibcspx background: coronavirus disease (covid- ) predisposes patients to a prothrombotic state with demonstrated microvascular involvement. the degree of hypercoagulability appears to correlate with outcomes, however optimal criteria to assess for the highest risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography (teg) measurements of coagulation would correlate with thromboembolic events. methods: patients admitted to an intensive care unit with covid- diagnoses that had teg analyses performed were studied. conventional coagulation assays, d-dimer levels, and viscoelastic parameters were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new onset renal failure. results: forty-four patients with covid- were included in the analysis. derangements in coagulation laboratory values including elevated d-dimer, fibrinogen, pt, and ptt were confirmed; viscoelastic parameters showed an elevated maximum amplitude and low lysis at minutes. a complete lack of lysis of clot at minutes was seen in % of patients and predicted vte with an auroc of . (p= . ). a d-dimer cutoff of ng/ml predicted need for dialysis with an auroc of . (p= . ). overall, patients with no lysis of clot at minutes and a d-dimer of greater than ng/ml had a rate of vte of % compared to % for patients with neither risk factor (p= . ) and had a hemodialysis rate of % compared to % (p= . ). conclusions: fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at minutes on thromboelastography, predicts thromboembolic events and need for hemodialysis in critically ill patients with covid- . further clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown. the novel coronavirus known as severe acute respiratory distress syndrome coronavirus (sars-cov- ), leading to coronavirus disease (covid- ) , emerged in wuhan, china in late and has become a worldwide pandemic. more than . million cases have been confirmed worldwide causing more than , deaths, with these numbers growing exponentially . a subset of patients infected with covid- progress to acute respiratory distress syndrome (ards), with % of critically ill patients requiring intubation and mechanical ventilation . viral infection associated inflammation clearly predisposes patients to prothrombotic states initial studies in wuhan that utilized multivariate regression analyses suggested a higher mortality based on age, sofa score, and d-dimer levels . furthermore, previous work during the h n viral pneumonia outbreak demonstrated that elevations in d-dimer levels suggest an increased thrombosis risk . specific coagulation pathway product analysis demonstrated decreased survival in patients presenting with covid- and elevations in the prothrombin time, d-dimer, and fibrin degradation products . broad evidence exists for using thromboelastography or the thromboelastogram (teg) to predict thromboembolic rates in other disease processes. across trauma, surgical, and mixed intensive care unit populations, hypercoagulability as demonstrated by teg, especially an elevated maximum amplitude (ma), has reliably predicted thromboembolic events (see discussion for references). the initial study of teg usage in covid- patients in italy demonstrated that the teg-ma and angle were elevated and the teg-r and k values were decreased, however these findings were not correlated with outcome measures such as rates of thrombotic events . based on prior data we hypothesize that abnormalities in teg parameters would correlate with thromboembolic risk. the aim of this study was to develop an improved screening tool to suggest the highest risk of thromboembolic complications including renal failure. all ( %) scored a (high flow oxygen), and patients ( %) scored a (oxygen by mask). all patients with vte had a score of other than one patient who died; likewise, all patients with arterial thrombus had a score of other than one patient who died. the patients' conventional coagulation parameters are listed in table (platelet counts, pt, ptt, d-dimer and fibrinogen). pertinent abnormalities include an elevated d-dimer level, elevated fibrinogen, with normal platelet counts in the majority of patients and mildly elevated pt and aptt with median values at or slightly above the upper limits of normal. the median isth dic score was ( - ), with no patients having a score higher that . teg variables were consistent with a hypercoagulable state with an elevated ma and low ly ( table ) . the receiver operating characteristic curve for vte was only significant for teg ly and vte with an area under the curve of . (p= . figure a ). the youden index for vte was identified at . in this patient cohort, % had this extreme lack of fibrinolytic activity. these patients were categorized as fibrinolysis shutdown based on the presence of elevated d-dimer and low fibrinolytic activity; fibrinolysis shutdown has previously been described as ly of less than . % but the more complete shutdown seen in these patients results in an ly of % as a diagnostic cutoff based on the youden index for maximizing sensitivity and specificity. descriptive variables of patient with fibrinolysis shutdown versus those without shutdown are listed in table . the only significant differences appreciated between groups were patients with fibrinolytic shutdown had a lower incidence of a history of hyperlipidemia and a lower teg angle, even though fibrinogen levels were similar. patients with fibrinolysis shutdown had a % rate of vte compared to % in patients without shutdown (p= . ). the time to vte was significantly shorter in patients with fibrinolysis shutdown (figure , log rank p= . ). overall, of the patients with severe covid- infection in the icu were placed on full therapeutic anticoagulation, despite only of these patients having documented vte or arterial thrombotic events; additional patients received therapeutic anticoagulation empirically based on physician concern for occult thrombotic events or bedside evidence of extreme hypercoagulability such as frequent clotting of central venous access or hemodialysis filters. the receiver operating characteristic curve for new onset need for dialysis was only significant for d- patients were grouped into coagulation cohorts using both ly and d-dimer inflection points. patients with neither risk factor for hypercoagulability were present in % of the patient population, one coagulation risk factor represented % of the patient population, and % of patients had both. the number of patients with vte increased from to % for patients with to coagulation risk factors respectively (p= . figure ) . similarly, the need for dialysis increased from % to % (p= . figure ). while not significant, thrombotic stroke rate was also increased from % to % (p= . in the trauma population, hypercoagulable teg parameters predict venous thromboembolism (vte) . - . fold higher based on higher maximum amplitude (ma) parameters despite appropriate prophylactic anticoagulation [ ] [ ] [ ] [ ] . in a broad surgical patient population, patients with a teg ma greater than were times more likely to have thrombotic events including vte, myocardial infarction, and cerebrovascular accident . in a mixed medical-surgical icu population with baseline abnormal coagulation parameters, a teg-ma of greater than predicted thromboembolic events more effectively than conventional coagulation parameters such as inr, ptt, fibrinogen, or platelet count . in a more recent study, a low ly suggestive of fibrinolysis shutdown was associated with an increased risk of thrombotic complications as early as hours from injury . medical inhibition of fibrinolysis with tranexamic acid has also been associated with an increased risk of thrombotic complications in trauma patients . teg ma in this covid- population was universally elevated regardless whether the patient developed thrombotic complications or not, but ly strongly differentiated those patients with and without vte. the first publication to utilize teg in the icu with covid- patients drew similar conclusions that viscoelastic testing demonstrated hypercoagulability in this patient population ; however, this study of patients from italy was descriptive and did not include any outcomes associated with teg indices. our results suggest an that teg ly serves as a prognostic marker that this patient population is at risk for thrombotic complications, and may have a better performance at identifying these at-risk patients than other coagulation measurements. elevated d-dimer levels were also associated with potential micro-thrombotic disease leading to recently, acute fibrinolysis shutdown has been demonstrated in early sepsis and found to correlate to increased morbidity and mortality . fibrinolysis shutdown and organ failure has historically been associated with dic , however the isth score of or greater to define overt dic the need for more aggressive anticoagulation or fibrinolytic therapy remains unclear, and there exist scant data to guide more aggressive therapies to mitigate the hypercoagulable state. microvascular thrombosis may contribute to acute respiratory distress syndrome, acute renal failure, and liver function test elevations frequently observed in these patients. it is unclear but biologically plausible that treatment of the hyperthrombotic state of these patients with covid- could prevent or decrease the extent of renal injury seen. there are inherent limitations to this retrospective descriptive study. first there was variability in the laboratory testing patterns based on intensivist preference. in addition, the teg and other coagulation parameters were drawn at variable times of the patient disease processes. studies done to evaluate for thromboembolic events were performed for clinical suspicion rather than routine screening and therefore some vte or arterial emboli were likely not captured or had delays in diagnosis. clotting of central lines and ihd/crrt circuits was commonly noted in these critically ill patients with covid- but was not reliably captured in our data set, again potentially leading to an underestimation of hypercoagulable outcomes. due to the sudden influx of patients with a covid- diagnosis, outcome data are inherently limited since many patients still remain hospitalized and there are logistical hurdles to effective diagnosis of vte. in addition, less common outcomes such as stroke and mortality would require a large cohort of patients to obtain adequate power to determine if the coagulation parameters we identified that were associated with vte and renal failure are also associated with these adverse events. covid- causes not only hypercoagulability but also fibrinolysis shutdown which is associated with vte, stroke, and renal failure. defining the optimum predictive test for micro-or macro-thromboses requires further study, however the teg in conjunction with the d-dimer appear to be a sensitive marker for severity of disease which will need to be studied in a prospective fashion. a teg ly of % and a d-dimer of greater than ng/ml together suggest complete fibrinolysis shutdown and markedly elevated risk of renal failure, vte, and thrombotic events. the optimum medical therapy to address this hypercoagulable and fibrinolytic state is still unknown, however these results suggest the need to consider therapeutic anticoagulation and potentially tpa therapy to directly addresses the failure in the coagulation cascade of this high-risk group of patients. clinical course and outcomes of critically ill 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refractory covid- associated acute respiratory distress syndrome (ards)? tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series salvage use of tissue plasminogen activator (tpa) in the setting of acute respiratory distress syndrome (ards) due to covid- in the usa: a markov decision analysis key: cord- - jriik authors: pizzolo, francesca; rigoni, anna maria; de marchi, sergio; friso, simonetta; tinazzi, elisa; sartori, giulia; stefanoni, filippo; nalin, francesca; montagnana, martina; pilotto, sara; milella, michele; azzini, anna maria; tacconelli, evelina; marchi, giacomo; girelli, domenico; olivieri, oliviero; martinelli, nicola title: deep vein thrombosis in sars-cov- pneumonia-affected patients within standard care units: exploring a submerged portion of the iceberg date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: jriik [figure: see text] the outbreak of the coronavirus disease (covid- ) spread rapidly throughout the world during the first months of reaching the pandemic status as a major global health issue. the main clinical and therapeutic concerns due to covid- relate to the respiratory distress and failure caused by pneumonia due to the severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . covid- , however, is not just a pulmonary disease. while respiratory complications and systemic inflammation unquestionably result in significantly higher morbidity and mortality rates, cardiovascular complications are also common [ ] . a number of cohort studies described an association with coagulopathy and venous thromboembolism (vte) among sars-cov- infected patients [ ] . sars-cov- predisposes to thrombotic events by means of different mechanisms such as hypoxia, inflammation, prolonged immobilization occurring in the context of different and various alterations of hemostatic pathways (e.g. from endothelial dysfunction to platelet activation, from inflammation-related and consumptive coagulopathy to thrombotic microangiopathy) [ ] . alterations of prothrombin time, fibrinogen, and d-dimer are often observed in covid- patients and are associated with a detrimental outcome [ ] . d-dimer has been specifically proposed as a potential prognostic marker, where high d-dimer levels predict higher inhospital mortality in covid- patients [ ] . consistently, anticoagulant and fibrinolytic drugs have been proposed as possible therapeutic tools [ ] . two studies in chinese and dutch populations showed a remarkably high cumulative incidence of symptomatic vte in patients admitted to the intensive care units (icu) [ , ] . the prevalence of deep vein thrombosis (dvt) in patients hospitalized for sars-cov- infection remains, however, not well defined, especially for those admitted to covid- standard care units (scu). therefore, we designed a study with the aims of assessing the prevalence of dvt among subjects with sars-cov- pneumonia in the setting of scu and investigating the clinical and laboratory characteristics associated with dvt in covid- patients. in april , we performed a one-week prevalence survey among in-patients within covid- scu at the verona university hospital, italy. forty-three subjects (median age years with interquartile range of years and minimum-maximum range - years, females . %, main duration of hospitalization days with interquartile range of days and minimum-maximum range of - days, ( . %) admitted from icu, no previous dvt history) were screened once by a whole leg venous ultrasound (examining both femoral veins, popliteal veins and calf veins). all of them, with proven sars-cov- pneumonia, had no overt signs and/or symptoms of vte at physical examination and were on thromboprophylaxis at standard dose with low-molecular-weight heparin (enoxaparin, , - , u/die) or heparin-calcium ( , u x - /die). four subjects taking full-dose anticoagulant therapy because of atrial fibrillation were excluded from the study. clinical information, laboratory data and padua prediction score calculation were collected consensually to the ultrasonography examination. the study was approved by the ethics committee of our institution (azienda ospedaliera universitaria integrata, verona, italy) and witnessed oral consent was obtained. all calculations were performed using the ibm spss . (ibm inc., armonk, ny, usa) statistical package. distributions of continuous variables in groups were expressed as median value with minimum-maximum range and analyzed by mann-whitney test. qualitative data were expressed as number and percentage with estimated % confidence interval (ci) and j o u r n a l p r e -p r o o f journal pre-proof analyzed with use of the χ test or fisher-exact test, when appropriate. all the variables showing an association with dvt at univariate analysis (p< . ) were included in a logistic regression model with backward stepwise selection of variables and the strength of association was estimated by calculating odds ratios (or) with %ci. a p value < . was considered significant. dvt was detected in out of ( . % with %ci . - . %) subjects. table summarizes the clinical and laboratory characteristics of the patients affected by dtv as compared to those without dvt. as expected, the %ci for the prevalence estimates were wide due the small sample size of this study cohort. patients with dvt were older than those without dvt. in the subgroup of subjects below years of age only out of subjects ( . % with %ci - . %) had dvt, while in the subgroup of those above years of age, the prevalence of dvt was . % with %ci . - . %. patients with dvt had a higher prevalence of diabetes, higher total white blood cell and neutrophil counts, while platelet count showed a trend toward the highest range but not statistically significant. the padua prediction score also tended to be higher in dvt group but a substantial number of patients with dvt (n= ) were considered at low risk on the basis of this risk assessment model. subjects in the study cohort were stratified according to d-dimer plasma concentration in subgroups, i.e. < , - , , and ≥ , mcg/l. these threshold levels were predefined on the basis of prior scientific literature. while d-dimer < mcg/l is the usually accepted threshold value to exclude vte in low-risk patients, d-dimer ≥ , mcg/l has been proposed as the cut-off value to predicting vte in covid- patients [ ] . very high plasma concentrations of d-dimer (≥ , mcg/l) was associated with dvt ( % with %ci . - . % versus . % with %ci . - . %, comparing patients with or without dvt respectively). however, dvt was observed also in subjects with d-dimer concentrations within the normal range value (< mcg/l). by including all the variables showing an association with dvt at univariate analysis (p< . ) in a logistic regression model with backward stepwise selection of variables, only high d-dimer levels (≥ mcg/l) maintained an association with dvt (or . with %ci . - . , p= . ). in this regard, our results are consistent with those from previous studies proposing high d-dimer levels as a potential useful tool for identifying covid- patients with poor prognosis [ , ] and/or with vte complications [ ] . on the other hand, no differences between dvt and non-dvt subjects were found for fibrinogen, pt and aptt, the inflammatory marker c-reactive protein, markers of renal and liver function, as well as the other clinical characteristics. of the dvt diagnosed, were limited and distal, while four patients had a significant thrombotic burden (all bilateral with proximal dvt). three of them underwent ctpulmonary angiography which revealed pulmonary embolism, while one patient died due to severe acute respiratory distress syndrome (ards) before performing the angio-ct. these findings thereby support the usefulness of ultrasound examination for a prompt shift to full anticoagulant therapy to prevent further vte complications. our data suggest that patients hospitalized for covid- have substantially high prevalence of venous thrombotic events regardless of a thromboprophylaxis regimen at standard dosage. this prevalence is impressively higher than that observed in acute medical ill patients [ ] , i.e. lower than %, and appears even comparable with that reported in previous studies of patients with severe sars-cov- pneumonia in icu [ , ] . in the study on chinese patients, for j o u r n a l p r e -p r o o f whom no thromboprophylactic therapy was reported, cui and colleagues described a vte prevalence of % [ ] . in the dutch study on patients undergoing an adequate thromboprophylaxis with standard doses of nadroparin, klok and colleagues observed a vte cumulative incidence of % [ ] . it should be noted, however, that both those studies identified symptomatic thrombotic complications without an intent of a systematic screening by way of performing a lower limb venous ultrasonography. therefore, we speculated that the real prevalence of total, symptomatic and asymptomatic, venous thrombotic complications in covid- patients in icu could be even higher than what was described, so far. in line with our hypothesis, a very recent study showed an extremely high prevalence of asymptomatic dvt by screening with compression ultrasonography of the lower extremities covid- patients in icu ( / - . %) [ ] . in our study sample, although out of subjects were admitted from icu, the prevalence of prior vte was low. however, it should be taken into account that all the screened subjects were asymptomatic for dvt and no systematic screening with leg venous ultrasound was performed in icu. those results and ours are consistent with recent evidences supporting the concept of a strong prothrombotic diathesis in covid- , which is characterized by severe hypercoagulability rather than consumptive coagulopathy [ , ] . sars-cov- infection may influence hemostatic pathways by different biological mechanisms at several levels. recent observations by autopsies in covid- patients documented pulmonary vascular endothelialitis and a high prevalence of in situ microthrombi in alveolar capillary vessels, consistent with thrombotic microangiopathy [ ] . the coagulopathy of covid- has been suggestively described as a perfect storm of immune-, cytokine-, and coagulation-driven processes that conspire to create a prothrombotic diathesis [ ] . however, the crucial drivers of all these alterations in the hemostatic balance, remain still uncertain as it does so the optimal management of covid- -associated vte risk. further studies are, therefore, needed to clarify such issues. the findings of a high prevalence of dvt in patients taking the usual thromboprophylaxis and estimated at low risk of thrombotic complications according to the traditional risk assessment model (such as the padua prediction score), emphasize some unsolved issues: i) potential sars-cov- -related hypercoagulable state, ii) appropriate vte risk stratification for hospitalized covid- patients, and iii) the choice of anticoagulant agents and relative doses, which require further investigations [ ] . it should be noted that there is a great debate on such issues with some controversial results [ , , ]. these crucial questions will be solved only by the ongoing randomized clinical trials. meanwhile, we can argue that early detection of dvt in covid- patients may allow a more appropriate management, for example by shifting rapidly from standard thromboprophylaxis to full anticoagulant therapy in patients with high thrombotic burden, like the reported subjects in whom ct-pulmonary angiography revealed pulmonary embolism. this study has some limitations owing to the small sample size, and its results should be then considered as hypothesis-generating. nonetheless, our results support the concept that a high index of suspicion for vte is crucial in patients with sars-cov- infection. further investigations with prospective clinical trials are urgently needed to define both clinical and laboratory predictors of vte and the possible role of anticoagulant therapy for the outcome of patients with covid- . zhong ns; china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study hospitalized covid- patients and venous thromboembolism: a perfect storm isth interim guidance on recognition and management of coagulopathy in covid- d-dimer levels on admission to predict in-hospital mortality in patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- low rate of intrahospital deep venous thrombosis in acutely ill medical patients: results from the aurelio study extremely high incidence of lower extremity deep venous thrombosis in patients with severe covid- in wuhan covid- -related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- high risk -score≥ highlights: .an association between covid- and venous thromboembolism (vte) is now recognized. the prevalence of vte is high in covid- patients hospitalized in standard care units. the prevalence of vte is high even though thromboprophylaxis and in patients estimated at low risk. a high index of suspicion for vte is crucial in patients with sars-cov- infection.j o u r n a l p r e -p r o o f key: cord- - l q s authors: hill, jason b.; garcia, david; crowther, mark; savage, bryan; peress, shira; chang, kevin; deitelzweig, steven title: frequency of venous thromboembolism in patients with covid- : a retrospective study date: - - journal: blood adv doi: . /bloodadvances. sha: doc_id: cord_uid: l q s patients infected with severe acute respiratory syndrome coronavirus (sars-cov- ) appear to be at increased risk for venous thromboembolism (vte), especially if they become critically ill with covid- . some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. the electronic health record (ehr) of a new orleans–based health system was searched for all patients with polymerase chain reaction–confirmed sars-cov- infection who were either admitted to hospital or treated and discharged from an emergency department between march and may . from this cohort, patients with confirmed vte (either during or after their hospital encounter) were identified by administrative query of the ehr.: between march and may , patients with covid- were identified; of these patients were admitted, while received care exclusively through the emergency department. in total, patients required mechanical ventilation and required renal replacement therapy. within the hospitalized cohort, the overall mortality rate was . % and vte occurred in patients ( . %). in the patients who required mechanical ventilation at some point during their hospital stay, developed vte ( . %). after a median follow-up of . days, vte had been diagnosed in of the admitted who were discharged alive ( . %). among patients with covid- who were hospitalized or treated in emergency departments, we did not find evidence of unusually high vte risk. pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary vte prevention in patients with covid- . venous thromboembolism (vte), consisting of deep vein thrombosis (dvt) and pulmonary embolism (pe), is a well-described complication of acute medical illness. among inpatients with an acute medical illness, validated risk-assessment models can identify subgroups at especially high risk to experience vte. , for example, study suggests that, in the absence of prophylaxis, % of medical inpatients with multiple risk factors will be diagnosed with symptomatic vte. the same studies showed that pharmacologic prophylaxis, with low doses of either unfractionated or low-molecular-weight heparin, significantly reduces the risk of vte; for example, if they received pharmacologic prophylaxis, only . % of patients in the highest-risk stratum of study was diagnosed with vte within a -day follow-up period. among the patients at highest risk, posthospital prophylaxis may further reduce the rate of vte in persons recovering from acute medical illness. there is a widespread perception that vte is a frequent complication of severe acute respiratory syndrome coronavirus (sars-cov- ) infection, and that this complication may occur despite pharmacologic prophylaxis. published evidence is equivocal. a report of patients from centers in the netherlands reported that approximately one-third of patients critically ill with covid- had pe. a second center in the netherlands reported that ; % of patients hospitalized for covid- ( admitted to the intensive care unit [icu]) had confirmed vte after a median follow-up of days. in contrast, a center in new york city has reported a vte rate of . % among patients with covid- , of whom required mechanical ventilation. authors from a center in northern italy found no cases of lowerextremity dvt among patients who were admitted to a non-icu bed and received standard low-molecular-weight heparin prophylaxis, even among the -patients subgroup screened for asymptomatic disease. to provide additional information about the association of vte with covid- , we present a large retrospective cohort study examining all polymerase chain reaction-confirmed covid- patients admitted to hospitals or treated in emergency departments affiliated with the ochsner health system. the ochsner health system is the largest academic health care system in louisiana; it encompasses an integrated care delivery network throughout all of louisiana and portions of southern mississippi. the ochsner health system operates under a single electronic health record (ehr), epic (verona, wi). the use of a single ehr platform permits large-scale data analyses to be performed on a network of . million patients from all payer sources. all data presented in this paper were derived using the epic "slicerdicer," a tool designed to query large data sets in the epic ehr. from the pool of all patients assessed at an ochsner health system facility between march and may , we identified all patients positive for sars-cov- on polymerase chain reaction-based testing. patients were seen in an emergency department and/or admitted to an inpatient unit at any of the hospitals affiliated with ochsner health. all patients were followed for vte until death or may . for our analysis, all patients who met our inclusion criteria were assumed to be continuously enrolled in the ochsner health system between march and may . this project was reviewed and approved by the ochsner health system institutional review board. we identified cases of new vte on hospitalized inpatients and those who were discharged by first searching for all patients with covid- who had a diagnosis of dvt or pe in their problem list. we then removed patients if the international classification of diseases, tenth revision code for "long-term current use of anticoagulants" was present at the time of the positive sars-cov- test. we performed further queries to identify patients with dvt or pe who may have been missed by the first search algorithm. the first query identified all patients with covid- who received apixaban, rivaroxaban, or dabigatran, excluding those with atrial fibrillation, those with stroke, and those on longterm anticoagulation. the second additional query identified patients with covid- who received an unfractionated heparin bolus, excluding patients with atrial fibrillation, patients with non-st-elevation myocardial infarction, patients with ischemic stroke, and those on chronic anticoagulation. unless they also had objectively confirmed vte based on chart review, we excluded patients whose indication for heparin bolus was thrombosis of an extracorporeal circuit (eg, renal replacement therapy or extracorporeal membrane oxygenation). we manually reviewed the charts of all cases flagged by the query for vte for objective documentation of thrombosis. confirmation of thrombosis required presence of a noncompressible deep venous segment on ultrasound, or evidence of an otherwise unexplained intraluminal filling defect on contrast examination, such as computerized tomographic pulmonary angiography. in case, v/q scanning was used to establish the diagnosis. all examinations were performed as a component of clinical care, and as such, both radiology department, and rarely, bedside ultrasonographic scans were included in our analysis. a flow diagram summarizing the search method is shown in figure . all data were stored in a secure database, and only deidentified data were uploaded to microsoft excel. the patients with covid- found to have patients whose problem list did not include long-term use of anticoagulants at time of admission pe = pulmonary embolism new vte by this strategy were further evaluated by chart review. all medical inpatients admitted to the ochsner health system are assessed for vte risk by the padua risk score, a widely accepted risk-stratification scheme that classifies patients with a score of or greater as high risk for vte and, unless the risk for vte is low, they receive mechanical or pharmacologic vte prophylaxis. routine pharmacologic prophylaxis consists of low-dose lowmolecular-weight heparin (enoxaparin, mg daily, or mg daily for crcl , or mg twice daily for body mass index [bmi] . ) or unfractionated heparin ( u every hours for bmi , and u every hours for bmi . ). mechanical prophylaxis includes elastic compression stockings or sequential compression devices and is used if the patient has a contraindication for pharmacologic prophylaxis. in the cohort used to derive the padua risk score, patients with a score of or greater had a -day vte rate of . % with thromboprophylaxis and % without prophylaxis. neither screening for asymptomatic vte nor postdischarge vte prophylaxis was routinely undertaken within the ochsner health system during the time described in this report. to estimate the rate of failure of vte prophylaxis among covid- -positive hospitalized patients, we defined failure as any dvt or pe event diagnosed $ days after the admission of a patient who had received $ days of evidence-based mechanical or pharmacologic vte prophylaxis immediately prior. evidence-based vte prophylaxis was defined as sequential compression devices (alone or in combination with elastic compression stockings), or lowmolecular-weight heparin or unfractionated heparin administered at usual prophylactic doses. between march and may , patients with covid- were admitted or evaluated in an emergency department; of these patients were admitted to the hospital, whereas received care exclusively through the emergency department. patient characteristics are presented in table . in total, vte events were diagnosed during a hospital stay; an additional cases were diagnosed and discharged from the emergency department. of the hospitalized patients who survived to be discharged between march and may , had experienced postdischarge vte on or before may . an additional single patient who had been evaluated and discharged was later diagnosed with (and hospitalized for) vte. of the inpatient vte events, ( %) were diagnosed with dvt and ( . %) were diagnosed with pe. nine ( . %) patients did not have confirmatory studies and were deemed to have vte based on clinical impression of the care team. there were various reasons for the absence of diagnostic testing, including rapid death of patients within hours of admission, right heart strain and elevated d-dimer on patients, contrast allergy in patients, and morbid obesity preventing proper dvt imaging in patients. of the other events, all were confirmed by standard definitions of appropriate objective testing. in addition, of the patients received venous thromboprophylaxis, and the who received no thromboprophylaxis were both categorized by the padua scale as being low risk for vte. there were patients identified with arterial thrombus: being embolic strokes, occurring in patients with concomitant cancer, and one an iliac artery thrombosis that proceeded to hospice care precluding further investigation. the overall proportion of patients with vte within the hospitalized cohort was / ( . %). considering only the subgroup of patients with covid- who required mechanical ventilation at some point during their hospital stay, the proportion who developed vte was / ( . %). of episodes of vte that occurred within the entire -patient cohort, were identified during a hospital admission, and were diagnosed after a prior hospital admission or emergency department visit. the remaining patients with vte were diagnosed and treated exclusively during a single emergency department encounter. for patients who were discharged alive, the mean duration of follow-up after hospital discharge was . days (median . days, interquartile range . to days). among the group of patients diagnosed with vte during or after hospital admission, ( %) had a "high-risk" padua score ( or greater); of these patients, ( % of all patients with vte) experienced vte during their hospital stay, and ( . % of all patients with vte) experienced a postdischarge vte. d-dimer values were captured on all patients in this study and were found to have a median value of . (interquartile range of . to . ), which is significantly elevated over those without dvt/ pe and which is dramatically elevated compared with normal values in the population. the frequency of clinical vte occurring after hospital discharge was low; of hospitalized patients who did not have an episode of vte during their inpatient stay and who survived until discharge, only experienced vte ( . %). of the patients diagnosed with new vte during their hospital stay, ( %) met our definition of prophylaxis failure. of these patients, received exclusively mechanical prophylaxis, received unfractionated heparin prophylaxis, received exclusively low-molecular-heparin prophylaxis, and received some combination of both mechanical and pharmacologic prophylaxis. finally, . % ( / ) of patients with a diagnosis of vte died by may . by comparison, the proportion of patients in the overall hospitalized cohort who had died was . % ( / ). within a cohort of patients hospitalized for covid- between march and may , . % had developed vte as of may . as expected, the proportion of mechanically ventilated patients who were diagnosed with vte was higher ( . %). the rate of posthospitalization vte among the admitted patients who were discharged alive and who did not experience an in-hospital vte was . %. although our overall rate of vte in hospitalized patients was low, half of our cases occurred in patients who were receiving effective vte prophylaxis prior to their vte. most patients with covid- are asymptomatic or have mild to moderate disease. despite this, our study confirms that hospitalization, particularly if it requires icu admission, is associated with a high mortality rate. however, our observation that vte occurred in , % of patients requiring mechanical ventilation (the vast majority of whom were probably receiving effective vte prophylaxis) suggests that the prophylaxis "failure rate" among very sick patients with covid- may not be dramatically different from what has been previously described in other critically ill populations. , among patients successfully discharged from the hospital, we found a rate of posthospital vte similar to that seen in other medically ill patients requiring hospitalization. in this data set, we found a second subgroup of patients (n ) that were on renal replacement therapy who experienced frequent clotting of their dialysis circuit requiring heparinization. this appears to be a clinically distinct entity from the dvt/pe population as these patients were significantly more ill ( % on ventilators and with an % mortality rate). this study presents overall rates of vte that are much lower than some previously published results , , but are consistent with others. , , the large difference in the rates of vte is not due to this cohort being a selected low-risk patient group; among those hospitalized, almost % died and . % required renal replacement therapy. an important explanation for some of the differences in published covid- -associated thrombosis rates is differences in outcome definitions. we focused only on vte, whereas other authors have included multiple forms of thrombosis (eg, arterial thrombosis, extracorporeal circuit thrombosis, or exclusively microvascular thrombosis) in their overall reported rates. this analysis has significant limitations. first, our ehr search strategy may have not captured vte cases. although we used several different strategies to minimize the number of missed vte cases, the authors recognize that an administrative ehr query can be less comprehensive than a manual record review. it is also possible that clinicians in some centers have a higher or lower threshold to order diagnostic testing, potentially impacting events rates. cattaneo et al have raised the intriguing possibility that the very high pe-to-dvt ratio reported by some centers might reflect a high frequency of in situ pulmonary artery thrombosis or occlusion, the pathophysiology of which may be different from traditional, clinically apparent vte. , as more data on covid- are published, it appears that average events rates are lower than initially suspected, possibly due to ascertainment bias in the initial papers. an event frequency that is quite similar to what we found. there are many possible explanations for the different vte rates reported at different centers; possibility is that there is a difference in the biology of the sars-cov- itself, that is, different genotypes may manifest with different clinical characteristics. second, outpatients who sought care outside the ochsner health system after hospital discharge would not be identified by our strategy, but the number of such patients is likely small because ochsner is a multistate system with comprehensive commercial and state payer contracts. third, our strategy would not have captured postdischarge vte events that either were fatal or did not lead the patient to seek medical attention. our study also did not employ any form of adjudication, and we systematically excluded patients with current use of anticoagulation at the time they tested positive for sars-cov- . many patients included in this analysis remain at risk of vte; further follow-up would likely reveal additional events. however, given the size of the present cohort, it seems unlikely that these study design characteristics would change our high-level observations. last, we did not systematically screen for venous thromboembolic events, so it is possible that such events, which were not clinically relevant, were not captured in this cohort. our findings, in combination with those previously published, suggest that vte rates (and the rate of prophylaxis failure) in hospitalized patients with covid- may be somewhat higher than expected. however, more information is needed, not only about the strength of the association between covid- and vte risk but also about the most effective way to reduce the risk of vte in this disease. until additional prospective outcome data are reported, and underlying mechanisms are better understood, our findings support a traditional approach to vte prophylaxis, both during and after hospitalization, for patients with covid- . contribution: j.b.h. compiled data for paper, composed methods and statistical analyses, and revised and edited background/results and discussion; m.c. and s.d. were the subject matter experts in thrombosis, and assisted in data validation and drafting the background section as well as editing and compiling the results and discussion; d.g. was the subject matter expert in thrombosis, assisted in data validation and drafting the background section as well as editing and compiling results and discussion, and completed the initial draft of figure ; s.p. and b.s. worked to complete validation of initial search query with manual chart abstraction; and k.c. verified statistical significance and analysis of data pulls and results. conflict-of-interest disclosure: the authors declare no competing financial interests. orcid profile: k.c., - - - . correspondence: jason b. hill, omc-ns hospital medicine, associate cmio, ochsner health system, medical center dr, slidell, la ; e-mail: jahill@ochsner.org. a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score predictive and associative models to identify hospitalized medical patients at risk for vte extended vs. standard-duration thromboprophylaxis in acutely ill medical patients: a systematic review and meta-analysis confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis incidence of venous thromboembolism in hospitalized patients with covid- clinical characteristics of covid- in new york city pulmonary embolism or pulmonary thrombosis in covid- ? is the recommendation to use high-dose heparin for thromboprophylaxis justified? vte incidence and risk factors in patients with severe sepsis and septic shock thromboprophylaxis in the intensive care unit: focus on medical-surgical patients pulmonary embolism in patients with covid- thrombosis in hospitalized patients with covid- in a new york city health system postdischarge venous thromboembolism following hospital admission with covid- high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study key: cord- -l b cv z authors: uppuluri, ellen m; shapiro, nancy l title: development of pulmonary embolism in a nonhospitalized patient with covid- who did not receive venous thromboembolism prophylaxis date: - - journal: am j health syst pharm doi: . /ajhp/zxaa sha: doc_id: cord_uid: l b cv z purpose: coronavirus disease (covid- ) has been associated with thrombotic complications such as stroke and venous thromboembolism (vte), and vte prophylaxis for hospitalized patients with covid- is recommended. however, extended postdischarge vte prophylaxis and vte prophylaxis for nonhospitalized patients with covid- are not routinely recommended due to uncertain benefit in these populations. summary: here we report development of a pulmonary embolism (pe) in a young patient without other vte risk factors who was treated for covid- in an emergency department (ed) and discharged home without vte prophylaxis, which was consistent with current recommendations. the patient presented to the ed days later with complaints of chest pain for day and was found to have a pe within the segmental and subsegmental branches of the left lower lobe. conclusion: this case suggests that nonhospitalized patients with covid- may be at higher risk for vte than patients with other medical illnesses and warrants further research into the risk of vte in outpatients with covid- . i nfection with severe acute respiratory syndrome coronavirus (sars-cov- ), a novel coronavirus first described in china in december , leads to the development of coronavirus disease . thrombotic complications related to covid- , such as stroke and venous thromboembolism (vte), have been reported. [ ] [ ] [ ] due to the observed risk of thrombosis, vte prophylaxis for hospitalized patients with covid- is recommended. , [ ] [ ] [ ] extended postdischarge vte prophylaxis and vte prophylaxis for nonhospitalized patients with covid- remain questionable practices and are generally not recommended. , [ ] [ ] [ ] in this article we report a case of pulmonary embolism (pe) in an ambulatory patient that developed weeks after discharge from an emergency department (ed) following diagnosis of covid- and treatment without dvt prophylaxis. a -year-old, overweight (weight, kg; body mass index, ) african american male with a past medical history significant for asthma (not managed with any medications) presented to the ed of an academic medical center with cough, shortness of breath, diffuse chest pain (associated with cough), fevers, chills, myalgia, and diarrhea that had developed over days. the patient's vital signs were stable aside from a temperature of . °c. an electrocardiogram (ecg) revealed normal sinus rhythm, and a chest x-ray revealed minimal hazy opacities within the right midlung. laboratory work included a basic metabolic panel (bmp) and complete blood count (cbc) with differential. results were normal except for a slightly low serum sodium concentration ( meq/l), chloride development of pulmonary embolism in a nonhospitalized patient with covid- who did not receive venous thromboembolism prophylaxis concentration ( mmol/l), and absolute lymphocyte count ( , /µl). the patient was suspected to have a viral upper respiratory infection or possibly covid- . a test for the covid- virus was performed and resulted positive the next day. the patient was informed, given isolation instructions, and discharged. the patient returned to the ed days later with complaints of leftsided pleuritic chest pain lasting day. he reported resolution of shortness of breath, fevers, chills, myalgia, and diarrhea and improvement in cough. he denied any recent hospitalizations, prolonged periods of immobility, trauma, smoking, or a history of cancer or prior vte. he also denied a family history of vte but reported a history of stroke in his mother. in the ed, vital signs and results of the bmp, cbc with differential, troponin i, b-natriuretic peptide, and liver function tests were normal except for a slightly low absolute lymphocyte count ( , /µl) and percentage of lymphocytes ( %) and an elevated percentage of neutrophils ( %). a repeat covid- test and measurements of d-dimer, c-reactive protein, and fibrinogen levels were not ordered. an ecg revealed normal sinus rhythm. a computed tomography pulmonary angiogram was positive for pe within the segmental and subsegmental branches of the left lower lobe. no right heart strain was identified. a lower extremity venous ultrasound was not performed. the patient was started on therapeutic weight-based enoxaparin therapy ( mg/kg twice a day), admitted for observation for a couple hours, and then, because he remained clinically stable, discharged home on enoxaparin within hours of arrival to the ed. the next day, following prior authorization approval, the patient was called and given appropriate instructions on how to switch from enoxaparin to an apixaban regimen of mg twice a day for days, then mg twice a day. the patient received routine phone follow-up by a new primary care provider days after discharge and by the medical center's direct oral anticoagulant (doac) screening service days after discharge. during these follow-up phone calls, he reported adherence to the prescribed apixaban regimen and continued to complain of chest pain but reported an improvement in pain severity. the patient also reported occasionally coughing up a small amount of blood-tinged sputum and denied any other signs or symptoms of bleeding. another routine phone follow-up was performed days after discharge by the doac screening service, and the patient continued to report improvement in chest pain and no significant bleeding. at the time of writing, the plan was for the patient to be treated with apixaban for at least months. the incidence of vte in patients with covid- is not well defined, as data are rapidly evolving and thromboprophylaxis varies among countries and institutions. some reports have described vte rates as high as % to % in patients hospitalized with covid- , with the majority of these patients admitted to an intensive care unit (icu). [ ] [ ] [ ] [ ] an article by middeldorp et al reported that % of patients hospitalized for covid- were admitted to an icu, and those patients were found to have a higher rate of symptomatic vte than patients admitted to a medical floor ( % vs . %) despite thromboprophylaxis. although the rate of symptomatic vte was lower in patients admitted to the medical floor, it was higher than the estimated rate of vte in acutely ill patients hospitalized with non-covid- medical illness who do not receive appropriate thromboprophylaxis ( %). poissey et al reported that . % of the first patients with covid- admitted to their icu experienced a pe; this was significantly higher than the frequency of pe in their icu over a similar time interval in ( . %) despite all patients in the former group receiving therapeutic or prophylactic anticoagulation. due to this reported risk of thrombosis, vte prophylaxis is recommended for all hospitalized patients with covid- . , [ ] [ ] [ ] vte rates in outpatients with covid- or immediately after hospital discharge following treatment for covid- have not been described. akel et al reported a case series of patients with covid- ( were years of age or older and was years old) who were not critically ill or affected by major risk factors for vte and mostly presented with a pe at the time of diagnosis of covid- ( patient presented with pe days following an admission for covid- ). that case series highlights the possibility of vte in noncritically ill patients with covid- . however, it does not provide insight into the risk of vte after discharge from a covid- -related hospital stay or in outpatients diagnosed as having covid- . to our knowledge, there are currently no published data regarding extended postdischarge vte prophylaxis and vte prophylaxis for nonhospitalized patients with • despite the observed risk of thrombosis in patients with covid- , extended postdischarge venous thromboembolism (vte) prophylaxis and vte prophylaxis for nonhospitalized patients with covid- remain questionable practices. • this report describes a case of development of a pulmonary embolism in a young, ambulatory patient without other risk factors for vte shortly after diagnosis of covid- . • this case suggests that nonhospitalized patients with covid- may be at a higher risk for vte than patients with other medical illnesses and warrants further research into the risk of vte in this population. covid- , and recommendations for vte prophylaxis in these populations are extrapolated from data on hospitalized patients with acute medical illness. patients hospitalized for certain medical illnesses have been shown to be at an increased risk for vte even after hospital discharge, which has led to research investigating extended thromboprophylaxis after hospitalization. this research has mainly been conducted in patients years of age or older with an acute medical illness requiring hospitalization and an increased risk of thrombosis due to reduced mobility, increased age, elevated d-dimer levels, or elevated scores on a risk scoring instrument such as the modified international medical prevention registry on venous thromboembolism (improve) vte risk score. [ ] [ ] [ ] results from these studies have not shown a consistent benefit of extended vte prophylaxis, which did not routinely lead to a reduction in vte or death; moreover, any reductions in vte or death were frequently associated with an increase in major or clinically relevant nonmajor bleeding. [ ] [ ] [ ] the results from these studies do not support the routine use of extended postdischarge thromboprophylaxis, and current guidelines do not recommend extended-duration outpatient vte prophylaxis in acutely ill hospitalized medical patients, critically ill medical patients, or medical outpatients with minor risk factors for vte, such as infection. , there may be a benefit in certain high-risk cohorts; however, this needs to be balanced with the risk of bleeding. based on data from studies reviewed here, extended postdischarge vte prophylaxis and vte prophylaxis for nonhospitalized patients is generally not recommended in patients with covid- . , - postdischarge vte prophylaxis, provided using food and drug administration-approved regimens, may be considered in patients with covid- who are at low risk for bleeding and high risk for vte (eg, those with reduce mobility, active cancer, or a d-dimer level of > times the upper normal limit, as well as those receiving intubation and sedation for several days or with morbid obesity and a caprini score of > ). , [ ] [ ] the patient described in this report would not have been considered at high risk for vte because he did not have reduced mobility, active malignancy, or a history of prior vte. he also would not have met the inclusion criteria of studies investigating extended thromboprophylaxis because he was not hospitalized, was less than years old, and did not experience reduced mobility. [ ] [ ] [ ] therefore, based on currently available data, thromboprophylaxis would not have been appropriate for him after diagnosis of covid- . however, this case of development of a pe in an ambulatory patient days after covid- diagnosis suggests that nonhospitalized patients with covid- may be at a higher risk for vte than patients with other medical illness and warrants further research into the risk of vte in outpatients with covid- . there are several ongoing trials exploring anticoagulation strategies in patients with covid- ; however, none are currently evaluating vte prophylaxis in nonhospitalized patients. current data do not support the routine use of vte prophylaxis in nonhospitalized or postdischarge patients with covid- . the reported case of a young, nonhospitalized patient with covid- developing a pe illustrates a need for further investigation into the risk of vte in ambulatory patients with covid- . isth interim guidance on recognition and management of coagulopathy in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum covid- ) treatment guidelines. national institutes of health website prevention, diagnosis and treatment of venous thromboembolism in patients with covid- : chest guideline and expert panel report implementation of a direct oral anticoagulation screening service at a large academic medical center provided by a pharmacist-managed antithrombosis clinic as a method to expand antithrombotic stewardship efforts prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- incidence of venous thromboembolism in hospitalized patients with covid- pulmonary embolism in covid- patients: awareness of an increased prevalence blood coagulation, fibrinolysis and cellular haemostasis: venous thromboembolic events in hospitalized medical patients pulmonary embolism: a complication of covid infection rivaroxaban for thromboprophylaxis in acutely ill medical patients extended thromboprophylaxis with betrixaban in acutely ill medical patients rivaroxaban for thromboprophylaxis after hospitalization for medical illness american society of hematology guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis considerations in prophylaxis and treatment of vte in covid- patients search result the authors have declared no potential conflicts of interest. key: cord- -j v i vm authors: marietta, marco; coluccio, valeria; luppi, mario title: covid- , coagulopathy and venous thromboembolism: more questions than answers date: - - journal: intern emerg med doi: . /s - - -x sha: doc_id: cord_uid: j v i vm the acute respiratory illnesses caused by severe acquired respiratory syndrome corona virus- (sars-cov- ) is a global health emergency, involving more than . million people worldwide with more than , deaths. among the clinical manifestations of covid- , the disease that results from sars-cov- infection in humans, a prominent feature is a pro-thrombotic derangement of the hemostatic system, possibly representing a peculiar clinicopathologic manifestation of viral sepsis. the severity of the derangement of coagulation parameters in covid- patients has been associated with a poor prognosis, and the use of low molecular weight heparin (lmwh) at doses registered for prevention of venous thromboembolism (vte) has been endorsed by the world health organization and by several scientific societies. however, some relevant issues on the relationships between covid- , coagulopathy and vte have yet to be fully elucidated. this review is particularly focused on four clinical questions: what is the incidence of vte in covid- patients? how do we frame the covid- associated coagulopathy? which role, if any, do antiphospolipid antibodies have? how do we tackle covid- coagulopathy? in the complex scenario of an overwhelming pandemic, most everyday clinical decisions have to be taken without delay, although not yet supported by a sound scientific evidence. this review discusses the most recent findings of basic and clinical research about the covid-associated coagulopathy, to foster a more thorough knowledge of the mechanisms underlying this compelling disease. in december , a cluster of acute respiratory illnesses caused by severe acquired respiratory syndrome corona virus- (sars-cov- ) virus occurred in wuhan, hubei province, china. the disease has rapidly spread from wuhan to many other countries, soon becoming a global health emergency. indeed, at the time of this writing, more than . million cases of covid have been reported worldwide with more than , deaths [ ] . although most patients have mild manifestations and good prognosis after infection, some of them develop severe symptoms and die from multiple organ complications [ ] [ ] [ ] . the pathogenesis of covid- , the disease that results from sars-cov- infection in humans, remains unclear, but it is very likely that the most severe manifestations of this disease may be linked to host-pathogen interaction immune mechanisms [ , ] . in critically ill covid- patients, indeed, massive cytokine storms (including il- , tnf-α, and other inflammatory biomarkers), as well as increments of circulating neutrophils and monocyte activation, are typically observed together with low t lymphocyte counts and functional exhaustion of effector t cell responses [ , ] . such ineffective and detrimental expansions of innate/ humoral responses, alongside t cell suppression, are reminiscent of classical features of sepsis, which is currently defined as a life-threatening organ dysfunction induced by dysregulated host response to infection, being characterized not only by systemic inflammatory response syndrome (sirs) with related endothelial and organ damage, but also by impairment of adaptive t cell immunity [ , ] . moreover, the derangement of the hemostatic system observed in end-stage covid- could well fit with the idea that severe covid- possibly represents a peculiar clinicopathologic form of viral sepsis, displaying a prominent prothrombotic feature instead of the hemorrhagic one observed in other viral diseases, such as lassa, marburg and ebola hemorrhagic fevers [ ] . from a clinical perspective, the extent of the derangement of coagulation parameters in patients affected by severe covid- pneumonia has been found to be associated with a poor prognosis [ , ] . in these patients, low molecular weight heparin (lmwh) or unfractionated heparin (ufh) at doses registered for prevention of venous thromboembolism (vte) seemed to be associated with a lower risk of death [ ] and is currently recommended by the world health organization [ ] and by several scientific societies [ ] [ ] [ ] [ ] [ ] [ ] [ ] (table ) . however, some relevant issues on the relationships between covid- , coagulopathy and vte have yet to be fully elucidated. data on this issue are puzzling, as the reported incidence of vte in covid- patients ranges from % to about % in general wards [ ] [ ] [ ] [ ] , and from to % in the icu setting, often despite adequate lmwh prophylaxis [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . an even higher rate of vte, up to %, has been reported in consecutive autopsies performed in covid- patients in whom vte was not suspected before death [ ] (table ) . several reasons may account for this discrepancy: just a few studies systematically screened patients for vte, and imaging in suspected cases is challenging in the setting of a striking pandemic, with overcrowded hospital wards, given the risk of transmitting infection to other patients or health-care workers and the technical problems in performing investigation for pulmonary embolism (pe) in critically ill patients in prone position. on this ground, it is conceivable that a non-negligible portion of pe episodes remains undiagnosed, because of these technical constraints. however, deep vein thrombosis (dvt) is rarely found in these patients [ ] , raising the question whether the occlusions observed in the pulmonary vascular bed of covid- patients result from embolization of a dvt or from a localized thrombotic microangiopathy [ ] . the question is not trivial, as the pathophysiological mechanism triggering the pulmonary vascular disease in covid- could impact on the treatment. indeed, whereas high doses of ufh or lmwh are the mainstay of treatment in case of established pulmonary embolism from peripheral vein thrombosis, the same treatment would be ineffective, or even dangerous because of the bleeding risk, in the hypothesis that a thrombotic microangiopathy would be mainly responsible for the pulmonary vascular occlusion observed in covid- patients in the absence of a proven dvt [ ] . on these grounds, a better knowledge of the pathogenesis of covid- coagulopathy is urgently needed to provide more precisely targeted treatments to this disease. how do we frame the covid- -associated coagulopathy, that is, dic, sic, cac or pic? despite a rapidly growing amount of literature on this topic [ , [ ] [ ] [ ] [ ] [ ] [ ] , the pathophysiological mechanisms underlying the derangement of the hemostatic system induced by sars-cov have not been fully elucidated yet. indeed, no evidence of an intrinsic procoagulant effect exerted by the sars-cov- virus is so far available. therefore, the most reasonable hypothesis is that the virus activates the coagulation cascade by eliciting a large-scale inflammatory response, similar to that observed in other forms of sepsis. several studies have already demonstrated the tight interconnection between thrombosis and inflammation, two processes mutually reinforcing each other [ , ] . both coagulation factors and platelets are directly implicated in the modulation of the host immune response, displaying proinflammatory functions independent of their hemostatic effects [ ] [ ] [ ] . moreover, the cytokines storm stimulates the expression of tissue factor on monocytes/macrophages and vascular endothelial cells, on whose surfaces the coagulation cascade is initiated. the thrombus formation at the microvascular level contributes to tissue ischemia and organ dysfunction [ ] . a remarkable inflammatory response can be observed in covid- patients, attested by a significant increase in fibrinogen, c-reactive protein (crp), erythrocyte sedimentation rate (esr), interleukin- (il- ) and ferritin levels [ , ] . moreover, the increase of il- levels has been found to correlate with that of fibrinogen, confirming the link between inflammation and procoagulant changes [ ] . the hypercoagulable state of covid- patients has been assessed mainly by viscoelastic methods [ ] [ ] [ ] or by an increase in d-dimer levels, whose extent correlates with the risk of death [ , , ] . this finding is not surprising, as increased d-dimer levels have already been demonstrated to be associated with a poorer outcome in other cohorts of septic patients [ ] . however, the exact role of d-dimer test in the context of covid- coagulopathy deserves some further comments. [ ] vte prophylaxis in severe or critically ill pts. strongly recommended with lmwh in pts. at low or moderate risk of bleeding and with no contraindication vte prophylaxis in mild and moderate pts. recommended with lmwh in pts. assessed to have a high or moderate risk of vte (padua or improve ram), in the absence of contraindication vte prophylaxis after hospital discharge consider prolonged outpatient vte prophylaxis with lmwh in pts with persistent risk factors for vte vte treatment curative anticoagulant parenteral treatment with lmwh recommended in pts. suspected for vte, in absence of contraindication ash [ ] vte prophylaxis in all hospitalized pts. recommended with lmwh or fondaparinux unless the risk of bleeding is judged to exceed the risk of thrombosis vte prophylaxis after hospital discharge consider extended thromboprophylaxis after discharge using a regulatory-approved regimen (doac up to days) anticoagulation forum [ ] vte prophylaxis in non-critically ill hospitalized pts. recommended with lmwh standard doses, regardless of vte risk assessment score vte prophylaxis in icu pts. recommended with increased doses of heparin (e.g., enoxaparin mg sc bid, enoxaparin . mg/kg sc bid, ufh iu sc tid or low-intensity iv vte prophylaxis after discharge not routinely recommended; consider on a case-by-case basis chest guidelines [ ] vte prophylaxis in acutely ill hospitalized pts. recommended with lmwh or fondaparinux at standard doses over intermediate or full treatment dosing or over doac vte prophylaxis in critically ill hospitalized pts. recommended with lmwh of ufh over fondaparinux or doac suggested current standard dose over intermediate or full treatment dosing vte prophylaxis after hospital discharge recommended inpatients prophylaxis only over inpatient plus extended prophylaxis after hospital discharge who world health organization, vte venous thromboembolism, od once daily, sc subcutaneously, bid twice daily, tid three times daily, iv intravenously, isth international society on thrombosis and hemostasis, pts patients, siset italian society on thrombosis and hemostasis, lmwh low molecular weight heparin, ufh unfractionated heparin, crcl creatinine clearance, pt prothrombin time, aptt activated partial thromboplastin time, crcl creatinine clearance, icu intensive care unit, ash american society of hematology, doac direct oral anticoagulants cattaneo [ ] gw pts on lmwh prophylaxis yes % dvt zhang [ ] gw pts. ( % on lmwh prophylaxis) yes % proximal dvt, % distal dvt (one ward) . % dvt (all the hospital) lodigiani [ ] gw pts ( % on lmwh prophylaxis) icu pts ( % on lmwh prophylaxis) yes gw: pe . %, % dvt (including uedvt), . % stroke icu: pe . %, . % isolated dvt (including uedvt), . % stroke middeldorp [ ] gw pts (standard lmwh prophylaxis) icu pts (doubled lmwh prophylaxis) yes ( % gw) gw: pe . %, % dvt (including uedvt) icu: pe %, % dvt (including uedvt) thomas [ ] icu pts (standard lmwh prophylaxis) no % pe, . % dvt (including uedvt) klok [ ] icu pts on lmwh prophylaxis no % pe, . % dvt (including uedvt) . % ate poissy [ ] icu pts ( % on vte prophylaxis) no . % pe cui [ ] icu pts not on lmwh prophylaxis yes % dvt llitjos [ ] icu pts ( % lmwh prophylactic, % therapeutic) yes % pe vte significantly higher in pts. on prophylactic vs therapeutic anticoagulation ( % vs. %) helms [ ] a recent review of nearly papers reporting original data on d-dimer levels in covid- showed some relevant bias, as most publications neither identified whether d-dimer values were reported as d-dimer units (ddu) or fibrinogen equivalent units (feu) (~ × differences), nor report on normal cutoff values [ ] . these methodological flaws greatly reduce the usefulness of this parameter on a clinical decision setting. moreover, the reliability of d-dimer test as prognostic factor in septic patients has already been questioned by semeraro and colleagues in a paper published before the onset of covid- pandemic [ ] . the the authors found that the d-dimer levels poorly correlate with the risk of death in a population of septic patients admitted to icu. on the other hand, they showed that d-dimer corrected for thrombin and plasmin generation (dd corr ) more properly reflects the tilting of coagulation-fibrinolysis balance, displaying a high prognostic value in septic patients [ ] . notably, the authors found the highest mortality in patients with low dd corr levels, which reflect the fibrinolytic shutdown associated with late and more severe phases of sepsis. the mechanisms behind fibrinolysis suppression are multiple and include pai- elevation, tafi activation, and release of nuclear products such as histones and dna. this finding warrants particular attention in the context of covid- coagulopathy, as it has been reported that fibrinolysis shutdown, assessed by elevated d-dimer levels and complete failure of clot lysis at min on thromboelastography, predicts thromboembolic events and need for hemodialysis in critically ill covid- patients [ ] . of note, in this population of covid- admitted to icu, the median isth disseminated intravascular coagulation (dic) score was ( - ), with no patients having a score higher than [ ] . consistent with this finding, other reports showed that covid- patients do not typically develop overt systemic dic, unless in the late stages of the disease, as demonstrated by the consistent observation that platelet count and fibrinogen concentration are not significantly reduced in these subjects, despite a marked increase in d-dimer concentrations [ , ] . moreover, only . % of subjects in a cohort of critically ill covid- patients have been found to meet the criteria for an infection-induced organ dysfunction and coagulopathy according to the sepsis-induced coagulopathy (sic) score of the international society on thrombosis and haemostasis [ , ] . these findings suggest that the linear progression from sic to dic usually seen in septic patients does not necessarily occur in the process of sars-cov infection, which seems to be rather associated with a peculiar form of coagulopathy, termed by some authors as "covid- -associated coagulopathy" (cac) [ ] . cac displays clinical and laboratory features distinct from either dic or sic, such as the lack of consumption of platelets and coagulation factors, first of all fibrinogen, the very low incidence of bleeding, and the main involvement of the pulmonary microcirculation, determining a localized microangiopathy, named by other authors as pulmonary intravascular coagulopathy (pic) [ ] . (table ). this peculiar involvement of pulmonary microvascular bed during the course of sars-cov infection fits well with the reported high rate of acute respiratory distress syndrome (ards) in covid- patients (about % of cases) [ ] . of note, ards itself has been identified as a hemostatic disease occurring as a result of endotheliopathy in critically ill patients. generalized endotheliopathy in turn activates in a vicious circle the inflammatory and microthrombotic pathway, which promotes consumptive thrombocytopenia, ttp-like syndrome, and hypoxic multi-organ failure [ ] . how do we gather these puzzling data on a unified clinicopathological picture, helpful to improve the management of cac? . although the mechanism underlying cac has not been fully elucidated, it is conceivable that the major role in its development is played by the activation of the thromboinflammation pathway induced by a "cytokines storm" elicited by sars-cov infection. . as in other forms of sepsis, endothelial dysfunction leading to widespread microthrombosis, mainly localized in the pulmonary vascular bed, is observed in covid- patients. in this regard, it has been demonstrated that sars-cov- uses angiotensin-converting enzyme (ace) receptor to facilitate viral entry into target cells [ , ] . thye ace system is a critical protective pathway against heart failure, myocardial infarction and hypertension, and against lung disease and diabetes mellitus [ ] . in experimental models of lung disease, catalytically active ace alleviates pulmonary injury and vascular damage and prevents pulmonary hypertension, decreases lung fibrosis and arterial remodeling, and improves right ventricular performance [ ] . ace is highly expressed on alveolar epithelial type ii cells (aecii), which can serve as a reservoir for viral invasion, and also in endothelial cells. sars-cov- infection can induce endothelial cell injury in several organs, because of direct viral involvement, of the host inflammatory response and of the induction of apoptosis and pyroptosis [ , ] . covid- -endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and the clinical sequelae in patients affected by this disease [ ] . . thrombotic microangiopathy, induced by an enhanced platelet-vessel wall interaction, mainly induced by the release of (ultralarge) von willebrand factor (vwf) mul-timers as a result of inflammation-induced endothelial cell perturbations, is thought to be a major component of the sic [ ] . the level of (ultralarge) vwf multimers in patients with sepsis has been shown to be inversely correlated with the plasma level of adamts- , and several studies have confirmed the association between low adamts- levels and sepsis severity. of note, very recently bazzan and colleagues reported significantly reduced adamts- levels in a cohort of covid- patients [ ] . moreover, they found that adamts- levels lower than % were significantly associated with a higher mortality, suggesting that low adamts- associated with high plasma vwf levels can have a role in the strong prothrombotic tendency observed in covid- patients [ ] . taken together, these findings suggest that the pathogenesis of cac, although multifactorial, is mainly localized at a microvascular level, with a late involvement of venous and arterial vessels. such a pathophysiological picture raises some questions about the effectiveness of fully antithrombotic doses of anticoagulants to effectively tackle this disease, as later discussed. among the coagulation abnormalities found in covid- patients, some reports of positivity for antiphospholipid antibodies (apl) are of particular interest [ ] [ ] [ ] (table ) . however, these findings are worth discussing. the tests for assessing apl are slippery ones, because their results are affected by several pre-, post-and analytical factors, including methodical problems due to the heterogeneity of the autoimmune antibodies, inadequate standardization of assays, differences in local working conditions, difficulties in correct interpretation of the results, lack of large prospective evaluation studies, lack of a link between antibody potency and clinical effect [ ] . notably, only the paper from harzallah and colleagues reported the results of lupus anticoagulant (la), anticardiolipin (acl) and anti-beta glycoprotein i (agpi) igg and igm tests [ ] , whereas current guidelines recommend performing all three tests to diagnose antiphospholipid syndrome (aps) [ ] . the same guideline recommends confirming the positivity of apl on two or more occasions, at least weeks apart [ ] , but the results of this further control, if performed, are not reported by the authors [ ] [ ] [ ] . moreover, the significance of positivity for acl and agpi iga, reported by zhang and colleagues, is controversial, and the implementation of these assays is not currently recommended [ ] . we should recall that apl positivity has been frequently observed during viral infections, but the association with thrombotic phenomenon on this setting is unclear, depending on the acl and agpi titers, especially in hepatitis b and c virus infections [ ] . of note, bowles and colleagues did not report the results of acl and agpi tests [ ] , whereas zhang and harzallah did not report the titers of these assays [ , ] . moreover, a recently published paper from galeano-valle and colleagues found only ( . %) cases with aca igm and agpi i igm weakly positive in a cohort of covid- patients with proven vte [ ] . in conclusion, we believe that there is no convincing evidence that apl plays a relevant role in the hypercoagulable tendency of covid- patients. therefore, we suggest that physicians should be very careful before adopting a more aggressive antithrombotic approach in covid- patients only based on apl positivity, given the many technical aspects that reduce the usefulness of these tests in such a specific setting. first reports from the front of wuhan showed that the use of lmwh or ufh at prophylactic doses reduced -day mortality in covid- patients with severe pneumonia and either an sic score ≥ (mortality rate . % vs . %, p = . ), or d-dimer levels > -fold the upper limit of normal (mortality rate . % vs . %, p = . ) [ ] . this finding prompted clinicians to look at the "good old heparin", ufh or lmwh, as the panacea for the treatment of covid- , because of its already well-known anticoagulant and anti-inflammatory properties [ , ] . indeed, lmwh has been shown to protect glycocalyx from shedding and to display immunomodulatory properties [ ] . moreover, in vitro and in vivo experimental studies have shown that human coronaviruses utilize heparin sulfate proteoglycans for attachment to target cells [ ] , suggesting a potential role for heparin in the therapeutic armamentarium against covid- . fondaparinux has been also proposed as a treatment for covid- [ ] , because of its anti-inflammatory and antiviral properties [ , ] . fondaparinux can be an attractive drug in this setting, as it is not associated with heparininduced thrombocytopenia, a fearful side effect of heparin treatment reported in a non-negligible part of covid- patients, which is associated with a worse prognosis [ ] . it is conceivable that doses of lmwh higher than those in use for the prevention of vte in acutely ill medical patients are able to display a more intense anti-inflammatory activity, lowering cytokines storm and improving the clinical course of the disease. however, no good evidence is available on the efficacy and safety of high dose of lmwh in covid- patients, and many issues remain to be addressed, regarding the proper timing and the proper dosages and administration schemes of anticoagulant drugs. the issue of the safety of heparin deserves close attention, as tang and colleagues found a non-significant trend toward a negative effect of the treatment with lmwh in patients with the less severe degree of coagulopathy, as assessed by an sic score < or d-dimer levels < -fold the upper limit of normal [ ] . as recently pointed out by landi and de servi, one-sizefits-all strategy cannot be applied to covid- patients, and an individualized approach carefully balancing thrombotic and hemorrhagic risk should guide the complex management of these patients [ ] . as shown in table , a puzzling discrepancy exists on the doses of heparin suggested in different clinical settings, and no evidence-based recommendations can be issued. this lack of knowledge prompted several researchers to design clinical trials, most of which randomized, comparing efficacy and safety of different doses of ufh or lmwh (mainly prophylactic vs therapeutic) in covid- patients (table ) . from a public health's perspective, these trials failed to recruit because of a massive drop of subjects infected by sars-cov . however, in the worst case scenario of a further outbreak of the pandemic, these already existing protocols could allow to rapidly obtain a stronger evidence about the best the covid- pandemic has disrupted many aspects of human life, forcing us to admit that medical knowledge is finite, and that the usual pathway to improve it can be too slow in the devasting scenario of an awfully fast spreading disease. the cac reliably illustrates this epistemological problem. the difficult journey toward a better understanding of the coagulation derangement observed in covid- patients has just started, and many questions on this issue still remain unanswered. it is therefore conceivable that physicians involved in the first-line management of covid- patients are tempted to adopt conceptual shortcuts to rapidly deal with the everyday clinical problems, without waiting for an evidence which is feared to arrive too late for the patients' needs. on this ground, the scientific community should spare no effort to ensure a faster, but always methodologically sound, process to improve medical knowledge, starting as usual from pathophysiology and cautiously moving toward a stronger evidence provided by properly designed randomized controlled trials. perhaps it can be a "long and winding road", but certainly it is worth traveling. conflict of interest the authors declare no potential conflicts of interest. this article does not contain any studies with human participants or animals performed by any of the authors. informed consent for this type of study, formal consent is not required. coronavirus disease (covid- ) situation report- clinical features of patients infected with novel coronavirus in wuhan prominent changes in blood coagulation of patients with sars-cov- infection clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china covid- : immunopathology and its implications for therapy fighting covid- exhausts t cells coagulopathy in covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel 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and other parameters of hemostasis covid- -related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure prominent changes in blood coagulation of patients with sars-cov- infection d-dimer is associated with severity of coronavirus disease : a pooled analysis d-dimer is a significant prognostic factor in patients with suspected infection and sepsis reporting of d-dimer data in covid- : some confusion and potential for misinformation d-dimer corrected for thrombin and plasmin generation is a strong predictor of mortality in patients with sepsis fibrinolysis shutdown correlates to thromboembolic events in severe covid- infection scientific and standardization committee on dic, and the scientific and standardization committee on perioperative and critical care of the international society on thrombosis and haemostasis. diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation levy jh covid- and its implications for thrombosis and anticoagulation covid- coagulopathy in caucasian patients acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target sars-cov- receptor and regulator of the renin-angiotensin system: celebrating the th anniversary of the discovery of ace hyperinflammation and derangement of renin-angiotensinaldosterone system in covid- : a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis the sars-cov- receptor, ace- , is expressed on many different cell types: implications for ace-inhibitor-and angiotensin ii receptor blocker-based cardiovascular therapies moch endothelial cell infection and endotheliitis in covid- the role of adamts- in the coagulopathy of sepsis low adamts plasma levels are predictors of mortality in covid- patients coagulopathy and antiphospholipid antibodies in patients with covid- lupus anticoagulant is frequent in patients with covid- lupus anticoagulant and abnormal coagulation tests in patients with covid- antiphospholipid antibody testing and standardization subcommittee on lupus anticoagulant/antiphospholipid antibodies. laboratory criteria for antiphospholipid syndrome: communication from the ssc of the isth risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis antiphospholipid antibodies are not elevated in patients with severe covid- pneumonia and venous thromboembolism the role of heparin in sepsis: much more than just an anticoagulant the versatile heparin in covid- both ufh and nah alleviate shedding of endothelial glycocalyx and coagulopathy in lps-induced sepsis human coronavirus nl utilizes heparan sulfate proteoglycans for attachment to target cells pulmonary thrombosis in -ncov pneumonia? fondaparinux pentasaccharide reduces sepsis coagulopathy and promotes survival in the baboon model of escherichia coli sepsis the . Å electron microscopy structure of adeno-associated virus-dj bound by a heparinoid pentasaccharide heparin-induced thrombocytopenia is associated with a high risk of mortality in critical covid- patients receiving heparin-involved treatment the burden of thrombotic complications in critically ill patients with covid- : charting the uncharted publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -ya r h t authors: dobesh, paul p.; trujillo, toby c. title: coagulopathy, venous thromboembolism, and anticoagulation in patients with covid‐ date: - - journal: pharmacotherapy doi: . /phar. sha: doc_id: cord_uid: ya r h t severe acute respiratory syndrome coronavirus (sars‐cov‐ )has led to a world‐wide pandemic, and patients with the infection are referred to as having covid‐ . although covid‐ is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. the pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. several observational studies have demonstrated surprisingly high rates of venous thromboembolism (vte) in both general ward and intensive care patients with covid‐ . many of these observational studies demonstrate high rates of vte despite patients being on standard, or even higher intensity, pharmacologic vte prophylaxis. fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. unfortunately, high quality randomized controlled trials are lacking. a literature search was performed to provide the most up‐to‐date information on the pathophysiology, coagulopathy, risk of vte, and prevention and treatment of vte in patients with covid‐ . these topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. although a number of international organizations have produced guideline or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with covid‐ , and they do not all agree. these statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of vte in patients with covid‐ . impairs the adaptive immune response through inadequate t-cell help to virus-specific cd + cytotoxic t-cells and β-cells. the impaired inf defense, enhanced monocyte/macrophage and neutrophils response producing excessive cytokine and chemokine levels, along with the impaired lymphocyte response produces a hyperinflammatory state that consequentially produces alveolar tissue damage initiating multiple thrombotic processes. this connection between the immune response inflammation and thrombosis has been termed immunothrombosis or thromboinflammation. the clotting cascade is stimulated through both the extrinsic and intrinsic pathways. the extrinsic pathway is initiated by release of tissue factor from cytokine-damaged alveolar endothelial cells. in the setting of significant inflammation, monocytes and macrophages can also express circulating tissue factor. the intrinsic cascade is activated through neutrophil release of neutrophil extracellular traps (nets). these nets contain various bioactive molecules in a process called netosis, which have the ability to stimulate activation of factor xii. nets also contain proteases that are able to inactivate endogenous anticoagulants, and therefore worsen the procoagulant state. the dual activation of the extrinsic and intrinsic clotting cascade leads to significant thrombin generation and thrombosis. the immune function of platelets has been well documented over the last decade. platelets are attracted to the area of cytokine-induced endothelial injury and become activated. through the process of platelet activation, molecules such as platelet factor and neutrophil-activating peptide- are released from platelet α-granules, which are involved in the recruitment and activation of monocytes/macrophages and neutrophils. additional immune actions of activated platelets include being an important source of proinflammatory il- β, as well as the further recruitment of neutrophils accepted article through interaction of platelet surface p-selectin. the impact of platelet on immune function and thrombosis has been specifically documented in patients with patients with covid- also have significant hypoxia, especially in severe disease. hypoxemia triggers expression of hypoxia inducible factors. hypoxia inducible factors can promote thrombosis by directly activating coagulation proteins and platelets and increasing tissue factor expression, as well as inhibiting endogenous protective functions such as increasing plasminogen activator inhibitor- (pai- ) and inhibiting anticoagulant protein s. hypercoagulability is further induced by hypoxia inducible factors due to their ability to promote further inflammation and augmenting blood viscosity. an inflammatory response and activation of thrombotic pathways occurs in a number of severe infections, and is not unique to sars-cov- . normal coagulation responses are often balanced with a fibrinolytic response to prevent fibrin deposition within alveolar tissues. this natural defense mechanism is initiated by the endogenous plasminogen activators, tissue plasminogen activator (t-pa) and urokinase plasminogen activator (u-pa). these are responsible for the conversion of plasminogen to the proteolytic enzyme plasmin, which controls the breakdown of fibrinogen and fibrin deposits into the breakdown products d-dimer and other fibrin degradation products. the increased thrombotic potential in patients with covid- is potentially a result of its interaction with ace . the binding of sars-cov- to ace produces a downregulation of the enzyme and consequentially an increase in at ii. angiotensin ii induces expression of pai- in endothelial cells, which directly inhibits the actions of t-pa and u-pa. therefore, in patients with sars and covid- , the balance between fibrinolysis with t-pa and u-pa is shifted to more hypofibrinolysis and thrombosis due to the excessive at ii and subsequent increase in pai- . the inability to breakdown and remove these fibrin deposits corresponds with poor clinical patient outcome as these deposits reduce normal gas exchange. although most of the direct tissue damage and inflammation occurs in the lung, the impact of thromboinflammation can be systemic. many institutions have reported an uncharacteristically high rate of vte events in both medical ward and icu covid- patients. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] although there is a significant risk of deep vein thrombosis (dvt) in patients with covid- , some evaluations have identified a higher number of pulmonary emboli (pe) than dvt. . . , this discrepancy between accepted article the frequencies of pe and dvt is unusual, since pe without dvt typically occurs in only about % of cases. therefore, in patients with covid- many of the pulmonary thrombotic cases are likely pulmonary thrombi and not pulmonary embolism. this would be consistent with the pulmonary inflammation, alveolar tissue damage, and alveolar fibrin deposits found on autopsy in patients with covid- . [ ] [ ] [ ] [ ] similar to autopsy findings from sars and mers, the primary finding associated with the cause of death is respiratory failure due to diffuse alveolar damage. [ ] [ ] [ ] [ ] [ ] [ ] in contrast to patients with sars and mers, the morphological damage in the lungs and other organs is less severe in covid- , explaining the lower mortality rate. whereas autopsies from cases of sars and mers did demonstrate fibrin deposits in the lungs, this seems to be amplified in cases of covid- . in a series of autopsy cases of patients with severe covid- from brazil, % had a variable number of fibrinous thrombi in small pulmonary arterioles. these thrombi were found in areas of both damaged and more preserved lung parenchyma. in a series of seven covid- cases from belgium, all had intraalveolar fibrin deposits and widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. finally, a series of covid- autopsy cases from austria reported that the most striking finding was obstruction of pulmonary arteries by thrombotic material found at both the microscopic and macroscopic level in all cases. interestingly, of these cases had received pharmacologic vte prophylaxis, and vte was not clinically suspected in any cases before autopsy as a contributor of death. the clinical spectrum of sars-cov- infection has broad presentation including asymptomatic infection, mild upper respiratory tract symptoms, up to severe viral pneumonia requiring mechanical ventilation, and even death (table ) . a number of studies have evaluated characteristics of patients with covid- , as well as those who progress to worse outcomes, such as icu admission, acute respiratory distress syndrome (ards), or death (table ) . , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] although most patients have a favorable prognosis, patients with worse outcomes have a pronounced increase in inflammatory markers, referred to as a "cytokine storm", approximately - days from the onset of initial symptoms. this can coincide with the development of pulmonary thrombosis or pe, which may explain the rapid pulmonary collapse observed in patients suddenly progressing to ards. in general, patients progressing to worse outcome are about to years older and have more this article is protected by copyright. all rights reserved comorbidities such as hypertension, diabetes mellitus, and cardiovascular disease (table ). laboratory findings demonstrate that patients with worse outcomes typically have more liver and renal dysfunction, and significantly lower lymphocyte counts. the sickest patients may also develop elevated procalcitonin and white blood cell counts, but these more likely represent acquired secondary bacterial infection versus caused by sars-cov- itself. patients with covid- often have elevated markers of inflammation. , one study in china reported that il- was elevated in %, ferritin in %, erythrocyte sedimentation rate in %, and c-reactive protein (crp) in % of patients. these numbers are even higher in sicker patients ( table ) . markers of coagulopathy are also present in patients with covid- . although the sars-cov- virus itself does not seem to have intrinsic procoagulant activity, the induced coagulopathy and thromboinflammation extend systemically and impact other organs, such as the kidney, and may eventually lead to multiorgan dysfunction and potentially death. patients with covid- typically have elevated fibrinogen levels, but the extent of increase does not differ based on the severity of disease. antithrombin activity can also be decreased in patients with covid- , but as demonstrated in a study from china, the significantly lower activity ( % in covid- vs. % in healthy volunteers; p< . ) still falls within the normal range (> %). prolongation of the prothrombin time (pt) or activated partial thromboplastin time (aptt) has been demonstrated, but is not a common finding. [ ] [ ] [ ] [ ] tang n and colleagues found that in patients who died of covid- , their pt was prolonged by about seconds compared to those who survived (table ) . a meta-analysis of studies reported an average increase in the pt of about % in patients with although antiphospholipid antibodies have been reported in patients with covid- , and thought to promote the hypercoagulable state, these data should be interpreted with caution. [ ] [ ] [ ] there is a high risk of false positive lupus anticoagulant testing in patients with covid- due to the elevated levels of crp. many assays for lupus anticoagulant are sensitive to crp and give a false positive finding. although most patients with covid- have normal platelet counts, thrombocytopenia has been reported in % to %, and is usually mild. , in a meta-analysis of nine studies, the platelet count was lower by about , x /l in severe cases compared to nonsevere cases, and about , x /l lower in nonsurvivors compared to survivors. these lower platelet counts may not be enough to register as marked thrombocytopenia, but do likely represent platelet recruitment into pulmonary or systemic thrombi. although not as common as other severe infectious diseases, the accepted article occurrence and severity of thrombocytopenia is associated with higher mortality in patients with in a study of patients with covid- , platelet counts of less than x /l occurred in % of patients with critical disease, % in severe disease, and % in those with moderate disease. the odds of death in patients with thrombocytopenia was . ( % ci . - . ). another study of patients with covid- demonstrated increasing mortality in patients with thrombocytopenia, as well as increasing mortality with decreasing platelet counts. nonsurvivors ( %) were significantly more likely to have thrombocytopenia compared to survivors ( . % vs. . %; p< . ), as well as lower nadir platelet counts ( vs . x /l; p< . ), respectively. patients with nadir platelet counts x /l or more had a mortality rate of . %, whereas mortality was . % in those with - x /l, . % in those with - x /l, and . % in those with - x /l. the incidence of a nadir platelet count of - x /l was relatively rare ( %) compared to those with a platelet count of x /l or more ( %). breakdown of fibrin or fibrinogen by u-pa or t-pa produces fibrin degradation products, one of which is d-dimer. an elevated d-dimer is typically a sign of excessive coagulation activation and hyperfibrinolysis. therefore, d-dimer is often used to detect active thrombus with high sensitivity but low specificity. the low specificity is due to other conditions, such as inflammation and infection that can also increase d-dimer in the absence of thrombosis, and are associated with covid- . d-dimer is elevated in % to % of patients with covid- , but is commonly elevated in hospitalized patients. elevations of d-dimer are higher in icu patients and those with worse outcomes by . to -fold (table ). , han h and colleagues found that d-dimer levels were elevated with increasing severity of disease, with levels at ng/ml for patients classified with ordinary disease, , ng/ml in those with severe disease, and , ng/ml in those considered critical, compared to ng/ml in healthy controls. since values are higher in patients with severe disease, d-dimer measurement may be associated with evolution toward worse clinical picture. as would be expected, d-dimer is also elevated in patients with covid- who develop vte. , , , [ ] [ ] [ ] [ ] it has been suggested that d-dimer levels above a certain cut off could be used to predict those with vte if appropriate diagnostic testing is not feasible. , , , , caution should be exercised in this myopic interpretation of elevated d-dimer levels. if elevated d-dimer is mainly due to coagulopathy and increased fibrinolysis of thrombi, this would suggest a consumption coagulopathy. this is supported by a study conducted by tang n and colleagues, where disseminated intravascular coagulation (dic) was more common in nonsurvivors compared to survivors ( . % vs. . %). dic is considered a consumption coagulopathy, with elevated d-dimer levels due to significant fibrinolysis and breakdown of fibrin and fibrinogen. most patients with covid- have elevated fibrinogen levels that is inconsistent with a consumption coagulopathy. the lack of consistent moderate to severe thrombocytopenia and inconsistent prolongation of the pt also are not supportive of dic being a common complication in patients with covid- . therefore, most of the elevations of d-dimer are likely due to the excessive inflammatory state, similar to the elevations in erythrocyte sedimentation rate, crp, and ferritin, and should not be considered to be solely from fibrinolysis. this is supported by data demonstrating that a d-dimer -fold above the upper limit of normal has been used in patients without vte to predict those at highest risk of development of vte. when dic does occur, it is likely in the last stage of covid pneumonia, when there may be increased systemic fibrinolysis and multiorgan failure. hypercoagulability, but not a consumption coagulopathy, is also supported by findings in two thromboelastography studies that evaluated patients with covid- compared to healthy volunteers. , patients with covid- had significantly higher d-dimer and fibrinogen levels compared to healthy controls ( table ), but normal pt and aptt. the first study demonstrated that patients with covid- had significantly shorter clot formation time and higher maximum clot firmness. the shorter clot formation time is reflective of the excessive thrombin generation and higher clot firmness reflects the increased fibrin and fibrinogen in these patients. the other study evaluated intubated icu patients with covid- , most of who were on vte prophylaxis, compared to health volunteers. similar to the previous findings, patients with covid- had a shorter clotting times and firmer clots. all patients with covid- also had reduced clot lysis at minutes. the lack of clot lysis at minutes does not support a hyperfibrinolytic state, which matches the pathophysiologic mechanism of impaired fibrinolysis from ace binding of sars-cov- . , , , in summary, the coagulopathy associated with sars-cov- infection typically presents with elevated d-dimer and fibrinogen levels with normal to slightly lower platelet counts, and normal to slightly elevated pt and aptt. with worsening disease severity, patients will have higher d-dimer levels, lower platelet counts, and eventually elevated pt and aptt. these coincide with increased accepted article markers of inflammation, such as il- and crp, as well as infection (lymphopenia and potentially leukocytosis), and organ dysfunction (renal and liver dysfunction). hospitalized patients with acute medical illness, such as infection, are at increased risk of vte. in general ward patients the rate of vte without prophylaxis ranges from % to % depending on the method of assessment. the use of pharmacologic prophylaxis lowers the rate to . % to %. in icu patients, the risk of vte is higher. rates from one meta-analysis ranged from % to %. another meta-analysis reported a rate of . % for icu patients mainly assessed by compression ultrasound (cus). use of pharmacologic prophylaxis lowers this rate to . % to . %. , a number of studies have reported a higher rate of vte than would be expected in general ward and icu patients with covid- (table ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] increased thromboembolic events were also documented with the sars, mers, and influenza a h n viruses. [ ] [ ] [ ] [ ] [ ] [ ] the true risk of vte in patients with covid- is difficult to determine since no placebo-controlled randomized trials have been conducted. rates of vte in general medical ward patients with covid- have been reported to be around % in clinically evaluated patients and as high as almost % in patients screened with cus (table ) . [ ] [ ] [ ] in the early phase of the outbreak, before the thrombotic potential of covid- was appreciated, patients in china did not commonly received vte prophylaxis based on the assumption that they are a lower risk population. in this setting, cui and colleagues screened covid- icu patients for vte with cus, none of which were receiving vte prophylaxis. the rate of dvt was %, which is at the high end of the range for an icu population. another study from china in which only about one-third of screened icu patients received vte prophylaxis had a rate of dvt of %. other trials have evaluated vte rates in cus screened icu patients with covid- receiving pharmacologic prophylaxis with rates as high as % to %, which are higher than reported in typical icu patients (table ) . , most institutions do not routinely screen patients for vte, even in the icu. observational studies on the rates of vte in icu patients with covid- when cus is only done based on clinical suspicion has also been conducted. in patients receiving prophylaxis the rate of vte ranges from % to %, which is -to -fold the rate demonstrated in typical icu patients (table ) . [ ] [ ] [ ] [ ] , [ ] [ ] [ ] , accepted article this article is protected by copyright. all rights reserved there have also been observational trials that have compared rates of vte in covid- patients to historical controls without covid- (table ) . [ ] [ ] [ ] marone and colleagues evaluated general ward patients all receiving cus for clinical suspicion of dvt with covid- to those without covid- at the same time the previous year. the rate of dvt was more than -fold higher in the patients with covid- . poissy and colleagues conducted a similar time frame comparison, but only evaluated patients with clinical suspicion and all received prophylaxis. the rate of pe was -fold higher in covid- patients compared to those without, but was also more than -fold higher than influenza patients specifically during the same time frame. finally, helms and colleagues conduced a matched case control study of ards patients with covid- compared to ards patients in the same icu between and . patients were evaluated based on clinical suspicion and the use of anticoagulation was similar between the groups. patients with covid- had over a -fold higher rate of thrombotic events and more than a -fold higher rate of pe, with no difference in dvt, compared to patients without covid- . most hospitalized patients with covid- are over age years and have a number of risk factors for vte, such as pneumonia, obesity, immobility, respiratory disease, elevated d-dimer levels, as well as potentially underlying heart failure, smoking, varicose veins, cancer, and previous vte. intensity may likely be the best approach. ultimately the optimal approach will depend on the results from several ongoing randomized, controlled clinical trials that will serve to inform clinicians on the best approach (nct , nct , nct , nct , nct , nct , nct ). until results from these trials are available, clinicians must rely on currently available evidence to craft treatment approaches for both the individual patient, as well as over-arching institutional guidelines to help the bedside clinician. typically, hospitalized medically ill patients should be evaluated with a validated risk assessment tool to determine if pharmacologic vte prophylaxis is needed (table ). , hospitalized patients with covid- , whether on the medical ward or icu, do not need to undergo the step of risk assessment. both medical ward and icu patients with covid- have several vte risk factors, known thromboinflammation, and unacceptable high rates of vte despite some form of pharmacologic prophylaxis (table ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , consequentially, all hospitalized patients with covid- should receive pharmacologic vte prophylaxis regardless of any risk assessment predictors unless the risk of bleeding is considered high. risk assessment should be performed with symptomatic patients with covid- treated at home, since a number of them may still have several vte risk factors, including immobility, and are at risk of thromboembolic events. , [ ] [ ] [ ] support for the paradigm that a higher intensity of anticoagulation than standard prophylactic doses of heparin comes from previously published evidence from the h n influenza pandemic in . an observational cohort study of critically ill patients with severe ards from h n viral pneumonia demonstrated that empiric systemic heparinization titrated to a goal heparin level of . - . anti-xa units/ml was significantly better at reducing vte rates than standard prophylactic doses of either ufh or lmwh. although these data were obtained only in critically ill patients with ards, they do support the idea that higher intensity anticoagulation may be needed in order to improve outcomes in patients with covid- . the first report evaluating the use of vte prophylaxis (ufh or lmwh) and the impact on mortality came from a retrospective review of patients from wuhan, china. patients with severe covid- in the icu received vte prophylaxis for at least seven days with ufh units two to three times daily (n= ), enoxaparin - mg daily (n= ), or no anticoagulation prophylaxis (n= ). overall, there was no difference in -day mortality between the % of patients that received either ufh or lmwh compared to patients who received no anticoagulation ( . % vs. . %; p= . , respectively). however, when looking at the subset of patients with significant hypercoagulability as defined by a d-dimer level of at least six-fold above the upper limit of normal (> . ng/ml), there was a significant decrease in mortality with the use of heparin compared with no anticoagulation ( . % vs. . %; p= . , respectively). when stratifying patients by a sepsis-induced coagulopathy score of > , there was also a significant reduction in mortality with the use of heparin versus no anticoagulation ( . % vs. . %; p= . , respectively). these same authors compared these patients with covid- in the icu to patients in the icu with non-covid- pneumonia, of which . % received heparin prophylaxis. although there was still no overall reduction in mortality in patients receiving heparin prophylaxis compared with no anticoagulation ( . % vs. . %; p= . , respectively), mortality is half what was seen in the covid- patients. interestingly, there was no difference in mortality between heparin users and non-users even when stratified for d-dimer and sepsis-induced coagulopathy in patients without covid- . although this report was the first to suggest that the use of ufh or lmwh could improve outcomes in severely ill patients with covid- , there are a number of limitations that should be considered. first, the benefit seen with prophylaxis was only demonstrated in a subgroup of the sickest patients evaluated. the observational nature of the study cannot account for potential confounding variables between the groups. in fact, the authors noted that during the time of the study medical resources were strained and mortality rates may have been higher than other parts of the world. the decision of whether to give lmwh or ufh, as well as doses used, were at the discretion of the clinician and were not controlled in the study. there is no information of the impact of actual vte events, as this is also an important endpoint. a second observational study from new york sought to identify the value of full therapeutic anticoagulation in patients hospitalized with covid- . this single center retrospective study evaluated patients with covid- , of which ( %) received therapeutic anticoagulation. overall, in-hospital mortality was not different between patients who received therapeutic anticoagulation vs those that did not ( . % vs. . %, respectively). patients who received therapeutic anticoagulation were more likely to require invasive mechanical ventilation ( . % therapeutic anticoagulation vs. . % no therapeutic anticoagulation; p< . ). consequentially, patients who were receiving mechanical ventilation (n= ) had a reduction of in hospital mortality by accepted article over % with the use of therapeutic anticoagulation compared with those who received no therapeutic anticoagulation ( % vs. %, median survival days vs. days; p< . , respectively). interestingly, major bleeding was not significantly increased in patients receiving therapeutic anticoagulation ( % therapeutic anticoagulation vs. . % no therapeutic anticoagulation; p= . ). in a multi-variate cox proportional hazards model, mortality risk was reduced with longer durations of anticoagulation. similar to the previous study, this report suffers from several limitations such as unaccounted for confounding variables. specific anticoagulant agents used for therapeutic anticoagulation were not specified, the indication for anticoagulation was not provided, and it is unclear if non-anticoagulated patients received prophylaxis dose anticoagulation or nothing. the median length of hospitalization was days and the median duration of anticoagulation was only days. despite these limitations, this report provides at least some insight into the role of higher levels of anticoagulation in the most severe patients with covid- , and support evaluating various levels of anticoagulation intensity in ongoing randomized controlled trials. a number of smaller reports also provide partial insight to the appropriate level of vte prophylaxis needed in patients with covid- . a retrospective observational study of icu patients with covid- evaluated coagulopathy parameters after a nadroparin dose of iu twice daily for vte prophylaxis, and then again after a iu twice daily dose ( iu twice daily in patients with body mass index > ). the increase in dose provided a significant reduction in fibrinogen and ddimer levels and an increase in antithrombin activity. an additional report in patients with severe covid- admitted to the icu reported a higher frequency of vte in patients receiving prophylactic compared to therapeutic anticoagulation ( % prophylactic vs. % therapeutic; p= . ), although all patients ( %) with pe were receiving therapeutic anticoagulation. as discussed previously, a number of observational studies have reported higher than expected rates of vte in critically ill patients with covid- , despite the use of standard dose anticoagulant prophylaxis. [ ] [ ] [ ] [ ] [ ] [ ] , , an important consideration within this area may be augmented renal clearance. augmented renal clearance is a process whereby renal clearance of medications is increased in the setting of critical illness. a report in icu patients with covid- identified patients ( . %) with augmented renal clearance. patients with augmented renal clearance had numerically more dvt ( % vs. %; p= . ) and significantly more pe ( % vs. %; p= . ) compared to those without, respectively. these data, although from a small group of patients, speaks accepted article to the potential need for higher doses of anticoagulant prophylaxis to address both significant hypercoagulability as well as augmented renal clearance. lastly, there is emerging information that standard doses of prophylaxis may be adequate to prevent dvt and pe, but higher doses may be need to prevent primary pulmonary thrombosis. this is consistent with a number of observations that demonstrated a higher rate of pulmonary events than dvt. , , , ultimately data from larger randomized controlled trials will help clarify many of these clinical questions. risk of vte in patients with covid- is unlikely to disappear at the time of hospital discharge. studies in medially ill non-covid- patients have demonstrated a high rate of vte in the days immediately after discharge. this is likely due to patients still recovering and continued immobility. two agents, betrixaban and rivaroxaban, are approved by the united states food and drug administration for extended vte prophylaxis in medically ill patients although betrixaban has recently been removed from the market due to a company acquisition. assuming the appropriate inclusion and exclusion criteria are met (table ) , both agents provided a significant reduction in vte events without significantly increasing major bleeding when used for approximately days post discharge. [ ] [ ] [ ] despite the lack of ability to get betrixaban, applying the criteria from the trial still has merit in appropriate patient selection for extended prophylaxis. if these agents cannot be used due to significant drug interaction or other reason, enoxaparin once daily can be used. although enoxaparin has also demonstrated the ability to significantly reduce vte events in the days post discharge, there is significantly more major bleeding with this regimen. apixaban should not be used since the trial with this agent did not demonstrate efficacy over placebo for thromboprophylaxis in medically ill patients, and it also had significantly more major bleeding. although none of these trials included patients with covid- , vte after hospital discharge has been reported in these patients. patients with covid- have prolonged hospital stays with significant deconditioning, immobility during recovery, high d-dimer levels, and additional risk factors. it is likely that a number of hospitalized patients with covid- would have met criteria to be included in the trials and should realize similar benefit from extended vte prophylaxis (table ) . regardless of the underlying cause, ards has been associated with fibrin deposition in the airspaces along with fibrin-platelet microthrombi at the level of the pulmonary vasculature. these observations have also been noted in the lung microvasculature of patient with covid- . [ ] [ ] [ ] [ ] accepted article conjunction with these findings, patients with covid- can demonstrate hypercoagulable and hypofibrinolysis findings on thrombelastography. , these findings have prompted the hypothesis that fibrinolytic therapy may have a role in managing patients with ards, and more specifically in patients with covid- who develop ards in the setting of a hypofibrinolytic thrombotic coagulopathy. data supporting the role of fibrinolytic therapy in the management of patients with covid- are limited at best. in a case series of three patients on mechanical ventilation, systemic t-pa at a dose of mg over hours followed by another mg administered over the subsequent hours has been evaluated. all three patients were experiencing ards related respiratory failure, and had improvements in their ventilatory parameters and oxygenation following t-pa therapy, however the effects were transient. a second case series of three patients with significantly worsening ventilatory parameters and oxygenation were administered t-pa. one patient received mg over hours ( mg/hr), while the over two received mg over hours . all patients experienced improvement in ventilatory parameters and oxygenation and were discharged alive. a final case series assessed the effects or aerosolized freeze-dried plasminogen in hospitalized patients with covid- . oxygenation and ventilatory parameters were also improved, but only transiently. a report using a markov decision analysis approach to evaluate whether t-pa may improve outcomes in patients with covid- demonstrated the use of fibrinolytic therapy in ards patients was associated with a mortality benefit, although this can be considered hypothesis generating only. given that systemic administration of fibrinolytics in the setting of pe is associated with a % risk of major bleeding and a - % risk of intracranial hemorrhage, additional information from randomized clinical trials is needed to validate whether t-pa has any role in the management of patients with covid- and ards. several trials are underway to address this clinical question (nct , nct ). based on the level of evidence currently available, routine fibrinolytic administration to patients with covid- ards cannot be recommended at this time. several clinical guidance and consensus statements have been developed and disseminated by international organizations to help guide clinicians in the management of the thromboembolic risks associated with covid- (table ). , , - these guidance statements have been developed in the absence of randomized controlled trials in patients with covid- , and hence are largely based this article is protected by copyright. all rights reserved on knowledge regarding the prophylaxis and treatment of vte in patients without covid- , as well as the initial observational publications. as such, some of the recommendations should be considered expert consensus. although these guidance statements attempt to include the most upto-date information, data regarding vte risk, prevention, and treatment in patients with covid- is rapidly evolving. at the time of this writing, data presented in this manuscript cannot be found in many of these guidance documents. also, each of the guidance documents do not address all the clinical issues, and not all of these organizations agree. therefore, a table of clinical considerations has been provided that considers these different guidance documents together, as well as incorporates the most recent published data ( table ) (table ) in the icu setting. for example, a study using standard doses of lmwh prophylaxis in icu patients with covid- reported a failure rate of %, which is -fold higher than prior reports in icu patients without covid- that documented a failure rate of . %. , evidence is also beginning to emerge that escalating the dose of vte prophylaxis in patients who have evidence of thromboinflammation due to a heightened inflammatory state (increased il- , d-dimer, fibrinogen, or teg findings) results in a significant decrease in inflammation and hypercoagulability. in-hospital vte prophylaxis and treatment should be provided with lmwh or ufh instead of a direct oral anticoagulant (doac). both lmwh and ufh have potential anti-inflammatory properties that accepted article may make them beneficial in patients with covid- . [ ] [ ] [ ] these agents also may prevent splitting of the s proteins of sars-cov- , which is necessary for incorporation into the host via ace . the impact of doacs on these properties is unknown. besides patients requiring dialysis, the use of a lmwh is preferred to ufh for both prevention and treatment of vte. prophylaxis with lmwh requires fewer injections per day compared to ufh, and treatment with lmwh can be give once or twice daily, with no need for the frequent monitoring and dose adjustments as is necessary with ufh. use of lmwh instead of ufh will reduce exposure of health care professionals to patients with covid- , as well as preserving personal protective equipment. the preference for lmwh over ufh for prophylaxis is also based on benefit of lmwh over ufh in other high risk patients, such as those with trauma, cancer, and high risk medically ill patients. [ ] [ ] [ ] [ ] [ ] [ ] patients receiving lmwh for vte prophylaxis should have dose adjustments for obesity and renal function. in patients with a bmi of to kg/m or greater, or weighing more than to kg, increased doses of lmwh, such as enoxaparin mg twice daily, mg once daily, or . mg/kg have demonstrated improved efficacy and similar safety to standard doses. , date also is available in patients undergoing bariatric surgery, as well as pregnancy, supporting the notion that doses of prophylaxis should be adjusted upwards based on the presence of elevated body weight. , if ufh is used for vte treatment, monitoring must be done with an anti-xa assay instead of the aptt. the aptt can be elevated or become elevated in patients with covid- , and therefore is unreliable for monitoring ufh. even though bleeding is rare in patients with covid- , the current evidence does not support the use of therapeutic lmwh or ufh for prevention of vte. the use of fibrinolysis outside of patients with hemodynamically compromised pe should also be avoided. the use of doacs in hospitalized patients, especially icu patients with covid- , can be problematic if invasive procedures are needed, requiring longer hold times that may delay procedures. the use of doacs may also be limited by drug interactions with certain antiviral therapies, such as lopinavir/ritonavir. if the perceived need for invasive procedures is low, and no drug interactions exist, doacs could be considered as initial therapy for treatment of vte in non-icu patients. after discharge, patients initiated on injectable therapy in the hospital should be considered for transition to a doac if possible, or warfarin. this article is protected by copyright. all rights reserved as all hospitalized patients with coivd- should receive vte prophylaxis, thrombocytopenia presents a conundrum. platelet count drops to less than x /l may represent the transition of the patient into a consumption coagulopathy, where withdrawal of anticoagulant therapy may worsen the patient's thrombotic potential. it is not uncommon to continue vte prophylaxis until platelet counts get below x /l or even x /l. with the high use of anticoagulation in patients with covid- , heparin-induced thrombocytopenia must also be considered, especially in patients receiving ufh. special attention to the timing and rate of platelet drop needs be considered. since a consumption coagulopathy occurs fairly late in the course of sars-cov- infection in the most severe cases, it is relatively rare, but also difficult to distinguish from the timing of heparin-induced thrombocytopenia. in these cases, switching to an alternative agent such as argatroban or fondaparinux seems prudent. patients with covid- should not only be considered to have a respiratory illness, but a thrombotic condition as well. sars-cov- not only produces an inflammatory and hypercoagulable state, but also a hypofibrinolytic state not seen with most other types of coagulopathy. the rate of vte observed is higher than expected for general ward and icu patients, especially for those receiving prophylaxis. all hospitalized patients with covid- should be considered high risk and receive anticoagulants for vte prophylaxis. although a number of approaches have been observed in the literature, there is unfortunately no high-quality data to help make more definitive recommendations at this time. although guideline statements differ on a number of the clinical issues, such as the best dose of anticoagulant for vte prophylaxis, duration of prophylaxis, and use of fibrinolytics in patients with ards, a number of randomized controlled trials are ongoing to answer these questions. until these randomized controlled trials become available, an understanding of the pathophysiology, coagulopathy, current guideline and consensus statements, and these clinical considerations (table ) are key resources to help clinicians care for patients with covid- . iu once daily to iu bid or 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in the treatment of venous thromboembolism patients with ards who died (n= ) vs. those with ards who survived (n= ) more liver and renal dysfunction more preexisting htn and dm higher il- higher d-dimer ( vs. ng/ml ards patients who died: older by years ( vs. years; p< . ) more liver and renal dysfunction higher il- ( . vs. . pg/ml higher d-dimer ( vs. ng/ml patients who died (n= ) vs. those who were discharged (n= ) patients who died: older by years ( vs higher sofa scores higher il- ( . vs. . pg/ml higher ldh ( vs. iu/l; p< . ) higher troponin ( vs. pg/ml higher d-dimer ( vs. ng/ml; p< . ) more with d-dimer > ng/ml patients with moderate (n= ) vs. severe (n= ) vs. critical covid- (n= ) moderate vs. severe vs. critical thrombocytopenia ( % vs. % vs. %) patients who died (n= ) vs. those who survived (n= ) patients who died: older by years ( vs higher d-dimer ( vs. ng/ml covid- =coronavirus infection htn=hypertension; dm=diabetes mellitus ldh=lactate dehydrogenase pt=prothrombin time; ards=acute respiratory distress syndrome pe=pulmonary embolism; bid=twice daily; pt=prothrombin time; tid=three times daily; ecmo=extracorporeal membrane oxygenation;ards=acute respiratory distress syndrome. table . vte risk assessment models , padua score † vte=venous thromboembolism; bmi=body mass index † a score of or higher demonstrates high risk of vte and pharmacologic prophylaxis should be used. ‡ patients with local or distant metastases and/or in whom chemotherapy or radiotherapy had been performed in the previous months. § anticipated bed rest with bathroom privileges (either because of patient's limitations or on physician's order) for at least days. ¶ carriage of defects of antithrombin, protein c or s, factor v leiden, g a prothrombin mutation, antiphospholipid syndrome. key: cord- -uidvtpjw authors: parks, anna l.; auerbach, andrew d.; schnipper, jeffrey l.; anstey, james e.; sterken, david g.; hecht, todd e.h.; fang, margaret c. title: covid- coagulopathy and thrombosis: analysis of hospital protocols in response to the rapidly evolving pandemic date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: uidvtpjw as the coronavirus disease (covid- ) pandemic spread to the us, so too did descriptions of an associated coagulopathy and thrombotic complications. hospitals created institutional protocols for inpatient management of covid- coagulopathy and thrombosis in response to this developing data. we collected and analyzed protocols from us academic medical centers developed between january and may . we found greatest consensus on recommendations for heparin-based pharmacologic venous thromboembolism (vte) prophylaxis in covid- patients without contraindications. protocols differed regarding incorporation of d-dimer tests, dosing of vte prophylaxis, indications for post-discharge pharmacologic vte prophylaxis, how to evaluate for vte, and the use of empiric therapeutic anticoagulation. these findings support ongoing efforts to establish international, evidence-based guidelines. as the coronavirus disease (covid- ) pandemic spread to the us, so too did descriptions of an associated coagulopathy and thrombotic complications. hospitals created institutional protocols for inpatient management of covid- coagulopathy and thrombosis in response to this developing data. we collected and analyzed protocols from us academic medical centers developed between january and may . we found greatest consensus on recommendations for heparin-based pharmacologic venous thromboembolism (vte) prophylaxis in covid- patients without contraindications. protocols differed regarding incorporation of d-dimer tests, dosing of vte prophylaxis, indications for post-discharge pharmacologic vte prophylaxis, how to evaluate for vte, and the use of empiric therapeutic anticoagulation. these findings support ongoing efforts to establish international, evidence-based guidelines. keywords: coronavirus, thrombosis, venous thromboembolism (vte), pulmonary embolism (pe), deep vein thrombosis (dvt), coagulopathy, anticoagulation descriptions of abnormal coagulation laboratory parameters and increased incidence of thrombotic complications emerged soon after the first case of covid- was diagnosed in the us in january . the subsequent months saw rapid accumulation of reports of coagulopathy and thrombosis but were often small or of variable quality. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] faced with a need to respond rapidly to new evidence and no clear external guidelines, hospitals caring for covid- patients were forced to react. to characterize their response, we collected and analyzed protocols from us academic medical centers for inpatient management of covid- coagulopathy and thrombosis that were developed in the months following the arrival of covid- in the us. this study is part of the hospital medicine reengineering network (homerun), a national network of investigators at academic medical centers. we invited homerun collaborative participants to submit their local protocols for compilation via email and direct request during a homerun webinar on covid- . representatives from participating institutions submitted inpatient protocols for incorporation in the analysis between april , and may , . for institutions that submitted additional updated protocols, we used the most recent version available at the time of the analysis. we collected additional information about the location, size of the hospital and date of protocol development. all institutions gave permission for inclusion of their protocols in this study. we developed a potential set of domains and key questions based on review of existing international specialty society interim guidance and extant literature. one additional domain was added after it emerged through review of protocols. two independent investigators reviewed each protocol submitted. reviewers extracted and synthesized the content from each protocol. disagreements were resolved via discussion until consensus was reached. we used descriptive statistics to quantify agreement and variation among protocols. a total of academic medical centers submitted their protocols for analysis. thirty-eight percent of centers (n= ) were located in the northeast, % (n= ) were in the midwest, % (n= ) were in the south, and % (n= ) were in the west. thirty-eight percent (n= ) were located in geographic regions with a cumulative incidence of covid- above the national mean at the time of the analysis. the mean number of hospital beds per institution was (sd +/- beds). the mean date of development for the protocols that supplied this information was april , (sd +/- days). the final structure covered by institutional protocols consisted of overarching themes on covid- associated coagulopathy and thrombosis: ) coagulopathy in covid- , ) approach to vte prophylaxis, ) approach to vte diagnosis, which was added after it emerged from protocol review, and ) approach to vte treatment. the areas with greatest representation from each theme are displayed in figure . we reported the proportion of protocols that addressed or did not address a given question. among the protocols that j o u r n a l p r e -p r o o f journal pre-proof addressed a clinical question, we then reported the proportion of institutions that supported a specific practice ("consensus"). we provided additional information on topics that had less than % consensus below. although there was near-universal agreement on the need for heparin-based vte prophylaxis for covid- inpatients without contraindications, recommended dosing strategies varied across institutions (figure a) . four protocols ( %) recommended using standard pharmacologic vte prophylaxis dosing for all covid- patients regardless of estimated vte risk; conversely, two institutions ( %) recommended higher-thanstandard prophylaxis dosing regardless of estimated vte risk. the most common recommendation was a tiered prophylactic vte dosing strategy, with standard dosing for patients considered at average vte risk and higher-than-standard prophylaxis dosing for those at high estimated vte risk ( %, n= ). there was little consensus on dosing or patient selection for intensified dosing prophylaxis. for non-obese patients with normal renal function, the four intensified prophylaxis regimens recommended were: enoxaparin mg subcutaneously every hours ( %, n= ), enoxaparin mg subcutaneously every hours ( %, n= ), enoxaparin mg/kg subcutaneously daily ( %, n= ), or enoxaparin . mg/kg subcutaneously every hours ( %, n= ). criteria for selecting which patients warranted higher prophylaxis dosing also exhibited variation: nine protocols recommended selecting patients based on elevated d-dimer or fibrinogen with or without additional clinical criteria, while the remaining three protocols used clinical criteria alone to support prophylaxis intensification. the most common criteria for intensification referenced clinical status, including whether the patient was critically ill, required mechanical ventilation, clinically deteriorated, or had recurrent clotting of venous or arterial access or extracorporeal circuits, or baseline risk factors, including sickle cell disease, malignancy, prior vte, or pregnancy. there was similar discord regarding which patients merit post-discharge pharmacologic vte prophylaxis, as well as agent, dose and duration. the most common indications cited were if the patient had received intensified inpatient prophylaxis, had ongoing immobility or had an elevated d-dimer at discharge. for confirmed vte, most protocols recommended initial therapeutic anticoagulation with low-molecular-weight heparin (lmwh) or unfractionated heparin (ufh) adjusted for weight and renal function (figure b) . the recommended duration was at least months. in the absence of confirmed vte, protocols ( %) suggested empiric therapeutic anticoagulation for select populations, but there was no consensus on how to make this decision. criteria ranged from consideration for all patients admitted to the intensive care unit or restricting to patients with elevated or rising d-dimer, clinical decompensation, or with high clinical suspicion for vte but who are unable to undergo confirmatory imaging. two protocols ( %) suggested consideration of tissue plasminogen activator for severely ill patients without confirmed vte, one as part of a clinical trial and one as empiric treatment. although most protocols addressed incorporating laboratory values of coagulopathy into management decisions, there was wide variability in how to act upon these values (figure c) . seventy-one percent of protocols (n= ) recommended specific laboratory testing on admission and periodically thereafter (range: daily to every hours). the most commonly recommended testing was a complete blood count with differential, prothrombin time and activated partial thromboplastin time, d-dimer and fibrinogen. three protocols ( %) recommended against transfusion based on coagulation abnormalities unless a patient was bleeding or had other high-risk features. three protocols ( %) recommended consideration of empiric therapeutic anticoagulation based on elevated d-dimer or fibrinogen alone. in contrast, four protocols ( %) specifically recommended against empiric therapeutic dosing of anticoagulation based on lab values in the absence of other clinical indications such as proven vte. nine protocols ( %) recommended escalation from standard to higher-dose prophylactic anticoagulation based on laboratory findings in combination with clinical variables. most protocols (n= , %) included some guidance on diagnosis of suspected vte, but specific recommendations were sometimes divergent (figure d) . one protocol ( %) recommended that all patients receive a baseline screening deep vein thrombosis ultrasound regardless of symptoms. with regard to j o u r n a l p r e -p r o o f journal pre-proof incorporating d-dimer into diagnostic decision-making for vte, three protocols ( %) recommended that elevated or rising d-dimer should prompt additional imaging to evaluate for vte. conversely, two protocols ( %) commented that d-dimer elevation alone without other clinical suspicion should not trigger diagnostic work-up for vte and also suggested that d-dimer below the upper limit of normal could be used to exclude vte. five protocols ( %) made specific mention of relying on diagnostic modalities performed at the bedside in lieu of ct-angiogram to evaluate for pulmonary embolism, such as deep vein thrombosis point-of-care ultrasound or transthoracic echocardiogram, to minimize the risk of infectious spread and conserve resources. our review of us academic medical center protocols for covid- coagulopathy and thrombosis developed during the early stage of the pandemic showed considerable variation in the approach to the prevention, diagnosis, and treatment of vte in covid- . we found no correlation between centers that had a cumulative incidence of covid- above the national mean with specific recommendations. the area of greatest concordance was use of heparin-based pharmacologic vte prophylaxis. however there was substantial disagreement on which patients should be considered high-risk for vte and the indications for escalated pharmacologic prophylaxis dosing or post-discharge pharmacologic prophylaxis. additionally, there was little consensus on how elevated d-dimer values should affect vte prophylaxis or treatment, the optimal diagnostic strategy for vte, and indications for empiric therapeutic anticoagulation for vte. the areas of consensus and disagreement identified in our study are reflected in the recommendations from recently released international professional society guidelines. [ ] [ ] [ ] aside from consistently recommending pharmacologic prophylaxis with lmwh or ufh, society guidelines emphasize the lack of definitive data and vary in their recommendations on issues of vte prevention, diagnosis and management. our study should not be considered representative of the wider us practice given the self-selected nature of protocol submission. we also can make no assertions on which specific practices should be recommended. until high-quality comparative effectiveness data are available, our findings serve as a framework for frontline providers and hospitals to evaluate their own practices and outcomes and support the urgent need for evidence in this area. figure (in color) : the x-axis displays the proportion of protocols that addressed a clinical question. for protocols that addressed a clinical question, the proportion of protocols that supported a specific practice ("consensus") is overlaid. solid blue bars denote the proportion of protocols that addressed a clinical question with > % consensus. patterned blue bars denote the proportion of protocols that addressed a clinical question with < % consensus. grey bars denote the proportion of protocols that did not address a clinical question. abbreviations: covid- -coronavirus disease , vte-venous thromboembolism, lmwh-low-molecular-weight-heparin, ufh-unfractionated heparin, cbc-complete blood count, ptprothrombin time, aptt-activated partial thromboplastin time. gave guidance on diagnostic workup for suspected vte but with < % consensus on algorithm recommended continuing chronic therapeutic anticoagulation unless contraindications but with switch to lmwh or ufh for severe illness recommended specific lab tests on admission and/or thereafter (most commonly cbc with differential, pt and aptt, d-dimer and fibrinogen) first case of novel coronavirus in the united states abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia incidence of venous thromboembolism in hospitalized patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study incidence of thrombotic complications in critically ill icu patients with covid- pulmonary embolism in covid- patients: awareness of an increased prevalence. circulation. ( ) thrombotic complications of patients admitted to intensive care with covid- at a teaching hospital in the united kingdom venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in the hospital medicine reengineering network (homerun): a learning organization focused on improving hospital care geographic differences in covid- cases, deaths, and incidence -united states covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up isth interim guidance on recognition and management of coagulopathy in covid- thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum key: cord- -pwmi q authors: middeldorp, saskia; coppens, michiel; van haaps, thijs f.; foppen, merijn; vlaar, alexander p.; müller, marcella c. a.; bouman, catherine c. s.; beenen, ludo f. m.; kootte, ruud s.; heijmans, jarom; smits, loek p.; bonta, peter i.; van es, nick title: incidence of venous thromboembolism in hospitalized patients with covid‐ date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: pwmi q background: coronavirus disease (covid‐ ) can lead to systemic coagulation activation and thrombotic complications. objectives: to investigate the incidence of objectively confirmed venous thromboembolism (vte) in hospitalized patients with covid‐ . methods: single‐center cohort study of hospitalized patients with covid‐ . results: seventy‐five patients ( %) were admitted to the intensive care unit (icu). at time of data collection, ( %) were still hospitalized and % had died. during a median follow‐up of days (iqr, ‐ ), patients ( %) were diagnosed with vte of whom ( %) had symptomatic vte, despite routine thrombosis prophylaxis. the cumulative incidences of vte at , and days were % ( % ci, ‐ ), % ( % ci, ‐ ) and % ( % ci ‐ ) respectively. for symptomatic vte, these were % ( % ci, . ‐ ), % ( % ci, ‐ ) and % ( % ci ‐ ). vte appeared to be associated with death (adjusted hr, . ; % ci, . ‐ . ). the cumulative incidence of vte was higher in the icu ( % ( % ci, ‐ ), % ( % ci, ‐ ), and % ( % ci, ‐ ) at , and days) than on the wards (any vte and symptomatic vte . % ( % ci, . ‐ ), . % ( % ci, . ‐ ), and . % ( . ‐ ) at , , and days). conclusions: the observed risk for vte in covid‐ is high, particularly in icu patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for dvt or pe. future research should focus on optimal diagnostic and prophylactic strategies to prevent vte and potentially improve survival. coronavirus disease (covid- ) is caused by the severe acute respiratory syndrome coronavirus- (sars-cov- ) and can lead to systemic coagulation activation. initial studies from china report increased d-dimers ( . mg/l or higher) in % to % of patients, as well as other signs of coagulation activation including mild thrombocytopenia and a moderately prolonged prothrombin time. , additionally, more pronounced coagulation activation seems to be correlated with a severe disease course, including admission to the intensive care unit (icu) and death. for example, patients who died of covid- had higher d-dimers on admission compared with those who survived, whereas d-dimer levels increased further during hospital stay in patients who died, but not in survivors. in another study, patients with d-dimer levels of . µg/l or higher had an -fold increased risk of death. one study used the international society on thrombosis and haemostasis definition of disseminated intravascular coagulation and found that a score of ≥ points was present in % of those who died compared with . % in survivors. none of these studies reported on the number of patients with thrombotic complications. since the pandemic spread of sars-cov- , there have been several anecdotal reports from colleagues on a high incidence of thrombotic complications, including thrombosis of extracorporeal the primary outcome was an objectively confirmed diagnosis of distal or proximal dvt, pe, or venous thrombosis at other sites including catheter-related thrombosis. the secondary outcome was symptomatic vte, excluding events detected by bilateral leg ultrasound screening. all outcomes were adjudicated by two of the authors (m.c. and n.v.e.). we did not adjudicate deaths to identify fatal pe because almost all deaths were due to hypoxemic respiratory failure, which can be indistinguishable from fatal pe, whereas autopsies were rarely performed in covid- patients. patient data were retrospectively reviewed from the day of admission to our hospital (also in case a patient was transferred from another hospital) until death, hospital discharge, transfer to another hospital, or end of data collection on april , . we collected data on demographics and blood tests on admission. d-dimer levels were included if measured on or within hours of admis- patient characteristics were compared between icu and ward patients using standard descriptive statistics. between march and april , , patients who were hospitalized because of covid- were identified. one patient was ex- patient characteristics are shown in table median follow-up duration was days in icu patients (iqr, , ) and days in ward patients (iqr, , besides icu stay, other risk factors associated with vte in univariable regression analyses were a higher white blood cell count (shr, . for every log-transformed unit increase; % ci, . - . ), higher neutrophil-to-lymphocyte ratio (shr, . for every log-transformed unit increase; % ci, . - . ), and a higher d-dimer level (shr, . for every log-transformed unit increase; % ci, . - . ) ( table ) . these associations remained materially unchanged when adjusted for age, sex, and icu stay (table ) we observed a very high risk of vte in patients with covid- . although the profound coagulopathy associated with covid- has been described soon after start of the pandemic, few data on clinical vte have been reported. in a cohort of icu patients in china, in which routine thromboprophylaxis was not the standard of care, the proportion of patients who were diagnosed with dvt was %; a follow-up duration or cumulative incidence was not reported. patients suggested that thrombosis prophylaxis was associated with a % to % reduction in mortality in patients with sepsis-induced coagulopathy, but not in other patients. only % of covid- patients received thrombosis prophylaxis, which is much less than expected according to guidelines on thrombosis prophylaxis in medical patients. currently, several randomized controlled trials are being planned or have started in which the optimal dose of thrombosis prophylaxis will be investigated. some of these trials use an pneumonia, although vte during the course of disease appeared to be associated with mortality in an exploratory analysis in our cohort. interestingly, none of the patients who were receiving therapeutic anticoagulation at admission (for other indications) developed vte. the % risk of vte among patients who were not admitted to icu is considerable, despite the standard use of thrombosis prophylaxis. in an italian single-center retrospective cohort study, the proportion of covid- patients with vte was % in ward patients, corresponding to a cumulative incidence of %. these reported risks appear to be higher than expected in medical hospitalized patients who are not critically ill. based on the present findings, we believe the threshold of sus- anticoagulant use at admission ( ) ( ) sd, standard deviation; shr, subdistribution hazard ratio; vte, venous thromboembolism variables with a non-normal distribution (ie, body weight, white blood cell count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and d-dimer) were analyzed log-transformed multivariable analysis were adjusted for age, sex, and intensive care unit admission clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia detection of sars-cov- in different types of clinical specimens correlation of chest ct and rt-pcr testing in coronavirus disease co-rads -a categorical ct assessment scheme for patients with suspected covid- : definition and evaluation prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis high risk of thrombosis in patients in severe sars-cov- infection: a multicenter prospective cohort study venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in milan. italy anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy american society of hematology guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients how to cite this article incidence of venous thromboembolism in hospitalized patients with covid- key: cord- - wrzw authors: moores, lisa k.; tritschler, tobias; brosnahan, shari; carrier, marc; collen, jacob f.; doerschug, kevin; holley, aaron b.; jimenez, david; legal, gregoire; rali, parth; wells, philip title: prevention, diagnosis and treatment of venous thromboembolism in patients with covid- : chest guideline and expert panel report date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: wrzw abstract: background emerging evidence shows that severe covid- can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and venous thromboembolism (vte). this recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of vte. methods a group of approved panelists developed key clinical questions by using the pico (population, intervention, comparator, and outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis and treatment of venous thromboembolism in patients with covid- . medline (via pubmed or ovid), embase and cochrane controlled register of trials were systematically searched for relevant literature and references were screened for inclusion. validated evaluation tools were used to grade the level of evidence to support each recommendation. when evidence did not exist, guidance was developed based on consensus using the modified delphi process. results the systematic review and critical analysis of the literature based on pico questions resulted in statements. very little evidence exists in the covid- population. the panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. conclusions the evidence on the optimal strategies to prevent, diagnose, and treat venous thromboembolism in patients with covid- is sparse, but rapidly evolving. remarks: the panel favors lmwh over ufh in order to limit staff exposure. the panel strongly cautions against the use of doacs in critically ill patients secondary to their hemodynamic instability, the high likelihood of drug-drug interactions, and the high incidence of acute kidney injury in these patients. in addition, there is a lack of evidence for anticoagulant thromboprophylaxis even in non-covid critically ill patients. against the use of antiplatelet agents for venous thromboembolism (vte) prevention. weight-based dosing) or full treatment dosing, per existing guidelines. remarks: although there has been some concern for increased risk of vte in hospitalized covid- patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials. weight-based dosing) or full treatment dosing, per existing guidelines. covid- patients occupy a different level of risk for vte than other severely ill nonsurgical, medical icu patients. there is also insufficient data regarding bleeding risk in this population, and given severity of illness, it may be just as likely that critically ill is not likely that adding mechanical prophylaxis in this population would cause major harm. we recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis. pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis. . in critically ill covid- patients, we suggest against routine ultrasound screening for the detection of asymptomatic deep vein thrombosis (dvt). adjusted lmwh or intravenous ufh. the use of lwmh will limit staff exposure and avoid the potential for heparin pseudo-resistance. in patients without any drug-todrug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. dabigatran and edoxaban can be used after initial parenteral anticoagulation. vitamin k antagonist therapy can be used after overlap with initial parenteral anticoagulation. remarks: the panel has downgraded the most recent accp recommendation regarding the use of oral anticoagulants in patients hospitalized with covid- secondary to the high risk of rapid clinical deterioration in these patients. in addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the doacs. thus lmwh or ufh are favored over oral anticoagulants. . for outpatient covid patients with proximal dvt or pe and no drug-to-drug interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. initial parenteral anticoagulation is needed before dabigatran and edoxaban. for patients who are not treated with a doac, we suggest vitamin k antagonists over lmwh (for patient convenience and comfort). parenteral anticoagulation needs to be overlapped with vitamin k antagonists. . in critically ill covid- patients with proximal dvt or pe, we suggest parenteral over oral anticoagulant therapy. in critically ill covid- patients with proximal dvt or pe who are treated with parenteral anticoagulation, we suggest lmwh or fondaparinux over ufh. in late december , a novel beta coronavirus, the severe acute respiratory syndrome coronavirus (sars-cov- ), which causes the coronavirus disease of (covid- ) was identified. it was officially declared a pandemic by the world health organization (who) in march of . emerging evidence shows that severe covid- can be complicated by coagulopathy. in the most severe cases, this manifests as disseminated intravascular coagulation (dic), which is a pro-thrombotic condition with a high risk of venous thromboembolism (vte). the presence of dic in these patients has been found to be a strong predictor of mortality. in a retrospective review of consecutive patients with covid- at a single institution, tang and colleagues noted that . % of nonsurvivors and . % of survivors showed evidence of overt dic (as defined by the validated international society on thrombosis and haemostasis dic score). the literature also demonstrates that many patients with covid- have highly abnormal d-dimer levels which were also prognostic. the incidence of vte in covid- patients is not well defined, but early reports suggest it may be higher than in non-covid hospitalized patients with similar degrees of illness, even in the presence of prophylactic anticoagulation. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the mechanism for this is likely multifactorial. in fact, it could be argued that the lungs of patients with covid- exhibit all components of virchow's triad-hypercoagulable state, endothelial injury, and stasis of blood flow. high plasma levels of several proinflammatory cytokines (il- , il- , granulocyte colony-stimulating factor, ip , mcp , mip a and tumor necrosis factor-α) have been observed in covid- patients admitted to the intensive care unit (icu). as in other critical illnesses, this systemic cytokine storm triggers the coagulation system and a hypercoagulable sate. there is also evidence of significant endothelial injury, as evidenced by reports of significantly elevated von willebrand factor (vwf) and factor viii (fviii) levels. finally, severe covid- is manifested as severe acute respiratory distress syndrome (ards). current evidence-based guidelines recommend positive pressure ventilation with high levels of positive end-expiratory pressure (peep) and fluid restriction, both of which may lead to decreases in pulmonary blood flow, leading to stasis and microthrombosis. the recognition of the coagulopathy with covid- , and the early evidence that suggests that thrombosis in these patients is higher than that seen in similarly ill hospitalized patients with other respiratory infections has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of vte. current evidence in this specific population is lacking, but reports are emerging daily. the goal of this guidance statement is to review the current evidence that is available and, wherever possible, translate this into practical recommendations. where this was not possible, the authors would like to remind readers that several well-done evidence-based guidelines regarding the management of patients with vte and dic in the non-covid population exist and should direct patient care until robust trials can be completed in the covid- population. [ ] [ ] [ ] [ ] [ ] [ ] given the rapidity with which new evidence is evolving, the authors consider this to be a living document with plans to update the guidance statements as appropriate. the primary aim of this chest panel was to provide practical guidance on the most urgent questions regarding the prevention, diagnosis, and treatment of vte in patients diagnosed with covid- . chest appointed a chair for the panel (lkm) who recruited panelists based upon their established expertise within the field of thromboembolism. the list of panelists was approved by chest leadership. all panel members were educated about the process and schedule. formal conflict of interest review was not performed by the professional standards committee given the timeline for the project, but all panelists were reminded that they would be required to disclose all relevant conflicts prior to voting and at the time of submission of the manuscript to the journal. the majority of panelists had no conflicts of interest to disclose. two panelists (mc, gl) do not receive any personal honoraria and/or consulting fees, but do receive funds that go directly to their institutional research fund. in order to reduce any perceived conflict, they abstained from voting on any statements that had overlap with their research or consulting relationships. search strategies and inclusion criteria were broad given the anticipated low level of evidence at the time they were conducted. screening and full text selection were performed in duplicate by the pairs. no meta-analyses or randomized controlled trials were available. most of the evidence included retrospective cohorts and case series. thus, none of the available direct and indirect literature provided sufficient evidence for the development of evidence tables or recommendations. the panel agreed that patients with covid- appear to be a unique population with evolving evidence that their risk of thrombosis is higher than other hospitalized acutely ill medical or icu patients. when this evidence was enough (albeit very low level) to adjust existing guideline statements, the panel made modifications to existing statements from chest guidelines. , when this was not possible, the panel simply applied existing guidance and adjusted the wording to this population. all of the statements in this document are thus expert opinion. when the perceived benefits outweighed perceived risks, the panel chose to "recommend" an intervention. when the balance of risk and benefit was less certain, the panel chose only to "suggest" an intervention. search results and suggestions written by the panel pairs for each pico question were shared with all panel members. during a conference call, suggestions were reviewed and subsequently re-written based on panel input. this was followed by another conference call with % participation, soliciting additional comments and input. all panel members participated in the development of suggestions to be incorporated in the initial round of the modified delphi survey. the modified delphi technique is a widely accepted method for the development of consensus among experts. to achieve consensus, a priori decision was made to conduct up to three rounds of anonymous voting or until consensus was achieved (defined a priori as consensus agreement at ≥ % with a minimal response rate of %) for each draft we found studies that reported on vte rates in patients diagnosed with covid- (table ). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] all were observational reports at high risk for selection bias, and / were retrospective. these studies included a total of , patients, the majority ( ( . %)) of whom were treated in an icu. one other study reported % ( / ) of inpatients have a high risk for vte by padua risk score, but did not report vte rates. this study, however, had major limitations (e.g., % of patients had missing values for age and missing values for other variables were not reported). prevalence and incidence rates of te are reported in tables and . given the heterogeneity of the studies, we chose not to pursue a pooled analysis. a qualitative review of the studies reporting vte prevalence and incidence is presented in table . patient selection procedures varied across studies and were often unclear. a detailed description of testing procedures was also lacking in most studies. some studies reported only deep vein thrombosis (dvt). , , only five studies specified whether pulmonary embolism (pe) was subsegmental or more proximal, , , , , and only three studies provided detailed information on dvt location. , , universal screening for events also varied across studies, and in many, outcomes were reported on patients still hospitalized. average duration of hospitalization and or the hospital day on which ctpa or lower extremity compression ultrasound (cus) was performed was variably reported. lastly, thromboprophylaxis rates in chinese hospitals are reported to be as low as % in some studies, , which affects interpretation of event rates in chinese covid- populations. the panel first aimed to address the need for vte prophylaxis in acutely ill hospitalized (general inpatient ward) and critically ill (icu) patients with covid- . our search identified singlecenter studies reporting estimates for the incidence of vte in acutely ill hospitalized patients ( table and ) . , , none of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs or doses. the majority of patients included in those studies received anticoagulant thromboprophylaxis at prophylactic or higher dose. lodigiani and colleagues reported a cumulative incidence of venous and arterial thromboembolic events of . % during hospital admission. a total of . % of the patients developed a pe, and . % of the patients were diagnosed with a symptomatic isolated proximal dvt of the lower extremities. as reported by middeldorp et al, the cumulative incidence of symptomatic vte was . % at days, comprising patient with proximal pe, patient with subsegmental pe, and patients with distal dvt. xu and colleagues reported confirmation of dvt in of ( . %) patients on the ward. noteworthy, most covid- patients would have been eligible for at least of the landmark randomized controlled trials of anticoagulant thromboprophylaxis in acutely ill medical inpatients. [ ] [ ] [ ] in these studies, the proportion of patients who developed symptomatic vte or any vte at - days was . - . % and . - . %, respectively. [ ] [ ] [ ] because the incidence of vte in acutely ill medical inpatients is too low (below % without thromboprophylaxis) to justify anticoagulant thromboprophylaxis -and incurred risk of bleeding -in every patient, several risk stratification scores have been developed to identify medical inpatients at higher risk of vte. the padua and improve risk scores are the most extensively validated scores, , but both showed heterogenous discriminatory performance in external validation studies - and they lack validation in an impact study. considering that hospitalized patients with covid- are confined to their room, immobilization, a major risk factor for vte in medical inpatients, affects many inpatients with covid- . infectious disease is an additional risk factor for vte, which is present in all patients with covid- . taking into account those risk factors and that the current estimates of the incidence of vte in non-critically ill patients with covid- is well above % even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with covid- at increased risk of vte. we therefore suggest against individualized vte risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patient with covid- in absence of contraindications. our search identified studies providing estimates for the incidence or prevalence of vte in critically ill patients with covid- ( table and ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] none of the studies allows for comparison between anticoagulant thromboprophylaxis and placebo, or comparison between different drugs. the proportion of critically ill patients with covid- diagnosed with vte on at least standard dose anticoagulant thromboprophylaxis ranged from to %; - , the reported cumulative incidence of vte during hospital stay ranged from to %. , , , one single-center retrospective cohort study of patients hospitalized in the tongji hospital in wuhan suggests that heparin at prophylactic dose is associated with an absolute mortality reduction of % in patients with sepsis-induced coagulopathy (sic) compared to no anticoagulant thromboprophylaxis. no mortality difference was shown in patients that were less sick. considering that low-molecular-weight heparin (lmwh) at prophylactic doses did not reduce mortality in a randomized placebo-controlled trial in critically ill patients with chronic obstructive pulmonary disease, the mortality difference in sick patients with covid- appears striking. however, the study has several major limitations. a total of only % of the patients received thromboprophylaxis; thromboprophylaxis was defined as the use of heparin ≥ days which may have introduced immortal time bias; and the analysis was not adjusted for other potential confounders. in critically ill medical patients without covid- , the failure rate of anticoagulant thromboprophylaxis in randomized controlled trials ranged from to %. [ ] [ ] [ ] the incidence of vte in cohort studies of critically ill medical patients varies depending on patient population. pooled risk estimates for benefits and harms of anticoagulant thromboprophylaxis in critically ill medical patients without covid- differ across meta-analyses, , , but practice guidelines consistently recommend anticoagulant thromboprophylaxis with lmwh (or unfractionated heparin [ufh]) over no such therapy. , we recommend anticoagulant thromboprophylaxis in all critically ill patients with covid- , because current evidence suggest that the failure rate of thromboprophylaxis in critically ill patients with covid- seems higher than in randomized controlled trials assessing anticoagulant thromboprophylaxis in critically ill medical patients without covid- and at least as high as the failure rate in prospective cohort studies of critically ill patients with severe sepsis or septic shock. recommend anticoagulant thromboprophylaxis over no anticoagulant thromboprophylaxis. we did not identify any studies allowing for comparisons between different anticoagulants for thromboprophylaxis in acutely ill hospitalized patients with covid- . lmwh, ufh, fondaparinux, and doacs have each been assessed in randomized trials of thromboprophylaxis in acutely ill hospitalized patients without covid- . compared to placebo, parenteral anticoagulant thromboprophylaxis with lmwh or fondaparinux reduces the risk of symptomatic pe and any dvt. pooled results indicate no statistically significant difference in symptomatic dvt, major bleeding or mortality. no difference in critical outcomes have been shown in randomized trials comparing lmwh and ufh; no randomized study compared fondaparinux with lmwh/ufh. compared to lmwh, doacs do not reduce the risk of pe or symptomatic dvt, but are associated with an increased risk of major bleeding (relative risk [rr], . ; % confidence interval [ci], . - . ). therefore, the panel recommends using lmwh, fondaparinux or ufh over the use of doacs in acutely ill hospitalized patients with covid- . considering the reduced nursing staff exposure with lmwh or fondaparinux due to the oncedaily administration and the possibly lower risk of heparin-induced thrombocytopenia with lmwh or fondaparinux compared to ufh, we suggest lmwh or fondaparinux over ufh in acutely ill hospitalized patients with covid- . patients requiring hospitalization to be substantially greater than the benefits of aspirin thromboprophylaxis. consequently, we do not consider antiplatelet agents a reasonable alternative to anticoagulant prophylaxis in these patients for vte events. against the use of antiplatelet agents for vte prevention. we found no studies that reported a comparison of one specific anticoagulant thromboprophylaxis regimen to another. one retrospective study reported a reduction in mortality with heparin at prophylactic doses (most were on - mg enoxaparin per day) compared to no prophylaxis in a highly select group of icu patients. this study suffers from confounding by indication for prophylaxis and lack of adjustment for co-factors in the specific analysis that found a mortality difference with heparin. for all comers in this study, there was no mortality difference related to heparin prophylaxis. in a single-center retrospective study of patients of whom ( %) received therapeutic anticoagulation, in-hospital mortality was similar between anticoagulated and non-anticoagulated patients ( . % vs. . %). among mechanically ventilated patients, in-hospital mortality was lower in patients who received anticoagulation ( %, median survival of days) than in those who did not receive anticoagulation ( %, median survival of days). in a multivariable cox proportional hazards model, longer duration of therapeutic anticoagulation was associated with a reduced risk of mortality. the risk of major bleeding was % and . % in anticoagulated and nonanticoagulated patients, respectively. of note, pulmonary hemorrhage was not part of the definition of major bleeding and the incidence of vte was not reported. while this study is hypothesis-generating and supports the rationale for randomized controlled trials evaluating thromboprophylaxis at therapeutic doses, it should not inform patient management due to its limitations. first, the authors did not specify anticoagulant agents, the indication for anticoagulation and whether non-anticoagulated patients did receive anticoagulant thromboprophylaxis. second, the results may be flawed by immortal time bias, confounding by indication and other residual confounding. finally, the median duration of anticoagulation was days which challenges the biological plausibility of the large mortality reduction observed among mechanically ventilated patients. several studies provide data that are indirectly relevant. a retrospective, observational report on icu patients (all mechanically ventilated and diagnosed with ards) reported no vte events in patients who had vte anticoagulant thromboprophylaxis titrated to serum coagulation studies and adjusted for body mass index (bmi). they used lmwh, anti-thrombin concentrate, and clopidogrel, and there is no report on bleeding rates. several other studies report high vte rates despite standard prophylaxis in critically ill covid- patients. , , because all identified studies of vte rates and anticoagulant thromboprophylaxis regimens for hospitalized covid- patients are observational with select populations, definitive interpretation is difficult. it seems critically ill, intubated patients with covid- can develop a profound coagulopathy and form clot at a high rate despite prophylaxis. while adjusting prophylaxis by coagulation studies seems reasonable, specific protocols have not been systematically studied nor bleeding rates reported. of note, several studies have reported critically ill covid- patients are at high risk for bleeding based on the improve bleeding risk score. , until we have more data, an accurate risk-benefit assessment of vte versus bleeding, particularly with increasing anticoagulant thromboprophylaxis above standard dosing, is not possible. a recent guideline reviewed the data on sic and dic in non covid- patients. the authors noted that sic/dic can lead to a pro-thrombotic coagulopathy. they concluded adjustment to standard anticoagulant thromboprophylaxis in the presence of sic/dic remains controversial but could be considered. whether covid- induces a different or more profound type of sic/dic remains unknown, but even if one assumes it is similar to non-covid- sic/dic, the optimal approach to anticoagulant thromboprophylaxis is uncertain. remarks: although there has been some concern for increased risk of vte in hospitalized covid- patients, there is insufficient data to justify increased intensity anticoagulant thromboprophylaxis in the absence of randomized controlled trials. our search identified no study reporting incidence of vte or major bleeding after hospital discharge in patients with covid- . in non-covid patients, a significant proportion of vte events associated with hospitalization occur after discharge. [ ] [ ] [ ] anticoagulant thromboprophylaxis up to days after discharge reduces the risk of vte following hospital admission (rr, . ; % ci, . - . ) but increases the risk of major bleeding (rr, . ; % ci, . - . ). a post-hoc analysis of the magellan trial suggests that extended thromboprophylaxis is associated with a net benefit in patients at high risk of vte as per modified improve score and low risk of bleeding (i.e., absence of active cancer, dual antiplatelet therapy, history of bronchiectasis or pulmonary cavitation, active gastroduodenal ulcer, or any bleeding in the previous months). however, in the mariner trial of , patients at risk of vte as per modified improve score, rivaroxaban mg daily for days after hospital discharge did not reduce symptomatic vte. the recent american society of hematology practice guideline recommend against the use of extended thromboprophylaxis, because they determined a net harm associated with extended thromboprophylaxis. many hospitalized patients with covid- would likely have been eligible for randomized controlled trials assessing extended thromboprophylaxis and it appears therefore justified to extrapolate relative treatment effects from those studies to hospitalized patients with covid- . assuming that patients with covid- incur the same risk of bleeding as patients without covid- at high risk of vte (i.e., . % at days after discharge without extended thromboprophylaxis in patients at low risk of bleeding) and that symptomatic vte is associated with a similar burden to patients as major bleeding, benefit. we were unable to identify any studies that reported on mechanical methods for prophylaxis in covid- patients. while it may seem reasonable to add mechanical to pharmacological prophylaxis in patients thought to be at high baseline risk for vte, a recent randomized controlled trial found no benefit to this approach. therefore, it seems unlikely that mechanical, in addition to pharmacological prophylaxis will affect vte rates in critically ill patients with covid- . likely that adding mechanical prophylaxis in this population would cause major harm. we recommend that providers adhere to existing guidance regarding the use of mechanical thromboprophylaxis. pharmacological thromboprophylaxis, we suggest the use of mechanical thromboprophylaxis. screening ultrasound for asymptomatic dvt is not routinely performed in critically ill patients. lower extremity ultrasound is reserved for critically ill patients with a clinical suspicion for vte. general screening ultrasound carries an increased risk of personnel exposure and resource utilization during the covid- pandemic. as we have noted, there is growing evidence to suggest that patients with covid- are at an increased risk of vte events. , this risk is exacerbated in critically ill icu patients compared those on a general medical ward. , middeldorp et al, reported an increased incidence of venous thrombosis in icu ( %) vs non-icu patients ( . %). lodigiani et al, reported similar venous thrombosis rates in icu ( . %) vs non-icu patients ( . %). cui et al, suggested a % ( out of icu patients) rate of dvts in their critically ill cohort, but none of the patients in the study were on pharmacological thromboprophylaxis. we found inconsistent methods of ultrasound screening in covid- patients. in the study by middeldorp et al, ultrasound was performed every days in icu patients, and days prior to data analysis in cross-sectional fashion for general ward patients. in a second study by lljitos et al, screening ultrasound was performed at the time of icu admission (between day and ) and then at day . we, therefore suggest against routine screening, but suggest a low threshold for performing lower extremity ultrasound or full body ultrasound in covid- patients who experience abrupt hypoxemia or clinical deterioration. tables and summarize the reported dvt incidence in the published literature. was employed and if imaging was triggered by clinical parameters or as screening as only dvts were found. the study suggested a % negative predictive value for d-dimer cut off of . ug/ml but did not compare to other biomarkers which correlated with vte. they also reported that other laboratory markers correlated with increased risk of vte including the aptt and lymphocyte count, but did not evaluate single cut points or trending values. klok et al. did not report on d-dimer levels but noted that prolongation of the pt > seconds or the aptt > seconds were independently predictors of vte. again, the vte surveillance was not well described. tang et al. did not report on vte incidence but noted derangement in coagulation and clotting markers -pt, aptt, d-dimer, fibrin degradation products-were higher in non-survivors. dramatic increase of d-dimer also correlated with increase in all-cause mortality. it may follow that thrombosis is a major contributor to increase in all-cause mortality, as survival improved when patients received parenteral anticoagulation. in conclusion, there is insufficient data to guide clinical practice for vte diagnosis based on laboratory values. we suggest as in other inpatient populations biomarkers not be employed in the diagnostic evaluation for suspected dvt or pe. our literature search did not identify any randomized trials assessing the efficacy and safety of anticoagulants for the treatment of acute vte in hospitalized or critically ill covid- patients. although clinical practice guidelines recommend the use of doacs for the vast majority of patients with acute symptomatic vte , , there are reasons to make different suggestions for the preferred anticoagulant in patients with covid- , particularly for the critically ill: ) many of these patients require administration of inhibitors or inducers of p-glycoprotein (p-gp) or strong inhibitors or inducers of cytochrome p (cyp) enzymes. treatment with potent p-gp inhibitors (e.g., antiretrovirals, azithromycin, others) was an exclusion criterion in most landmark randomized trials that assessed the efficacy and safety of doacs in patients with acute vte. - a recent study enrolled consecutive patients on doacs who were hospitalized with severe covid- . for each patient, c-trough doac level was compared with the one measured before hospitalization. on average, c-trough levels were times higher during hospitalization than in the pre-hospitalization period; ) gastrointestinal dysfunction is a common problem in the critically ill patient, and can significantly affect the pharmacokinetics of oral drugs; and ) acute renal failure is also common in the setting of critical illness, and doacs are contraindicated in patients with severe (e.g., creatinine clearance < ml/min) renal failure. for these reasons, the panel endorsed that in critically ill covid- patients with proximal dvt or pe, parenteral anticoagulation might be preferred to oral anticoagulant therapy. unfractionated heparin has an unpredictable dose response and a narrow therapeutic window; therefore, monitoring is essential to ensure optimal efficacy and safety. alternatively, lmwhs and fondaparinux have more predictable pharmacokinetics and a greater bioavailability than ufh. due to these pharmacologic features, body weight-adjusted doses of lmwh or fondaparinux can be administered subcutaneously without laboratory monitoring in the majority of these patients. ufh, not lmwh, can be effected by the phenomenon of heparin resistance which can "pseudo", in which the aptt does not reflect the anti xa effect (best managed by avoiding the aptt and monitoring by anti xa levels), and true resistance in which case acute phase reactants common in inflammatory states increase ufh clearance and can greatly increase the doses required. the former situation is common with elevated fviii levels, common in covid- patients. the latter situation may delay attainment of therapeutic levels of anticoagulation, which is highly undesirable in an acute vte situation. , based on this, and to avoid risk of exposure for staff, we suggest that lmwh or fondaparinux be used over ufh in critically ill covid- patients with proximal dvt or pe. ufh might be preferred over lmwh or fondaparinux in patients at high bleeding risk (including those with severe renal failure [creatinine clearance < ml/min]), or in those with overt or imminent hemodynamic decompensation due to pe, in whom primary reperfusion treatment may be necessary). outpatients with covid- and acute pe have not been described, but the approach to these patients can follow existing guidelines. patients with vte in the setting of covid- are considered to have a provoking factor, and thus initial treatment should be for at least three months. initial parenteral anticoagulation with therapeutic weight adjusted lmwh or intravenous ufh. the use of lwmh will limit staff exposure and avoid the potential for heparin pseudo-resistance. in patients without any drug-to-drug interactions, we suggest initial oral anticoagulation with apixaban or rivaroxaban. dabigatran and edoxaban can be used after initial parenteral anticoagulation. vitamin k antagonist therapy can be used after overlap with initial parenteral anticoagulation. remarks: the panel has downgraded the most recent accp recommendation regarding the use of oral anticoagulants in patients hospitalized with covid- secondary to the high risk of rapid clinical deterioration in these patients. in addition, it is likely that many of these patients will be on concomitant therapy (antiviral agents or other investigational treatments) that can significantly affect the pharmacodynamics of and bleeding risk associated with the doacs. thus lmwh or ufh are favored over oral anticoagulants. interactions, we recommend apixaban, dabigatran, rivaroxaban or edoxaban. initial parenteral anticoagulation is needed before dabigatran and edoxaban. for patients who are not treated with a direct oral anticoagulant, we suggest vitamin k antagonists over lwmh (for patient convenience and comfort). parenteral anticoagulation needs to be overlapped with vitamin k antagonists. . in critically ill covid- patients with proximal dvt or pe, we suggest parenteral over oral anticoagulant therapy. in critically ill covid- patients with proximal dvt or pe who are treated with parenteral anticoagulation, we suggest lmwh or fondaparinux over ufh. remarks: ufh might be preferred over lmwh or fondaparinux in patients at high bleeding risk (including those with severe renal failure), or in those with overt or imminent hemodynamic decompensation due to pe, in whom primary reperfusion treatment may be necessary. the decision to use ufh should be balanced with the risks associated with extra staff exposure and issues with heparin resistance as above. our literature search did not identify any randomized trials or prospective cohort studies assessing the efficacy or safety of any thrombolytic therapies for the management of critically ill patients with covid- without objective evidence of vte and vte-associated hypotension. this includes either systemic delivery or catheter-directed thrombolysis. due to the absence of direct evidence, the guideline panel decided to consider indirect evidence from another population of patients receiving thrombolysis. in a randomized trial of normotensive patients without covid- but with objectively confirmed pe and right heart strain, systemic thrombolysis was associated with major bleeding in . % of patients. the risk of major bleeding has not been systematically assessed during covid- . diffuse alveolar damage and frank alveolar hemorrhage have been identified in autopsy specimens from covid- patients , suggesting bleeding risk could be high. therefore, we recommend against thrombolytic therapy in covid- patients without objectively confirmed pe and pe-induced hypotension (systolic blood pressure < mm hg or blood pressure drop >= mm hg lasting for longer than minutes). , patients with objectively confirmed pe who are normotensive represent a wide spectrum of disease. some are very low risk of adverse outcome. others are at the more severe end of the spectrum, and may present with signs, imaging, or laboratory markers that suggest the presence of right ventricular dysfunction. as we have stated in earlier chest guidelines, these patients should be monitored closely for signs of deterioration. clearly patients who develop hypotension meet criteria for thrombolytic therapy. deterioration that has not resulted in frank hypotension may also prompt the use of thrombolytic therapy (progressive increase in heart rate, progressive decrease in systolic blood pressure, an increase in jugular venous pressure, worsening gas exchange, signs of shock, progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers). this recommendation was based on the trial by meyer et al, in which almost % of patients with intermediate risk pe who received rescue thrombolysis survived. none of the existing scores for assessing bleeding risk in patients with vte have been studied or validated in patients with covid- . until recently, we lacked any scores that were derived specifically from patients being treated with anticoagulants for vte. thus, we cannot recommend a specific risk score in patients with covid- . several risk scores have been suggested, and many of the variables overlap between scores. we suggest that providers rely on institutional methods for assessing bleeding risk and would refer the reader to items noted to be associated with increased risk of bleeding as outlined in the most recent chest guidelines (age, previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, previous stroke, diabetes, anemia, antiplatelet therapy. poor anticoagulant control, comorbidities, recent surgery, frequent falls, alcohol abuse, non-steroidal anti-inflammatory use). due to the absence of direct evidence, the guideline panel decided to consider indirect evidence (low-quality) available from other another population at high risk of recurrent vte, patients with cancer-associated thrombosis. there are no studies assessing the treatment of recurrent vte despite anticoagulation with doacs. one retrospective study reported reasonable outcomes (recurrent vte of % [ % ci: to %]) when using therapeutic weightadjusted lmwh in patients with recurrent vte despite oral anticoagulation with vitamin k antagonists. two small retrospective cohort studies have also reported reasonable outcome by increasing the dose of lmwh to % and % in patients with recurrent events despite therapeutic weight-adjusted lmwh. , the rate of recurrent vte and major bleeding was . % ( / , % ci . - . %) and . % ( / ; % ci . - . %), respectively, among patients receiving increased dose ( to %) of lmwh. finally, an international society of thrombosis and haemostasis registry showed comparable findings to the aforementioned studies. based on indirect comparisons, we expect the net benefit of increasing the dose of lmwh by to % in patients with covid- and recurrent vte despite therapeutic anticoagulation with lmwh and switching to lmwh in patients failing oral anticoagulation with a doac or vitamin k antagonist. therapeutic weight adjusted lmwh (and documented compliance), we suggest increasing the dose of lmwh by to %. dabigatran, rivaroxaban or edoxaban (and documented compliance), or vitamin k antagonist therapy (in the therapeutic range) we suggest switching treatment to therapeutic weight-adjusted lmwh. the guidance statements in this document were specifically created to address what were felt to be common, urgent clinical questions that frontline providers are likely to face regarding venous thromboembolism and hypercoagulability in patients with covid- . there are important limitations with this guidance. first is the lack of direct evidence to inform the guidance. clearly more is being shared on a daily basis, but this emphasizes the importance of enrolling patients in clinical trials wherever possible and the need for international collaboration in collecting and rapidly disseminating relevant clinical experience, gaps in knowledge, and the research agenda. second, due to the urgency of the situation, the panel was unable to address all of the likely questions that have arisen. as we consider this a living document that will be updated, we will incorporate additional questions to these updates as needed. finally, and perhaps most importantly, the current body of evidence does not allow us to delineate between macro (dvt/pe) and microthrombosis, and the approach to these may differ. it is possible that studies looking for the prevalence of dvt and pe fail to represent the microthrombosis which could drive at least a portion of mortality in these patients. the strengths of this document are the multidisciplinary panel that was composed of experienced clinicians and researchers in the field, many with extensive experience in the development of evidence-based guidelines. in addition, despite the lack of a robust evidence base, the panel followed a robust methodologic approach to formulate specific questions, evaluate the literature, and seek consensus. we must acknowledge that there are over other international guidelines, guidance statements, or online references that address this topic (although most focus on prevention, not diagnosis or treatment). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] while this can seem overwhelming, the authors would like to emphasize the relative consistency in these statements. most of these guidelines recommend vte prevention in all hospitalized patients with covid- , , , , - while some do recommend risk assessment to guide the decision. , , as we discussed earlier, given the underlying risk factors present in these patients and that the current estimates of the incidence of vte in non-critically ill patients with covid- is well above % even on anticoagulant thromboprophylaxis, the panel considers all hospitalized patients with covid- at increased risk of vte. we therefore suggest against individualized vte risk assessment and suggest anticoagulant thromboprophylaxis in all hospitalized patient with covid- in the absence of contraindications. almost all of these documents recommend standard dosing for anticoagulant thromboprophylaxis. one mentions escalating the dose, stating that it can be considered in patients with a large increase in the d-dimer level or severe respiratory failure. another suggests increased dosing in the critically ill patient with covid- , but recognizes that this was based largely on expert opinion. the statements are consistent in the recommendation for the use of lmwh or ufh in covid- patients. those that address the use of mechanical prophylaxis note that it should be used in patients with a contraindication, , , , , or can be added to anticoagulant thromboprophylaxis in patients who are completely immobilized. , finally, only a few of these statement address the issue of extended duration prophylaxis. bikdeli and colleagues note that there is no data in this population, although they state that it would be reasonable to take an individualized approach in each patient after risk stratifying for both thrombosis and bleeding risk. the italian society on thrombosis and haemostasis recommends prophylaxis throughout the hospitalization and for an addition - days post discharge. the american society of hematology recommends following current guidelines, which recommend against extended duration prophylaxis in hospitalized medical patients. , as we noted earlier, we endorse this approach because the post-discharge vte and major bleeding rates in covid- patients are currently unknown. it is our hope that clinicians caring for patients with covid- will find this document helpful. clearly, we still need well designed randomized trials to answer many of our pressing questions. these include optimal dosing of prophylactic anticoagulant therapy, patients who might benefit from full dose anticoagulant treatment, and the unique role of macro and microthombosis in covid- . we hope that this version of guidance will serve as a call to enroll patients in clinical trials wherever possible. we would also like to use this document as a call to reason. we are in a time of unprecedented economic, social, and medical uncertainty. we have been trained to accept uncertainty, and to be wary of undesirable consequences of acting too quickly on new observations that may not affect our usual care. as physicians, we are trained to practice evidence-based medicine. we need to always remember that any intervention can cause harm. in a time when our decisions may be driven by emotion, we risk the tendency to rely on anecdotes and early, small case series or cohorts. as recently stated by zagurly-orly and schwartzstein, "we must reason critically and reflect on the biases that may influence our thinking processes, critically appraise evidence in deciding how to treat patients, and use anecdotal observations only to generate hypotheses for trials that can be conducted with clinical equipoise. we must act swiftly but carefully, with caution and reason". we look forward to updating this guidance when well-designed trials have been completed. cardiovascular complications in covid- disseminated intravascular coagulation in patients with -ncov 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communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with covid‐ date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: k f p l the novel coronavirus disease of (covid‐ ) pandemic, as declared by the world health organization, is caused by the severe acute respiratory syndrome coronavirus (sars‐cov ). cardiovascular disease and, in particular, venous thromboembolism (vte) has emerged as an important consideration in the management of hospitalized patients with covid‐ . the diagnosis of vte using standardized objective testing is problematic in these patients, given the risk of infecting non‐covid‐ hospitalized patients and hospital personnel, coupled with the usual challenges of performing diagnostic testing in critically‐ill patients. early reports suggest a high incidence of vte in hospitalized covid‐ patients, particularly those with severe illness, that is similar to the high vte rates observed in patients with other viral pneumonias, including severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers‐cov). this article is protected by copyright. all rights reserved the novel coronavirus disease of (covid- ) pandemic, as declared by the world health organization, is caused by the severe acute respiratory syndrome coronavirus (sars-cov ) [ , ] . cardiovascular disease and, in particular, venous thromboembolism (vte) has emerged as an important consideration in the management of hospitalized patients with covid- . the diagnosis of vte using standardized objective testing is problematic in these patients, given the risk of infecting non-covid- hospitalized patients and hospital personnel, coupled with the usual challenges of performing diagnostic testing in critically-ill patients. early reports suggest a high incidence of vte in hospitalized covid- patients, particularly those with severe illness, that is similar to the high vte rates observed in patients with other viral pneumonias, including severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers-cov) [ ] [ ] [ ] [ ] . covid- is associated with marked abnormalities in markers of hypercoagulability, including elevated levels of d-dimer, fibrinogen, and factor viii, a shortened activated partial thromboplastin time (aptt) and an elevated sepsis induced coagulopathy (sic) score [ ] . investigational therapies for the management of severely ill covid- patients may carry an increased risk for vte or have implications for drugdrug interactions with established agents used for the acute and chronic management of vte, such as the direct oral anticoagulants (doacs) and vitamin k antagonists such as warfarin. hospitalized covid- patients share similar strong clinical intrinsic and extrinsic risk factors for vte, which include advanced age, obesity, immobility/stroke with paralysis, a history of cancer/active cancer, management in an intensive care unit (icu)/coronary care unit (ccu) setting, a prior history of vte or known thrombophilia, that are present in hospitalized medically ill patients [ , ] . however, risk stratification for vte and the optimal intensity and duration of anticoagulant thromboprophylaxis, including post-hospital discharge prophylaxis, remains uncertain in hospitalized covid- patients. the overall objective of this guidance from the scientific and standardization committee (ssc) of the isth, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide practical guidance for the management of vte in hospitalized patients with suspected or confirmed covid- infection. specific objectives are: ) to provide an approach to the diagnosis of vte; ) to provide guidance on thromboprophylaxis strategies in icu and non-icu settings, including the duration of prophylaxis; and ) to provide guidance on the treatment of vte. this article is protected by copyright. all rights reserved this guidance statement is a collaborative effort of the perioperative and critical care thrombosis and haemostasis, along with members of the control of anticoagulation and disseminated intravascular coagulation subcommittees of the scc. the guidance provided is anchored on a narrative review of pertinent literature, with a search occurring until april , , coupled with responses to a standardized and independently administered survey of preferred practices related to the diagnosis, prevention, and treatment of vte in covid- patients (appendix) and conducted by the mcmaster centre for transfusion medicine using an independent, multi-institutional, and multidisciplinary panel of experts in the field of thrombosis and haemostasis. the survey of experts was done using a single cross-sectional assessment approach with an expectation that all ( %) panelists would select a pre-specified management option or to indicate, through the "other option" category that alternative management was preferred. this one-time approach, rather than a multi-step, iterative approach (e.g., delphi method), was deemed appropriate in the context of the topic (covid- and thrombosis) where requisite evidence, typically used in an iterative approach, is not available. our aim was to identify where consensus existed and, of equal importance, to identify where there was a lack of consensus on clinical management. the diagnostic assessment of suspected vte in hospitalized covid- patients is challenging, especially for critically ill patients in whom, typically, it is important to reliably confirm or exclude vte. imaging studies for deep vein thrombosis (dvt) or pulmonary embolism (pe) may be avoided due to concerns of transmitting infection in non-covid- hospital wards or to healthcare workers. the frequent finding of an elevated d-dimer in very ill hospitalized covid- patients may prompt an aggressive diagnostic approach for vte, despite the controversy that a very elevated ddimer (> . mg/l) may not be a reliable predictor of vte in this population but rather a marker of poor overall outcome [ , ] . one recent study found a sensitivity of . % and specificity of . % for diagnosing vte in patients with d-dimer levels > . mg/l, but the study was based on a small sample size [ ] . bedside imaging studies such as point-of-care compression ultrasonography to assess this article is protected by copyright. all rights reserved for lower and upper extremity dvt or bedside echocardiography to assess for right ventricular strain associated with pe may be difficult to obtain due to patient instability or the requirement of prone positioning in patients with acute respiratory distress syndrome (ards), and may lack sufficient specificity and sensitivity to diagnose vte as patients with pneumonia may have right ventricular strain without pe [ ] . however, in the clinical context of unexplained sudden deterioration of pulmonary status or acute lower extremity erythema or swelling, these tests may be useful in aiding the clinical suspicion for vte. these concerns should be balanced by emerging data that the incidence of vte in hospitalized covid- patients with severe pneumonia or in icu settings is higher than that reported by historical data in similar patients, with an incidence of vte of % ( % confidence interval [ci]: - ) in one study using standard thromboprophylaxis and an incidence of % in another study without prophylaxis [ , ] . these findings are consistent with high rates of vte in patients with other severe viral pneumonias, such as influenza h n , in whom there was an -to -fold higher risk for vte compared with control patients [ ] . this article is protected by copyright. all rights reserved hospitalized acutely-ill medical patients, including those with infections such as viral pneumonia, are at increased risk for vte, and antithrombotic practice guidelines recommend thromboprophylaxis with twice-or thrice-daily subcutaneous unfractionated heparin (ufh) oncedaily subcutaneous low-molecular-weight heparin (lmwh), or fondaparinux to reduce this risk, although fondaparinux is infrequently used due to its long half-life and reversibility concerns [ , ] . patients hospitalized with severe covid-associated pneumonia may have a further heightened risk of vte, but this issue remains unresolved. preliminary reports in patients with severe pneumonia due to covid- as well as previous reports of severe pneumonias/severe acute respiratory syndromes from other viruses such as influenza h n or middle east respiratory syndrome (mers-cov) suggest a multi-fold higher risk for vte and, in particular, in increased risk for pe [ ] . in addition, patientspecific vte risk factors such as advanced age, a prior history of vte, a history of or active cancer, immobility, and thrombophilia, had been incorporated prior to the covid- era to assess overall vte risk using standardized vte risk assessment scores such as padua vte or improve vte risk scores [ , , ] , which had been externally validated [ ] [ ] [ ] . a recent study from china in hospitalized medical patients with covid- reported that % of patients had a high risk of vte using the padua vte model, although the use of thromboprophylaxis was not reported [ ] . the optimal vte risk stratification scheme for hospitalized covid- patients requires further study, including the use of very elevated d-dimer levels (> times the upper limit of normal [uln] ) that appear to be a consistent predictor of thrombotic events and poor overall prognosis in this population [ ] . however, given the relatively high rates of vte found in early reports, the use of a "universal" thromboprophylactic strategy for all hospitalized patients with covid- appears more appropriate than an individualized vte risk assessment approach at present. all hospitalized patients with covid- should be considered for thromboprophylaxis with either ufh or lmwh unless there are absolute contraindications. advantages of lmwh over ufh include once daily versus twice or thrice daily injections and less heparin-induced thrombocytopenia. although some doacs are approved for in-hospital prophylaxis, these agents should be considered with caution in covid- patients in whom co-administration of immunosuppressant, antiviral and this article is protected by copyright. all rights reserved other experimental therapies may potentiate or interfere with doac therapy [ ] . many institutions have adopted prophylaxis protocols that use a "stepped up" or intermediate-dose lmwh dose regimens based on emerging evidence suggesting increased thrombogenicity with covid- , especially in sicker patients [ ] . for patients in whom anticoagulant therapy is contraindicated, mechanical thromboprophylaxis, preferably with intermittent pneumatic compression devices, should be utilized, although there is limited evidence of efficacy in hospitalized medically ill patients [ , ] . should be used after careful assessment of bleed risk, with lmwh as the preferred agent. intermediate-dose lmwh may also be considered ( % of respondents). severe thrombocytopenia (i.e. platelet counts of , x per liter or , x per liter) or deteriorating renal function. hospitalized covid- patients who are managed in an icu or ccu setting have an overall poor prognosis, with the proportion of severe cases approaching % ( % ci: . - . ) and reported case-fatality rates of % [ ] . the presence of co-morbid conditions (e.g., cardiovascular disease, obesity), a sic score ≥ , and elevated levels of d-dimer (> times uln), c-reactive protein and troponins, and other markers of disseminated intravascular coagulopathy (dic) as assessed by the isth scoring system are associated with a worse prognosis [ , ] . it is uncertain whether changes in haemostasis parameters are a direct consequence of the sars-cov virus or a result of a systemic inflammatory response syndrome (sirs) that is produced by a cytokine storm after viral infection [ ] . in addition, the heightened prothrombotic tendency in the critically ill hospitalized patients with covid- pneumonia, leading to vte and especially, in situ pulmonary artery microthrombi, is evident in case series and pathologic studies as an endpoint of pulmonary inflammation [ , ] . one study reported an incidence of vte of % ( / ) and a mortality of % ( / ) among patients hospitalized with severe covid- pneumonia who had vte; another study found an incidence of this article is protected by copyright. all rights reserved vte and arterial thromboembolism of % and . %, respectively, in covid- patients who were in an icu setting and were receiving standard-dose thromboprophylaxis [ , ] . lastly, the use of tissue plasminogen activator in the treatment of covid- -associated ards was associated with only transient improvement of pulmonary function [ ] . the optimal thromboprophylaxis strategy in the critically ill hospitalized covid- patient population is uncertain. emerging clinical data suggests that the use of either prophylactic to intermediate doses of lmwh (e.g., enoxaparin, - mg daily) in very sick covid- patients (ddimer > times uln; sic score ≥ ) is associated with improved outcomes and a better prognosis [ ] . a previous report that assessed treatment-dose ufh in patients with ards who were afflicted with influenza h n , found that patients with h n -associated ards who received therapeutic anticoagulation had -fold fewer vte events than those treated given prophylactic-dose ufh or lmwh [ ] . expert clinical guidance statements and clinical pathways from large academic healthcare systems favor the use of standard-dose regimens with lmwh or ufh (especially for patients with a creatinine clearance < ml/min), mechanical thromboprophylaxis (intermittent pneumatic compression) when anticoagulants were contraindicated, use of multimodal (anticoagulant and mechanical) prophylaxis strategies in the critically ill and completely immobile covid- population [ , ] , and the use of vte risk stratification using either clinical criteria (body mass index [bmi] > kg/m ), vte risk scores and/or biomarkers (e.g., very elevated d-dimer levels) to suggest intermediate-or higher-dose lmwh or ufh regimens (e.g. enoxaparin . mg/kg twice-daily; enoxaparin mg twice-daily, intravenous ufh targeted to an anti-factor xa level of . - . iu/ml). many institutional protocols of hospitalized covid- patients now incorporate obesity (bmi > kg/m ) or morbid obesity (bmi > kg/m ) to administer intermediate-dose lmwh for thromboprophylaxis [ ] .the use of empiric therapeutic-dose anticoagulation has been advocated by some for the critically ill hospitalized covid- patients, especially in icu settings; however, data on the efficacy and safety of this approach is limited [ ] . there are ongoing randomized trials that aim this article is protected by copyright. all rights reserved should be considered for a % increase in the dose of thromboprophylaxis. treatment-dose heparin should not be considered for primary prevention until the results of randomized controlled trials are available. the risk of hospital-associated vte extends for up to weeks post-hospital discharge in high vte risk medically ill patients, including those with pneumonia, sepsis, and any condition requiring management in an icu setting [ ] . at least % of all vte events in medically ill patients occur in the post-hospital discharge period, with the first weeks being associated with a greater than -fold increased risk in fatal pe [ ] . earlier studies of extended thromboprophylaxis with doacs revealed either limited efficacy or an increase in major bleed risk, and particularly due to these safety concerns, the most recent antithrombotic guidelines recommended against routine post-discharge thromboprophylaxis in medically ill patients, including those with pneumonia [ ] . however, more recent data reveals that in selected populations at high vte risk and low bleed risk, based on key risk factors or risk models for thrombosis and bleeding, extended-duration thromboprophylaxis for approximately weeks with prophylactic-dose lmwh (e.g., enoxaparin, dalteparin, tinzaparin) or a doac (e.g. rivaroxaban, betrixaban) provides a net clinic benefit by reducing vte risk without incurring a significant increase in the risk of major bleeding [ ] [ ] [ ] . this benefit appears more pronounced in patients whose index hospitalization was due to infectious disease, particularly pneumonia [ ] . recent data also supports that a modified improve vte score using established cut-offs plus elevated d-dimer (> times uln) identifies patients at an almost three-fold higher risk for vte in whom there is a significant benefit for extended-duration thromboprophylaxis [ ] . this finding may be especially relevant for post-discharge vte risk mitigation in covid- patients. in this article is protected by copyright. all rights reserved the absence of covid- -specific data, it is reasonable to consider extended-duration thromboprophylaxis with lmwh or a doac for at least weeks and up to weeks post-hospital discharge in selected covid- patients who are at low risk for bleeding and with key vte risk factors such as advanced age, stay in the icu, cancer, a prior history of vte, thrombophilia, severe immobility, an elevated d-dimer (> times uln), and an improve vte score of or more. there are multiple validated and approved strategies to treat hospitalized patients with a new vte including the use of ufh/lmwh bridging therapy to dose-adjusted warfarin, the use of ufh/lmwh lead-in therapy with a switch to dabigatran/edoxaban, or a monotherapy approach with rivaroxaban/apixaban [ ] . in hospitalized covid- patients, parenteral anticoagulation with ufh or lmwh may have advantages over other strategies due to the absence of known drug-drug interactions with antiviral agents or investigational therapies used to treat covid- . moreover, the use of lmwh may have further advantages in this setting due to lack of routine monitoring and decrease healthcare worker exposure to infection due to frequent blood draws necessary with iv ufh, which may require higher than usual doses from possible heparin resistance due to acute phase reactants. doacs may also have further disadvantages in this setting due to potential drug-drug interactions via cyp a mechanisms with certain antivirals (i.e., lopinavir/ritonavir) and immunomodulatory investigational covid- therapies, as well as potential for lack of reversal agents or specific antidotes in some hospitals [ , ] . however, in the post-hospital discharge setting, doacs provide advantages over vitamin k antagonists such as warfarin due to the lack of the need this article is protected by copyright. all rights reserved for routine monitoring and subsequent minimization of patient contact with the healthcare environment. c) the duration of treatment should be at least months ( % of respondents). covid- is emerging as a highly contagious disease with coagulopathic manifestations that appear to have unique characteristics. initial data support a high incidence of thromboembolic disease, and especially vte, in hospitalized covid- patients, as well as poorer outcomes for covid- patients with pre-existing cardiovascular disease [ , ] . due to the risk of infectivity with a need to minimize contact with healthcare workers and the health system, the diagnosis of vte in critically ill, unstable hospitalized covid- patients (especially in the icu) that may need prone positioning and may not be able to undergo standard objective testing, the potential for new vte risk stratification strategies using novel dosing intensities of established thromboprophylaxis regimens, new paradigms of post-hospital discharge and extended thromboprophylaxis, and careful considerations of antithrombotic management due to the potential for drug-drug interactions with investigational or immunomodulatory therapies, healthcare workers will need to understand special considerations for the management of vte in hospitalized covid- patients. this article is protected by copyright. all rights reserved there is an urgent need for high quality data, especially from randomized controlled trials, using a coordinated effort by healthcare funding agencies, organizations dedicated to thrombotic disorders, and professional societies, to answer some of the most urgent questions. these urgent questions are included in the table. there is currently one large international registry on vte (riete) that is capturing data elements for covid- patients with vte, and other ongoing registries (corona-vte and core- ) that are capturing hospital and post-hospital discharge data elements for patients with covid- . there is also a new registry by the american heart association planned for cardiovascular outcomes of these patients. lastly, ongoing and planned randomized trials will address key clinical questions, especially the effect of anticoagulation on outcomes in critically ill covid- patients and whether more intense thromboprophylaxis strategies improve morbidity and mortality in hospitalized covid- patients. this guidance document, using a consensus-based approach, has attempted to provide useful directions for healthcare practitioners managing vte-related issues in hospitalized covid- patients. we acknowledge that the lack of an iterative process in our survey produced some guidance statements that may not have been supported by a majority of expert panel members. as more data is forthcoming, especially high quality data, there needs to be rapid dissemination of this data that addresses some of the most urgent clinical issues in this patient population. clinical features of patients infected with novel coronavirus in wuhan, china novel coronavirus ( -ncov) situation reports n.d incidence of thrombotic complications in critically ill icu patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza a h n acute respiratory distress syndrome patients coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mers-cov and lessons from the past cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease (covid- ) pandemic new paradigms in venous thromboprophylaxis of medically ill patients accepted article this article is protected by copyright. all rights reserved isth interim guidance on recognition and management of coagulopathy in covid- early use of echocardiography in patients with acute pulmonary embolism: findings from the riete registry prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score predictive and associative models to identify hospitalized medical patients at risk for vte validation of risk assessment models of venous thromboembolism in hospitalized medical patients external validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (vte-valourr) external validation of the risk assessment model of the international medical prevention registry on accepted article this article is protected by copyright improve) for medical patients in a tertiary health system attention should be paid to venous thromboembolism prophylaxis in the management of covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy stratified meta-analysis of intermittent pneumatic compression of the lower limbs to prevent venous thromboembolism in hospitalized patients clinical characteristics of coronavirus disease (covid- ) in china: a systematic review and meta-analysis cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) covid- : consider cytokine storm syndromes and immunosuppression vander heide r. pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans acute pulmonary embolism and covid- pneumonia: a random association? tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- n emergence of institutional antithrombotic protocols for coronavirus new paradigms of extended thromboprophylaxis in medically ill patients rivaroxaban for thromboprophylaxis in acutely ill medical patients improved benefit risk profile of rivaroxaban in a subpopulation of the magellan study extendedduration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the magellan study modified improve key: cord- -u ea fc authors: zuo, y.; zuo, m.; yalavarthi, s.; gockman, k.; madison, j. a.; shi, h.; knight, j. s.; kanthi, y. title: neutrophil extracellular traps and thrombosis in covid- date: - - journal: medrxiv : the preprint server for health sciences doi: . / . . . sha: doc_id: cord_uid: u ea fc here, we report on four patients whose hospitalizations for covid- were complicated by venous thromboembolism (vte). all demonstrated high levels of d-dimer as well as high neutrophil-to-lymphocyte ratios. for three patients, we were able to test sera for neutrophil extracellular trap (net) remnants and found significantly elevated levels of cell-free dna, myeloperoxidase-dna complexes, and citrullinated histone h . neutrophil-derived s a /a (calprotectin) was also elevated. given strong links between hyperactive neutrophils, net release, and thrombosis in many inflammatory diseases, the potential relationship between nets and vte should be further investigated in covid- . severe acute respiratory syndrome coronavirus (sars-cov- ) causes the disease known as coronavirus disease . it most commonly presents with influenza-like illness and viral pneumonia, but in its most severe manifestation progresses to acute respiratory distress syndrome (ards) and multi-organ failure . to date the viral pandemic has resulted in more than two million infections worldwide (https://coronavirus.jhu.edu/map.html). in covid- , elevated levels of blood neutrophils predict severe respiratory disease and unfavorable outcomes , . neutrophil-derived neutrophil extracellular traps (nets) play a pathogenic role in many thrombo-inflammatory states including sepsis , , thrombosis [ ] [ ] [ ] , and respiratory failure , . nets are extracellular webs of chromatin and microbicidal proteins that are an evolutionarily conserved aspect of innate immune host-defense ; however, nets also have potential to initiate and propagate inflammation and thrombosis , . nets deliver a variety of oxidant enzymes to the extracellular space, including myeloperoxidase, nadph oxidase, and nitric oxide synthase , while also serving as a source of extracellular histones that carry significant cytotoxic potential , . nets are drivers of cardiovascular disease by propagating inflammation in vessel walls . furthermore, when formed intravascularly, nets can occlude arteries , veins , and microscopic vessels . early studies of covid- suggest a high risk of morbid arterial events , and the risk of venous thromboembolism (vte) is increasingly revealing itself as more data become available . descriptive and mechanistic studies to date that examine covid- pathophysiology have focused on monocytes and lymphocytes more so than neutrophils and their effector productsincluding nets. here, we describe four cases of vte in patients hospitalized with covid- and provide evidence for neutrophil hyperactivity. we identified four patients admitted to a large academic medical center with covid- who also developed vte (either deep vein thrombosis or pulmonary embolism) despite immediate initiation of prophylactic-dose heparin. three of the patients were diagnosed with vte within hours of admission. all three had markedly elevated d-dimers and neutrophil-to-lymphocyte ratios ( table ) . for two of the early vte patients, we were able to access sera for measurement of net remnants. three different net-associated markers (cell-free dna, myeloperoxidase-dna complexes, and citrullinated-histone h ) were elevated in both patients all rights reserved. no reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint ( table ) . we also detected elevated levels of the classic marker of neutrophil activation, s a /a (also known as calprotectin). neither patient had positive testing for antiphospholipid antibodies . we identified a fourth patient who developed vte several weeks into his hospitalization. this -year-old man's course was complicated by respiratory failure requiring mechanical ventilation beginning on day . he received prophylactic-dose heparin throughout his hospitalization, but was nevertheless diagnosed on day with extensive right-lower-extremity deep vein thrombosis. we were able to test serum from day of his hospitalization for net remnants ( table ) . interestingly, markers of neutrophil activation including net remnants were already significantly elevated on day ( table ) ; this is in contrast to d-dimer and neutrophil count, which were only mildly elevated. both d-dimer and neutrophil count were all rights reserved. no reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint elevated by the time the patient was diagnosed with deep vein thrombosis on day ( table ) . the patient did not have elevated levels of antiphospholipid antibodies . hyperactivity of the coagulation system is a common finding of severe covid- . indeed, many patients have a profile to suggest a prothrombotic diathesis including high levels of fibrin degradation products (d-dimer), elevated fibrinogen levels, and low antithrombin levels , . here, we report four cases of covid- -associated vte. we measured three markers commonly used to detect net remnants in blood (cell-free dna, myeloperoxidase-dna complexes, and citrullinated-histone h ), as well as a fourth marker, s a /a (calprotectin), which is commonly used to track neutrophil activation. all tests were elevated in patients diagnosed with vte, including as early as days prior to detection of vte in one case. given the known link between nets and venous thrombosis in many inflammatory diseases, these data suggest that the role of nets in covid- -associated thrombophilia warrants systematic all rights reserved. no reuse allowed without permission. was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which this version posted may , . . investigation. while a recent report suggested antiphospholipid antibodies may be drivers of thrombosis in some covid- patients , such antibodies were not detected here. examples of nets as drivers of thrombosis are myriad, as intravascular net release is responsible for initiation and accretion of thrombotic events in arteries, veins, and microvessels, where thrombotic disease can drive end-organ damage in lungs, heart, kidneys, and other organs , . mechanistically, dna in nets may directly activate the extrinsic pathway of coagulation , while nets also present tissue factor to initiate the intrinsic pathway . serine proteases in nets such as neutrophil elastase dismantle brakes on coagulation such as tissue factor pathway inhibitor . bidirectional interplay between nets and platelets might also be critical for covid- -associated thrombosis as has been characterized in a variety of disease models , . approaches to combatting nets , include the dismantling of nets with deoxyribonucleases and strategies that prevent initiation of net release such as neutrophil elastase inhibitors and peptidylarginine deiminase inhibitors. as we await definitive antiviral and immunologic solutions to the current pandemic, we posit that anti-neutrophil therapies may be part of a personalized strategy for some individuals affected by covid- . furthermore, those patients with hyperactive neutrophils may be at particularly high risk for vte and might therefore benefit from more aggressive anticoagulation while hospitalized. human samples. blood was collected into serum separator tubes by a trained hospital phlebotomist. after completion of biochemical testing ordered by the clinician, the remaining serum was stored at °c for up to hours before it was deemed "discarded" and released to the research laboratory. serum samples were immediately divided into small aliquots and was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which this version posted may , . was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which this version posted may , . . sars-cov- : a storm is raging immune phenotyping based on neutrophil-to-lymphocyte ratio and igg predicts disease severity and outcome for patients with covid- early warning score: a multi-parameter screening tool to identify highly suspected patients advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation new strategies for treatment of infectious sepsis adenosine receptor agonism protects against netosis and thrombosis in antiphospholipid syndrome vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis ectonucleotidase tri(di)phosphohydrolase- (entpd- ) disrupts inflammasome/interleukin beta-driven venous thrombosis neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and 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infection and vascular thrombosis coagulopathy and antiphospholipid antibodies in patients with covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia prominent changes in blood coagulation of patients with sars-cov- infection biological basis and pathological relevance of microvascular thrombosis platelets, neutrophils, and neutrophil extracellular traps (nets) in sepsis neutrophil extracellular traps promote thrombin generation through platelet-dependent and plateletindependent mechanisms tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases neutrophil extracellular traps: villains and targets in arterial, venous, and cancer-associated thrombosis at the bedside: neutrophil extracellular traps (nets) as targets for biomarkers and therapies in autoimmune diseases netting neutrophils in autoimmune small-vessel vasculitis the work was supported by a covid- yz and jsk also thank all members of the "covid- network" for their helpful advice and key: cord- - g wb qi authors: tal, shir; spectre, galia; kornowski, ran; perl, leor title: venous thromboembolism complicated with covid- : what do we know so far? date: - - journal: acta haematol doi: . / sha: doc_id: cord_uid: g wb qi coronavirus disease (covid- ) is caused by the novel severe acute respiratory syndrome coronavirus (sars-cov- ) and is responsible for the ongoing – pandemic. venous thromboembolism (vte), a frequent cardiovascular and/or respiratory complication among hospitalized patients, is one of the known sequelae of the illness. hospitalized covid- patients are often elderly, immobile, and show signs of coagulopathy. therefore, it is reasonable to assume a high incidence of vte among these patients. presently, the incidence of vte is estimated at around % of patients hospitalized in the intensive care unit for covid- even under anticoagulant treatment at prophylactic doses. in this review, we discuss present knowledge of the topic, the unique challenges of diagnosis and treatment of vte, as well as some of the potential mechanisms of increased risk for vte during the illness. understanding the true impact of vte on patients with covid- will potentially improve our ability to reach a timely diagnosis and initiate proper treatment, mitigating the risk for this susceptible population during a complicated disease. since december , , a cluster of cases of "pneumonia of unknown origin" in humans, associated with the huanan seafood wholesale market, has been reported in wuhan, china. the disease, which is the third coronavirus infection [ ] , is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) and was named coronavirus disease (covid- ) by who [ ] . up to april , , over million patients were infected and more than , died in countries [ ] . upon initial recognition, patients can be asymptomatic carriers or have a range of symptoms with a presentation resembling pneumonia, showing mainly fever, cough, fatigue, and dyspnea [ ] [ ] [ ] [ ] . several recent studies suggest a hypercoagulable state in patients presenting with covid- . laboratory findings show high crp, leukopenia, lymphocytopenia, mild thrombocytopenia, prolonged pt, high d-dimers, and high fibrinogen levels early in the disease course, which may be complicated by low fibrinogen later on in severe cases [ ] [ ] [ ] . imaging shows bilateral pneumonia in about % of patients [ , ] , but can also show other patterns such as ground glass opacities, patchy shadowing, and consolidation [ , ] . the diagnosis is confirmed with a real-time protein chain reaction (rt-pcr) assay [ , , ] . the differential diagnosis is wide. respiratory infections such as influenza and other flu-like upper respiratory viral diseases, bacterial pneumonia, and copd exacerbation all commonly present during winter time, coinciding with the emergence of the pandemic. in addition, cardiovascular morbidity such as heart failure and venous thromboembolism (vte) may lead to respiratory distress symptoms resembling covid- . vte is the third most frequent acute cardiovascular disease, following myocardial infarction and stroke, with an annual incidence rate of - per , population for pulmonary embolism (pe) and an incidence rate of - per , population for deep vein thrombosis (dvt) [ ] . it is the cause of over , deaths annually and is considered the most preventable cause of death in hospitalized patients in the usa [ ] . there is a somewhat higher incidence of vte among hospitalized patients, which is more in high-income countries compared to low-and middle-income countries ( . vs. %) [ ] . many of the hospitalized covid- are elderly patients who suffer from severe infectious illness, some immobile in an intensive care unit (icu) setting. therefore, a relatively high incidence of vte among patients diagnosed with covid- is expected, due to the severity of their disease and distinctive risk factors. the aims of this review are to present the current knowledge of the unique challenge of diagnosis and treatment of vte as well as some of the potential mechanisms that link vte to patients with covid- . patients with covid- have a relatively prolonged disease, with a duration that ranges between and days. [ ] although most patients have a favorable prognosis, older patients and those with chronic underlying conditions may have worse outcomes. at the writing of this paper (april , ), the average death rate worldwide is about . % [ ] . about one third of the worsened patients [ , ] and up to . % [ ] suffer from complications such as respiratory failure, acute respiratory distress syndrome (ards). in addition, they may have heart failure, secondary bacterial infections, and septic shock. during their illness the patients may require high-flow oxygen, inhalations, vasopressors, mechanical ventilations, and even ecmo. the complexity of disease in many patients necessitates a large number of highly qualified medical personnel to deal with these unique challenges. patients with covid- infection are at high risk of developing thromboembolic complications. however, so far there have been only two studies describing vte: dvt or pe in patients with covid- , as well as several case reports. klok et al. [ ] reported a high incidence of vte in critically ill patients admitted to the icu despite the use of at least prophylactic anticoagulation. they evaluated icu patients -mean age ± years, ( %) of which were male, from dutch university hospitals and dutch teaching hospital, positive to co-vid- . of these patients, died ( %), were discharged alive ( %), and ( %) were still in the icu on april , . computer tomography pulmonary angiogram (ctpa) and/or ultrasonography done by clinical suspicion confirmed vte in % ( % ci - %) and arterial thrombotic events in . % ( % ci, - . %). pe was the most frequent thrombotic complication (n = , %). age (adjusted hazard ratio . /year, % ci . - . ) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > s or activated partial thromboplastin time > s (adjusted hazard ratio . , % ci . - . ), were independent predictors of thrombotic complications. none of the patients developed disseminated intravascular coagulation. in a small study describing autopsies from brazil, / patients who died from covid- had pulmonary microthrombi [ ] . cui et al. [ ] described the course of patients diagnosed with covid- pneumonia in the icu of tongji medical college, huazhong university of science and technology. their mean age was . years (range - years) and ( %) were male; ( %) patients have been discharged from the hospital, ( %) had died, and the rest ( %) remained hospitalized. no preventive anticoagulation was administered; / patients ( %) developed lower-extremity venous thrombosis. the rate of pe or of ruled-out pe was not mentioned in the article. however, patients with dvt were confirmed, and these were older ( . ± . vs. . ± . years, p < . ), had lower lymphocyte counts ( . ± . vs . ± . × /l, p < . ), longer aptt ( . ± . vs. . ± . s, p = . ), and higher d-dimer ( . ± . vs. . ± . μg/ml, p < . ). cui et al. [ ] also showed that if a cut-off value of . µg/ml d-dimer was used to predict vte, the sensitivity was . %, the specificity was . %, and the negative predictive value was . % in contradictory fashion, yao et al. [ ] that d-dimer elevation (≥ . mg/l) upon admission was present in . % ( / ) of patients with co-vid- in whom vte was theoretically ruled out. however, ruling out vte in their trial was based mainly on the wells score, while doppler ultrasound and ctpa was performed in only patients with a high clinical suspicion for vte. in the report, d-dimer was associated with both increased disease severity and in-hospital mortality. a ddimer level of > . mg/l predicted in-hospital mortality with a sensitivity of . % and specificity of . %. danzi et al. [ ] described a -year-old covid- -positive female patient hospitalized with bilateral pneumonia who was diagnosed with intermediate-/highrisk pe who was hemodynamically stable. she had no predisposing factors other than the acute infection with covid- . the diagnosis was confirmed with ctpa showing bilateral filling defect. echocardiography demonstrated a dilated and severely hypokinetic right ventricle (rv) with a mean derived pulmonary arterial pressure of mm hg. she had high crp ( mg/l), troponin i ( , . ng/ml), and d-dimer ( µg/ml). lower limb compression ultrasonography was negative. she was treated with low-molecular-weight heparin (lmwh), lopinavir/ritonavir, and hydroxychloroquine. xie et al. [ ] reported cases from wuhan, china, of a -year-old male and a -year-old male. both had pneumonia positive to covid- with fever, cough, dyspnea, and bilateral ground-glass opacities on ct at admission on day and of symptoms, respectively. due to respiratory deterioration and high d-dimer both went through ctpa which confirmed the diagnosis of pe, on day and of admission, respectively. patients presenting with covid- typically have a long course of disease, lasting up to several weeks [ ] . some will need high oxygen supply and others will be intubated or treated with vasopressors. during this extended period of time, signs, symptoms and laboratory tests pointing to the diagnosis of vte can be masked and attributed to co-vid- or other complications occurring in the prolonged and sometimes complex hospitalization. d-dimer is increased in most of the patients, and usually cannot eliminate the presence of vte. therefore, timely diagnosis of vte is anticipated to pose a significant challenge. the clinical signs and symptoms of acute pe, the most menacing vte event, are nonspecific [ , ] . some of the patients are asymptomatic and others have dyspnea, chest pain, hemoptysis, presyncope or syncope, and up to hemodynamic instability. they can overlap with the symptoms of covid- infection or its associated complications, such as ards, pleural effusion, or myocarditis [ ] [ ] [ ] [ ] . having one or more of the predisposing factors for vte can be a clue to the diagnosis that otherwise can be missed. covid- patients may have such factors at baseline or acquire them during their illness and hospitalization -older age, elevated crp, d-dimer, fibrinogen levels, tachypnea, fever, critical illness, infectious etiology, and immobility [ ] [ ] [ ] ] . risk scores such as the wells score or the geneva clinical prediction score may also be useful, sparing unnecessary tests when predicting low risk for vte. hypoxemia, ecg changes indicating rv strain, sinus tachycardia, or atrial fibrillation may be present but they are not specific for pe and can be attributed to other complications of covid- . the diagnostic approach of pe [ , ] is different between unstable and stable patients. the workup of hemodynamically unstable patients requires ctpa which is the method of choice for imaging. mobilizing critically ill patients outside of the icu for imaging may be burdensome and puts both the patients and their surroundings at additional risk of contamination. transthoracic echo (tte) and troponin levels are also part of the workup of unstable patients. tte may indicate rv overload and/or dysfunction or even a right-sided thrombus. nevertheless, elevated troponin is present in many of the patients positive to covid- and indicates a severe infection [ , ] . in many cases it is a marker of myocardial injury among these patients [ , ] . therefore, in the covid- patient, an abnormal echocardiography test or high troponin levels can also be attributed to the severe pulmonary disease, the "cytokine storm" associated with the viremia, and its systemic effects. it is therefore crucial to note that while both tte and troponin levels can assist in reaching the diagnosis of pe, one needs a high level of suspicion in order to actively search for vte and perform the confirmatory tests. stable patients with suspected pe can be initially evaluated with a d-dimer test if they are at low or intermediate clinical probability for vte. however, many of the covid- patients may present with high levels of d-dimer due to other causes -inflammation, disseminated intravascular coagulation, advanced age, or infection [ ] suggesting the need for ctpa as an initial rule-out test as well. nonetheless, as suggested by yu et al. [ ] , who showed that d-dimer levels were significantly correlated with inflammation, in cases where the inflammatory state subsides, when the levels of d-dimer are nonproportionally high, vte should be considered. v/q scintigraphy (ventilation/perfusion lung scan) is also a feasible part of the workup in stable cooperative patients with suspected pe. however, this test exposes nuclear medicine workers to aerosolized secretions due to leakage of the aerosol to the room and because the patients frequently cough after inhalation. using a n- mask may reduce the risk of infection, and it is possible to perform perfusion scans only (without the ventilation part), but choosing ctpa as the foremost imaging modality may be a better option [ ] . finally, compression ultrasonography shows dvt only in - % of patients with pe, but has a sensitivity of > % and a specificity of ≥ % for proximal symptomatic dvt [ ] , in which case it is a class i indication for the diagnosis of pe [ ] . this test must therefore be considered in patients with covid- as well, in appropriate cases. as for the diagnosis of dvt in covid- patients, a low d-dimer level may help in ruling out the diagnosis. nevertheless, most patients cannot be regarded as low probability risk, and if clinically suspected, compression ultrasonography is the method of choice, starting from proximal ultrasound and if negative performing wholeleg ultrasound with a sensitivity of - % and specificity of . % for lower-extremity dvt [ ] . covid- is very contagious with an average reproduction number (r ) of . [ ] , which indicates the transmissibility of the virus by an infectious person in a totally naive population. this complicates the workup of patients, when compared with other patients who are not infected. every single physical examination, laboratory test, or imaging examination of the patients, including ctpa or echocardiography, requires the full protection of the staff. in addition, all machinery must go through sterilization after use -a process which is time-consuming and may add hardship to what is an already strained health care system. this makes every contact with the patients bothersome, as well as precarious, for both the medical team and other patients within the medical facility. treatment of patients suffering from pe [ , , ] , in a similar fashion to the diagnosis of pe, is also different in unstable and stable patients. in the unstable patient, reperfusion therapy by thrombolysis and unfractionated heparin (ufh) is the treatment of choice. nevertheless, many of the patients with covid- have an absolute or a relative contraindication to thrombolysis, such as coagulopathy, thrombocytopenia, a recent invasive procedure, pericarditis, and age > years [ , , ] . moreover, even those who are able to receive thrombolysis may require further invasive diagnostics or interventions regarding their covid- infection which thrombolysis may prevent (such as insertion of central-line, pericardiocentesis, insertion of a chest tube, or performing ecmo). it may be difficult to differentiate, but one also needs to keep in mind that if the hemodynamic instability is due to the infectious disease and not to vte, the treatment of choice is not thrombolysis. one of the indications for pe as a cause for hemodynamic instability is the function of the rv. rv failure related to pe may also respond to a fluid challenge or to vasopressors, both of which may already be administered for some of the covid- patients. no cases of thrombolytic therapy for pe in co-vid- patients have been published so far. however, thrombolysis was used off-label for acute ards [ , ] . the anticoagulation therapy of stable pe patients is usually lmwh or direct oral anticoagulants (doacs). in patients with intermediate-/high-risk pe, ufh may be preferred due to its short half-life and the opportunity to give the patients protamine sulfate as an antidote in case of the need for an urgent procedure or bleeding. on the other hand, ufh requires close monitoring which we may want to avoid in such a contagious disease. therefore, in covid- patients, lmwh may be preferred. for practical reasons, some institutions will prefer do-acs in order to reduce the contact between the nurses and covid- patients [ ] . however, drug interaction between doacs and medical treatment for covid- infection should be considered, as well as the potential risk of organ deterioration in these patients and lack of an effective reversal agent in some centers [ , ] . inferior vena cava filters should be considered in selected patients with acute pe and absolute contraindications to anticoagulation, or in case of recurrence despite proper anticoagulant treatment [ ] . graduated compression stockings are no longer recommended for the treatment of dvt [ ] . as for the timing of initiation of therapy, the recent european society of cardiology (esc) pe guidelines [ ] are most relevant in covid- patients due to the very possible delay in diagnosis on account of protection of the medical team, sterilization of the machinery, and the difficulty in transporting hemodynamically unstable or intubated patients out of the icu. as previously mentioned, patients with covid- may present variably, from asymptomatic carriers up to a severe disease requiring admission to the icu [ ] [ ] [ ] . therefore, the treatment of vte in these patients must be tailored personally, according to their infectious condition, vte severity, and general status [ ] . figure presents our suggestion for pe management algorithm in the covid- patient which combines all the abovementioned factors. a retrospective analysis of covid patients and non-covid patients in tongji hospital showed that prophylactic anticoagulation therapy ( - mg enoxaparin per day or ufh , - , u/day) can reduce mortality, compared to those who do not receive it, only in the covid group [ ] . another trial of the same group [ ] showed that heparin treatment for days in out of patients with covid- reduced -day mortality only in patients with a sepsis-induced coagulopathy score ≥ ( % vs. . %, p = . ) or patients with d-dimer > -fold of the upper limit of normal ( . vs. % p = . ). in the study by klok et al. [ ] , all patients hospitalized in the icu received at least standard thromboprophylaxis doses. we may assume that the rate of vte without prophylaxis would have been much higher. guidelines from britain recommend vte prophylaxis with lmwh for all high-risk patients as well as considering the search for pe in patients with sudden onset of oxygenation deterioration, respiratory distress, and reduced blood pressure [ ] . finally, based on the correlation between high levels of d-dimer and severe covid- disease [ , ] as well as higher mortality rate [ , ] , the international society on thrombosis and haemosthasis (isth) and american society of hematology (ash) guidelines [ ] advises prophylactic lmwh in all hospitalized covid- patients in the absence of any contraindications (active bleeding and platelet count less than × /l) [ , ] . in view of the high thromboembolic risk in patients with covid- despite anticoagulation treatment [ ] , and in view of the thrombotic coagulopathy and extremely high d-dimers with no evidence of clinical bleeding in covid- patients, some institutes like our own recommend considering higher prophylactic doses of anticoagulation such as enoxaparin . mg/kg b.i.d. or enoxaparin mg/kg once daily. as in other critically ill patients, patients with co-vid- fulfill at least two out of three criteria of virchow's triad -reduced venous flow from immobility and prothrombotic changes due to inflammatory state [ ] . prone position, being used in some of the co-vid- patients, placing the heart at a hydrostatic level above the head and four extremities, may explain some of the reduction in venous return [ , ] . there is evidence to suggest that the third criteria of virchow's triad -vessel wall changes -may also exist in patients with covid- . as was previously reported, serum levels of angiotensin are significantly elevated in covid- patients, activating the renin-angiotensin system, which may cause widespread endothelial dysfunction [ ] . in addition, the virus can bind to the endothelial cells via angiotensin receptors, which are most commonly found in the alveolar epithelial cells, followed by endothelial cells -a process which may ultimately damage blood vessels and increase the risk of thrombogenicity [ , ] . as previously published in the literature [ ] , diagnosis of vte is quite common in hospitalized patients, and in particular in patients with severe systemic infection. a previous retrospective trial of , pneumococcal pneumonia patients and , controls showed that there was higher risk of developing dvt and pe ( . fold and . -fold, respectively) in patients with pneumococcal pneumonia compared to controls [ ] . this suggests a causal with infectious etiology and eludes to the fact that covid- patients might also have a higher incidence of vte due to their inflammatory condition. in addition, antiphospholipid antibodies that can arise transiently in patients with critical illness and various infections may possibly develop among covid- patients as well. a case report [ ] of critically ill patients with confirmed covid- from wuhan, china, described patients with clinically significant coagulopathy -ischemia of the lower limbs, multiple cerebral infracts, and antiphospholipid antibodies (anticardiolipin iga, antiβ -glycoprotein i iga, and igg). two of the patients, a -year-old male and a -year-old female, had thrombocytopenia with , and , platelets, respectively. the former also had high troponin ( . pg/ml) and d-dimer levels (> mg/l). another possible mechanism is activation of the complement system. this theory is based on evidence from studies in murine models investigating complement activation by coronavirus infections, sars and middle east respiratory syndrome (mers), showing laboratory markers consistent with excessive complement activation: elevated lactic dehydrogenase, d-dimer, and bilirubin in addition to decreased platelets, mild anemia, and renal and cardiac injury such as in diffuse thrombotic microangiopathy and atypical hemolytic uremic syndrome [ ] . one more final possible mechanism for the high coagulability in covid- patients is hypoxia, as observational and experimental studies show that conditions of hypoxia are associated with increased risk of thrombosis [ ] . vte is a common entity in hospitalized patients [ ] and a preventable cause of death [ ] . in patients with covid- vte poses a unique challenge. first, one needs to suspect the diagnosis despite the wide differential diagnosis of respiratory entities and causes of hemodynamic deterioration in these patients, such as second- ary bacterial infection, ards, heart failure, and septic shock. subsequently, if the suspicion is high enough, one needs to consider initiating full-dose anticoagulation and the risk accompanied by the diagnostic workup, in terms of the chance of contamination and the mobilization of the hemodynamic/respiratory unstable patient out of the icu. as is expected in the midst of a pandemic breakthrough, there is presently paucity of data regarding the true incidence and characteristics of vte among co-vid- -positive patients. in fact, there are presently only two trials [ , ] describing an incidence of % for vte in patients hospitalized in the icu receiving prophylactic anticoagulation and % for dvt in patients hospitalized in the icu for covid- (with no mention of the incidence of pe), as well as a few case reports [ , ] . more information will certainly be published in the near future. although covid- is a prolonged, complicated, and sometimes fatal disease, most of the patients are expected to eventually recover. nonetheless, during the admission, several complications may occur which will impact the prognosis of these patients. such is the case with vte, especially due to the risk of underdiagnosis and under-treatment. thus, the importance in understanding the actual burden of vte among these patients, and the proper treatment algorithms under these unique circumstances, cannot be overemphasized. a validated treatment for covid- does not exist yet, but vte is a well-established medical entity, with potentially preventable and treatable consequences. escaping pandora's box -another novel coronavirus the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china world health organization. coronavirus disease (covid- ) pandemic prevalence of comorbidities and its effects in patients infected with sars-cov- : a systematic review and meta-analysis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. lancet epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china prevalence of venous thromboembolism in 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a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus infection covid- : abnormal clotting common in more severe disease association between pneumococcal pneumonia and venous thromboembolism in hospitalized patients: a nationwide population-based study coagulopathy and antiphospholipid antibodies in patients with covid- will complement inhibition be the new target in treating co-vid- related systemic thrombosis? circulation the stimulation of thrombosis by hypoxia the authors have no conflict of interest to declare. the authors have no funding sources to declare. all authors contributed to the study design and revised the manuscript which was drafted by dr. tal and dr. perl. all authors approved the final version submitted for publication. key: cord- -jzjxsetx authors: mazo, jahinover; singh, sukhdev; khan, zohaib; foster, allison; komarnitsky, ecaterina; nagaraj, abhiram; patel, soham; kikkeri, vinaya title: more than just pneumonia: acute pulmonary embolism in two middle-aged patients with covid- date: - - journal: case rep med doi: . / / sha: doc_id: cord_uid: jzjxsetx background: although severe pneumonia and respiratory compromise have remained the predominant complications of coronavirus disease , we are now learning this virus is much more varied in its presentation. in particular, there are increasingly reported cases of thromboembolic events occurring in infected patients. case report. in this report, we present two patients, both under the age of with known risk factors for venous thromboembolism, who presented with respiratory distress. both patients were diagnosed with sars-cov- pneumonia and pulmonary embolism requiring management with anticoagulation. both patients were discharged after a short course in the hospital. conclusion: the discussion of a hypercoagulable state induced by coronavirus disease has been well documented; however, the exact mechanisms remain unknown. we suspect that a prothrombotic inflammatory response provoked by coronavirus disease could be the culprit, acting as an additive effect on middle-aged patients with known risk factors for venous thromboembolism. we recommend clinicians closely monitor those with known risk factors for pulmonary embolism. e outbreak of coronavirus disease , caused by sars-cov- , rapidly spread globally in early . as of may , , the world health organization has reported covid- has been responsible for over , deaths with over . million confirmed infections worldwide. according to data from china, where the virus originated, % of covid- patients were between the age - years [ ] . e most common symptoms amongst those infected were fever, cough, fatigue, muscle pain, diarrhea, and pneumonia [ ] . e most critical cases progressed to respiratory failure, septic shock, and multiorgan failure [ ] . an often-unrecognized complication of covid- pneumonia is pulmonary embolism (pe). recent studies indicate that pe in covid- patients had a prevalence of % [ ] . even with dvt prophylaxis and initial improvement, the risk of pe remains high [ ] . lab findings of elevated d-dimer, thrombocytopenia, and increased coagulation parameters are associated with worse outcomes [ ] . interestingly, autopsy findings of covid- patients have shown evidence of pulmonary microthrombi and pulmonary hemorrhage that suggest hypercoagulability may be a key but infrequently reported feature of this disease [ ] . we further suspect that middle-aged patients with known risk factors for venous thromboembolism are at an even higher risk due to covid- . a -year-old obese male presented to the emergency department (ed) for worsening dyspnea and palpitations over the past three days. earlier in the day, he described feeling like his heart was "jumping out from his chest." his occupation requires him to sit for long periods and he endorsed that for the past week, he had progressively worsening pain in his legs. he is a former smoker; however, he quit three years ago. vitals on presentation were a temperature of . °c, blood pressure of / mmhg, pulse rate of beats/ minute, respiratory rate of breaths/minute, and oxygen saturation of % on ambient air which improved to % on a non-rebreather mask. chest auscultation was notable for bilateral crackles, wheeze, and stridor. laboratory abnormalities included thrombocytopenia ( k/μl), elevated d-dimer ( . μg/ml), elevated aptt ( . s), elevated lactate dehydrogenase ( u/l), and a positive rt-pcr for sars-cov- . ekg showed sinus tachycardia with rightward axis deviation. chest x-ray (see figure ) demonstrated patchy infiltrates peripherally in the right upper lung and left mid to lower lung with mild elevation of right hemidiaphragm. computed tomography angiography (cta) done a few hours later (see figures and ) showed extensive prominent multifocal acute bilateral pulmonary embolism and findings consistent with viral pneumonia. he was given heparin iv , units in the ed as prophylaxis for dvt as per hospital protocol; however, he was subsequently switched to a one-time subcutaneous injection of enoxaparin mg. enoxaparin was held as the patient's aptt levels were noted to be elevated. however, on day three, he was started on the oral anticoagulant, apixaban mg twice daily. after a seven-day hospitalization, he was clinically stabilized and discharged on home oxygen along with instructions to continue oral anticoagulation for three months and follow up as an outpatient. a -year-old female with a history of hypertension was sent to the ed from an urgent care facility after a chest x-ray revealed worsening bilateral infiltrates. she complained of progressively worsening left-sided chest and flank pain for three days. e pain was exacerbated by deep inspiration and associated with severe shortness of breath. she was presumed to be sars-cov- positive by her primary care physician due to her husband's recent positive test. associated symptoms included cough, fever, sore throat, diarrhea, and body aches for - weeks. she was prescribed a -day course of azithromycin and a five-day course of hydroxychloroquine. on follow-up, the patient's repeat chest x-ray showed new infiltrates, and she was started on a seven-day course of levofloxacin. although most of the covid- related symptoms subsided with treatment, the patient endorsed mild intermittent hemoptysis. e patient's history also revealed the use of oral contraceptives since . vitals on presentation were a temperature of . °c, blood pressure of / mmhg, pulse rate of beats/ minute, respiratory rate of breaths/minute, and oxygen saturation of % on ambient air. physical examination was notable for left-sided chest wall tenderness extending from midaxillary line to the scapular region. labs were notable for hemoglobinemia ( . g/dl), lymphopenia ( . k/μl), and reactive thrombocytosis ( k/μl). rt-pcr for sars-cov- was positive. ekg demonstrated normal sinus rhythm with no ischemia or right ventricle failure. cta (see figures and ) demonstrated a filling defect in the left lower lobe consistent with lobar and segmental pulmonary embolism and findings consistent with the known history of pneumonia. during hospital stay, she was started on iv heparin , units as per hospital protocol for dvt prophylaxis and was consequently admitted to the general medical floor for management. during day two of hospital stay, she was switched from iv heparin to subcutaneous enoxaparin mg twice daily for treatment of pe. after a three-day hospital course, she was discharged with instructions to start and continue apixaban for two months and follow up as an outpatient. reports of covid- patients presenting with thromboembolic events have been steadily increasing as the pandemic continues. in a recent study of patients with confirmed covid- pneumonia, thrombotic events were reported to occur in % of patients, despite appropriate thromboprophylaxis [ ] . % of these were confirmed cases of acute pulmonary embolism [ ] . in another study examining covid- patients with diagnosed thromboembolic events, half occurred within twenty-four hours of hospital admission [ ] . while the explanation of the observed phenomena eludes us, evidence suggests a combination of prothrombotic and proinflammatory mediators may hold some answers. supporting evidence of an existing hypercoagulable state has been demonstrated by observed increases in prothrombotic factors. factor viii, which plays a key role in the coagulation cascade during homeostasis, is known to be bound to von willebrand factor (vwf) in circulation. activation of factor viii leads to a trickling effect, resulting in thrombin activation and thromboembolism formation. factor viii was shown to be elevated in patients with covid- associated thrombotic events, whereas derangements of anticoagulant factors were not commonly seen [ ] . in addition to coagulation factor abnormalities, other reported findings of increased d-dimers, ferritin, and lactate dehydrogenase further support the assertion that a prothrombotic response to the virus is driving the thromboembolic events among covid- patients [ ] . supplementary studies have demonstrated elevations in partial thromboplastin, prothrombin times, fibrinogen, and d-dimer levels, suggesting widespread activation of the clotting cascade [ ] . additionally, factors such as fibrinogen resulting in increased d-dimers have also correlated with higher mortality [ ] . in a study of sixteen covid- patients with thromboembolic complications, the following striking lab values were discovered: elevated clot strength, elevated d-dimer, hyperfibrinogenemia, and elevated il- levels [ ] . ere have also been reports of patients who suffered strokes despite having sufficient anticoagulation in therapeutic ranges [ ] . in these patients, d-dimer elevations were nearly eight times greater than the median of normal reported for covid- patients [ ] . severe covid- infections have also been associated with an inflammatory prothrombotic state, also potentially playing a key role behind the increase in reported thromboembolic complications. elevations in inflammatory mediators in infected patients include il- , il- , and tumor necrosis factor-α [ , ] . ese proinflammatory cytokines, associated with the severity of infection, can injure the endothelium and activate mononuclear cells, leading to tissue factor expression which, in turn, activates the coagulation cascade [ ] . tnf and il- are known to exert an antifibrinolytic effect by stimulating the production of plasminogen activator inhibitor- , thus promoting a prothrombotic state [ ] . ese cytokines are also responsible for stimulating the release of vwf multimers and increasing the production of factor vii and tissue factor [ ] . furthermore, damage to vessels releases vwf, which demonstrates evidence of endothelial injury in patients with proven thrombotic events [ ] . e final product of the coagulation cascade is the formation of thrombin, which, in the case of severe inflammation, overwhelms the body's natural anticoagulants resulting in platelet activation leading to thromboembolism and ultimately pulmonary embolism [ ] . in both cases presented, our patients had existing risk factors for venous thromboembolism. in case , there was a history of smoking, obesity, and prolonged periods of stasis. in case , long-term oral contraceptive use was noted. ese risk factors have been well studied and reported in the literature as precipitants of a hypercoagulable state. we suspect that the existing risk factors present along with the superimposed prothrombotic state induced by covid- induced inflammatory response may have precipitated the development of the venous thromboembolism resulting in pe. e chest guideline and expert panel report on management of venous thromboembolism (vte) in covid- patients outlines various recommendations for management of acute vte. e guidelines recommend that hospitalized covid- patients who develop dvt or pe should receive anticoagulation with lmwh (low-molecular-weight heparin) or iv unfractionated heparin (ufh) [ ] . lmwh or fondaparinux is preferred over ufh in critically ill patients. direct oral anticoagulants (doac) are recommended for outpatient management of covid- patients with acute dvt/pe [ ] . e recommended duration of anticoagulation treatment is three months [ ] . for patients with vte recurrence despite proper anticoagulation, lmwh adjusted for weight is the current recommendation. dosage increases of lmwh by - % is advised in refractory cases [ ] . at present, the efficacy of thrombolytic therapy in hemodynamically stable covid- patients is not well established and requires further investigation. erefore, thrombolytics should only be considered in patients with acute ischemic stroke, myocardial infarction, massive pe, and hemodynamic instability [ ] . can be assessed for risk of developing venous thromboembolism using an appropriate scoring system for critically ill patients. various scores exist including the improve, padua, and caprini prediction scores. international medical prevention of venous romboembolism (improve) estimates the three-month risk of developing venous thromboembolism in hospitalized patients [ ] . e padua prediction score is used to determine the risk of developing a venous thromboembolism and when to initiate thromboprophylaxis to minimize the impending outcome [ ] . caprini categorizes patients into four categories including low risk, moderate risk, high risk, and highest risk based on various criteria [ ] . each of these scoring systems has various criteria, and all include a prior history of venous thromboembolism, active or prior cancer, thrombophilia, and immobilization [ ] [ ] [ ] . although higher scores for each risk assessment model demonstrate an increased likelihood of the patient developing a venous thromboembolism and warrant the initiation of thromboprophylaxis, many clinicians have advocated for prophylactic thromboprophylaxis in covid- patients regardless of projected risk. it is essential to use a patient-specific approach and evaluate any underlying risk factors for vte which include history of previous vte, active cancer, immobility, or thrombophilia [ ] . ose with contraindications to medication should be placed on compression devices and regularly monitored [ ] . for critically ill patients, both pharmacologic and mechanical vte prophylaxis is recommended [ ] . dosing requirements should be tailored to the patient group. e antithrombotic practice guidelines on thromboprophylaxis for non-icu hospitalized covid- patients recommend subcutaneous unfractionated heparin twice-or thrice-daily, or once-daily subcutaneous lmwh or fondaparinux [ ] . in acutely ill patients, the chest guidelines recommend standard dose of anticoagulation with a preference for lmwh or fondaparinux over ufh [ ] . for critically ill patients, lmwh is the preferred agent. obi et al. and their ad hoc committee recommend thromboprophylaxis that consists of lmwh at a dose of mg daily or mg twice daily, or subcutaneous heparin at a dose of , units three times daily [ ] . critically ill covid- patients should receive the standard dose thromboprophylaxis with a preference for lmwh [ ] . patients with confirmed or high suspicion of thromboembolic disease should receive higher doses of anticoagulation [ ] . with improvement, the dose can be reduced to standard vte once the patient has been downgraded from the icu to the general medical floor [ ] . following discharge, some covid- patients may require vte prophylaxis. a multidisciplinary approach involving the patient and health care team should be implemented [ ] . some of the indications for outpatient vte prophylaxis include patients who required icu management, were mechanically ventilated, and were paralyzed for a prolonged period or those with vte risk factors identified on discharge [ , ] . suggested regimens include enoxaparin ( - day course), rivaroxaban ( - day course), and betrixaban ( - day course) [ ] . e derangements of coagulation parameters and systemic inflammation coupled with pre-existing risk factors provide the perfect storm for the development of thromboembolic disease. it is imperative to monitor middle-aged patients case reports in medicine who have known risk factors for hypercoagulability closely, take proper precautions, and be prepared for such events. e authors declare that they have no conflicts of interest. characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china early clinical and ct manifestations of coronavirus disease (covid- ) pneumonia acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography pulmonary embolism and increased levels of d-dimer in patients with coronavirus disease e emerging spectrum of cardiopulmonary pathology of the coronavirus disease (covid- ): report of autopsies from houston, texas, and review of autopsy findings from other united states cities incidence of thrombotic complications in critically ill icu patients with covid- venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in hypercoagulability of covid- patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis characteristics of ischaemic stroke associated with covid- e use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the perspectives of clinical immunologists from china romboinflammation and the hypercoagulability of covid- e procoagulant pattern of patients with covid- acute respiratory distress syndrome hyperinflammation and derangement of renin-angiotensinaldosterone system in covid- : a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis cytokines as regulators of coagulation prevention, diagnosis, and treatment of vte in patients with covid- predictive and associative models to identify hospitalized medical patients at risk for vte modified im-prove vte risk score and elevated d-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score rombosis risk assessment as a guide to quality patient care romboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum practical diagnosis and treatment of suspected venous thromboembolism during covid- pandemic key: cord- - zotqreu authors: dong, fen; zhen, kaiyuan; zhang, zhu; si, chaozeng; xia, jiefeng; zhang, tieshan; xia, lei; wang, wei; jia, cunbo; shan, guangliang; zhai, zhenguo; wang, chen title: effect on thromboprophylaxis among hospitalized patients using a system-wide multifaceted quality improvement intervention: rationale and design for a multicenter cluster randomized clinical trial in china date: - - journal: am heart j doi: . /j.ahj. . . sha: doc_id: cord_uid: zotqreu abstract background venous thromboembolism (vte) is a life-threatening disease that can affect each hospitalized patient. but the current in-hospital thromboprophylaxis remains suboptimal and there exists a large gap between clinical practice and guideline-recommended care in china. methods to facilitate implementation of guideline recommendations, we conduct a multicenter, adjudicator-blinded, cluster-randomized clinical trial, aiming to assess the effectiveness of a system-wide multifaceted quality improvement (qi) strategy on vte prophylaxis improvement and thromboembolism reduction in clinical setting. hospitals are randomized into intervention or control group. in intervention group, hospitals receive the concept of appropriate in-hospital thromboprophylaxis plus a multifaceted qi which encompasses four components: ( ) an electronic alert combining computer-based clinical decision support system and electronic reminders, ( ) appropriate prophylaxis based on dynamic vte and bleeding risk assessments, ( ) periodical audit and interactive feedback on performance, ( ) strengthened training and patient education. in control, hospitals receive the concept of recommended prophylaxis alone without qi. thromboprophylaxis will be at the discretion of hospitals and conducted as usual. with a final sample size of hospitalized patients in hospitals on mainland china, this trial will examine the effect of qi on improvement in thromboprophylaxis and patient-centered outcomes. this is an open-label trial that patients and healthcare professionals will know group allocation after enrollment, but endpoint adjudicators and statisticians will be blinded. rct# nct conclusions the system-wide multifaceted qi intervention is expected to facilitate implementation of recommended vte prophylaxis in hospital, thereafter reducing vte incidence and relevant adverse events among hospitalized patients in china. venous thromboembolism (vte) is an emerging health threat affecting hospitalized patients. approximately - % vte are hospital-associated vte (ha-vte) that occur during hospitalization or within days after discharge , underlying more than % of vte burden on population . it is a global problem faced across countries to enhance healthcare providers' adherence to recommended care and facilitate implementation of appropriate thromboprophylaxis, we develop a system-wide multifaceted quality improvement (qi) strategy. a multidisciplinary group of hospital staff (doctors, nurses, administrators, pharmacists, etc) from a wide range of departments will be engaged to carry out the qi. given that each inpatient has at least one vte risk factor during hospital stay , , qi strategy needs to be comprehensive and systematic for the delivery of thromboprophylaxis to all patients. to examine its effectiveness on vte reduction and determine how best to implement the recommended prophylaxis, we conduct a multicenter cluster randomized trial. eligible hospitals will be selected from chinese prevention strategy for venous j o u r n a l p r e -p r o o f / conduct this multicenter trial to assess effect of qi on thromboprophylaxis in a large-scale patient population. initially, this trial was scheduled to start in february but delayed due to covid- outbreak. currently, the epidemic is under control and hospitals are returning to normal work. we will continue to perform this study with a baseline survey to assess hospital eligibility in april and complete hospital randomization in the following month. the primary objective of this study is to determine whether the system-wide multifaceted intervention increases appropriate vte prophylaxis rate in hospitalized patients and decreases incidence of any hospital-associated vte within days after hospital admission. the secondary objective is to reduce safety events, including death incidence (i.e. all-cause mortality, vte-related mortality) and complications related to prophylactic interventions (e.g. major and clinically relevant non-major bleeding, thrombocytopenia) during the -day follow up. in this multicenter two-armed adjudicator-blinded cluster randomized trial, eligible hospitals are selected from chips-vte study network, which includes secondary and tertiary hospitals across mainland china. randomization and interventions are convened at hospital level. during the study period, hospitals in both arms will receive the concept of appropriate vte prophylaxis. in qi group, a multifaceted j o u r n a l p r e -p r o o f / intervention will be delivered systematically to facilitate implementation of the recommended care while hospitals in control just receive the concept without qi. in-hospital thromboprophylaxis will be at the discretion of hospitals according to usual care. this is an open-label trial that group allocation will not be blinded to either patients or healthcare professionals. to objectively assess outcomes, adjudicators not involving in study design will assess outcomes. the study is anticipated to be completed in months, starting from hospital selection, patient enrollment, intervention in hospital, -day follow up after admission, and data collection of the last patient ( figure ). to ensure implementation of quality improvement intervention during study period, participating hospitals will be selected from tertiary hospitals where electronic information systems are accessible and computer-based clinical decision support system (cdss) can be embedded. the eligible hospitals will be determined within chips-vte network ( figure s ). we plan to select hospitals fulfilling eligible criteria and enroll patients consecutively at each hospital (table ) . see statistical analysis plan section for details on sample size estimation. the enrollment is expected to be completed within the first - months. the study population comprises patients admitted to nine high-risk departments ( enrolled consecutively until the sample size is met. intervention is applied to all inpatients admitted to the target departments. we will conduct a baseline survey for hospital eligibility assessment, including hospital characteristics (hospital grade, availability of his, medical and surgical departments, etc.), hospital directors' willingness to participate in the study, and current status of in-hospital thromboprophylaxis. there are tertiary and secondary hospitals in chips-vte network. we deploy a stratified sampling method to select hospitals from the network ( figure s for details). stratified permuted block randomization will be adopted to assign hospitals into either qi or usual care group. hospitals are units for randomization with group allocated at hospital level. by stratifying hospitals into those above or under the median prophylaxis rate obtained in baseline survey, hospitals alphabetically ordered by names will be randomized into each group with a varying block size of or within strata. the randomization procedures will be organized centrally by statisticians in the randomization center. to guarantee blindness to group allocation, hospital j o u r n a l p r e -p r o o f / enrolment phase, an independent recruiter responsible for enrollment will be masked to hospital allocation. they will not know the allocation sequence until eligible patients are enrolled. afterwards, interventions assigned to the hospital will be delivered to individual patients by doctors. at each hospital, we schedule to enroll eligible patients consecutively with an average number of hospitalized patients enrolled from departments. patients admitted to the targeted departments and signing informed consent will undergo assessment for eligibility in screening phase. the enrolled patients and those with screen failure will be compared to evaluate potential selection bias. after enrollment, patients receive interventions assigned to hospitals. in the newly issued guidelines - , risk stratification is recommended to guide appropriate thromboprophylaxis. each patient needs undergo vte and bleeding risk assessments, particularly when they are admitted, transferred to another department, or their disease conditions change greatly. validated risk score toolkits are utilized for this dynamic risk monitoring. identifying patients at diverse risk for vte and bleeding helps determine appropriate prophylactic interventions. if patients are at risk of vte and have bleeding risk factors (eg, recent bleed, thrombocytopenia, active bleeding) , mechanical intervention, eg. graduated compression stockings, j o u r n a l p r e -p r o o f / intermittent pneumatic compression, and venous foot pumps, is the appropriate prophylaxis approach. it is an alternative for patients contraindicative to anticoagulant prophylaxis, the use of which could lead to bleeding and safety events. if patients have low bleeding risk, pharmacological prophylaxis is preferred over mechanical ones. overall, both thrombosis and bleeding risk assessments are recommended for an optimal decision-making in clinic practice. thromboprophylaxis approaches may need adjustment accordingly due to patients' changing risk during hospital stay ( figure , figure ). to implement the aforementioned recommendations, we design a multifaceted qi intervention, which entails four components that interact mutually. it is applied in a wide variety of inpatient settings, including surgical and medical patients. conditions, transfer to another department and discharge. data in emr will be captured to ascertain the implementation of risk assessment and appropriateness of prophylactic prescriptions. in case of uncompleted risk assessment or improper prophylaxis intervention, medical records submitted by medical staff will be blocked and an e-alert will be sent to remind the staff to correct. performance adjustments are needed until requirements are met. all the computer programs and e-alertness will be well designed and tested in the hospitals assigned to qi group. simultaneously, real-time data monitoring and feedback will be accomplished via the electronic system. a cyclical model of predefined performance measures is designed to automatically analyze and provide feedback on quality of prophylaxis. when administering qi intervention, doctors and nurses' behaviors will be reviewed and audited by health administrators. some in-process metrics (vte and bleeding risk assessments within hours after admission, dynamic risk assessment, appropriate vte prophylaxis) and outcome metrics (ha-vte incidence, clinically relevant bleeding and mortality) will be calculated and sent to medical staff and health j o u r n a l p r e -p r o o f / administrators via cdss for audit. ( ) dynamic vte/bleeding risk assessments risk factors for hospital-associated vte are well characterized, enabling the use of vte risk assessment to identify high-risk population for early and appropriate prophylaxis. according to existing evidence , , we recommend the use of caprini risk score for vte risk assessment in surgical patients while padua risk score be used to assess vte risk in medical patients ( table ). all admitted patients undergo vte assessment. nurses perform the initial assessment and doctors confirm the results. meantime, patients' age, comorbidities, trauma history, medications, invasive procedures and other factors are assessed for bleeding risk by doctors. as disease conditions change during hospital stay, patients need to be assessed for vte and bleeding risk repeatedly. dynamic assessments are scheduled to be done at admission, transfer to another department, a significant change in disease conditions, and at discharge. ( ) regular audit and interactive feedback on performance performances of medical staff (doctors and nurses) are audited monthly by vte prevention committee, which comprises hospital directors, medical and nursing directors, and health administrators. using the audited data, the committee sends reports to medical staff, including the overall thromboprophylaxis, in-process and outcome metrics, root-cause analysis of vte safety events, and measures for quality improvement. in the context of missed risk assessments or inappropriate prophylaxis j o u r n a l p r e -p r o o f / delivered, an electronic alert will remind health administrators, who in return send feedback to responsible medical staff and urge them to administer interventions in accordance with the recommended care. the initial feedback will be followed by an electronic reminder. medical staff's performances may need to be adjusted until the expected prophylaxis is delivered properly. ( ) strengthened hospital staff training and patient education on vte hospital directors and health administrators will receive trainings on the concept of ha-vte prevention, overall goal and operation mechanisms, and challenges that need to be tackled with. the trainings will be provided within days after hospital randomization. medical education focusing on vte risk assessment, prevention, diagnosis and treatment will be convened to doctors, nurses, pharmacists and other medical staff per quarter. the knowledge of vte are based on newly published guidelines and consensus - , - . likewise, education sessions will be offered to patients and family caregivers to increase their awareness on vte general knowledge. doctors or nurses provide the education when patients are admitted and discharged. during hospitalization, nurses will also instruct patients on the use of graduated compression stockings (gcs) or intermittent pneumatic compression (ipc). if not using correctly, patients will receive strengthened education until using these devices correctly. at discharge, guidance on thromboprophylaxis or anticoagulant regimen will be provided for patients or those remaining at high risk of vte. j o u r n a l p r e -p r o o f / in hospitals allocated to control group, patients will undergo usual care at the discretion of hospitals. vte risk assessment and prophylactic interventions will be performed according to existing practice in hospitals. nearly % surgeons responding to the survey routinely prescribed lmwh for patients with lung resection during hospitalization. acetylsalicylic acid was still used as a prophylaxis approach in common practice. time for starting vte prophylaxis was usually day after operation. the two surveys display current prophylaxis for ha-vte in china. to better understand usual care in control group in this study, we will conduct a baseline survey in recruited hospitals before cluster randomization, collecting information on vte and bleeding risk assessment, prophylactic approaches, initiating time for prophylaxis, etc. as our study population are medical or surgical patients admitted to the nine j o u r n a l p r e -p r o o f / departments with high vte incidence, patients in both arms will receive treatments targeted to diseases responsible for the admission. the treatment patterns and disease management will be at the discretion of doctors. additionally, vte incidence and bleeding events within days are important outcomes for effect and safety assessment. to enhance patients' self-reported outcomes, education on signs and symptoms of vte and bleeding will be delivered to patients during hospitalization in both groups. due to the nature of interventions, both doctors administering interventions and patients will know group allocation after enrollment. to ensure equal attention to two arms, data collectors, endpoint adjudicators, and statisticians will be blinded to group allocations. before intervention, a randomization schedule for hospitals will be pre-generated by an independent statistician unaware of hospital identity. during the intervention period, data managers and statisticians remain blinded to group assignment in data collection and monitoring. an independent data monitoring board will evaluate the trial data and safety. in order to objectively evaluate outcomes, adjudicators assessing thromboprophylaxis implemented in hospitalized patients, imaging results for vte diagnosis and other endpoints will be blinded. the primary endpoint is appropriate prophylaxis rate in hospitalized patients, defined bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, temporary cessation of study treatment, or discomfort of pain or impairment of activities of daily life . hit is a fall in platelet count of > % from the highest platelet count after the start of heparin use with a positive laboratory test . safety events will be collected by phone visits at day and after admission. any endpoint or adverse events occurring during study period will be recorded. during study period, some key in-process and outcome metrics will be regularly monitored (table s ). caprini or padua scores, begun with the initial assessment within hours at admission until the last one at discharge, will be recorded in medical records. bleeding assessments are recorded simultaneously. appropriate prophylaxis is determined by vte and bleeding risk. mechanical or pharmaceutical interventions are adopted accordingly. to enhance medical staff's awareness on appropriate prophylaxis, trainings on indications and contraindications to mechanical prophylaxis or therapeutic anticoagulation treatment will be delivered per quarter. for to mechanical or therapeutic treatment are embedded into cdss system to prompt doctors while prescribing prophylactic regimen. in this study, data collection starts from patient enrollment and continues until completion of the last patient follow up. figures s demonstrates the process of data management and quality control. sample size is estimated based on the primary analysis of group difference in vte prophylaxis rate among hospitalized patients. the nationwide survey on thromboprophylaxis in china demonstrates an appropriate prophylaxis rate of . % in hospitalized patients . assuming a target clinical difference of % absolute increase through qi intervention, we anticipate an appropriate prophylaxis rate of . % in qi group. in this cluster trial with hospitals as unit of randomization, between-cluster variation is indicated by intra-cluster correlation coefficient (icc), one typically used index for such variation . icc is determined as . according to prior studies , . given the same cluster size with an equal number of patients per hospital (cluster), we plan to enroll patients from each hospital and approximately patients from each of the nine target departments. to compare between-group prophylaxis rates with : allocation, % power, % significance level, a cluster size of , . icc and % attrition, the sample size is calculated as patients according to j o u r n a l p r e -p r o o f / accessible to study investigators or authorized personnel. to comply with data safety regulations, only staff at the study center have access to patients' information. this study is approved by ethics committee in china-japan friendship hospital (approval number -ssw- ) and will be approved by ethnic committee in each hospital. it has been registered at www.clinicaltrials.gov (nct ). in this multicenter cluster randomization trial, intervention is applied at hospital level. written consent will be obtained from directors at hospital level with agreement for participation and randomization, avoiding selection bias potentially induced by differences in consent refusal between hospitals [ ] [ ] [ ] . qi intervention is supposed to be beneficial in ha-vte prevention among hospitalized patients through effective implementation of recommended prophylaxis. each participating hospital prefers to receive the qi interventions. to reduce hospital withdrawal, the qi interventions, if proven effective, will be delivered to all hospitals randomized to control group after completion of this study. in patient enrollment process, informed consent will be obtained from patients as well. written consent includes consent for information routinely collected in hospital, willingness to provide complementary data specific to this study, and permission for -day follow up. due to chronology of individual patient recruitment after hospital randomization in clustered randomization trial , this study is prone to selection bias j o u r n a l p r e -p r o o f / induced by unblinded recruiters or patients who are informed or aware of hospital allocation. to prevent such bias, recruiters in each hospital will be blinded to group allocation and enroll patients independently. partial information rather than full information will be provided to patients in enrollment process to avoid opt-out option in patients. the hospital allocation will not be specified to patients until they are enrolled and undergo intervention. chinese hospitalized patients and their unmet need in thromboprophylaxis . the qi can also be introduced into routine clinical practice to enhance care quality and reduce vte-related safety events. a systematic approach for ha-vte prevention in nhs england has been demonstrated to be effective in reducing post-discharge deaths with a . % reduction in -day mortality , indicating importance of a system-wide and multifaceted intervention for effective prevention of ha-vte and its related deaths. given the great disparities in health care systems, hospital protocols and structures across nations and cultures, chips-vte study will provide data on systematic and multifaceted implementation's effect on patient outcomes in developing countries. the present study has the following unique features: ( ) a multi-center cluster randomized trial is designed to minimize contamination across groups; ( ) uses of cdss and e-alertness in a wide variety of inpatient settings increase their applicability in daily practice. application of cdsss in this study will meet the increasing demand for health information technology regarding the growing concerns about quality of medical care in hospital; ( ) real-time and mutually interactive quality control via cdss enable qi intervention implemented properly among multidisciplinary hospital staff; ( ) a pilot study has been done to test the feasibility of multifaceted qi in clinical setting, enhancing feasibility of this multi-center trial; ( ) behavioral intervention in healthcare professionals through qi and usual practice in control will provide real-world evidence on effectiveness of qi on thromboprophylaxis improvement. the pragmatic design increases generalizability of meanwhile, there are several inherent limitations in this study. first, this is a cluster randomization trial with hospitals being randomized as clusters. hospital randomization occurs before patient enrollment, making allocation concealment difficult. selection bias may arise when unblinded recruiters don't enroll patients because their hospitals are not allocated to the group they expect to be in, which may also lead to hospital withdrawal . in addition, consent bias could be induced by patients who have been informed of or get known the group allocation before enrollment , . to minimize these bias inherent in methodology, informed consent needs to be handled differently from traditional randomized trials, in which randomization and intervention are administered at individual level. we will obtain well-informed written consent from hospital directors and agree to provide qi intervention to hospitals in control group after completion of the study. in patient enrollment phase, information on group allocation will not be provided to patients until they are enrolled. a blinded recruiter unaware of hospital allocation will recruit patients independently. with respect to effectiveness evaluation in this study, qi to select representative hospitals, we deploy a stratified sampling method based on geographic regions (northeast, north, east, south central, northwest, and southwest china) and baseline vte prophylaxis quality (median prophylaxis rate by region obtained from the survey). in each region, the number of selected hospitals will be proportional to the number of candidate hospitals. noteworthily, some core hospitals that provide optimal care in the region will be chosen purposively to represent the high quality of care in china. taking non-response into consideration, we increase the sampling rate to approximately %. if directors in selected hospitals decline to participate, the remaining unselected hospitals will be sampled randomly until a total of eligible hospitals are recruited. during the study period, information on patients' demographic characteristics, care provided, risk assessments, interventions and others will be entered into cdss. illogical data entries, ( ) tertiary hospitals with > beds that provide vte diagnosis and care, deliver medical education, and conduct research. ( ) have departments in which admitted patients are at increased risk for vte and thrombotic events can easily occur in routine procedures. the departments that typically have high vte incidence are respirology, icu, neurology, orthopaedics, general surgery, vascular surgery, neurosurgery, oncology, and gynecology. ( ) hospital electronic information system is accessible and cdss can be embedded for real-time monitoring and mandatory implementing qi intervention during the study; ( ) directors of hospitals wish to improve in-hospital vte prophylaxis and are willing to conduct multifaceted qi intervention systematically. ( ) hospitals that have already conducted qi intervention systematically preventing hospital associated venous thromboembolism interventions for implementation of thromboprophylaxis in hospitalized patients at risk for venous thromboembolism the cochrane database of systematic reviews trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients vte risk profiles and prophylaxis in medical and surgical inpatients: the identification of chinese hospitalized patients' risk profile for venous thromboembolism (dissolve- )-a cross-sectional study trends in hospitalization and in-hospital mortality from vte antithrombotic therapy for vte disease: chest guideline and expert panel report prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis prevention and management of hospital-associated venous thromboembolism prevention, treatment and management of hospital-asociated venous thromboembolism guidelines on the diagnosis, management and prevention of pulmonary thromboembolism heparin-induced thrombocytopenia measures of between-cluster variability in cluster randomized trials with binary outcomes primary care management for optimized antithrombotic treatment [picant]: study protocol for a cluster-randomized controlled trial developments in cluster randomized trials and statistics in medicine. statistics in medicine methods for sample size determination in cluster randomized trials effect of a quality improvement intervention with daily round checklists, goal setting, and clinician prompting on mortality of critically ill patients: a randomized clinical trial participant informed consent in rationale and design for a multicenter cluster randomized clinical trial in china fen dong admin ; tieshan zhang, md ; lei xia phd , , , ; on behalf of chinese prevention strategy for venous thromboembolism graduate school of peking union medical college, chinese academy of medical sciences and peking union medical college, beijing, china; department of information management formal analysis, writing -original draft, visualization. kaiyuan zhen: investigation, writing -original draft, visualization. zhu zhang: investigation, writing -review & editing. chaozeng si: software, jiefeng xia: software, resources. tieshan zhang: software, resources. lei xia: investigation, resources. wei wang: investigation, resources. cunbo jia: resources. guangliang shan: methodology. zhenguo zhai: conceptualization, methodology effect on thromboprophylaxis among hospitalized patients using a system-wide multifaceted quality improvement intervention: rationale and design for a multicenter cluster randomized clinical trial in china fen dong admin ; tieshan zhang, md ; lei xia phd , , , ; on behalf of chinese prevention strategy for venous thromboembolism graduate school of peking union medical college, chinese academy of medical sciences and peking union medical college, beijing, china; department of information management we thank all hospital directors within chips-vte network to participate in baseline survey and hospital eligibility assessment. doctors, nurses, health administrators, researchers, and patients' engagement in the study will be appreciated. j o u r n a l p r e -p r o o f  unmet clinical need in thromboprophylaxis remains in chinese hospitalized patients  the first pragmatic trial for improving in-hospital thromboprophylaxis in china  multifaceted quality improvement facilitates implementation of thromboprophylaxis  hospitals are randomized to either quality improvement intervention or routine care  real-world effectiveness of intervention on thromboprophylaxis is assessed key: cord- -h zwlyz authors: watson, ryan a.; johnson, drew m.; dharia, robin n.; merli, geno j.; doherty, john u. title: anti-coagulant and anti-platelet therapy in the covid- patient: a best practices quality initiative across a large health system date: - - journal: hospital practice doi: . / . . sha: doc_id: cord_uid: h zwlyz the coronavirus disease (covid- ) pandemic due to severe acute respiratory syndrome coronavirus (sars-cov- ) has challenged health-care systems and physicians worldwide to attempt to provide the best care to their patients with an evolving understanding of this unique pathogen. this disease and its worldwide impact have sparked tremendous interest in the epidemiology, pathogenesis, and clinical consequences of covid- . this accumulating body of evidence has centered around case series and often empiric therapies as controlled trials are just getting underway. what is clear is that patients appear to be at higher risk for thrombotic disease states including acute coronary syndrome (acs), venous thromboembolism (vte) such as deep vein thrombosis (dvt) or pulmonary embolism (pe), or stroke. patients with underlying cardiovascular disease are also at higher risk for morbidity and mortality if infected. these patients are commonly treated with anticoagulation and/or antiplatelet medications and less commonly thrombolysis during hospitalization, potentially with great benefit but the management of these medications can be difficult in potentially critically ill patients. in an effort to align practice patterns across a large health system (jefferson health , staffed inpatient beds and intensive care unit (icu) beds across facilities), a task force was assembled to address the utilization of anti-thrombotic and anti-platelet therapy in covid- positive or suspected patients. the task force incorporated experts in cardiology, vascular medicine, hematology, vascular surgery, pharmacy, and vascular neurology. current guidelines, consensus documents, and policy documents from specialty organizations were used to formulate health system recommendations. objective: our goal is to provide guidance to the utilization of antithrombotic and antiplatelet therapies in patients with known or suspected covid- . covid- ; anti-coagulation; anti-platelet; thrombosis; acute coronary syndrome; venous thromboembolism; stroke; peripheral arterial disease; left ventricular assist device; extracorporeal membrane oxygenation coronavirus (covid- ) due to severe acute respiratory syndrome coronavirus (sars-cov- ) is a global pandemic with over . million confirmed cases worldwide and over , deaths as of may . currently, the united states leads all countries with over . million confirmed cases and over , deaths [ ] . disease severity ranges from asymptomatic to critical illness resulting in fatality. early studies revealed an increased prevalence of acute cardiovascular events leading to a higher risk of mortality [ ] [ ] [ ] [ ] . covid- patients may present with hemodynamic instability and increased biomarkers of cardiac injury, specifically troponin and b-type natriuretic peptide. this may be due to an acute coronary syndrome (acs), myocarditis, type myocardial infarction, coronary vasospasm, or stress-induced cardiomyopathy. the specificity of these biomarkers in this setting is uncertain. additionally, markedly elevated d-dimer levels are associated with severe illness and high mortality. this has been postulated to be due to micro thrombosis but alternatively may be due to disseminated intravascular coagulation (dic) secondary to an increased inflammatory state. patients also appear at higher risk of venous thromboembolism (vte) due to critical illness, immobility, and inflammation. managing patients acute antiplatelet and anticoagulant regimens can be difficult without clear consensus on diagnosis and treatment. many patients are on antiplatelet and anticoagulants for preexisting conditions when they present to the hospital and thus the balance of further ischemic/thrombotic events vs. bleeding events must be weighed. the margin of error appears to be narrower in patients with multi-system failure where fluctuating organ function can impact drug metabolism. we aim to provide guidance for the management of various clinical scenarios encountered in covid- infected patients recognizing that these recommendations may change given the rapidly evolving understanding of covid- pathophysiology. the diagnosis of acs in the covid- patient can be challenging given that patients often have elevated troponin levels. biomarkers are nonspecific measures of cardiac injury and may represent a myriad of cardiac conditions including myocardial ischemia secondary to either plaque rupture or demand ischemia,, myocarditis, stress cardiomyopathy, or coronary spasm. in order to assist with diagnosis and treatment, it is important to take into consideration the patient's clinical presentation, electrocardiogram (ecg), and point of care ultrasound to evaluate ventricular wall motion. typically, with acs there is a characteristic rise and fall in troponins which represents myocardial tissue necrosis due to hypoperfusion, as opposed to myocarditis which can often lead to elevated but relatively stable troponin levels that represent ongoing myocardial inflammation and injury. a recent report demonstrated that st-elevation myocardial infarction (stemi) activation is down % in the united states [ ] with growing concern that patients do not seek immediate medical attention due to fear of exposure to covid- leading to missed events. we recommend in all patients with concern for acs, nonenteric coated aspirin - mg should be given immediately if no contraindication exists followed by daily low dose aspirin ( mg) indefinitely. p y inhibitor (clopidogrel, ticagrelor, or prasugrel) should be considered in these patients with guidance from cardiology with a length of therapy for year in most patients [ ] [ ] [ ] . for patients on anticoagulation prior to acs, triple therapy should be used for the shortest duration possible. a regimen of a direct oral anticoagulant (doac) with clopidogrel with short duration of aspirin is now considered the standard of care and triple therapy with warfarin should be avoided [ ] [ ] [ ] [ ] [ ] [ ] . all stemi patients should receive standard medical therapy including full dose aspirin, high-intensity statin, unfractionated heparin (ufh), and nitrates for chest pain if hemodynamics allow. there has been considerable discussion regarding best practices for patients who present with stemi in the covid- era with the debate over fibrinolytic therapy versus primary percutaneous coronary intervention (pci). based on early experience out of peking union medical college hospital in china, it was recommended that all stemis be treated with thrombolytic therapy given its efficacy and ease of administration and to limit health-care worker exposure [ ] . in the united states, approximately % of stemis prior to the covid- era had fibrinolytic reperfusion strategies due to the inability to access hospitals with pci capabilities within minutes [ ] . to ensure staff safety, there can be considerable system delays in patients who present with stemi and have concern for covid- . these delays may cause patients to no longer receive standard of care primary pci within the designated door to balloon time of minutes, and the mortality benefit of primary pci may no longer be significant compared to fibrinolytic therapy [ ] . finally, there is concern about transmission of infection from patient to staff and resources needed for these patients that fibrinolytic therapy may be considered in the covid- patient population [ ] . despite the initial push for fibrinolytic therapy, there is hesitation with this strategy as it can lead to unnecessary use of thrombolytics in the case of 'stemi-mimicker,' patients with covid- who have non-obstructive coronary artery disease on coronary angiography despite stemi on ecg [ , ] . the use of fibrinolytics in this population would lead to no clinical benefit and potential significant harm. even in those patients who receive thrombolytics for stemi, approximately % require rescue pci and thus the benefit of thrombolytics seems to be low in patients where pci can be performed. due to these concerns, the current society for cardiovascular angiography and interventions (scai) consensus document suggests continuing primary pci for stemi patients as the treatment of choice with the use of fibrinolytic therapy only for selected lower-risk patients (those with inferior stemi without rv involvement and those with lateral stemi without hemodynamic compromise) [ ] . the recommendation for primary pci in the covid- patient was reiterated in a consensus statement from scai, american college of cardiology (acc) and the american college of emergency physicians (acep) and a pharmacoinvasive approach should only be considered if primary pci is not feasible [ ] . we agree that primary pci should remain standard of care if a patient is at a pci capable hospital. the lack of familiarity with fibrinolytics dosing for many providers, their increased risk of significant bleeding, and the possibility of treating patients without coronary thrombosis makes this a less attractive first-line therapy. in patients with whom primary pci is not possible due to access to a cardiac cath lab, we recommend a pharmacoinvasive approach with fibrinolytic therapy followed by transfer to a pci capable hospital for possible intervention [ ] . if pci is performed, dual antiplatelet therapy with aspirin and p y should ideally be continued for year. the diagnosis of type nstemi (plaque rupture) is difficult in the covid- era due to the elevated troponin levels in a significant proportion of patients [ ] . the true incidence of type myocardial infarctions is not well known and thus covid- positive patients with elevated troponins should be risk stratified to determine the most appropriate management. all patients should receive medical therapy with full dose aspirin, high-intensity statin, parental anticoagulation (heparin or low molecular weight heparin (lmwh)), beta blocker if hemodynamics allow, and possible nitrate therapy if ongoing chest pain [ ] . in patients undergoing early invasive strategy, we recommended using heparin over lmwh as an anticoagulant of choice due to the ability to titrate the medication and to measure the degree of anticoagulation in the cardiac catheterization lab with activated clotting times. patients who are covid- negative should be considered for early invasive therapy [ ] . in patients who are covid- positive or still under investigation, we recommend invasive strategy in patients who have grace score > [ ] or those with high-risk clinical features such as refractory chest pain, unstable arrhythmias, heart failure, or hemodynamic instability. in covid- positive patients with low-risk nstemi, we recommend a delayed invasive approach and upfront medical management [ ] . these patients receive less benefit from early-invasive primary pci compared to high-risk nstemi. we believe that the risks of resource utilization, risk of virus transmission to hospital workers, and lack of definitive diagnosis is higher than the potential benefit of invasive angiography and potential pci in this population. we recommend lmwh preferentially over ufh due to the ease of administration, lack of medication titration, and fewer lab draws that could lead health-care professionals to unnecessary exposures. in medically treated nstemi patients, aspirin ( mg) with either clopidogrel ( mg) or ticagrelor ( mg bid) should be given if no contraindication exists. prasugrel is not indicated for patients being treated medically for nstemi [ ] . consideration for outpatient testing and coronary angiography can be considered in these patients in the future once their infection has resolved in accordance with scai/acc/ acep recommendations [ ] . patients with covid- may present on therapy from previous coronary intervention irrespective of their current hospital admission. data is limited in this patient population, and we, therefore, rely on established guidelines for antiplatelet recommendations [ ] . patients with covid- may have thrombocytopenia and other coagulopathies similar to dic which can make the use of anti-platelet agents more challenging. it is important for providers to understand the indication for the patient's antiplatelet therapy in sihd as it can help guide therapy in those patients at higher bleeding risk. all patients with previous stent placement should be continued on single antiplatelet therapy regardless of indication unless at very high bleeding risk. in patients on therapy with platelet count > , mm and at a low risk of bleeding, we recommend continuing outpatient anti-platelet therapy for the duration recommended in the acc/ aha guidelines [ ] . in patients with a platelet count between , mm to , mm we recommend continuing aspirin therapy and if platelet count < , mm discussion with cardiology regarding the ongoing benefits of aspirin therapy (i.e. location of stents, previous ischemic history, size of stents, timing of stent) with the risk of bleeding. acute and chronic respiratory illnesses are risk factors for atrial fibrillation [ , ] . covid- patients, commonly present with shortness of breath secondary to viral pneumonia with critically ill patients progressing to acute respiratory distress syndrome (ards). unfortunately, the rate of new atrial fibrillation in these patients is unknown. management of patients with atrial fibrillation includes oral anticoagulation which is recommended for patients with cha ds -vasc score of or more in men or or more in women as long as the benefit of anticoagulant outweighs the risk of bleeding [ ] . in most scenarios, direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin due to large randomized controlled trials showing noninferiority or superiority for stroke reduction and superiority for bleeding risk in patients with non-valvular atrial fibrillation [ ] [ ] [ ] [ ] . in the inpatient setting, there is less guidance on the initiation of anticoagulation for new onset atrial fibrillation and decisions to continue outpatient oral anticoagulation can be more difficult due to rapid fluctuations in clinical status, need for invasive procedures, and renal/liver function changes. the risk of endothelial damage, vascular inflammation, and vascular thrombosis appears heightened in severe covid- patients and thus could pose an increased risk of arterial thrombosis in this patient population. the use of ufh or lmwh may be considered in patients with high potential stroke risk and new onset atrial fibrillation; however, heparin drips require constant monitoring and titration of dosing during hospitalization leading to increased nursing exposure to potential covid- patients. in this group, therapeutic enoxaparin mg/kg every hours could be used instead of unfractionated heparin. inpatient anticoagulation will be recommended for de novo af based on the risks of benefits of the individual patients with men with cha ds -vasc ≥ and women ≥ being most likely to benefit from anticoagulation. in this context, the annual stroke risks are between % and % in patients with cha ds -vasc or , and > % in patients with cha ds -vasc ≥ [ ] . we would recommend lmwh over heparin as long as creatinine clearance (crcl) ≥ and no need for invasive procedures. in patients who are established on anticoagulation due to previous diagnosis of atrial fibrillation, continuing oral anticoagulation should be considered in patients at low risk of clinical decompensation or bleeding. in patients who are critically ill, we recommend holding outpatient oral anticoagulation and consideration of using a parenteral agent (heparin/ lmwh). the risks and benefits of stroke vs. bleeding as well as duration of time without oral anticoagulation should be considered in all cases. for patients who do not have prohibitive bleeding risk and cha ds -vasc score ≥ or previous thromboembolic event, we would recommend a parental agent with lmwh considered first-line therapy if crcl ≥ [ ] . patients with mechanical heart valves and atrial fibrillation who require invasive procedures should be bridged with heparin or lmwh [ , ] . the acc manageanticoag app can be used to help providers determine the need for anticoagulation interruption and bridging in case by case scenario (figure ). despite the concern for increased thrombotic risk in covid- patients, there are no published reports of prosthetic valve thrombosis in this patient population. as such, we recommend anticoagulation in accordance with the latest acc/aha valvular guidelines. all patients with a mechanical heart valve should continue anticoagulation with a vitamin k antagonist (vka) with their previously recommended goal international normalized ratio inr [ , ] . all patients with mechanical valve prostheses should also be continued on mg aspirin daily [ ] , and it is reasonable for patients with bioprosthetic valve prostheses to be continued on asa mg daily [ ] . anticoagulation with doacs should be avoided in patients with mechanical valve prostheses [ ] . in patients on anticoagulation due to mechanical valve, anticoagulation should not be interrupted for low bleeding risk procedures. if, for a procedure, anticoagulation needs to be interrupted, then bridging with lmwh or heparin is reasonable for patients with mechanical mitral valve, mechanical aortic valve with risk factor(s) (atrial fibrillation, low ef, hypercoagulable state, or previous vte), or older generation mechanical aortic valve [ ] . we suggest that warfarin only be continued upfront in those patients who are not critically ill or at high bleeding risk. in all others, suggest transition to a parental agent with a bridge until warfarin can be resumed. currently, the most common neurologic manifestations of covid- that should prompt strong consideration of an acute cerebrovascular event include dizziness, headache, focal neurologic deficits, and encephalopathy [ ] . in four early studies, ischemic and hemorrhagic stroke complicated covid- infection in about % of patients at a median days after symptom onset and the incidence, particularly of stroke due to large vessel occlusion, continues to rise in the united states [ ] [ ] [ ] [ ] . in addition to common cardiovascular comorbidities in the elderly covid- positive population, mechanisms for ischemic stroke in infected patients of all age groups include hypercoagulability from proinflammatory state, embolism from virus-related cardiac injury, and infection-induced disseminated intravascular coagulation. intracerebral hemorrhage and hemorrhagic conversion of ischemic stroke may also occur due to possible coagulopathy, specifically thrombocytopenia, in the severely ill, fluctuating blood pressures due to viral-binding to ace receptors [ ] , and potential interactions between anticoagulants and medications now commonly used for covid- patients (table ) . non-contrast computed tomography (ct) head is the appropriate initial imaging in covid- patients with neurologic symptoms particularly prior to initiation of antithrombotic agents. while most serum studies are not required prior to emergent iv-tpa use based on guidelines, it may be reasonable to await results of coagulation studies and complete blood count in critically ill covid- suspected or positive patients prior to thrombolytic administration. patients with large vessel occlusion remain eligible for endovascular therapy despite infection. antithrombotic recommendations for secondary prevention of stroke in the suspected or positive covid- patient are currently unchanged from the general population assuming the absence of coagulopathy and prothrombotic state. for ischemic stroke due to small and large vessel atherosclerotic disease as well as embolic strokes of undetermined source, antiplatelet therapy with aspirin, clopidogrel, or aspirin/dipyridamole remains the appropriate first-line therapy [ , ] . dual antiplatelet therapy should be reserved for symptomatic intracranial atherosclerotic disease [ ] , certain carotid cases, recent stenting, and patients with recent minor stroke or highrisk tia [ ] . outcomes in available covid- patient data do not suggest clear benefit over risk of therapeutic anticoagulation for primary stroke prevention. however, assuming low risk of hemorrhagic conversion, therapeutic anticoagulation with lmwh is frequently initiated for secondary stroke prevention in the critically ill with significantly elevated d-dimer and no other clear etiology of ischemic stroke. in addition to patients with atrial fibrillation, consider anticoagulation with ufh/ lmwh, warfarin, or doacs in patients with ischemic strokes that are embolic appearing with cardiac etiology, nonocclusive thrombi, recurrent ischemic strokes, atypical intracranial stenosis, venous sinus thrombosis, extracranial dissection with ischemia, and pro-thrombotic state [ ] . minimize the use of triple therapy to avoid intracranial hemorrhagic complications. the appropriate timeframe to initiate anticoagulation in the ischemic stroke patient remains heavily individualized based on age, comorbidities, stroke size and location, imaging characteristics, and medication choice. the decision to initiate antithrombotic therapy in covid- positive patients with acute neurologic symptoms should be made in conjunction with a neurologist. peripheral arterial disease is a common cardiovascular disorder that is highly under-recognized with significant cardiovascular morbidity, mortality, and quality of life impairment. in patients with symptomatic peripheral arterial disease, anti-platelet medication with either aspirin ( - mg per day) or clopidogrel ( mg per day) is recommended as first-line therapy [ ] . the use of dual antiplatelet therapy is beneficial only in those patients who have undergone revascularization [ ] . patients should remain on these medications throughout their hospitalization unless high bleeding risk. acute limb ischemia (ali) is associated with significant morbidity and mortality and is defined as < weeks of severe hypoperfusion of the limb characterized by features of pain, pallor, pulselessness, poikilothermia, paresthesias, and paralysis [ ] . patients who present to the hospital with ali should be emergently evaluated to assess limb viability and systemically anticoagulated with heparin unless contraindicated. in early single-center retrospective studies, the incidence of ali in covid- patients appears to be higher than the general public and includes patients with no traditional risk factors [ , ] . the success of revascularization was also decreased felt to be secondary to the virus-induced hypercoagulable state [ ] . in patients with covid- , it is important to remain hypervigilant for signs and symptoms of ali. emergent consultation with vascular surgery should be obtained and early initiation of parental anticoagulation is paramount due to the hypercoagulable state observed in some patients. we suggest that patients undergo limb salvage procedures in accordance with standardized guidelines due to the high risk of morbidity and mortality without acute intervention. acro-ischemia has been described in patients who are critically ill with covid- pneumonia and, despite treatment with lmwh, there was no clinical improvement and there was a high rate of mortality [ ] . in these patients, a palliative approach should be considered. recent data suggests a high rate of vte in the hospitalized, critically ill covid- patient [ , ] . the mechanism by which these patients are developing vte at significant rates have been hypothesized including immobility, severe inflammatory response, and coagulopathy including dic. decision algorithms of testing patients for asymptomatic and symptomatic vte as well as treatment of vte are not well defined. patients should be risk stratified (high, intermediate, or low risk) on presentation to help guide therapy [ , ] . for covid- patients who present with or develop acute vte during hospitalization, we recommend treating with anticoagulation if no contraindication exists. for all patients with symptomatic pe, we recommend activating the pulmonary embolism response team (pert) to provide interdisciplinary care and make individualized decisions based on the patient's clinical status, co-morbidities, and hospital factors [ , ] . in patients with high-risk pe, we recommend systemic or catheter-directed thrombolysis in patients with low bleeding risk or those who deteriorate after initial anticoagulation (i.e. development of worsening hypoxia, tachycardia, rv failure) [ , , ] . in patients at high bleeding risk, the use of catheter-directed mechanical thrombolysis or surgical removal should be considered in consultation with the pert team [ ] . in the intermediate-risk patient, debate remains over the best treatment. risk calculators such as the pesi or bova score can help further risk stratify these patients to help guide therapy [ , ] . anticoagulation remains the mainstay of treatment for this population and we suggest the use of parental anticoagulation with heparin or enoxaparin instead of a doac due to potential decompensation [ , , ] . enoxaparin is preferred if crcl is ≥ . the use of catheter-directed thrombolysis or thrombectomy for intermediate-risk pe should be made on a case by case basis with guidance from the pert team. due to the risk of infectivity, there should be a higher threshold to perform invasive procedures that have not been shown to improve mortality [ ] . once patients have stabilized, we recommend the use of doac over the use of warfarin or lmwh therapy [ , ] . in the low-risk patient, we recommend treatment with a doac without the need of parental anticoagulation (apixaban or rivaroxaban) to avoid increasing length of stay. the use of inferior vena cava filters should not be considered for routine use and only considered in those patients who have absolute contraindications for anticoagulation with clinically relevant vte [ ] . in a patient who requires an ivc filter, anticoagulation should still be restarted once the bleeding risk has passed. the incidence of thrombotic complications in critically ill covid- patients in the icu has been shown to be at least - % in observational studies [ , ] . this increased rate of thrombotic complications appears to be related to a hypercoagulable state similar to dic or thrombotic microangiopathy yet with unique differences including the appearance of a positive lupus anticoagulant in patients [ , , ] . in order to attempt to decrease the rates of thrombotic complications, preventative measures should be used whenever possible [ ] . heparin, enoxaparin, and fondaparinux are all recommended for vte prophylaxis by the american college of chest physicians [ ] . one retrospective study of critically ill covid- patients with d-dimers > x uln compared ufh or lmwh plus antiviral therapy versus no pharmacologic prophylaxis plus antiviral therapy. the combination therapy of pharmacologic plus antiviral group had a significantly decreased -day mortality [ ] . lmwh was preferentially used in this study due to its previously reported anti-inflammatory effect. another retrospective trial in critically ill patients in china confirmed lower mortality in those patients who were treated with pharmacologic prophylaxis, yet stated that asian populations have a low incidence of vte and thus higher doses of anticoagulation may be necessary in other populations [ ] . there remains concern throughout the medical community that in the most critically ill patients, pharmacologic prophylaxis is not enough to reduce the risk of thrombosis. a french cohort of icu patients on pharmacologic prophylaxis found a high prevalence of thrombotic complications including pe, stroke, circuit clotting of continuous renal replacement therapy or extracorporeal membrane oxygenation (ecmo) with minimal bleeding risk suggesting the need for higher doses of prophylactic anticoagulation in this patient population [ ] . in another retrospective study, mechanically vented patients were found to have a significantly decreased risk of mortality if treated with fulldose anticoagulation compared to those not on anticoagulation, yet this mortality benefit was not seen in all covid- patients admitted to the hospital [ ] . the use of higher dose thromboprophylaxis or full-dose anticoagulation is currently being investigated in multiple randomized control trials (nct , nct , nct , and nct ). we recommend that all patients on admission be assessed for the risk of vte. for patients with platelet counts greater than , , we recommend using pharmacologic prophylaxis for all covid- positive patients if no contraindication exists. while anecdotal and retrospective data may support higher doses of pharmacologic prophylaxis in critically ill patients, there is considerable risk of bleeding in these populations and thus without higher-level evidence, we remain hesitant to adopt these practices. as such, we continue to recommend standard dose pharmacologic prophylaxis with an understanding that our recommendations may change as data continues to evolve. enoxaparin is the preferred agent for patients with a crcl ≥ ml/min. for those with impaired renal function, heparin can be used as an alternative agent with a dosing regimen based on patient weight. for heparin dosing, patients < kg use , units q hours, for patients - kg we recommend , units q hours, for > kg we recommend , units q hours. for enoxaparin dosing, we recommend mg qday for those < kg, mg qday for patients - kg, and mg twice a day for patients > kg. we recommend mechanical prophylaxis in addition to pharmacologic prophylaxis for all icu patients without contraindication. for patients that are unable to be on pharmacologic prophylaxis due to low platelets or active bleeding we recommend mechanical prophylaxis (figure ). critically ill patients who survive to discharge are still at increased risk of thromboembolic events [ ] . given that thromboembolic events seem to be elevated in the covid- population, this risk may be even higher. we recommend that all patients be assessed for vte risk at discharge for consideration of extended vte prophylaxis. multiple studies pre-covid- have shown the benefit of extended prophylaxis for high-risk patients following discharge. the decreased incidence of thrombotic events is at the expense of a slight increase in bleeding. multiple agents have shown efficacy with extended prophylaxis including enoxaparin, rivaroxaban, and betrixaban [ ] [ ] [ ] . we recommend that patients should be risk assessed for vte and bleeding on discharge for extended prophylaxis using the improved for vte and improve bleeding risk indices [ ] [ ] [ ] [ ] . the patient should have a creatinine clearance and liver function panel in addition to platelet count (> , mm ) prior to the initiation of extended prophylaxis. we preferentially recommend rivaroxaban mg daily for weeks for extended prophylaxis. enoxaparin mg qday subcutaneously can be used as an alternative agent if the crcl ≥ ml/min. if patients are unable to receive pharmacologic prophylaxis, we recommend knee high compression stockings ( - or - mmhg) and encourage ambulation. patients should be educated on the symptoms and signs of dvt/pe and report such events to their primary care provider. dic can be seen in hospitalized patients with severe illness [ ] . it can accompany the acute respiratory failure and multiorgan failure from covid- and is associated with poor prognosis [ ] . yet, further studies suggest that while similar to dic, the coagulopathy of covid- has distinct features with only mild thrombocytopenia and normal fibrinogen levels early in the course [ , ] . there also appear to be similarities to thrombotic microangiopathy with elevated ldh and ferritin levels [ ] . these coagulation abnormalities appear to promote the hypercoagulable hypothesis of covid- which has been further suggested by autopsy reports showing micro thrombosis of the lungs and various other organs [ ] . the optimal initial approach to dic or dic like coagulopathy is to treat underlying causes, and in this case to support o and co exchange, metabolic functions, and possibly use antiviral agents and anti-cytokine release syndrome agents. clinically, close attention for these patients should be directed to unexpected bleeding or thrombosis. in addition to clinical monitoring, lab tests to monitor for the development and progression of dic are the cbc, pt and aptt, and fibrinogen. serial comparisons of the labs are essential as the development of dic during hospitalization is a poor prognostic indicator [ ] . d-dimer, while not specific for dic has also been shown independently to be a predictor of morbidity and mortality when significantly elevated [ , , ] . despite the incidence of dic being a poor prognostic indicator, the treatment of these patients remains the previous standard of care. in accordance with the guidance from the international society of thrombosis and hemostasis (isth), these patients should be treated with prophylactic dose enoxaparin if no contraindication exists [ ] . there is no role for therapeutic anticoagulation in dic, in the absence of an acute thrombotic event. while bleeding in covid- patients remains less common than thrombosis, bleeding risk increases as the platelet count goes below , mm , the pt and ptt rise to > . x uln, or when fibrinogen falls below mg/dl. there is no role for giving blood products to correct lab abnormalities in the absence of bleeding [ ] . if bleeding occurs, blood product(s) should be given to replace the depleted components. factor viia and prothrombin complex concentrate use are discouraged, as the risk of serious thrombosis is high. in the covid- era, there is an influx of drugs aimed to improve patient's morbidity and mortality. the only fda approved therapy at this time for covid- is remdesivir, and there remains over pharmacological trials on clinicaltrials.gov attempting to find further treatment for this disease [ ] . the effect of these medications on anti-platelet agents and anticoagulants is important for the individualized patient and the prescriber. pathways that are most important for identifying drug-drug interactions appear mediated via cytochrome p (cyp ) and/or transporter permeability glycoprotein (p-gp). the most common medications being used include hydroxychloroquine/chloroquine, azithromycin, remdesivir, lopinavir/ritonavir, and tocilizumab which may affect the efficacy of antiplatelets and anticoagulants. p y inhibitors are commonly used in a wide spectrum of cardiovascular disease states as described above. their interactions with treatments for covid- are not well known and rely on package inserts and anecdotal experience. the only medication with significant known interactions with p y inhibitors is lopinavir/ritonavir, a protease inhibitor previously used for the treatment of hiv. early studies in patients with covid- have found no decrease in morbidity or mortality with this medication combination [ ] , yet ongoing trials continue to look at the impact of this combination on patients with covid- . it is a known inhibitor of cyp a metabolism and has significant effects on clopidogrel and ticagrelor, yet no significant effect on prasugrel. inhibition of cyp a in patients taking clopidogrel can decrease its efficacy; however, inhibition of cyp a leads to increased effects of ticagrelor and thus neither is recommended to be administered in patients on lopinavir/ritonavir [ , ] . despite advances in doacs for reducing systemic thromboembolism and systemic bleeding compared to warfarin, doacs have drug-drug interactions that must be considered in all patients. cyp a is important for the metabolism of apixaban ( - %) and rivaroxaban ( %) with no significant effect on dabigatran and edoxaban while p-gp is an important mediator for apixaban, dabigatran, and rivaroxaban. the fda recommends avoiding concurrent use of apixaban and rivaroxaban with inducers of p-gp or cyp a [ ] . there is limited data on the in vivo effects of these medications with doac concentrations and unless explicitly known we do not have recommendations regarding avoiding or dose changes of these medications. table summarizes the interactions between the investigational drugs and commonly prescribed doacs. further drug-drug interactions between doacs and commonly used medications can be found in the ehra practical guidelines [ ] . hydroxychloroquine, used primarily in auto-immune disease, has not been found to interact with cyp a or p-glycoprotein. azithromycin is an inhibitor of p-gp and thus could increase the serum concentration of dabigatran especially in conjunction with other cardiac p-gp inhibitors such as amiodarone. it is not recommended to decrease dabigatran dosing. however, patients on edoxaban should only be prescribed the mg dose for vte. lopinavir/ ritonavir is known strong inhibitors of both cyp a and p-glycoprotein and thus could have significant effects on the pharmacokinetics of all doacs leading to increased concentration and potential bleeds. the european heart rhythm association practical guidelines suggests that doacs should not be given in patients taking ritonavir [ ] . however, the package insert of apixaban recommends dose reduction by % and should not be co-administered if patient is on low dose apixaban ( . mg bid). we suggest to avoid doacs in patients with whom lopinavir/ritonavir is being prescribed. tocilizumab is known to decrease serum concentrations of cyp a substrates and thus could decrease the effectiveness of apixaban or rivaroxaban. finally, remdesivir has little pharmacokinetic data available although it is believed that there are no significant clinical interactions with cyp a enzyme. (table ) conclusions covid- has challenged our thinking about the management of critically ill patients. the mechanisms of this disease and its complications' continue to be elucidated. that being said the principles of managing these patients are built on the foundations of evidence-based medicine in severely ill patients. there is a narrow therapeutic index between prevention and treatment of venous and arterial thrombosis in these patients and the risk of bleeding. this document can be used to help guide providers to treat cardiovascular patients at high risk during this pandemic (figure ). only by adhering to the principles of practicing what we know and maintaining openness to what we don't can we stand up to the greatest challenge of our professional lives. the contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. the authors report no conflicts of interest for their manuscript. a reviewer on this manuscript has disclosed that their institution has received research grants, and they have received honoraria for cme programs and consulting for companies developing novel antithrombotic therapies. the other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose. table . takeaway points from paper. . covid- patients have much in common with other critically ill patients where there may be a narrow margin for ac and apt of benefit (preventing thrombotic events) and risk (bleeding). . the rationale for ac should be carefully examined in all inpatients, balancing risk and benefit. for example: a patient on ac with cha ds -vasc of for men and for women. point of care risk calculators and apps to assist in evaluating the risk and benefit should be used when available. . in covid- confirmed or expected patients, it is reasonable to continue outpatient anticoagulation unless they become critically ill in the icu or if they have invasive procedures planned. . if interrupted, bridging should not be offered in low risk thrombosis patients. . routine use of aspirin increases bleeding risk by as much as % and benefit should be carefully assessed. . prolonged dapt beyond months for elective stenting and beyond a year for acs should be examined, balancing risk and benefit. . warfarin based triple therapy for patients with stenting and af is inferior to doac based regimen with p y and short duration aspirin. . decision to bridge either with ufh or lmwh in a covid- patient exposes nursing to a greater degree. this is not worthwhile in a low thrombotic risk patient. . when there is the potential for significant drug-drug interactions, consultation with pharmacy is invaluable. . careful consideration is required in weighing the risks and benefits of any intervention not only to the covid- confirmed or expected patient, but also to the health care workers who are directly involved in patient care. special consideration should be given when possible to limiting health care worker exposure to covid- . references . world health organization. coronavirus disease. 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statement from the coagulation abnormalities and thrombosis in patients with covid- high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study. intensive care med american society of hematology guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis difference of coagulation features between severe pneumonia induced by sars-cov and non-sars-cov anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with covid- efficacy and safety of extended thromboprophylaxis for medically ill patients. a meta-analysis of randomised controlled trials extended-duration venous thromboembolism prophylaxis in acutely ill medical patients 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interim guidance on recognition and management of coagulopathy in covid- guidelines for the diagnosis and management of disseminated intravascular coagulation. british committee for standards in haematology pharmacologic treatments for coronavirus disease (covid- ): a review a trial of lopinavir-ritonavir in adults hospitalized with severe covid- prescribing information. brilinta (ticagrelor) impact of booster antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites select drug-drug interactions with direct oral anticoagulants: jacc review topic of the week european heart rhythm association practical guide on the use of non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation we want to acknowledge the following people who helped with formulation of our best practice initiative for our institution: key: cord- -toeq xq authors: smith, kelly; krajewski, kristin c; krajewski, michael p title: practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with covid- date: - - journal: am j health syst pharm doi: . /ajhp/zxaa sha: doc_id: cord_uid: toeq xq purpose: there are increasing reports in the literature of high rates of coagulopathy and venous thromboembolism (vte) among hospitalized patients with coronavirus disease (covid- ). understanding of these abnormalities is continually evolving, but these conditions may pose a risk to covid- patients beyond the risk typically seen in critically ill patients. summary: there are currently no widely accepted evidence-based guidelines regarding specifics related to treatment and prevention of covid- –related coagulopathies. areas of management requiring clinical equipoise include agent selection and dosing, continuation vs interruption of home oral anticoagulant therapy during hospital admission, and postdischarge vte prophylaxis. clinicians may wish to consider use of a stratified, -tiered approach of low-intensity anticoagulation, intermediate-intensity anticoagulation, and therapeutic-dose anticoagulation. patients can be categorized by tier depending on their risk factors for vte, acuity of illness, and laboratory values such as d-dimer level. conclusion: practical guidance on anticoagulation considerations and dosing suggestions are provided to assist clinicians faced with challenging anticoagulation-related situations in caring for hospitalized covid patients until formal evidence-based guidelines become available. t here are increasing reports in the literature of high rates of coagulopathy and venous thromboembolism (vte) among hospitalized patients with coronavirus disease (covid- ). [ ] [ ] [ ] [ ] [ ] hematologic abnormalities commonly seen in patients with covid- include elevations in d-dimer and fibrinogen, prolonged prothrombin time and activated partial thromboplastin time (aptt), and changes in levels of inflammatory markers such as c-reactive protein (crp), interleukin- , and ferritin. understanding of these abnormalities is continually evolving, but they may pose a risk to patients with covid- beyond the risk typically seen in critically ill patients. tang et al reported that abnormalities in coagulation markers are indicators of disease severity and that higher d-dimer levels are associated with increased mortality. a retrospective analysis of patients with severe covid- found that those experiencing vte were more likely to be older and to have prolonged aptt and elevated d-dimer levels. furthermore, the incidence of thrombotic complications has been reported to be % to % in critically ill patients with covid- despite use of standard vte prophylaxis. , poissy et al reported an increased incidence of pulmonary embolism (pe) amongst covid- patients admitted to an intensive care unit. of the patients who developed pe, patients ( %) were receiving vte prophylaxis. in an encouraging sign for treatment of patients with covid- , available anticoagulants have shown some benefit. a small observational study found that among patients with a d-dimer level greater than times the upper limit of normal (uln), those treated with heparin had -day mortality approximately percentage points lower than those not treated with heparin ( . % vs . %; p = . ). in an additional observational study of patients hospitalized for covid- in new york city, promising results were reported for systemic, treatment-dose anticoagulation in mechanically ventilated patients; those who received treatment-dose anticoagulation experienced in-hospital mortality of . %, compared with a death rate of . % among those who did not. although some helpful guidance has been published recently, there are currently no widely accepted evidence-based guidelines available regarding specifics related to treatment and prevention of covid- related coagulopathies. [ ] [ ] [ ] [ ] [ ] areas of current clinical uncertainty include dose and agent of choice, continuation vs interruption of home oral anticoagulant therapy while admitted, and postdischarge vte prophylaxis. additional challenges are found in use of vte risk stratification tools that do not incorporate covid- as a risk factor. [ ] [ ] [ ] [ ] this article discusses practical considerations in anticoagulation management in the context of covid- to assist clinicians until more formal evidence-based guidelines become available. guidance from the international society on thrombosis and haemostasis recommends prophylactic anticoagulation for all patients who require hospital admission for covid- in the absence of any contraindications such as active bleeding and a platelet count less than × /µl. for critically ill patients with covid- , barriers to obtaining diagnostic testing to confirm or rule out active bleeding, such as endoscopy or colonoscopy, may be present, further complicating treatment decisions. low-molecular-weight heparin (lmwh) has been suggested as the anticoagulant of choice (in preference to unfractionated heparin [uh]) for reducing healthcare staff contact with patients in the absence of a compelling reason not to use it. fondaparinux may be considered for patients with a history of heparin-induced thrombocytopenia or aversion to receipt of porcine derivatives. there is some evidence to suggest heparins have anti-inflammatory properties , ; theoretically, this may have added benefit in covid- cases where proinflammatory cytokines are markedly elevated. however, clinicians may wish to consider patient-specific factors in order to guide their decisions. these factors include but are not limited to concurrent comorbidities, relevant laboratory values, acuity, mobility, weight, renal function, bleeding risk, and need for invasive procedures or interventions. upon review of the available evidence, we believe that clinicians may wish to consider a -tiered approach to stratifying anticoagulation intensity ( figure ), with consideration of the aforementioned factors to guide and assist in decision making. the tiers are low-intensity anticoagulation (tier i), intermediate-intensity anticoagulation (tier ii), and therapeuticdose anticoagulation (tier iii). we recognize this tiered approach is not universally accepted; however, there is increasing evidence that many patients may develop vte despite receipt of standard vte prophylaxis. further, not all patients require therapeutic anticoagulation; therefore, tier ii anticoagulation has been suggested as an option. , an additional area of clinical controversy involves patients' use of home oral anticoagulants while admitted to the inpatient setting. hospitalized patients, particularly critically ill patients, may require invasive procedures, which may require interruption of oral anticoagulation therapy. for any patient who is already taking an oral anticoagulation at home, it may be prudent to transition to therapeutic-dose lmwh or parenteral ufh infusion for the duration of hospitalization unless contraindications exist. further, there is little published data regarding the use of oral anticoagulants in the covid- patient population. in the setting of renal dysfunction, use of intravenous ufh along with antifactor xa (anti-xa) monitoring may be preferred. tier i. patients with covid- who may be appropriate candidates for tier i anticoagulation include those with indications for standard prophylaxis. this tier should be considered for patients without known thrombi or known malignancy; these are generally lower-acuity patients, such as noncritically ill medical patients. this approach may be considered for patients with d-dimer levels less than times the uln that are not trending upward. • covid- is a hypercoagulable state, and many patients with covid- may experience venous thromboembolism (vte) despite standard vte prophylaxis. • evidence from randomized controlled trials to guide decisions regarding anticoagulation in patients with covid- is currently lacking. • this article offers practical guidance based on current experiential evidence in real-world settings to assist clinicians in managing anticoagulation in patients with covid- . tier ii. tier ii, or intermediateintensity, anticoagulation may be appropriate for a patient with covid- who requires a higher-intensity standard prophylaxis regimen. a patient may be categorized into tier ii based on acuity and/or vte risk factors (eg, a patient who is on a general medical floor but clinically deteriorating, with an upward trend in inflammatory marker and/or d-dimer levels). tier ii therapy could be considered for patients whose d-dimer level is above times the uln. to determine vte risk factors that may place patients in this category, clinicians may wish to consider risk stratification models such as the caprini score, improve risk score, and padua prediction score models, all of which have been used in acutely ill hospitalized patients. - vte risk figure . flowchart of -tiered approach to stratification of anticoagulation intensity. anti-xa indicates anti-factor xa; bmi, body mass index; crcl, creatinine clearance; iv, intravenous; lmwh, low-molecular-weight heparin; scr, serum creatinine; sq, subcutaneously. am j health-syst pharm | volume xx | number xx | xxxx xx, factors considered when using the padua prediction score model are listed in table . additionally, all critically ill patients should be considered for tier ii therapy, at a minimum, if they do not have risk factors for vte and/ or the clinician team is otherwise not concerned about vte development. klok et al and connors et al showed that vte incidence was higher in critically ill patients with covid- than in other critically ill patients despite their receipt of vte prophylaxis; therefore, it is not unreasonable to consider intensified vte prophylaxis in criti cally ill patients with covid- . tier iii. tier iii therapy may be chosen for those patients with covid- who have known or strongly suspected vte. patients presenting with acute coronary syndrome should be categorized into this tier. this tier can strongly be considered for any patient with a d-dimer level greater than times the uln or in a continued upward trend. moreover, therapeutic anticoagulation should be strongly considered for any patient with clinical sequelae of possible vte, including an otherwise unexplained increase in oxygen requirement (in the absence of another obvious cause, such as worsening radiographic evidence of acute respiratory distress syndrome), a need for mechanical ventilation, alveolar dead space (ie, the area occupied by alveoli that do not participate in gas exchange), and organ failure (eg, acute kidney injury) with concern for microvascular thrombi. agent selection for tiered anticoagulation therapy tier i. for low-intensity anticoagulation, clinicians may wish to consider lmwh at standard prophylactic doses. for example, enoxaparin subcutaneously once daily. for obese patients with a body mass index (bmi) greater than , an increase in lmwh dose may be considered. based upon bariatric data available, enoxaparin mg subcutaneously every hours may be employed for standard vte prophylaxis. in the presence of renal insufficiency, lwmh can be renally dose-adjusted (for example, enoxaparin mg subcutaneously daily) or subcutaneous ufh therapy can be used instead. preference may be given to subcutaneous ufh when renal function is poor or labile. increased doses of ufh (eg, heparin , units subcutaneously every hours) may be an option for obese patients with a bmi of > in the setting of renal insufficiency. , monitoring of anti-xa levels during use of lmwh is not generally recommended; however, assaying anti-xa levels to target a goal anti-xa value of . to . unit/ml may be considered for obese patients. blood sampling for determination of the anti-xa level should occur approximately hours after a subcutaneous dose is administered and (to ensure a steady-state concentration) after approximately doses. in the event the level falls outside the target range, it is recommended to exercise best clinical judgment in adjusting doses. in cases where heparin may be contraindicated and renal function allows, fondaparinux administered at a dosage of . mg subcutaneously daily may be considered for vte prophylaxis. tier ii. for patients in whom intermediate-intensity anticoagulation is appropriate, employing a higherthan-standard dose may be considered under the assumption that it may confer additional benefit in vte prevention. enoxaparin mg subcutaneously every hours may be an option for patients with a bmi of < . alternatively, a regimen of enoxaparin . mg/kg subcutaneously every hours may be considered, especially if the patient is obese. , in the setting of renal insufficiency, heparin can be used at a higher dose ( , units subcutaneously every hours). anticoagulation should be strongly considered. currently available data are not sufficient to support employment of therapeutic-dose prophylaxis for patients in this tier. , tier iii. recommendations for high-intensity anticoagulation in critically ill patients with covid- call for use of a therapeutic dosage of lmwh, such as enoxaparin mg/kg subcutaneously every hours (for patients with creatinine clearance [cl cr ] above ml/min) or mg/kg subcutaneously once daily (for those with cl cr of less than ml/min) or intravenous ufh titrated to maintain institutionspecific therapeutic levels. enoxaparin . mg/kg subcutaneously daily may be considered for a non-critically ill patient (with stable and preserved renal function) in order to reduce the need for patient contact. monitoring of ufh therapy via anti-xa assay should be used preferentially if available due to potentially elevated baseline aptt levels in patients with covid- . use of lmwh is advantageous due to a need for less frequent laboratory monitoring and a lower workload burden on nursing staff. in obese patients, clinicians may wish to consider use of enoxaparin at a dosage of mg/ kg subcutaneously every hours (for patients with cl cr above ml/min), with monitoring of anti-xa levels to target a goal anti-xa value of . to . unit/ml. blood samples for anti-xa level determination should be drawn approximately hours after a subcutaneous dose is administered and after approximately doses. again, if the anti-xa level falls outside the target range, clinical judgement is necessary for dose adjustment. ufh may be preferred when bleeding risk is elevated because it has a short half-life and its effects are easily reversible. (factors to consider in bleeding risk evaluation are listed in figure .) intravenous ufh may also be an option for patients requiring invasive procedures. for critically ill patients, intravenous ufh may be the preferred agent due to their risk of acute renal dysfunction. therapeutic heparin should also be considered for all critically ill patients receiving dialysis, including continuous renal replacement therapy (crrt), and initiated according to institutional crrt or vte protocols. it is important to post-hospital discharge vte prophylaxis represents another area of clinical uncertainly that will require a careful weighing of the risks vs potential benefits of ongoing therapy. we suggest that upon discharge all patients, regardless of tier, be assessed for ongoing need for continued prophylaxis. careful examination of additional risk factors for vte, such as prolonged immobility while in quarantine, as well as trends in laboratory values, such as d-dimer, crp, ferritin, and lactate dehydrogenase levels, should be reviewed. elevated inflammatory markers may indicate an increased risk of vte upon a patient's discharge to home, and continued prophylaxis may be warranted. in the absence of randomized, controlled clinical trials, clinicians may wish to consider use of lmwh instead of direct-acting oral anticoagulants (doacs) or other agents due to the former's anti-inflammatory effects. doacs, however, may become an option if compliance concerns arise (eg, a patient's unwillingness to use parenteral therapy or inability to self-inject). additionally, patient-specific factors such as insurance and cost considerations must be considered. duration of prophylactic therapy should be determined on a case-by-case basis, taking into account bleeding risk. consideration of extended prophylaxis of up to days may be appropriate in patients at increased risk for vte who are at low risk for bleeding. for patients who had been using a doac at home and were transitioned to parenteral anticoagulation during an inpatient stay, a transition back to home doac therapy may be considered in the absence of evidence of treatment failure. upon discharge of patients with confirmed or suspected vte, continuation of anticoagulation treatment for minimum months for provoked vte can be chosen. treatment with therapeutic-dose lmwh or doac therapy can be considered in preference to warfarin, in accordance with current guidelines. if vte is not confirmed at time of discharge due to lack of test availability, the clinician may wish to treat according to conventional protocols for vte. follow-up with primary care or specialty providers for ongoing reevaluation and extension of therapy must be ensured. we recognize that the guidance presented in this article has significant limitations, and we hope that clinicians will benefit from a growing body of evidence-based and standardized guidelines on the issues discussed here. as with all treatment options for patients with covid- , this is a fluid situation. the preceding is not intended as a practice management protocol; rather, the intent is to provide practical suggestions for clinicians treating this novel disease. abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- incidence of venous thromboembolism in hospitalized patients with covid- pulmonary embolism in covid- patients: awareness of an increased prevalence anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up for subcommittee on perioperative and critical care thrombosis and haemostasis of the scientific and standardization committee of the international society on thrombosis and haemostasis. practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- . thrombosis uk website covid- treatment guidelines panel, national institutes of health. coronavirus disease (covid- ) treatment guidelines thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum a risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the padua prediction score completion of the updated caprini risk assessment model ( version) the improvedd vte risk score: incorporation of d-dimer into the improve score to improve venous thromboembolism risk stratification predictive and associative models to identify hospitalized medical patients at risk for vte fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis comparison of the effects of enoxaparin and heparin on inflammatory biomarkers in patients with st-segment elevated myocardial infarction: a prospective open label pilot clinical trial covid- and its implications for thrombosis and anticoagulation assessing an enoxaparin dosing protocol in morbidly obese patients safety and efficacy of high-dose unfractionated heparin versus highdose enoxaparin for venous thromboembolism prevention in morbidly obese hospitalized patients efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients weight-based dosing of enoxaparin for vte prophylaxis in morbidly obese, medically-ill patients implementation of an enoxaparin protocol for venous thromboembolism prophylaxis in obese surgical intensive care unit patients american college of chest physicians evidence-based clinical practice guidelines treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis antithrombotic therapy for vte disease: chest guideline and expert panel report the authors wish to acknowledge their employment by as well as the support and resources of veterans affairs western new york healthcare system and state university of new york at buffalo school of pharmacy and pharmaceutical sciences. the authors wish to acknowledge jessica swiderek and laura wilkinson, pharmd, for their contributions to the article manuscript. the authors have declared no potential conflicts of interest. key: cord- - ij pjjy authors: nopp, stephan; moik, florian; jilma, bernd; pabinger, ingrid; ay, cihan title: risk of venous thromboembolism in patients with covid‐ : a systematic review and meta‐analysis date: - - journal: res pract thromb haemost doi: . /rth . sha: doc_id: cord_uid: ij pjjy background: venous thromboembolism (vte) is frequently observed in patients with coronavirus disease (covid‐ ). however, reported vte‐rates differ substantially. objectives: we aimed at evaluating available data and estimating the prevalence of vte in covid‐ patients. methods: we conducted a systematic literature search (medline, embase, who covid‐ database) to identify studies reporting vte‐rates in covid‐ patients. studies with suspected high risk of bias were excluded from quantitative synthesis. pooled outcome rates were obtained within a random effects meta‐analysis. subgroup analyses were performed for different settings (intensive care unit (icu) vs. non‐icu hospitalization and screening vs. no screening) and the association of d‐dimer levels and vte‐risk was explored. results: eighty‐six studies ( , patients) were identified and ( , patients, mean age: . years, % men, % icu‐patients) were included in quantitative analysis. the overall vte‐prevalence estimate was . % ( %ci . ‐ . ), . % ( %ci . ‐ . ) with ultrasound‐screening and . % ( %ci . ‐ . ) without screening. subgroup analysis revealed high heterogeneity, with a vte‐prevalence of . % ( %ci . ‐ . ) in non‐icu and . % ( %ci . ‐ . ) in icu patients. prevalence of pulmonary embolism (pe) in non‐icu and icu patients was . % ( %ci . ‐ . ) and . % ( %ci . ‐ . ). patients developing vte had higher d‐dimer levels (weighted mean difference . µg/ml ( %ci . ‐ . ) than non‐vte patients. conclusion: vte occurs in . % of patients with covid‐ in the icu, but vte risk is also increased in non‐icu hospitalized patients. patients developing vte had higher d‐dimer levels. studies evaluating thromboprophylaxis strategies in patients with covid‐ are needed to improve prevention of vte. the coronavirus disease , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) and formally declared a pandemic by the world health organization (who) in march , is an infectious disease with a global impact on public health. it affects primarily the respiratory system, however, involvement of other organ systems may occur, especially with increasing severity of the disease. the high inflammatory burden associated with covid- and inflammation in the vascular system can also result in cardiovascular complications with a variety of clinical presentations. [ ] [ ] [ ] early studies already reported on coagulation abnormalities and coagulopathy with a rather prothrombotic phenotype in patients with ] with the better understanding of covid- and its clinical course, venous thromboembolism (vte), a disease entity covering pulmonary embolism (pe) and deep vein thrombosis (dvt), has been recognized as a particular complication of the disease. initial studies have found alarmingly high rates of pe in patients with severe covid- treated at intensive care units (icu), reporting vte incidences of up to %. [ ] in response to the clinical challenges and the absence of high-quality evidence, experts groups and scientific societies have released guidance statements to address questions concerning diagnosis, prevention, and treatment of vte in patients with covid- which suggest the broad application of thromboprophylaxis in patients with severe covid- in the absence of high bleeding risk. [ , ] in several studies of different design, size, and quality, rates of vte in patients with covid- have been reported. however, a definitive and robust estimate of the vte risk in patients with covid- is currently not available as of the high variability of reported rates. therefore, the true underlying burden of vte in covid- patients is still not fully understood. in the light of the ever-growing infection rates worldwide and the clinical challenges in patient management, understanding of the true frequency of vte in covid- is important and may help to support clinical decision making. we conducted a systematic review of the literature and meta-analysis of available data to determine the prevalence of vte in patients with covid- . our aim was to provide an overall estimate of vte by aggregating reported rates and to thoroughly accepted article explore differences in the vte prevalence according to study design and the health care setting, which may account for the high degree of heterogeneity in reported rates. this article is protected by copyright. all rights reserved we conducted a systematic review of the literature and meta-analysis of published data on the prevalence of vte in patients with covid- . the study protocol was prepared prior to the initiation of the literature research according to the preferred reporting items for systematic review and meta-analysis protocols (prisma-p) [ ] and submitted to prosepero (international prospective register of systematic reviews) on june th , (protocol-id: crd ). the study was conducted according to the "preferred reporting items for systematic reviews and meta-analyses" (prisma) and the guidance for reporting meta-analysis of observational studies in epidemiology (moose) . [ , ] full-text articles, letters, brief reports, editorials, and correspondences published in or with available title and abstract in english were eligible for inclusion. inclusion criteria comprised studies reporting on patients with objectively confirmed covid- in combination with reporting rates of vte as outcome of the study (dvt and/or pe). study designs eligible for inclusion were cohort studies (prospective and retrospective), cross-sectional studies, and interventional studies with vte reported as an outcome or adverse event. study designs that did not allow prevalence estimates such as case reports and case-series including autopsy studies were excluded. we systematically searched embase, medline, and the who covid- research database with distinct predefined search algorithms to identify relevant publications. the exact search protocol is available in the supplementary methods. search for additional studies not identified by the search criteria (e.g. due to pre-print status) was conducted by inquiring databases of pre-print servers (medrxiv) and by manual research of relevant journals. publications in pre-print status were only eligible if they had undergone full peer-review at the date of literature research. duplicate search this article is protected by copyright. all rights reserved results were excluded prior to eligibility screening. two researchers (sn, fm) screened title and abstract of the identified studies and potentially eligible studies underwent fulltext evaluation. the inclusion of a study was based on the consensus of its suitability by the two researchers. where consensus opinion could not be reached, a third reviewer was consulted to make the final decision (ca). all three literature researchers are medical doctors with a thorough research background in the field of thrombosis. the most recent literature research was conducted on august th , . figure displays the process of study identification following a prisma flow-diagram. studies that fulfilled the predefined inclusion criteria and did not meet any exclusion criteria were subjected to data extraction. in the case of multiple studies reporting on the same patient cohort, results were merged and considered only once. data extraction of pre-defined baseline and outcome variables was performed. these included methodological specifics of the studies (study design, health care setting), clinical information of the study population (demographics, comorbidities, disease severity, use of pharmacological thromboprophylaxis, ultrasound screening, and d-dimer levels), and outcome specifics (definition, type, and rate of vte). the full list of extracted variables is provided in the supplementary methods. all data were independently extracted from eligible studies by two authors (sn, fm) to ensure data reliability, with inconsistencies resolved by discussion with a third author (ca). methodology of identified studies was assessed independently by two researchers (fm & sn) . risk of bias of included studies was independently rated with a validated tool for assessing studies reporting prevalence data (joanna briggs institute critical appraisal checklist; supplementary appendix). [ ] this tool consists of categories each classifying the study as low risk of bias, high risk of bias, or unclear. subsequently, an overall evaluation based on these categories was derived. studies with suspected high risk of bias were excluded from the subsequent quantitative data synthesis. potential this article is protected by copyright. all rights reserved publication bias was assessed graphically within a funnel-plot, plotting the prevalence estimate of vte against its' standard error (supplementary figure s a&b) . the primary outcome of the present meta-analysis is vte, defined as dvt (including catheter-related thrombosis), pe, or the composite of both, as defined within the respective study. thrombotic occlusions of mechanical components of extracorporeal devices such as dialysis machines or ecmo devices were not counted as outcome event. the prevalence estimate of the primary outcome is reported stratified by the use of systematic ultrasound screening for thrombosis in the respective studies. secondary outcomes included (i) the pooled prevalence of vte (excluding studies only reporting isolated pe or isolated dvt rates), (ii) the pooled rate of pe, and (iii) the pooled rate of dvt. outcomes of the secondary analyses were reported stratified for icu patients and non-icu hospitalized patients at study baseline and by the performance of dvt screening. the icu cohort comprised patients admitted to the icu, or alternatively those who were defined as being critically ill, or in need of mechanical ventilation at baseline. further, an exploratory analysis of differences between baseline levels of ddimer between patients experiencing vte and those who did not was conducted. outcome definitions throughout the different studies were varying. some studies reported pure incidence, while others reported prevalence, e.g. including patients who have been admitted due to vte and covid- . in this systematic review, we have decided to aggregate the proportion of patients, who have been diagnosed with vte as reported in the included studies. all statistical analyses were performed with the commercially available package stata . (stata corp., houston, tx, usa). summary statistics were aggregated from included studies. pooled prevalence of outcome variables was estimated by aggregating study results within a random-effects meta-analysis utilizing the stata package this article is protected by copyright. all rights reserved metaprop. [ ] the freeman-tukey double arcsine transformation was utilized to normalize variance, and % confidence intervals (ci) were estimated by the score method. heterogeneity of included studies is reported by i as a measure of betweenstudy variability beyond random variation. to explore differences in baseline d-dimer between vte and non-vte patients, mean d-dimer levels and corresponding standard deviation were calculated from reported median, interquartile range (iqr) and sample size according to wan et al. [ ] weighted mean differences (wmd) in baseline d-dimer levels were calculated within a pooled-analysis weighted by corresponding sample sizes. lastly, differences in vte risk according to sex and comorbidities was explored within a random effects meta-analysis utilizing the mantel-haenszel procedure. we identified records upon literature research after the removal of duplicates. title and abstract of these identified studies were screened for conformity with our predefined in-and exclusion criteria and records were subsequently included in the full-text evaluation. from those, studies were included in the qualitative data synthesis. figure displays the screening and selection process, and the reasons for excluding studies. pooled summary characteristics of the eligible studies reporting on vte in covid- patients are displayed in table this article is protected by copyright. all rights reserved a comprehensive summary of each study including the respective study design, demographics, thromboprophylaxis strategy, and outcome rates is presented in tables s & . pooled patient characteristics and comorbidity data are displayed in table . the overall weighted mean age of patients was . years (standard deviation [sd] . ) and % were male. weighted mean age of patients in icu-only studies was . years (sd . ) and . % were male. risk of publication bias was evaluated separately for studies on non-icu hospitalized and icu patients to enhance interpretability. upon visual inspection of the funnel plots, no indication for publication bias was detected, with outliers in the distribution being explained by differences in ultrasound screening strategies. (figures s a&b) secondly, we conducted an exploration of potential time-dependencies in vte rates of published studies suggesting a decrease of vte rates over time upon visual inspection and fitting a regression line of the vte rate and the last patient inclusion date of each respective study. (figure s ) thirdly, a methodological assessment of included studies was conducted in order to evaluate the risk of underlying bias regarding the reported rate of vte. importantly, this evaluation is not to be regarded as a general evaluation of quality and goodness of included studies but rather an evaluation of the generalizability of reported vte rates. in our quality assessment, low risk of bias was attributed to our identified studies in median in of categories (range: - , maximum: low risk of bias in all categories). the results of our structured methodological assessment of all studies are presented in table s . in consensus among the reviewers, studies were excluded from quantitative synthesis upon a strong suspicion of bias in the structured assessment. reasons for exclusion include selection bias ( studies), reporting/information bias ( study), and lack of background information on setting and outcomes ( study). therefore, the remaining studies (including studies reporting on icu patients and studies this article is protected by copyright. all rights reserved reporting on non-icu hospitalized patients) were included in quantitative data synthesis. [ , - ] after excluding studies with a high risk of underlying bias, quantitative results from studies were aggregated within a meta-analysis, including , patients ( , figure shows a forrest plot of vte rates, together with information on health care setting, the performance of screening and outcome definition of respective studies. the rates of vte within our primary analysis strongly differed between studies, depending on the specifics of the study setting, design, and outcome definition. therefore, in order to further explore heterogeneity of the reported vte rates, we conducted detailed subgroup analyses based on the health care setting (non-icu hospitalized vs. icu patients), and the performance of dvt screening (screening vs. no screening). in addition, within these subgroup analyses, we have separately estimated rates of vte, pe, and dvt. available baseline characteristics of patients with vte compared to those without vte were aggregated and analyzed weighted by sample size of the respective study (table ) . mean weighted age of vte and non-vte patients was similar, with a mean age of . years (sd . ) and . years (sd . ), respectively. men were . times more likely to develop vte ( %ci: . - . ), while comorbidities did not differ between the two groups. d-dimer levels at baseline were available in studies, including , patients. patients developing vte had higher baseline d-dimer levels compared to those without vte (weighted mean d-dimer levels: . µg/ml (sd . ) vs. . µg/ml (sd . )) with a wmd of . µg/ml ([ %ci: . - . ], p < . ; i²: . %). (figure ) this article is protected by copyright. all rights reserved in this systematic review and meta-analysis, data from studies reporting on rates of vte in patients with covid- were aggregated to estimate the prevalence of vte. we found that the burden of vte associated with covid- is substantial, with an overall vte prevalence estimate of . % across all identified studies. however, rates of vte varied across different health care settings (icu vs. non-icu hospitalized patients), depending on whether systematic screening was performed or not, and on outcome definitions in the selected studies. in subgroup analysis, rates of vte ranged from . % in non-icu hospitalized patients without ultrasound screening to . % in icu patients undergoing screening strategies. since no pe screening was performed, the pe prevalence of . % in non-icu hospitalized patients and . % in icu patients might provide a robust estimate and strongly highlights the high risk of vte in patients with covid- , especially in those requiring intensive medical care. it is known from large clinical trials in critically ill patients with various underlying diseases that the rate of vte in the icu setting is elevated, with vte rates ranging from to %. [ ] [ ] [ ] [ ] [ ] higher vte rates in covid- patients in the icu and also non-icu this article is protected by copyright. all rights reserved interestingly, autopsy studies in covid- patients revealed severe endothelial injury, endotheliitis, increased angiogenesis, and widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. [ , , [ ] [ ] [ ] based on such findings, the aetiology of the increased pe rates reported in covid- patients has been discussed and two not mutually exclusive pathomechanisms have been proposed. on the one hand, it has been suggested that in-situ pulmonary thrombi, which develop on the basis of diffuse alveolar and local vascular damage, microangiopathy, and inflammation in the pulmonary circulation triggered by the virus, rather than "classical" pe itself may contribute to the high prevalence of pe observed in patients with on the other hand, dvt rates of up to % in studies, where ultrasound screening was performed in icu patients, support the hypothesis of embolism originating from peripheral thrombosis rather than pulmonary in-situ thrombosis largely contributes to the substantial burden of pulmonary artery occlusion observed in patients with covid- . however, the exact role, data on frequency, and clinical consequences of in-situ pulmonary thrombosis in covid- need further investigations. we believe that our meta-analysis is representative of covid- patients requiring hospitalization, as our systematic review confirmed the previously reported sex differences in covid- patients (higher proportion of men among more severe disease). [ ] the sex differences further increased among patients admitted to the icu suggesting that men were more likely to suffer from greater disease severity than women. [ ] correspondingly, men were at higher risk to develop vte, but we observed no association between comorbidities and risk of vte. interestingly, age did not differ between the groups. this suggests that in contrast to the general population, age did not contribute to the vte risk in covid- patients. [ ] similar results have been reported for vte risk in patients with cancer suggesting that the high vte baseline risk of the underlying disease overwhelms general risk factors such as age. [ ] furthermore, explorative analysis has revealed that d-dimer levels were higher in patients developing vte compared to those who remained free from a vte event. our findings support guidance statements from experts and scientific societies which suggest that thromboprophylaxis is a key element in the medical care of patients with covid- , especially in those with severe illness. [ , , [ ] [ ] [ ] however, vte this article is protected by copyright. all rights reserved occurred in many patients despite the use of thromboprophylaxis, and even patients with therapeutic anticoagulation developed vte. therefore, the ideal anticoagulation approach to reduce the high risk of vte in patients with covid- needs to be established. further, the observed higher baseline d-dimer levels in patients who had vte strengthens the idea that d-dimer-guided thromboprophylaxis strategies should be evaluated in prospective randomized-controlled trials. the main limitation of our meta-analysis is the high heterogeneity of included studies with regard to design, clinical setting, local practice (e.g. with respect to thromboprophylaxis strategies), and consequently highly variable event rates. additionally, the disproportionate number of icu studies with higher vte rates than the general ward population may confound the overall estimation of vte prevalence in patients with covid- . to address this issue, we aimed at thoroughly describing the respective clinical settings and provide subgroup analysis, e.g. icu vs. non-icu hospitalized patients or according to diagnostic approaches (studies with screening vs. no screening for dvt) to provide a more precise estimate of vte rates. further, early reports of high vte rates in patients with covid- might have led to the implementation of more specific and intensive thromboprophylaxis approaches over time, which might have confounded the outcomes in subsequently conducted studies. we have analyzed studies according to the date of the last patient recruitment and visual inspection reveals a decrease of vte rates of reported studies over time ( figure s ) . we also provided data on thromboprophylaxis modalities for the respective studies to allow a better interpretation of differences observed in the studies. however, the generalizability of the results of our systematic review and meta-analysis still needs to be interpreted with caution, because only data from patients in north america, europe, and asia were available and included in the meta-analysis. upon visual inspection, vte rates across continents and countries seem to be mainly related to between-study heterogeneity with respect to study design, clinical setting, and local clinical practice with regard to thromboprophylaxis ( figure s ) . given the high mortality especially in icu patients with covid- , competing risk of death might lead to an underdiagnosis of vte. further, the concern of restricting the use of imaging to avoid disease exposure to healthcare worker might further lead to this article is protected by copyright. all rights reserved false-low rates of vte in patients with covid- . these uncontrollable factors in a study level analysis should be considered upon interpreting and generalizing our findings. also, the practice of avoiding imaging due to concerns about healthcare worker exposure should be critically reviewed given the risk of underdiagnosis and consequently undertreatment of patients. furthermore, exploratory analysis of d-dimer levels between patients developing vte and those who did not is limited by the lack of patient-level data and the inability to adjust for between assay variability. therefore, this exploration should be interpreted with appropriate caution and regarded as hypothesis generating. lastly, there is some evidence that non-hospitalized covid- patients are at increased risk of developing vte as well. [ ] as of the unavailability of sufficient data within our meta-analysis, we were unable to provide prevalence estimates for this population of patients and our findings are therefore not representative for the outpatient setting of covid- . in summary, we found a high prevalence of vte in patients with covid- in hospitalized non-icu patients, and especially high vte rates in those being critically ill and requiring intensive medical care. there is a clinical need for further research to better understand the risk and prevent vte in patients with covid- . these findings support the broad use of thromboprophylaxis, specifically in icu patients. future randomized clinical trials are needed to assess whether patients with covid- may benefit from an intensified anticoagulation approach compared to standard thromboprophylaxis or whether a biomarker-based personalized thromboprophylaxis regimen reduces the high prevalence of vte in patients with covid- . this article is protected by copyright. all rights reserved addendum author contributions: s. nopp and f. moik contributed to study design, data collection, data interpretation, statistical analysis, and drafting of the manuscript. c. ay contributed to study design, data interpretation, and critical review of the manuscript. i. pabinger contributed to data interpretation and critical review of the manuscript. s. nopp, f. moik, c. ay are the guarantor of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. all authors have read the manuscript and approved its submission. this article is protected by copyright. all rights reserved pulmonary embolism in covid- patients: awareness of an increased prevalence venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography venous 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dyslipidaemia , icu, intensive care unit this study was supported by research funding from the austrian science fund (fwf) this article is protected by copyright. all rights reserved key: cord- -cfiekxr authors: giorgi-pierfranceschi, matteo; paoletti, oriana; pan, angelo; de gennaro, fabio; nardecchia, anna laura; morandini, rossella; dellanoce, claudia; lombi, samuele; tala, maurizio; cancelli, vanessa; zambelli, silvia; bosio, giancarlo; romanini, laura; testa, sophie title: prevalence of asymptomatic deep vein thrombosis in patients hospitalized with sars-cov- pneumonia: a cross-sectional study date: - - journal: intern emerg med doi: . /s - - - sha: doc_id: cord_uid: cfiekxr the association between coronavirus disease (covid- ) pneumonia and venous thrombotic disorders is still unclear. we assessed the association between covid- infection-related pneumonia and proximal deep-vein thrombosis (dvt) in a cohort of patients admitted to our hospital during the european outbreak in the front line of cremona, lombardy. in a single-center cross-sectional study, all patients hospitalized for more than days in internal medicine department with confirmed covid- pneumonia received -point compressive ultrasound assessment (cus) of the leg vein system during a single day. ninety-four percent of patients received enoxaparin as standard pharmacological prophylaxis for venous thromboembolism. the presence of dvt was defined as incompressibility of popliteal or common femoral vein. out of patients with covid- pneumonia (mean age . , . % males) hospitalized on march st, stayed in hospital for over days and of them underwent cus of deep venous system of the legs. the presence of asymptomatic dvt was found in patients ( . %). no symptomatic dvt was found. patients with dvt showed mean age = . years, mean d-dimer levels = . ng/ml and all of them received enoxaparin for thromboprophylaxis, except one. computed tomography pulmonary angiogram confirmed pulmonary embolism in five patients. one every seven patients with covid- -related pneumonia, hospitalized for more than days, had asymptomatic proximal dvt and half of them had confirmed pe despite standard pharmacological thromboprophylaxis. this observational study suggests the need of an active surveillance through cus in patients hospitalized with acute sars-cov- and underline the need of a more intense thromboprophylaxis. the world health organization on march th declared the novel coronavirus infection covid- a global pandemic [ , ] . italy, particularly the area of cremona located in the northern region, was notified as the first european country where severe acute respiratory syndrome due to covid- (sars-cov- ) was spreading [ ] . from february st until the end of march, patients were admitted to the hospital of cremona with confirmed diagnosis of covid- pneumonia. as known, patients hospitalized for acute medical illnesses, such as pneumonia, congestive respiratory failure, acute infection, rheumatic disorders, acute arthritis, or inflammatory bowel disease, show an increased risk for venous thromboembolism (vte). moreover, prolonged immobilization, the association of other acquired or individual risk factor, such as age > years, cancer, previous venous thromboembolism, obesity or sepsis, further increase thromboembolic risks [ ] [ ] [ ] [ ] [ ] [ ] [ ] . vte represents a frequent and potentially fatal complication in hospitalized patients. pharmacological thromboprophylaxis has shown to significantly reduce vte events, both in surgical and medical patients, with a relatively low risk of adverse events [ ] [ ] [ ] [ ] . evidence-based guidelines recommend use of low-dose parenteral anticoagulants in medically ill patients at high risk for thromboembolism for - days; while, an extended thromboprophylaxis could be advantageous in patients with additional and persistent risk factors [ , , ] . standardized thromboprophylaxis in acute medical ill patients include low dose of parenteral drugs such as unfractionated heparin (uh), low-molecular weight heparin (lmwh), or fondaparinux [ ] [ ] [ ] [ ] [ ] [ ] . the incidence of vte in medically ill patients treated with validated dosages of lmwh is nearly . % [ ] but optimization of thromboprophylaxis has been underlined in special settings such as in sepsis and in obese patients [ ] [ ] [ ] [ ] . currently, lmwh enoxaparin mg daily represents the standard of care for venous thromboembolism prevention in acute ill patients in our hospital. aim of our study was to evaluate the prevalence of deep vein thrombosis of the legs in a cohort of patients admitted to internal medicine of cremona hospital, with severe sars-cov- infection and treated with standard thromboprophylaxis, in a period between and days from hospitalization. the study was conducted in the internal medicine department of cremona hospital, in italy. starting from february , , the -bed hospital was transformed to admit patients with covid- pneumonia. patients were hospitalized in four different covid dedicated areas: departments of infectious disease, internal medicine, pneumology, and intensive care unit. patients not needing mechanical ventilation were indistinctly admitted to infectious disease, internal medicine or pneumology departments, altogether including four hundred beds. this single-center cross-sectional study was approved by the local ethics committee. cross-sectional studies are characterized by the collection of relevant data at a given time-point and this study design is the most relevant design when assessing the prevalence of a disease. flow chart of the study is detailed in fig. . on admission at the emergency department, all patients underwent high-resolution computed tomography (hrct) of the lung or chest x-ray to diagnose pneumonia and a standard lmwh prophylaxis (enoxaparin mg daily) was immediately started. in a single day (may , ), all patients who had been hospitalized in internal medicine department for at least days underwent -point compressive ultrasonography of the legs regardless of the presence of dvt symptoms. the following data were recorded in a structured data-base: -demographic, weight, main clinical characteristics such as presence of chronic coexisting diseases, prior vte, active cancer, in-hospital length of stay (los) -pharmacological thromboprophylaxis -respiratory failure and severity of pneumonia: respiratory failure was diagnosed when arterial blood gas analysis showed arterial partial pressure of oxygen (pao ) less than mmhg. pneumonia was categorized according to pao and fraction of inspired oxygen (fio ) ratio on admission. three mutually exclusive categories based on degree of hypoxemia were defined: mild ( - mm hg); moderate ( - mm hg); severe (< mm hg). the attending physician established the need of oxygen and/or c-pap support, case by case. reduced mobilization was considered as bedrest with bathroom privileges (either due to patient's limitations or on physician's order) for at least days [ , ] . oropharyngeal swabs were obtained on hospital admission. sars-cov- rna was searched using commercial rt-pcr methods (elitechgroup, paris, france). gene-finder™ covid- plusrealamp kit detects sars-cov- by amplification of rdrp gene, e gene and n gene according to the who recommended protocol [ ] . plasma samples were collected within the first h from hospitalization in vacuum plastic tubes (vacutainer, becton-dickinson, plymouth, uk), containing . % trisodium citrate ( : vol/vol, blood/anticoagulant), centrifuged within h from collection at g for min and immediately tested. d-dimer was assessed using a quantitative method (sta liatest d-dimer) on sta-r, a fully automated multiparameter coagulometer (stago, france). a cut-off below . µg/ml, as recommended by manufacturer for vte exclusion, was considered as normal plasma level. diagnosis of dvt was performed by a two-region ultrasound protocol according to the recommendations from the society of radiologists ultrasound for lower extremity deep venous thrombosis [ ] . all eligible patients underwent bedside bilateral proximal lower limb compressive ultra-sound (cus) performed by physicians with trained experience in vascular ultrasound, using the mindray dc- ultrasound machine with a . -mhz linear probe (fig. ) . the common femoral vein and the proximal tract of femoral vein were examined first, with the patients lying supine. the popliteal vein to its trifurcation was evaluated with the patients in a (left or right) lateral decubitus or less frequently in the prone position. all compressions were done using b-mode imaging with transverse views by applying compression along the deep venous system of each patient. the diagnostic criterion for dvt was the inability to fully compress the lumen of the vein in the transverse plane [ ] . patients with finding of dvt underwent computed tomography pulmonary angiography (ctpa) examination performed using md ge revolution evo equipment, after administration of - ml of non-ionic, high-concentration contrast media ( mg/ml) followed by ml saline chaser at at - ml/s. angiographic images were acquired in the supine position and cranio-caudal direction with collimation of . mm, reconstructed with standard algorithm, and slices thickness and interval of . mm. ct scans were reviewed by expert radiologist in thoracic imaging. as per the internal protocol, all the admitted patients with covid- -associated pneumonia, received thromboprophylaxis with once-daily subcutaneous administration of a standard dose of enoxaparin mg daily. descriptive analysis was performed. continuous variables are expressed as mean and standard deviation, or median ± standard deviation (sd) and range. categorical variables are expressed as frequencies and percentages. on march st , out of patients with covid- -associated pneumonia were hospitalized for at least days in the department of internal medicine of the hospital of cremona; of them, were included in the analysis, while four patients were not tested due to their absence in the ward at the moment of the test for different procedures. we scanned patients asymptomatic for dvt from admission to the time point. the mean age was . years (± ); patients were mostly males ( . %). the mean timing of respiratory symptoms onset was . (± . ) days before hospital admission. reduced mobilization affected the % of patients. the mean body weight was kg (± ). sixty-one % of the patients had respiratory failure (severe %; moderate %; mild %). no patient had clinical and laboratory pattern of disseminated intravascular coagulation (mean values of pt was . ± . ; aptt . ± . ; fibrinogen ± mg/dl). the mean value of creatinine clearance was . ± . ml/min, and no patient had values less than ml/min. the mean length of hospital stay (los) was . days (± ). ninety-four percent of the study population received thromboprophylaxis at admission: patients, enoxaparin mg daily. nine patients received enoxaparin mg daily because of a perceived higher risk of thrombosis by the attending physician. five patients were not treated with lmwh because of thrombocytopenia and recent history of bleedings ( table ). none of the scanned patients had symptoms of dvt. among patients, a proximal dvt was confirmed in patients ( . %), and ruled out in patients; of them, patients without varices had superficial venous thrombosis (svt). in patients with finding of dvt, a ctpa was performed. seven patients of nine were scanned; two patients did not undergo the test because of their critical condition. pulmonary embolism (pe) was confirmed in five cases, as shown in fig. . nine patients had proximal asymptomatic dvt. the mean age was . (± ) years, los was . (± ) days, they were all males, and the mean body weight was (± ). eight out of nine patients had mobility limitations. only one of them had mild pneumonia, while out of had moderate to severe respiratory failure ( moderate; severe; / needed c-pap support). all patients had asymptomatic proximal dvt, bilateral in cases. one patient had a prior dvt. one dvt was catheter associated. ctpa was assessed in seven patients and pe was confirmed in five of them ( . % of the analyzed patients). the main demographic and clinical characteristics of the patients with dvt are shown in table discussion our study shows that in patients admitted to a hospital medical ward because of covid- -associated pneumonia, the prevalence of silent proximal dvt was as high as . %, despite standard anticoagulant prophylaxis. this finding could partially explain the high incidence of pulmonary embolism described in previous study and autoptic series [ , ] . furthermore, dvt was frequently bilateral and it was found only in male patients; similarly, a higher prevalence in male subjects has been reported even in a previous study in non-icu patients [ ] . the novel coronavirus covid- is causing hospitalization of thousands of patients with pneumonia admitted for severe respiratory syndrome [ , , , ] . at hospitalization, patients are managed in relation to severity of respiratory distress and general clinical conditions and admitted to icu or clinical wards. acute medical illness, such as congestive heart failure or respiratory failure, from long time are recognized as clinical conditions at high risk for venous thromboembolism [ , ] and standardized parenteral low-dose anticoagulant drugs are recommended and enoxaparin mg daily represents the most commonly adopted regimen in our country. patients admitted to cremona hospital with covid- are usually treated, in the absence of contraindications such as severe thrombocytopenia, renal impairment, or active bleeding, with standard dose of enoxaparin mg daily for vte prevention, independent of age and weight. our observational study aimed to evaluate the prevalence of asymptomatic dvt in covid- hospitalized patients, treated with the standard regimen of prophylactic lmwh. patients were frequently bedridden ( %) with respiratory failure ( %) and, in this specific clinical condition in which respiratory distress is the main persistent symptom associated with decreased pao , other causes of possible impairment, other than covid- pneumonia, could have been easily overlooked. furthermore, patients may have also a reduced reactivity to promptly refer symptoms suggestive for dvt that, in any case, should be always confirmed through radiological exams due to poor specificity of clinical signs [ ] . this high prevalence of asymptomatic dvt patients, even with a standard thromboprophylaxis, poses us a crucial question: how and when to suspect vte in this particular medical condition? previous studies showed the high mortality rate in patients hospitalized with acute medical illness with asymptomatic proximal dvt [ , ] . since prevalence of vte in this study population treated with standard dose of lmwh is as high as that observed in the absence of prophylaxis in medical patients [ ] , we can suppose that it should be even higher without a pharmacological prevention. peculiar characteristics of this viral infection can cause prolonged immobilization, possible dehydration, a massive inflammatory response of the organism that in more severe cases may evolve towards acute respiratory distress syndrome (ards), severe coagulopathy and multi-organ failure, all conditions that increase thromboembolic complications. this condition can be associated with increased risks with the need of higher doses of heparin thromboprophylaxis as previously suggested [ , , [ ] [ ] [ ] [ ] [ ] [ ] ; furthermore, acquired antithrombin deficiencies may also occur in these clinical situations, thus causing heparin resistance [ , ] . the role of d-dimer in relation to vte diagnosis in this study population deserves a special consideration. as shown in tables and , high d-dimer levels have been measured in all patients, despite the result of cus. therefore, in this setting, on one hand d-dimer showed a poor usefulness in relation to its high negative predictive value; whereas, on the other, its correlation between elevated d-dimer levels and vte should be better investigated and specific cut-off defined [ , [ ] [ ] [ ] [ ] [ ] [ ] . waiting for further data regarding the proper use of d-dimer in this clinical condition and based on currently evidences, we consider that early surveillance could be reasonable to promptly avoid dvt complications. as stated before, the importance of this first study, conducted in hospitalized covid- patients is the evidence of a high prevalence of asymptomatic dvt, despite a standard anticoagulant prophylaxis. on this basis, in our opinion, three important elements should be kept into consideration to properly define the global vte risk of each single patient in addition to acute infectious disease: (a) individual risk factors, such as age, weight, sex, cancer, history of previous vte, that independently increase thromboembolic risk; (b) time of disease onset and time of bed rest and immobilization, to promptly start lmwh prophylaxis; (c) posology of heparin, that should be increased to reach the correct prophylaxis range which may not be "a fixed dose for all", as already proposed in patients with sepsis [ , [ ] [ ] [ ] . for the above considerations and highlighting the very high thromboembolic risks of hospitalized covid- patients on standard prophylaxis, we conclude that: (a) routinely compressive ultrasound of the legs should be performed during the first week of hospitalization; (b) lmwh prophylaxis should be started immediately at the onset of acute covid- pneumonia; (c) lmwh prophylaxis should be ensured to all patients, adapting doses in relation to weight, renal function with the target to maintaining upper levels of prophylactic range (axa = . - . ui/ml) [ , ] . this study presents several limitations due to its monocenter design and the relatively small sample size; however, it represents the first evidence of the high prevalence of asymptomatic dvt in patients hospitalized with covid- pneumonia, outside intensive care units and despite standard prophylactic dose of lmwh. probably, our data underestimated occurrence of dvt, first because we studied only patients with los more than days without knowing the right time of the onset of the disease and the mobility limitation before hospitalization. second, in our protocol, we use a point of care ultrasound, widely used also in the medical wards [ ] consisting of a two-point cus evaluation that may underestimates the presence of isolated femoral dvt and does not look at all for calf dvt [ , ] . finally, based on the high frequency of both dvt and pe despite standard anticoagulant prophylaxis, an important knowledge gap remains regarding the optimal time for cus examination during and after hospital discharge, as well as the optimal lmwh prophylactic treatment and its duration. our observation highlights the high prevalence of asymptomatic proximal dvt in patients hospitalized with covid- pneumonia and the need to implement appropriate active patient surveillance strategies using ultrasound, as well as the adoption of adequate pharmacological thromboprophylaxis. these findings may have prognostic implications, but larger dedicated studies are warranted. author contributions mg-p and st designed the study, collected all data, wrote and revised the draft. they had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. acquisition, analysis, or interpretation of data, revision of the manuscript: all authors. mg-p, st: drafting of the manuscript. critical revision of the manuscript for important intellectual content: all authors. mg-p, st: statistical analysis and supervision. conflict of interest all authors have no conflict of interest. ethics approval ethics committee approval was requested. informed consent no informed consent was requested beacuse of compressive ultrasound is a standard of care. the novel coronavirus originating in wuhan, china: challenges for global health governance world health organization (who) ( ) coronavirus disease (covid- ) situation report - incidence of venous thromboembolism in hospitalized patients vs community residents a validation study of a retrospective venous thromboembolism risk scoring method assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the medenox study meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients prevention of vte 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hospitalized patients attention should be paid to venous thromboembolism prophylaxis in the management of covid- a systematic review of clinical practice guidelines on the use of low molecular weight heparin and fondaparinux for the treatment and prevention of venous thromboembolism: implications for research and policy decision-making guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism heparin resistance heparin, coumarin, protein c, antithrombin, fibrinolysis and other clotting related resistances: old and new concepts in blood coagulation d-dimer for the diagnosis of acute venous thromboembolism in the emergency department: a janus-face marker clinical characteristics of deceased patients with coronavirus disease : retrospective study hematological findings and complications of covid- guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism review of d-dimer testing: good, bad, and ugly clinical decision rules and d-dimer in venous thromboembolism: current controversies and future research priorities point of care ultrasonography from the emergency department to the internal medicine ward: current trends and perspectives isolated deep venous thrombosis: implications for -point compression ultrasonography of the lower extremity can the us examination for lower extremity deep venous thrombosis be abbreviated? a prospective study of examinations key: cord- -v bq bx authors: barco, stefano; bingisser, roland; colucci, giuseppe; frenk, andré; gerber, bernhard; held, ulrike; mach, francois; mazzolai, lucia; righini, marc; rosemann, thomas; sebastian, tim; spescha, rebecca; stortecky, stefan; windecker, stephan; kucher, nils title: enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease- (the ovid study): a structured summary of a study protocol for a randomized controlled trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: v bq bx objectives: the ovid study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged or older diagnosed with covid- , a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. trial design: the ovid study is conducted as a multicentre open-label superiority randomised controlled trial. participants: inclusion criteria . signed patient informed consent after being fully informed about the study’s background. . patients aged years or older with a positive test for sars-cov in the past days and eligible for ambulatory treatment. . presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature > . ° c. . ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves . ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. . ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. . ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. exclusion criteria . any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (vte), acute confirmed symptomatic vte, acute coronary syndrome. . anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. any of the following events occurring in the prior days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous vte, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past months, or recurrent, or metastatic, or inoperable. . any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within days prior to randomization or sign of acute bleeding. . intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. . haemoglobin < g/dl and platelet count < x ( ) cells/l confirmed by recent laboratory test (< days). . subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. . severe renal insufficiency (baseline creatinine clearance < ml/min calculated using the cockcroft-gault formula) confirmed by recent laboratory test (< days). . contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. . current use of dual antiplatelet therapy. . participation in other interventional studies over the past days. . non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. . cognitive impairment and/or inability to understand information provided in the study information. patient enrolment will take place at seven swiss centres, including five university hospitals and two large cantonal hospitals. intervention and comparator: patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of , iu anti-xa activity ( mg/ . ml) once daily for days. patients randomized to the comparator group will receive no anticoagulation. main outcomes: primary outcome: a composite of any hospitalization or all-cause death occurring within days of randomization. secondary outcomes: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within days, days, and days of randomization; (ii) each component of the primary efficacy outcome, within days, days, and days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within days, days, and days of enrolment; (iv) primary efficacy outcome, within days, and days of enrolment; (v) disseminated intravascular coagulation (isth criteria, in-hospital diagnosis) within days, days, and days of enrolment. randomisation: patients will undergo block stratified randomization (by age: - vs. > years; and by study centre) with a randomization ratio of : with block sizes varying between and . randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (redcap, vanderbilt university, v . . ). blinding (masking): in this open-label study, no blinding procedures will be used. numbers to be randomised (sample size): the sample size calculation is based on the parameters α = . ( -sided), power: −β = . , event rate in experimental group, pexp = . and event rate in control group, pcon = . . the resulting total sample size is . to account for potential dropouts, the total sample size was fixed to with patients in the intervention group and in the control group. trial status: protocol version . , april . protocol version . , may recruiting start date: june . last patient last visit: march . trial registration: clinicaltrials.gov identifier: nct first posted: may , last update posted: july , full protocol: the full protocol is attached as an additional file, accessible from the trials website (additional file ). in the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. . / . . pending clinical study with imp category b. clinical phase iiib. coronavirus disease (covid- ) has emerged as a pandemic and a public health crisis of global proportions. as of april , , a total of , , covid- cases have been diagnosed with the severe acute respiratory syndrome corona virus (sars-cov- ) across more than countries. of one of the most frequently described poor prognostic features in patients with covid- is the development of coagulopathy. an increase in d-dimers, which reflects the presence of disseminated intravascular coagulation, is usually observed in the most severe cases of covid- and it correlates with in-hospital mortality ( ) ( ) ( ) . in hospitalized patients with sepsis-induced coagulopathy or with markedly elevated d-dimer associated with covid- infection, anticoagulation with low-molecular-weight heparin (lmwh) was associated with lower mortality. covid- emerged as a dramatic prothrombotic condition and it appears now clear, a few months after the first patients described in china, that covid- patients are characterized by a substantial risk of developing acute pulmonary embolism (pe) or deep vein thrombosis (dvt) due to local and systemic inflammation, reduced mobility, hypoxia, endothelial dysfunction. in particular, the cumulative incidence of vte in covid- patients is approximately - % (up to % in icu patients undergoing vte screening). this contrasts with the risk of vte observed in medically ill patients (< %). moreover, half of the vte events, mostly pe, were diagnosed at hospital admission, suggesting that these events developed during home quarantine. recent guidances stated that prophylactic-dose lmwh, such as enoxaparin, should be considered in all patients who require hospital admission for covid- in the absence of any contraindications. one of the better known non-anticoagulant properties of heparins, their anti-inflammatory function, include binding to inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of the positively charged peptide complement factor c a, and sequestering acute phase proteins: this may provide a benefit in covid infection where proinflammatory cytokines are markedly raised and acute respiratory distress syndrome represents a feared and life-threatening complication. covid- patients are characterized by systemic inflammation, reduced mobility, hypoxia, endothelial dysfunction, signs of myocarditis and heart failure, and the underlying coagulopathy, all factors increasing the risk of developing thromboembolic events. it remains unclear whether covid- patients not admitted to the hospital due to non-severe clinical conditions should receive thromboprophylaxis and whether this provides a clinical benefit weighed against the risk of anticoagulant-associated bleeding. the evidence is scarce also for non-covid- patients. the most recent american society of hematology (ash) guidelines state that "in medical outpatients with minor provoking risk factors for vte (eg, immobility, minor injury, illness, infection), the ash guideline panel suggests not using vte prophylaxis (conditional recommendation, very low certainty in the evidence of effect)." our hypothesis is that enoxaparin may prevent or limit coagulopathy, including the occurrence of thromboembolic events, in the presence of a mild covid disease in an outpatient setting. the ovid study will show whether prophylactic-dose enoxaparin improves survival and reduces any hospitalizations in ambulatory patients aged or older diagnosed with covid- , a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. the primary efficacy outcome is a composite of any hospitalization or all-cause death occurring within days of randomization. the study will be conducted as a multicentre randomized open-label controlled trial. in the study, a total of , adult patients aged or older with covid- and candidates to ambulatory treatment will be randomized to receive enoxaparin mg sc qd or no treatment for a total of days. the primary outcome will be assessed within days of enrolment. inclusion criteria ) signs patient informed consent after being fully informed about the study's background. ) patients aged years or older with a positive test for sars-cov in the past days and eligible for ambulatory treatment. ) presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature > . ° c. ) ability of the patient to travel to the study center by private transportation, performed either by accompanying person from same household or by the patient him/herself. ) ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. ) ability to walk from car to study center or reach it by wheel chair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. ) ability to self-administer prefilled enoxaparin injections after instructions received at the study center or availability of a person living with the patient to administer enoxaparin. any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior vte, acute confirmed symptomatic vte, acute coronary syndrome. anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. any of the following events occurring in the prior days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous vte, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past months, or recurrent, or metastatic, or inoperable. any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within days prior to randomization or sign of acute bleeding. intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial hemorrhage. hemoglobin < g/dl and platelet count < x cells/l confirmed by recent laboratory test (< days). subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. severe renal insufficiency (baseline creatinine clearance < ml/min calculated using the cockcroft-gault formula) confirmed by recent laboratory test (< days). ) contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. current use of dual antiplatelet therapy. ) participation in other interventional studies over the past days. non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. ) cognitive impairment and/or inability to understand to information provided in the study information. we implemented two logistical solutions to integrate the process of sars-cov testing, pre-screening, screening (hot-line and flyers), in-hospital recruitment, enrolment and randomization/allocation. a nationwide ovid hot-line telephone number will be made available in languages (german, french, italian) for interested patients or test centers to contact the hot-line. standard hygiene precautions will be met at the study centers to avoid spreading of sars-cov among other patients or health care workers. principles of patient and investigator safety will be applied. standard procedures concerning privacy, discussion with patients on details of the study, collection of informed consent, and instruction on how to administer the study medication will be maintained in conformity with gcp recommendations. this will also include outcome measurements to be conducted by telephone with standardized questionnaire. enoxaparin (clexane®) will be given at the recommended dose of , iu antixa activity ( mg/ . ml) once daily by sc injection for days. no study drug. the sample size calculation is based on the parameters = . ( sided), power = − = . , event rate in experimental group, = . and event rate in control group, = . . the resulting total sample size is . to account for potential drop-outs, the total sample size was fixed to . this will be the maximum sample size, no increase in sample size is planned. results will be reported in terms of risk ratios (rr) between experimental and control group, i.e. we anticipate that the estimated rr will be < . we obtained official data on fatality and hospitalization rates observed in the swiss population until . . : a total of . patients aged years or older tested positive for sars-cov- , of whom ( . %) died and . ( . %) were hospitalized irrespective of whether this consisted of a primary hospitalization (after evaluation at the emergency department) or a secondary hospitalization for clinical deterioration after initial ambulatory treatment. assuming that two thirds of deaths and of any hospitalization occurred in ambulatory patients, we estimated that the primary efficacy outcome rate would occur in % (any hospitalization %, case fatality rate %). as we anticipate that a substantial number of the primary endpoint is due to venous or arterial thromboembolic complications, which would be prevented by the use of prophylactic-dose enoxaparin, we estimated that enoxaparin will decrease the primary efficacy outcome to % (rr . ). prior studies of thromboprophylaxis in hospitalized patients with medical illnesses were also considered for estimating the benefit of enoxaparin use in medical patients and sample size calculation. months the primary efficacy outcome analysis will be conducted in the intention-to-treat (itt) population, consisting of all randomized subjects who signed a valid informed consent. descriptive statistics of the patient characteristics at baseline will include mean and standard deviation for continuous variables, median and interquartile range for the ordinal or non-normal variables, as well as numbers and percentages of total for the categorical variables. for the primary outcome, the relative risk will be calculated for the experimental group as compared to control group, with % confidence interval. refined analyses include the stratification variables in order to reduce unexplained heterogeneity. for that, the mantel haenszel method as well as multiple logistic regression models will be used. a single interim analysis is planned. the aim of the interim analysis is to stop the trial early for efficacy (superiority) or futility. this study will be conducted in compliance with the protocol, the current version of the declaration of helsinki, the ich-gcp guideline as well as all national legal and regulatory requirements. b. demographics, medical history. c. vital signs (respiratory rate, heart rate, arterial blood pressure, body temperature, arterial oxygen saturation), height, weight. d. laboratory tests (blood cell count, hemoglobin and creatinine). e. the dispense of study medication and the administration of the first dose will be done at the study center after appropriate instruction and under medical supervision. the following doses will be administered from an instructed person of the same household or self-administered at home until day . instructions on how to administer enoxaparin will also made be available in paper and video from the product manufacturer. f. any hospitalization or all-cause death. g. pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke; major bleeding, non-major clinically relevant bleeding. before this study will be conducted, the protocol, the proposed participant information and consent form as well as other study-specific documents will be submitted to a properly constituted competent ethics committee (cec) and competent authorities (swissmedic) in agreement with local legal requirements, for formal approval. any amendment to the protocol must as well be approved. the decision of the cec and swissmedic concerning the conduct of the study will be made in writing to the sponsor-investigator before commencement of this study. the clinical study can only begin once approval from all required authorities has been received. any additional requirements imposed by the authorities shall be implemented. the study will be registered in the swiss federal complementary database (swiss national clinical trial portal (snctp) and in the international trial registry clinicaltrials.gov (clinicaltrials.gov). category b. the current label of enoxaparin (study medication) does not cover ambulatory patients with acute infectious diseases without additional venous thromboembolism (vte) risk factors. the efficacy and safety of prophylactic-dose enoxaparin has not been studied in covid- ambulatory patients, as sars-cov has been described first in . approval from the appropriate constituted competent ethics committee is sought for each study site in the clinical trial. the reporting duties and allowed time frame are respected. no substantial amendments are made to the protocol without prior sponsor and cec approval, except where necessary to eliminate apparent immediate hazards to study participants. premature study end or interruption of the study is reported within days. the regular end of the study is reported to the cec within days, the final study report shall be submitted within one year after study end. amendments are reported according to chapter . . the sponsor will obtain approval from swissmedic before the start of the clinical trial. reporting will be done within the allowed time frame. planned or premature study end are reported within and days, respectively. the final report will be submitted to the ca within one year after the end of the study. amendments are reported according to chapter . . the study will be carried out in accordance with principles enunciated in the current version of the declaration of helsinki, the guidelines of good clinical practice (gcp) issued by ich, and swiss competent authority's requirements. cec and competent authorities will receive annual safety and interim reports and be informed about non-substantial amendments, the course of the study, and the study stop/ end in agreement with local requirements. no conflicts of interest. the investigator must explain to each participant the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail. each participant must be informed that the participation in the study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent medical treatment. the participant must be informed that his/her medical records may be examined by authorized individuals other than their treating physician. all participants for this study will be provided a participant information sheet and a consent form describing this study and providing sufficient information for participants to make an informed decision about their participation in this study. the participant information sheet and the consent form will be submitted with the protocol for review and approval for the study by the cec and by swissmedic. the formal consent of a participant, using the approved consent form, must be obtained before that participant is submitted to any study procedure. the participant should read and consider the statement before signing and dating the informed consent form, and should be given a copy of the signed document. the consent form must also be signed and dated by the investigator (or his designee) and it will be retained as part of the study records. the investigator affirms and upholds the principle of the participant's right to privacy and that they shall comply with applicable privacy laws. especially, anonymity of the participants shall be guaranteed when presenting the data at scientific meetings or publishing them in scientific journals. individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. subject confidentiality will be further ensured by utilising subject identification code numbers to correspond to treatment data in the computer files. such medical information may be given to the participant's personal physician or to other appropriate medical personnel responsible for the participant's welfare, if the patient has given his/her written consent to do so. for data verification purposes, authorised representatives of the sponsor-investigator, a competent authority (e.g. swissmedic), or an ethics committee may require direct access to parts of the medical records relevant to the study, including participants' medical history. the sponsor-investigator may terminate the study prematurely according to certain circumstances, e.g.:  early evidence of benefit or harm of the experimental intervention, e.g. for superiority or futility as defined in statistical methods, (section . );  insufficient participant recruitment, e.g. < % of the expected number of patients six months after the enrolment of the first patient, also based on the course of sars-cov infections in switzerland;  when the safety of the participants is doubtful or at risk, respectively, based on recommendations received from dsmb committee;  changes in accepted clinical practice that make the continuation of a clinical trial unwise, including the results of similar studies or the publication of international guidances. substantial amendments (significant changes) are only implemented after approval of the cec and ca respectively. significant changes to be authorised by the cec are the following:  changes affecting the participants' safety and health, or their rights and obligations;  changes to the protocol, and in particular changes based on new scientific knowledge which concern the trial design, the method of investigation, the endpoints or the form of statistical analysis;  a change of trial site, or conducting the clinical trial at an additional site; or  a change of sponsor, coordinating investigator or investigator responsible at a trial site. significant changes to be authorised by swissmedic are the following:  changes to the therapeutic product, or to its administration or use;  changes based on new preclinical or clinical data which may affect product safety; or  changes concerning the production of the therapeutic product which may affect product safety. under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of human participants may proceed without prior approval of the sponsor and the cec/ca. such deviations shall be documented and reported to the sponsor and the cec/ca as soon as possible. all non-substantial amendments are communicated to the ca as soon as possible if applicable and to the cec within the annual safety report (asr). coronavirus disease (covid- ) has emerged as a pandemic and a public health crisis of global proportions. as of april , , official data on fatality vary across countries due to differences in the age structure of populations, number of screening tests performed, local capacities of healthcare facilities, and criteria used for the compilation of vital certificates reporting the underlying causes of death. comparisons with historical data in some european countries suggest, however, that the mortality may be at least four times higher than what is estimated based on official covid- reports, indicating that a substantial number of deaths occurred at home and were not classified as covid- -related ( ). in switzerland, the vast majority of covid- -related deaths have been recorded in patients aged years or older with age-dependent mortality and hospitalization rates: < . % mortality and % hospitalization rate between - years, % and % between and years, % and % between and years, and % and % above years, respectively. one of the most frequently described poor prognostic features in patients with covid- is the development of coagulopathy ( ) . an increase in d-dimers, which reflects the presence of disseminated intravascular coagulation, is usually observed in the most severe cases of covid- and it correlates with in-hospital mortality ( ) ( ) ( ) . in hospitalized patients with sepsis-induced coagulopathy or with markedly elevated d-dimer associated with covid- infection, anticoagulation with low-molecular-weight heparin (lmwh) was associated with lower mortality; this association was stronger for higher d-dimer levels: odds ratio for anticoagulation . ( . although non-survivors with covid- had higher d-dimer levels than survivors, d-dimer has not been studied as a potential predictor of death or vte events as it represents an non-specific marker. indeed, the increased levels may reflect acute fibrinous and organising pneumonia characterised by extensive intra-alveolar fibrin deposition ( ). its potential use as a surrogate marker of a prothrombotic condition is in its infancy and cannot serve to drive medical decisions i.e. on whether to administer anticoagulation or a higher dosage of antithrombotic prophylaxis. neither the measurement of d-dimers nor the screening with ultrasound are currently recommended in covid- outpatients by international guidelines to provide the indication for thrombosis prophylaxis ( ) . there are no validated cut-off values for the introduction of d-dimer for risk assessment in covid- and the vast majority of covid- studies adopted incorrect methodology to build prediction models, also concerning the use of d-dimer ( ). in a recent covid- consensus paper, it is stated that "elevated d-dimer levels, is a common finding in patients with covid- , and does not currently warrant routine investigation for acute vte in absence of clinical manifestations or other supporting information."( ) covid- emerged as a dramatic prothrombotic condition and it appears now clear, a few months after the first patients described in china, that covid- patients are characterized by a substantial risk of developing acute pulmonary embolism (pe) or deep vein thrombosis (dvt) due to local and systemic inflammation, reduced mobility, hypoxia, endothelial dysfunction. during prior viral outbreaks, such as in patients with severe acute respiratory syndrome (sars), myocardial infarction and venous thromboembolism were frequent causes of death ( ) . these results emerged from clinical studies and post-mortem examinations (recently reviewed in ( )). small reports on influenza a (h n ) patients requiring intensive care unit (icu) admission and advanced mechanical ventilation indicated that pe represented a common finding ( ) ( ) ( ) . published, peer-reviewed reports in the biomedical literature have been consistently showing that dvt and, especially, pe represents a key manifestation of covid- ( ) ( ) ( ) ( ) ( ) ( ) ( ) . we have provided here a brief chronological summary of the most recent evidence that is now growing almost on a daily basis. an analysis of patients admitted at intensive care units in the netherlands showed that thromboembolic events occurred in %, of whom the majority had symptomatic vte. pe was the most frequent thrombotic complication (n = ). age (adjusted hazard ratio (ahr) . /per year, %ci . - . ) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > s or activated partial thromboplastin time > s (ahr . , %ci . - . ), were independent predictors of thrombotic complications ( ) . these results suggested that a higher dosage of lmwh thromboprophylaxis may be needed in icu patients due to their extremely high thrombotic risk. in icu patients with covid- diagnosed in china, the incidence of vte was %: of patients with vte, died ( ) . there was no routine screening for vte in this study, whereas the use of thromboprophylaxis was not clearly documented. systematic assessment of vte using complete duplex ultrasound was performed in anticoagulated covid- patients admitted to french intensive care units (icu) ( ) . the overall rate of vte in patients was %. the proportion of vte was significantly higher in patients treated with prophylactic anticoagulation when compared to the other group. in a recent analysis of italian hospitalized patients with covid- novel and relevant data emerged. first, a total of ( % of total) patients underwent vte imaging tests and were positive ( % of tests), suggesting substantial underestimation of thromboembolic complications in these patients. second, half of these events were diagnosed on admission, indicating that vte did not develop during hospitalization, but in the ambulatory setting ( ) . therefore, the key question would not (only) be whether hospitalized covid- patients should receive a higher dosage of lmwh thromboprophylaxis during hospitalization, but if current ambulatory thromboprophylaxis strategies are adequate ( - ). a recent analysis from a french group showed that the rate of thromboembolic complications in covid- patients with ards was much higher ( . %) than what observed in a historical control group of non-covid- ards patients ( . %), despite anticoagulation ( ). in a british cohort study of icu patients, the cumulative incidence estimate of vte was %. however, only patients received ctpa, of whom were positive for pe ( ) . the authors of a french study ( ) showed that the cumulative incidence of pe was % among icu patients and events occurred after a median of days after hospital admission with % of events diagnosed during the first hours. the authors investigated the incidence of objectively confirmed venous thromboembolism (vte) in hospitalized patients with covid- in a single-center cohort study. seventy-four patients ( %) were admitted to the intensive care unit (icu). during a median follow-up of days (iqr, - ), patients ( %) were diagnosed with vte of whom ( %) had symptomatic vte, despite routine thrombosis prophylaxis. the cumulative incidences of vte at and days were % ( % ci, . - ) and % ( % ci, - ), respectively. vte was associated with death (adjusted hr, . ; % ci, . - . ). future research should focus on optimal diagnostic and prophylactic strategies to prevent vte and potentially improve survival. the authors concluded that "future research should focus on optimal diagnostic and prophylactic strategies and assessing the risk of vte in post-discharge and non-hospitalized patients with covid- ." preprint available at: https://www.preprints.org/manuscript/ . /v . taking this information into account, it is clear that covid- represents an unprecedented and highly prothrombotic condition for which current thromboprophylaxis schemes may be inadequate and novel strategies are warranted. only well-conducted randomized controlled trial can provide physicians with useful information to guide clinical decisions. data from the pre-covid- era indicate that flu and other seasonal viral infections increase the risk of developing vte in the general population, but do not represent per se an indication to give thromboprophylaxis in the outpatient setting ( ) . no large interventional studies have ever been conducted in the outpatient setting to investigate this point. indeed, there are two key differences with the covid- outbreak: ) the vast majority of people aged or older (as well as other "fragile" population subgroups) are routinely vaccinated against influenza, the most feared and prevalent respiratory infection in the elderly. this is obviously not the case for sars-cov . ) the burden of viral respiratory infection-associated vte, at least based on indirect data from hospitalized patients, does not appear to be dramatic or extreme as among covid- patients. there are further methodological and epidemiological aspects to consider: -the field of viral infection-associated thromboembolism is in its infancy: although up to % of unprovoked vte events may be due to viruses, e.g. cytomegalovirus, ( ) this patient population has not been object of focused investigations; -there is data from case-control studies informing us about the prevalence of prior (or recent) influenza infection in patients with vs. without acute vte, but evidence on the absolute risk of vte among patients with a respiratory/influenza infection is less firm and usually concerning hospitalized patients ( ); -approximately % of acute vtes occur in the outpatient setting and acute respiratory infection is one of the highest prevalent risk factor after cancer and recent hospitalization/surgical intervention. it is known from the literature that hospitalized non-icu patients with medical illnesses receiving adequate thromboprophylaxis are characterized by rates that are close to % during the first weeks of hospitalization, and indeed not exceeding % ( - ). covid- patients with chronic coronary artery disease and those with risk factors for atherosclerotic cardiovascular disease have an increased risk to develop myocardial infarction during acute infections, as shown previously in epidemiologic and clinical studies of influenza ( , ) . acute cardiac injury was reported in % of covid- cases in a small case series in the lancet. another study suggested a rate of . % among patients from another hospital in wuhan ( ). shi et al. and guo et al. showed that patients with myocardial injury had a higher prevalence of hypertension, coronary artery disease, heart failure, and diabetes, as well as more severe inflammation, than those with normal levels of troponin ( , ) . in china, covid- patients with signs of myocardial injury had much higher short-term mortality rates ( , ) . as with other coronaviruses, sars-cov- can elicit the intense release of multiple cytokines and chemokines that can lead not only to vascular inflammation and plaque instability but also to myocardial inflammation ( ) . the possibility of direct viral infection of vascular endothelium and myocardium via the host ace- receptor has also been raised ( ) . the usz was largely involved in the study of the pathophysiology and complications of covid- ( , ) , and identification of key pathophysiological mechanisms: ) coronavirus binds to the ace- respiratory receptor and causes a respiratory infection, ) coronavirus binds on the ace- receptors of the endothelium and penetrates the endothelial cells and causes severe endothelitis in many organs with high amounts of receptors (virus direct detection in the endothelium),( ) ) coronary virus causes severe endothelitis that we do not see in other viral diseases, ) «extreme» coagulation activation and coagulopathy, measurable and strongly increased fibrinogen and d-dimers, ) vte, micro-thrombosis also in other organs, cardiovascular events ( , , ) . a recent isth ssc guidance stated that prophylactic-dose lmwh, such as enoxaparin, should be considered in all patients who require hospital admission for covid- in the absence of any contraindications ( ). one of the better known non-anticoagulant properties of heparins, their anti-inflammatory function, include binding to inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of the positively charged peptide complement factor c a, and sequestering acute phase proteins: this may provide a benefit in covid infection where proinflammatory cytokines are markedly raised and acute respiratory distress syndrome represents a feared and life-threatening complication ( , ). a paper published in , has also shown that heparin can reduce myocardial inflammation and decrease collagen deposition in an animal model of (chronic) myocarditis ( , ) , a frequent finding in covid- patients. furthermore, in vitro experiments showed that lmwh may be characterized by a protective effect against sars-cov and sars-cov viruses, particular limiting the sars-cov invasion at the early attachment phase during the initial phase and inhibit virus cell invasion ( ) . according to international consensus documents and guidelines, lmwh thromboprophylaxis should be considered in most hospitalized patients with medical illnesses. currently, there is no firm evidence that lmwh thromboprophylaxis should be routinely used in ambulatory medical patients. in switzerland, as in many other european countries, lmwh is approved for thromboprophylaxis in patients with bed rest and acute medical illnesses, such as (i) heart failure, (ii) acute respiratory insufficiency, or (iii) acute infectious or rheumatological conditions in combination, the latter, requiring an additional risk factor or immobilization. a practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- stated that the risk of vte must be assessed in all patients admitted to hospital, and preventive measures should be taken in all high-risk patients according to international guidelines on thromboprophylaxis in medical patients (nice/ash) ( ). several scientific societies, such as the american society of hematology, thrombosis uk, isth, and the gesellschaft für thrombose-und hämostaseforschung (gth), recommend the use of lmwh over new oral anticoagulants for thromboprophylaxis in covid- patients in the presence of vte risk factors. of note, bleedings rarely occur in patients with covid- ( ) . however, the lack of firm evidence prevents the release of more specific recommendations. a recent review on the topic addressed this point ( ) with a general statement "while routine use of thromboprophylaxis in outpatients is not recommended, use in immobile infected outpatients, especially with other increased risks for vte, can be considered on a case by case basis based on severity of illness or as incorporated into local practice". taking into accounts all these factors, anticoagulant prophylaxis is being used in the vast majority of covid- patients admitted to the hospital as the thromboembolic risk of these patients is perceived to largely exceed that of bleeding. due to the substantial societal burden posed by this outbreak, most western countries developed strategies to handle as many patients as possible on an ambulatory basis. admitted covid- patients represent a minority, even among the elderly. ambulatory treatment includes testing, general assessment of the vital parameters, blood withdrawal, and supportive therapy. although there is heterogeneity across regions and countries, quarantine represents the most adopted public health measure to limit viral transmission by isolating patients positive for sars-cov . it remains unclear whether patients not admitted to the hospital due to non-severe clinical conditions should receive thromboprophylaxis and whether this provides a clinical benefit weighed against the risk of anticoagulant-associated bleeding. the evidence is scarce also for non-covid- patients. the most recent american society of hematology (ash) guidelines state that "in medical outpatients with minor provoking risk factors for vte (eg, immobility, minor injury, illness, infection), the ash guideline panel suggests not using vte prophylaxis (conditional recommendation, very low certainty in the evidence of effect)." however, it may be dangerous to extrapolate this low-evidence-level recommendations to patients who may be characterized by a substantial burden of vte due to coagulation activation, local and systemic inflammation, reduced mobility ( ) . the following points represent, in summary, the rationale for studying the use of thromboprophylaxis in ambulatory patients with covid- : ) the risk of thromboembolic events in patients with covid- during anticoagulant prophylaxis exceeds that observed in medical patients, usually < %, even in the presence of seasonal viral infections ( , ) ) the cumulative risk of vte in hospitalized covid- patients is at least %, but possibly higher, as described in several publications ) the absolute vte risk in covid- patients requiring intensive care is % if screening strategies are implemented ( ) ) half of the vte events, mostly pe, were diagnosed at hospital admission, suggesting that these events developed during the quarantine period ( ) . our hypothesis is that early thromboprophylaxis may prevent or limit coagulopathy, and reduce thromboembolic complications leading to hospitalization or death, in the presence of a mild covid disease among outpatients. enoxaparin sodium is a low molecular weight heparin marketed under the trade names clexane ® and associated names. this anticoagulant is used in the treatment and prophylaxis of thromboembolic disorders. it is given as an injection subcutaneously or intravenously. the principal pharmacological properties of enoxaparin include antifactor xa and antifactor iia (antithrombin) activity, which are dependent on its binding affinity for antithrombin. clexane ® and associated names solution for injection is currently approved in more than countries worldwide including all the european union (eu) member states as well as switzerland. the first marketing authorisation (ma) was granted in france on april . the product is currently registered in europe under concentrations of mg/ml (equivalent to iu anti xa/ml) in prefilled syringes, multi-dose vials, ampoules, and mg/ml (equivalent to iu anti xa/ml) in prefilled syringes. vials of mg/ ml and a pen of x mg (equivalent to x iu anti xa) are also authorised. one mg of enoxaparin exhibits iu anti-xa, this allows an easy conversion and representation of the anti-xa activity for the prescriber, and referring to mg instead of biological activity units has been commonly used throughout clinical trials. overall, the general principles of prophylactic and therapeutic indications of enoxaparin are reflected in the pis across europe, however the section was harmonised to address variations in the exact wording in these types of indication, which were different between states. enoxaparin is indicated in adults for: • prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery. • prophylaxis of venous thromboembolic disease in medical patients with reduced mobility and an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases at increased risk of venous thromboembolism). • treatment of deep vein thrombosis (dvt) and pulmonary embolism (pe), excluding pe likely to require thrombolytic therapy or surgery. • prevention of thrombus formation in extracorporeal circulation during haemodialysis. • acute coronary syndrome: -treatment of unstable angina and non st-segment elevation myocardial infarction (nstemi), in combination with oral acetylsalicylic acid. -treatment of acute st-segment elevation myocardial infarction (stemi) including patients to be managed medically or with subsequent percutaneous coronary intervention (pci). there are few differences in the various country labels regarding the indication prophylaxis of vte in medical patients. while e.g. the term "bedridden" appears in many countries as a key criteria, some countries have more open definition such as "whose position can be defined at risk" or "temporary immobilised". the accp guidelines recommend: for acutely ill hospitalised medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with lmwh, low-dose unfractionated heparin (lduh) twice a day (bid), lduh three times a day (tid), or fondaparinux: grade b. the revised wording is based on the inclusion criteria and the results of the medenox study ( ) . the harmonised wording for the indication in this population therefore includes "disease in medical patients with an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of venous thromboembolism". in switzerland, enoxaparin is approved for the same prophylactic indications. in medical patients with acute illness, the recommended dosage is mg qd s.c. given as a subcutaneous injects for a period of - days, until complete mobility is not reached. the benefit is not established for a treatment longer than days. from the swiss product monograph (swissmedic-genehmigte fachinformation): «prophylaxe von thromboembolischen erkrankungen venösen ursprungs bei bettlägerigen medizinischen patienten mit einer akuten erkrankung, wie: herzinsuffizienz (nyha klasse iii oder iv); akute respiratorische insuffizienz; akute infektiöse oder rheumatische erkrankungen verbunden mit einem/anderen thromboembolischen risikofaktor/en.» in acutely ill medical patients, the american society of hematology (ash) guideline panel suggests using unfractionated heparin, lmwh, or fondaparinux rather than no parenteral anticoagulant (conditional recommendation, low certainty in the evidence of effects). among these anticoagulants, the panel suggests using lmwh (low certainty in the evidence of effects) or fondaparinux (very low certainty in the evidence of effects) rather than ufh (conditional recommendation). besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse effects at mg/kg/day in the -week sc toxicity studies both in rats and dogs and at mg/kg/day in the -week sc and iv toxicity studies both in rats, and monkeys. enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the ames test, mouse lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. studies conducted in pregnant rats and rabbits at sc doses of enoxaparin sodium up to mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. enoxaparin sodium was found to have no effect on fertility or reproductive performance of male and female rats at sc doses up to mg/kg/day. enoxaparin has been used for more than years and represented the reference treatment for the large majority of phase iii trials studying direct oral anticoagulants (rivaroxaban, dabigatran etexilate, apixaban, edoxaban) for the prevention of vte in medical ( ) and surgical orthopaedic patients ( ) and for the acute treatment of vte ( ), including cancer-associated vte ( ) and pregnancy-associated vte ( ) . it remains one of the treatments of choice for these indications ( - ). the proposed dose, mg/day, and treatment duration ( days) is in line with the product label, which are primarily based on the results from the medenox study ( ) where this was effective, as opposed to the mg/day dose that was not. the medenox study evaluated enoxaparin at both ui and ui. only enoxaparin at ui demonstrated the efficacy for the prevention of vte in medical patients. in addition, the mean duration of treatment is days, up to days in the medenox study. the harmonised treatment duration is aligned with the data from the medenox study ( to days), as there is no evidence that a shorter duration may be effective ( ). risk assessment models (i.e. the padua and the improve scores) are used to identify patients who should receive in-hospital thromboprophylaxis based on a risk benefit assessment according with international guidelines ( ) . enoxaparin may be used in ambulatory patients with acute infectious illness, if an additional vte risk factor is present. therefore, no treatment represents the current standard of care for the covid (+) patients without additional vte risk factor. published data and studies under review (co-authors are the ovid investigators) suggest that (i) covid- is highly prothrombotic, (ii) a significant number of vte events occur in ambulatory patients and is detected at the time of initial evaluation. therefore, higherdosage thromboprophylaxis has been postulated for admitted patients and routine thromboprophylaxis may be useful for ambulatory patients in order to prevent potential thromboembolic complications before the patients´ general conditions precipitate. enoxaparin is effective in preventing vte in medical patients with acute illness. its antiinflammatory and antithrombotic profile may be highly beneficial in the setting of covid- . initial report in admitted covid- patients shows that lmwh appears to be beneficial in the presence of coagulation activation ( ). the ambulatory administration of injectable anticoagulants, including lmwh and the pentasaccharide fondaparinux, has been and is standard of care for a number of clinical conditions, including thromboprophylaxis after major orthopedic surgery and, especially in the era preceding the approval of direct oral anticoagulants, also the treatment of acute vte. indeed, the initial use of lmwh remains standard of care for patients, especially the elderly, with contraindications to the use of direct oral anticoagulants. in this setting, patient instructions are usually given during the initial in-hospital visit, corresponding to the day of hospital discharge after orthopedic surgery or the day of acute vte diagnosis; subsequently, patients self-administer the prefilled anticoagulant injections, alone or with the help of family members, in the ambulatory setting and, depending on the indication, for a period of - days (i.e. days after hip arthroplasty, days after knee arthroplasty). of note, -month (ambulatory) therapy with subcutaneous lmwh still represents the therapy of choice of the treatment of acute vte among several groups of cancer patients ( ) . in-hospital follow-up visits after the start of prophylactic-dose anticoagulant administration were not part of the study procedures of recent orthopedic trials on thromboprophylaxis, which usually included early phone follow-up intermediate to verify compliance and the potential occurrence of adverse events ( , ) . enoxaparin is characterized by a high safety profile and has been used for multiple indications for over years. a recent meta-analysis of thromboprophylaxis trials in medically ill patients showed that a major bleeding event occurred in of ( . %) of patients during short-course administration ( days of lower). the two largest and most recent phase iii trials on extended thromboprophylaxis in medically ill patients, the magellan and mariner study, had major bleeding rates of . % and . %, respectively ( , ) . it must be further noted that approximately % of the general population receive therapeutic-dose anticoagulant treatment for the prevention of embolic events due to atrial fibrillation or for the treatment of vte. this prevalence of anticoagulant users exceeds - % among the elderly. anticoagulant treatment is one of the best-known medical therapies used in western countries and the management of potential complications is part of routine clinical practice. the risk of heparin-induced thrombocytopenia in lmwh-treated patients is negligible ( . %) and of those who develop heparin-induced thrombocytopenia only a minority would develop a thromboembolic event ( % of . % = . % of patients receiving lmwh) ( ) . as reported in section . . . enoxaparin does not accumulate in the body after multiple administrations in the absence of severe renal dysfunction, one of the key exclusion criteria of the ovid study. moreover, the study will include only patients in whom the self-administration of enoxaparin (or the administration by a person living in the same house) after instructions is deemed possible (see inclusion criteria). this is in line with current practice, e.g. after orthopaedic surgery or in cancer patients with acute vte. currently, in switzerland there is no specific follow-up strategy for patients who are tested positive for sars-cov and are candidates to an ambulatory treatment. the current standard of care for outpatient covid treatment at some centers is as follows: ) patient goes to the test center with symptoms; ) the physician performs a sars-cov test and triage the patient concerning potential hospitalization. this may include standard assessment of the presence of dvt or pe, if deemed necessary. if not, the patient is discharged to home quarantine without taking blood and without performing any laboratory diagnostics. ) there is no direct contact with doctors and care in the home quarantine in order not to endanger personnel. ovid may increase the level of safety compared to standard of care for study patients because frequent telephone visits are planned (day , , , , ) . this regards also patients who are not randomized to the intervention arm. this approach is now becoming standard of care at some covid- centers: however, this is not uniform across the country and the planned contacts are less frequent than in the ovid study. thus, being part of a clinical study with predefined phone contacts will allow the patient to be constantly followed by medical and study personnel. the standardized visit questionnaire ensures that relevant bleeding is not missed. there is substantial uncertainty regarding the routine use of thromboprophylaxis for covid- in the outpatient setting. as previously discussed, recommendations are based on expert consensus and are largely adapted on local protocols. the present study hypothesizes a potential benefit of thromboprophylaxis, which could reduce the number of hospitalizations (primarily due to thromboembolic complications) and the number of deaths among enoxaparin-treated patients. the thromboembolic manifestations of covid- have been object of extensive media coverage. therefore, we anticipate that patients may be worried of being randomized to the control group and not receiving anticoagulant prophylaxis. the investigators will make clear during the patient consent procedure that (i) the potential benefits of thromboprophylaxis have not been demonstrated yet, (ii) the use of enoxaparin is characterized by a low (and well-quantifiable from prior studies) risk of major bleeding, < % within weeks of treatment, (iii) the risk benefit balance should be objective of investigation in the context of a phase iii trial, as there is no current evidence supporting the routine use of thromboprophylaxis. the study population was selected based on the following reasons: -covid- -patients years or older are those characterized by the highest hospitalization and fatality rates and, therefore, those who may benefit most from a prophylactic therapy with enoxaparinwe will include only symptomatic patients who presented with fever or respiratory symptoms, therefore aiming to minimize the number of incidental positive tests done for screening reasons.patients at the highest risk of vte, including patients with cancer or with prior vte, will be excluded as it would not be appropriate to include those, as the authors believe that they should routinely receive ambulatory thromboprophylaxis. -at the same time, patients characterized by a high bleeding risk will be excluded, including those with intracranial malignancy, recent bleeding, or strong dual antiplatelet therapy. -recent data suggest that several vte and deaths are recorded during "secondary" hospitalization which followed a diagnosis of covid- and an initial ambulatory treatment. -the almost totality of covid- trials is currently focusing on hospitalized patients: therefore, our study will not be competing with other studies for enrolment; -of note, patient with an initial suspicion of symptomatic vte (i.e. upon sars-cov testing) will and should undergo standard assessment by vte imaging and, in the case that vte is confirmed, the patient cannot be considered eligible for inclusion in the ovid study. the screening strategies upon sars-cov testing are left at the discretion of the treating physicians as at the moment there is no evidence that those should be implemented. the ovid study will show whether enoxaparin improves survival and reduces hospitalization in ambulatory patients aged or older diagnosed with covid- , a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. the purpose of this study is to show the superiority of ambulatory thromboprophylaxis with enoxaparin versus no treatment to prevent any hospitalization and all-cause death within days of randomization in patients aged or older with covid- . key secondary objectives for this study are to determine if enoxaparin administration versus no treatment reduces specific cardiovascular and thromboembolic complications, namely venous thromboembolism, myocardial infarction or stroke, within days, days and days of randomization, and if this intervention is associated with a net clinical benefit, accounting for major bleeding events. subgroup analysis to study treatment effects of enoxaparin (versus no treatment) will be conducted in specific subgroups of patients categorized by sex, age ( - vs. > years), renal function (estimated renal function < ml/min vs. ml/min or higher), and concomitant antiplatelet therapy. the study will assess the safety of thromboprophylaxis in covid- ambulatory patients aged or older and quantify the risk of major bleeding, non-major clinically relevant bleeding, and adverse events. a composite of any hospitalization or all-cause death occurring within days of randomization. composite outcome of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within days, days, and days of randomization ) each component of the primary efficacy outcome, within days, days, and days of randomization. net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within days, days, and days of enrolment. primary efficacy outcome, within days, and days of enrolment. disseminated intravascular coagulation (isth criteria, in-hospital diagnosis) within days, days, and days of enrolment. important cardiovascular events have been listed as secondary outcomes as we anticipate that appropriate imaging tests may be underused in this population, leading to an underestimation of these rates in both groups. in light of the above, information on secondary outcomes will be retrieved from medically certified discharge letters and ambulatory/laboratory reports, therefore not requiring formal event adjudication. not applicable. the principal safety outcome is major bleeding, defined as overt bleeding associated with a decrease in the hemoglobin level of g/dl ( . mmol l − ) or more, bleeding that led to transfusion of or more units of packed red cells or whole blood, bleeding that occurred in a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding (isth criterion) ( ) . the other safety outcome is non-major clinically relevant bleeding and adverse events. non-major clinically relevant bleeding is defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, temporary cessation of the trial regimen, or pain or impairment of activities of daily life (isth criterion) ( ) . all serious adverse events potentially related to the study medication (i.e. local and systemic bleeding complications, allergic reactions) and reasons for hospitalizations except the study outcomes (vte-related death, myocardial infarction, stroke, symptomatic vte [dvt and pe], bleeding events) will be collected. the study will be conducted as a multicentre randomized open-label controlled trial. in the study, a total of , adult patients aged or older with symptomatic covid- , without other indications to anticoagulant therapy, and candidates to ambulatory treatment will be randomized to receive enoxaparin mg sc qd or no treatment for a total of days. the primary outcome is any hospitalization or all-cause death within days of enrolment. a final -day phone contact is planned. patient enrolment will last up to months and will take place at swiss centers, including five university hospitals and two large cantonal hospitals. the study period will therefore consist of a total of approximately months. patients will undergo block stratified randomization (by age - vs. > years and study center) with a randomization ratio of : with block sizes varying between and . no blinding procedures will be used in this study for logistical reasons. predefined questionnaires will serve to guide telephonic contacts with patients during (pre-)screening and follow-up visits. the adoption of objective study efficacy outcomes (any hospitalizations, all-cause death) aims at minimizing the risk of subjective interpretation. not applicable. an average of patients will be enrolled at each of the study centers, represented by all the university swiss hospitals and two large cantonal hospitals. it is expected that patients will be enrolled over - months, corresponding to an average of approximately one patient per day per center. in case the enrolment goals are not met after the first months from study start, the participation of additional centers will be considered, as well as the extension to other european countries upon positive application for public funding. and eligible for ambulatory treatment. ) presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature > . ° c. ) ability of the patient to travel to the study center by private transportation, performed either by accompanying person from same household or by the patient him/herself ) ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. ) ability to walk from car to study center or reach it using a wheel chair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. ) ability to self-administer prefilled enoxaparin injections after instructions received at the study center or availability of a person living with the patient to administer enoxaparin. the presence of any one of the following exclusion criteria will lead to exclusion of the participant: ) any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior vte, acute confirmed symptomatic vte, acute coronary syndrome. ) anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. any of the following events occurring in the prior days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous vte, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past months, or recurrent, or metastatic, or inoperable. ) any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within days prior to randomization or sign of acute bleeding. ) intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial hemorrhage. ) hemoglobin < g/dl and platelet count < x cells/l confirmed by recent laboratory test (< days). ) subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. ) severe renal insufficiency (baseline creatinine clearance < ml/min calculated using the cockcroft-gault formula) confirmed by recent laboratory test (< days). ) contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. ) current use of dual antiplatelet therapy. ) participation in other interventional studies over the past days. ) non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. ) cognitive impairment and/or inability to understand to information provided in the study information. we considered three main screening scenarios preceding the in-hospital baseline visit: -scenario : screening at the study center on the day of sars-cov testing -scenario : referral from the patient (via hot-line or study center). -scenario : referral from covid testing centers or primary care physicians (via hot-line or study center). scenario : enrolment at the study center on the day of sars-cov testing ) test for sars-cov : i.e. at the emergency room or at covid testing center at the study site. ) the patient waits for the results of sars-cov (i.e. done with rapid tests) at the same center, as per local standard practice in a deputed room. ) discussion with the study investigator, signature of pic , evaluation of the eligibility criteria. if not available, additional blood tests (blood cell counts, renal function) will be performed as part of the study screening using standard measurement or point of care devices. ) details on randomization, allocation, and instructions are given in the next paragraph ("in-hospital visit"). scenario : referral from the patient. ) the patient undergoes sars-cov test and gets to know about the ovid study (flyer). ) the patient goes home and waits for the test results being communicated by the test center. ) the patient is informed by the testing center about his/her positive sars-cov test. ) he/she phones the trilingual hot-line or directly the referral study center and the potential study participation is evaluated first, particularly concerning the formal ovid eligibility criteria (see pre-screen questionnaire for hot-line and study centers). ) if the patient is potentially eligible, the hot-line personnel or the study center plans a further in-hospital visit at the closest study center within days from positive sars-cov test. ) see the paragraph "in-hospital visit" for further details. scenario : referral from covid testing centers or primary care physicians. ) the patient undergoes sars-cov test and gets to know about the ovid study (flyer and pic ) and potential eligibility. ) the patient allows the test center personnel to inform the study physicians about (i) his/her positive test and (ii) his/her contact information (signature of pic ). ) the patient goes home and waits for the test results being communicated by the test center. ) the test center informs the hot-line or study center about (i) patient's positive test and (ii) his/her personal information. ) the hot-line or study center phones the patient and the potential study participation is further evaluated, particularly concerning the formal ovid eligibility criteria (see prescreen questionnaire). ) if the patient is potentially eligible, the hot-line personnel of the study center plans a further in-hospital visit at the closest study center within days from positive sars-cov test ) see the paragraph "in-hospital visit" for further details. patient recruitment will be centrally organised and coordinated also with the aid of a national hot-line in three languages (german, french, italian), ensuring a one-time contact with patients to preliminary verify the eligibility criteria and plan an in-hospital visit for screening and recruitment. the hot-line number will be published on official websites and will be made available as part of an awareness campaign organized by the communication department of the usz. deputed personnel receiving following precise instructions given by the study investigators will be available during working hours to discuss with patients. a predefined pre-screening questionnaire will be completed telephonically following a step-by-step standardized procedure. if the patient is not eligible, i.e. one red box is checked in the questionnaire, the questionnaire will be destroyed immediately after compilation by the hot-line personnel and no personal data will be registered. if the patient is potentially eligible, a study visit will be planned from the hot-line at the closest study center or the study center will be contacted directly by the patient. the hot-line will provide the study investigators at each study center with a copy of the questionnaire containing prescreening information. the study site is then asked to complete the questionnaire with the data and time of the in-hospital visit and return the questionnaire to the study e-mail address: ovidstudie@usz.ch. trained staff for the hot-line may include physicians, nurses, medical students, and administrative personell, who is also educated to encourage the patient (i) to bring any medical documents to the in-hospital visit that may facilitate enrolment, e.g. medication lists or medical reports or the results of recent laboratory testing and if applicable a copy of the signed pic . in addition the hot-line personnel will provide the study information and consent form (pic ) by email if desired by the patient. the hot-line personnel instructs the patient to come by private car, use the reserved parking spaces and stay in the car until he/she gets further instructions from the study personnel. information concerning the precise location of the parking place at each study center will be given telephonically to the patients and may be sent via e-mail upon patient's request by local study personnel. . the study personal reaches the car of the patient and provides him/her and if applicable his/her companion with face masks and desinfectant. the patient will then follow the study coordinator to the assigned study rooms. if the patient is dependent on a wheel chair, he/she must be able to transfer him/herself or with the aid of the companion into the wheel char. the accompanying person is only allowed to enter the study rooms and attend the study visit, if he/she is determined to apply the clexane injections. in this case, the accompanying person gets the clexane administration instruction. . the study physician will discuss the scope of the study and answers all questions of the patient. is the patient willing to participate in the study, he/she will sign the pic . after signature of pic , a further check of inclusion and exclusion criteria will be performed by the treating physician, using if available medical documents. a blood test will be performed, if no blood test results are available. during blood analysis, the other parameters for the screening visit can be collected, e.g. vital signs, demographics, etc. (see paragraph study assessment). . if the blood test is in line with the inclusion and exclusion criteria, the study physician performs the final check of the eligibility. if eligibility cannot definitively be confirmed, no randomization will be performed and the patient will be counted as screening failure. . if eligibility is confirmed, randomization will be done. the patient receives a study participant card, where the contact data from the study team are reported and information on study drug allocation. . for patients from the control group, patient will return home by private car transport. for patients form the enoxaparin group, instruction for use of enoxaparin injections will be provided. for interested patients, a link for a video instruction will be provided. the first injection of study drug will be performed at study center, if possible by the patient. if patient does not inject the study drug, the accompanying person gets the instruction and will perform the first injection. . for patients of the treatment group, the required amount of study drug will be provided to the patients with instructions for documentation. the patients are encouraged to fill in the study diary, which is provided by the study team and will be instructed to take note of doses that are forgotten or missed. this form will be handed to the patients with a pre-stamped reply covert to simplify the return process. the study visit is planned for at least minutes for all patients who received the ovid patient information by email in advance. the study visit is planned for at least minutes for all patients who did not receive the ovid patient information by email in advance to provide enough time for considering study participation. only one in-hospital visit is planned. as previously described, the best care will be taken to minimize the discomfort for the patient and maximize safety for the investigators. to reduce the infection risk, only a study physician will be in the study room with the patient. if needed, the blood test (hemoglobin, platelet count, creatinine) may be performed by the use of a point-of-care device, which guarantees a result within minutes and the study physician will be informed about the results immediately. all the participating centers agreed to fulfil these logistic requirements and will be able to guarantee the same standard of care by signing a contract. these requirements were part of the criteria for the selection of the study sites. definition: all patients who signed the informed consent (pic ) but were not eligible for randomization. a screening log will be filled out at each study center, listing all patients with date and reason of screening failure. this document will be signed by the local principal investigator at the end of the recruitment period and returned to the sponsor. these recruitment and study procedures have been object of a survey among general patients aged years or older recruited through a patient organization conducted between - april , who confirmed that what we propose is in line with their expectations. in particular, % stated that they feel able to reach a covid- testing site without public transportation, % would be willing to read an information sheet on location regarding possible inclusion in a clinical study whilst waiting to have the test sample taken, , % would agree to receive a paper copy of the informed consent at home (delivered by postal mail), % would travel to the local center/hospital to obtain study medication after receiving notice of a positive covid- test, % would accept to receive courier delivery of study medication at home. randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria. randomization will be performed by an instructed assistant, study coordinator, or investigator directly through the electronic data capture software (redcap, vanderbilt university, v . . ). additional details concerning the setting and timing of randomization are provided in the study procedures. if the subject permanently discontinues treatment before day or is hospitalized, then he/she needs to have the remaining scheduled visits. because the primary efficacy analysis of the study is based upon the intention-to treat principle, the subject will be contacted for the remaining scheduled visits. if the subject cannot be contacted telephonically, the site should collect as much follow-up information as possible, including contacting a legally acceptable representative or the treating physician by telephone or by mail to determine vital status and if a hospitalization has occurred. vital status will be obtained by reviewing the subject's medical or public records or discharge letters from other institutions, as reported in the patient information. if the subject withdraws consent from the study, this must be documented in the source document and the subject will be asked to supplement the withdrawal of consent with a signed written statement documenting refusal sent per post for all subsequent contact. if the patient does not wish to send a written statement, study withdrawal will take place immediately after giving verbal notification. enoxaparin is a lmwh with a mean molecular weight of approximately , daltons, in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. the drug substance is the sodium salt. in the in vitro purified system, enoxaparin sodium has a high anti-xa activity (approximately iu/mg) and low anti-iia or anti thrombin activity (approximately iu/mg), with a ratio of . . these anticoagulant activities are mediated through anti-thrombin iii (atiii) resulting in anti-thrombotic activities in humans. beyond its anti-xa/iia activity, further antithrombotic and antiinflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models. these include atiii-dependent inhibition of other coagulation factors like factor viia, induction of endogenous tissue factor pathway inhibitor (tfpi) release as well as a reduced release of von willebrand factor (vwf) from the vascular endothelium into the blood circulation. these factors are known to contribute to the overall antithrombotic effect of enoxaparin sodium. when used as prophylactic treatment, enoxaparin sodium does not significantly affect the aptt. when used as curative treatment, aptt can be prolonged by . - . times the control time at peak activity. the pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-xa activity and also by anti-iia activity, at the recommended dosage ranges after single and repeated sc administration and after single iv administration. the quantitative determination of anti-xa and anti-iia pharmacokinetic activities was conducted by validated amidolytic methods. absorption the absolute bioavailability of enoxaparin sodium after sc injection, based on anti-xa activity, is close to %. different doses and formulations and dosing regimens can be used. the mean maximum plasma anti-xa activity level is observed to hours after sc injection and achieves approximately . , . , . and . anti-xa iu/ml following single sc administration of , iu, , iu, iu/kg and iu/kg ( mg, mg, mg/kg and . mg/kg) doses, respectively. a , iu ( mg) iv bolus immediately followed by a iu/kg ( mg/kg) sc every hours provided initial maximum anti-xa activity level of . iu/ml (n= ) and average exposure corresponding to % of steady-state levels. steady-state is achieved on the second day of treatment. after repeated sc administration of , iu ( mg) once daily and iu/kg ( . mg/kg) once daily regimens in healthy volunteers, the steady-state is reached on day with an average exposure ratio about % higher than after a single dose. after repeated sc administration of the iu/kg ( mg/kg) twice daily regimen, the steady-state is reached from day to with mean exposure about % higher than after a single dose and mean maximum and trough anti-xa activity levels of about . and . iu/ml, respectively. injection volume and dose concentration over the range - mg/ml does not affect pharmacokinetic parameters in healthy volunteers. enoxaparin sodium pharmacokinetics appears to be linear over the recommended dosage ranges. intra-patient and inter-patient variability is low. following repeated sc administration, no accumulation takes place. plasma anti-iia activity after sc administration is approximately ten-fold lower than anti-xa activity. the mean maximum anti-iia activity level is observed approximately to hours following sc injection and reaches . iu/ml and . iu/ml following repeated administration of iu/kg ( mg/kg) twice daily and iu/kg ( . mg/kg) once daily, respectively. the volume of distribution of enoxaparin sodium anti-xa activity is about . litres and is close to the blood volume. enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. enoxaparin sodium is a low clearance drug with a mean anti-xa plasma clearance of . l/h after a iu /kg ( . mg/kg) -hour iv infusion. elimination appears monophasic with a half-life of about hours after a single sc dose to about hours after repeated dosing. renal clearance of active fragments represents about % of the administered dose and total renal excretion of active and non-active fragments % of the dose. special populations based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal. however, since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see sections . and . ). hepatic impairment in a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium , iu ( mg) once daily, a decrease in maximum anti-xa activity was associated with an increase in the severity of hepatic impairment (assessed by child-pugh categories). this decrease was mainly attributed to a decrease in atiii level secondary to a reduced synthesis of atiii in patients with hepatic impairment. a linear relationship between anti-xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. anti-xa exposure represented by auc, at steady-state, is marginally increased in mild (creatinine clearance - ml/min) and moderate (creatinine clearance - ml/min) renal impairment after repeated sc , iu ( mg) once daily doses. in patients with severe renal impairment (creatinine clearance < ml/min), the auc at steady state is significantly increased on average by % after repeated sc , iu ( mg) once daily doses (see sections . and . ). enoxaparin sodium pharmacokinetics appeared similar than control population, after a single iu, iu or iu/kg ( . , . or . mg/kg) iv dose however, auc was two-fold higher than control. after repeated sc iu/kg ( . mg/kg) once daily dosing, mean auc of anti-xa activity is marginally higher at steady state in obese healthy volunteers (bmi - kg/m ) compared to non-obese control subjects, while maximum plasma anti-xa activity level is not increased. there is a lower weight-adjusted clearance in obese subjects with sc dosing. when non-weight adjusted dosing was administered, it was found after a single-sc , iu ( mg) dose, that anti-xa exposure is % higher in low-weight women (< kg) and % higher in low-weight men (< kg) when compared to normal weight control subjects (see section . ). no pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when administered concomitantly. water for injections. shelf life years. clexane ® forte syringes , iu ( mg)/ . ml and , iu ( mg)/ ml: solution for injection in graduated pre-filled syringes (type i glass) fitted with rubber stopper (chlorobutyl and bromobuytl) and injection needle (with automatic safety system eristm or preventis™ or without an automatic safety system). supplied in packs of , , , , , , pre-filled syringes and in multi-packs of x pre-filled syringes. not all pack sizes may be marketed. pre-filled syringes are ready for immediate use. for method of administration see section . . use only clear, colourless to yellowish solutions. pre-filled syringes are supplied with or without an automatic safety system. the instructions for use are presented in the package leaflet. each syringe is for single use only. used syringes will be discarded into regular trash without trying to recap the already automatically retracted needle. any unused medicinal product (enoxaparin prefilled injections) should be returned back to the study center at a later timepoint (> days) due to potential contamination. no treatment. the sponsor will label the study medication centrally and ship an initial amount of the study medication to the participating centers, which should be sufficient for the enrolment of the first patients per center and will consist of -and -syrynge packages. the shipment will be performed in accordance with storage requirements (see below). upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt log filled out and signed by the person accepting the shipment. it is important that the designated study staff counts and verifies that the shipment contains all the items noted in the shipment inventory. any damaged or unusable study drug in a given shipment will be documented in the study files and the sponsor will be notified by the study-site personnel within hours after being aware of the event. the investigator is responsible for ensuring that all study drug received at the site is inventoried and accounted for throughout the study. the dispensing of study drug to the subject must be documented on the drug accountability form, signed and dated by the study team. do not store above °c. do not freeze. enoxaparin (clexane ® ) will be given at the recommended dose of , iu antixa activity ( mg)/ . ml once daily by sc injection for days. the first dose of enoxaparin will be administered on the day of randomization. the subsequent doses of enoxaparin will be administered or self-administered at home. instructions on how to administer enoxaparin will be provided during the screening/baseline visit. additional details are reported in the study procedures. solution for injection in pre-filled syringes. clear, colourless to yellowish solution, phvalue . - . . enoxaparin should not be administered by the intramuscular route. for the prophylaxis of venous thromboembolic disease following surgery, treatment of dvt and pe, treatment of unstable angina and nstemi, enoxaparin sodium should be administered by sc injection. the pre-filled disposable syringe is ready for immediate use. sc injection technique: injection should be made preferably when the patient is lying down. enoxaparin sodium is administered by deep sc injection. do not expel the air bubble from the syringe before the injection to avoid the loss of drug when using pre-filled syringes. the administration should be alternated between the left and right anterolateral or posterolateral abdominal wall, and upper legs. not applicable. in accordance with the label of enoxaparin, no dose modification is requested. in case of hospitalization (component of the primary efficacy outcome) or bleeding (secondary outcome) or any other adverse event that may occur, the dose can be modified based on what decided by the treating physician, as per standard clinical practice. this will not influence the primary efficacy outcome analysis, which will be conducted on a intention-to-treat basis. the study team will assess and track participant compliance during the scheduled phone follow-up visits (day , and day ) and according with a pre-defined questionnaire evaluating the use of the study medication and potentially related adverse events. if a patient withdraws from the study, data until the date of withdrawal will be used for analysis. if a subject has a serious bleeding event during study drug treatment, the following routine measures should be considered: -delay the next study drug administration, or discontinue treatment if indicated. temporary cessation of study drug may allow control of bleeding. consider the usual treatment measures for bleeding events, including fluid replacement and hemodynamic support, blood transfusion, and fresh frozen plasma, if physical examination and laboratory testing suggest benefit could be obtained. in case of life-threatening bleeding occurring during enoxaparin administration, protamine may be used for reversal, as per standard management, although it is known that it only partially reverses the anti-xa activity and there are very limited data on clinical effectiveness. if deemed necessary, enoxaparin reversal can be determined based on the following table (lovenox [package insert]. sanofi-aventis u.s. llc; bridgewater, nj. october ): ≤ hours since heparin dose: mg protamine for every mg enoxaparin; > hours since heparin dose: . mg protamine for every mg enoxaparin; > to hours since heparin dose: depending on dose received and renal function, protamine reversal may not be necessary due to enoxaparin metabolism. all concomitant and/or rescue treatment(s) have to be recorded in the ecrf. the use of other anticoagulant agents is not recommended during the study period, as it may significantly increase the risk of bleeding. if another anticoagulant agent is deemed necessary (i.e. for a new diagnosis of atrial fibrillation), the switching from enoxaparin to the new anticoagulant agent will be performed according with standard procedures. paracetamol should be considered the drug of choice to treat fever or pain. the use of ibuprofen (or other nsaids) is not forbidden, although its administration should be discussed with the treating or study physician. similarly, the introduction of an antiplatelet therapy should be discussed with the treating physicians and principally be avoided in the absence of a major (e.g. cardiologic) indication. investigational product supplies, which will be provided to the principal investigator of each site, must be kept in a secure, limited access storage area under the recommended storage conditions. lot number and expiry date should be listed. the investigator will maintain accurate and adequate records including dates, lot number, quantities received, usage. in addition, a study diary will be handed to patients in the treatment group and patients will be encouraged to document forgotten or missed doses (as described in . ). a missed injection can be made up for up to hours, not used study products should be returned to the site. the used study product will not be collected, but disposed through the regular household waste. at the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. this reconciliation will be logged on the drug accountability form, signed and dated. any discrepancies noted will be investigated, resolved, and documented. drug destroyed on site will be documented in the study files. the primary outcome (any hospitalization or all-cause death) will be assessed by direct telephone contact with the patient, with the contact person, or with the treating physicians ( day , , , ) . due to the unquestionable nature of the primary efficacy outcome, no adjudication of the events is deemed necessary. the investigators will be allowed by the patient to obtain clinical information from discharge letters in case of hospitalization or medical treatment. all the information collected telephonically based on a predefined questionnaire and conversation notes will be documented (patient questionnaire, visits - ); the document will be regarded as source document. additional source documents will be represented by admission/discharge letters in the case the patient will undergo ambulatory visits or will be admitted to the hospital (documentation of outcomes). primary and secondary endpoints must be documented by written reports of the treating physicians. after termination of the phone call, all information will be transferred into the ecrf. telephone contact will occur at predefined timepoints: patients (or the first contact person) will be contacted on the day of the planned contact. in case the patient (or the first contact person) cannot be contacted, a second phone call will take place two hours later. in case of no answer, the second contact person will be immediately contacted and the same procedure will take place. if the patient (or contact persons) cannot be reached by phone, the treating physicians will be alerted due to safety reasons. thromboembolism, myocardial infarction or stroke) will be evaluated at day , , , and equivalently to the primary outcome ( . . ). assessment of safety outcomes major bleeding and non-major clinically relevant bleeding will be evaluated at day , , , , by asking specific questions on the phone (cf. question list file "crf variables list, page "phone visit", "primary outcome", "secondary outcome"). if the patient cannot be reached by phone or if clarification is needed, the treating physician of the patient will be contacted. recording of serious adverse event is described in section . no information on specify laboratory parameters will be routinely assessed during the course of the study as part of the study outcomes: the follow-up visits will take place telephonically. no information on vital signs will be routinely assessed during the course of the study as part of the study outcomes: all the follow-up visits will take place telephonically. no additional investigation is planned in participants who voluntarily stop the study for non-medical reasons. pre-screening (day - to ) will take place according with the scenarios summarized in section . as the process of screening may vary according with individual capacities and setting of initial sars-cov testing. procedures for pre-screening, irrespective of the scenario: -signature of pic (if applicable) -discussion with the patient on study participation (pre-screen survey) -referral to the closest study center. procedures at baseline visit, irrespective of the scenario: -signature of pic -collection of demographic and baseline characteristics, including comorbidities and comedications -vital signs assessment: respiratory rate, heart rate, systolic blood pressure, diastolic blood pressure, body temperature, oxygen saturation, height, weight, body mass index -if not available, additional blood test analysis with point of care or standard assays. -if the subject signed pic and meets all of the inclusion and none of the exclusion criteria, he or she is eligible to be randomly assigned to receive enoxaparin or no therapy (randomization) -allocation to study treatment -if applicable, patients will be instructed on how to administer the study medication via personal communication, remote instructions, and/or video material. for bleeding events, subjects and family members as appropriate, will be instructed: -to seek medical attention if they develop bleeding -to contact the investigative site staff or study investigator before the next dose of study medication is due -to inform treating health care providers about study participation subjects and family members, as appropriate will also be instructed: -about the subject's risk of dvt and pe -about the signs and symptoms of dvt and pe -to seek medical attention if they develop any of these signs or symptoms -to contact the investigative site staff or study investigator as soon as symptoms develop and before the next dose of study medication is due -to inform treating health care providers about hospitalization or death. the subject's family should be instructed to have a low threshold to contact the site (a patient card is given). follow-up visits: phone contact and assessment of the primary/secondary study outcomes (day , , , , and ), suspected serious adverse events (day , , , , and ), vital status (day , , , , and ), drug compliance (day , and ). information on symptoms potentially pointing to a study outcome or sae will be adequately collected during the follow-up visit and the patient may be instructed to seek in-person medical assistance if deemed necessary by the study personnel, i.e. in the case of a suspected thromboembolic event (dvt, pe, myocardial infarction stroke), bleeding with characteristics of severity (i.e. occurring at critical sites), substantial worsening of the respiratory symptoms compared with baseline, onset of new symptoms, sae. the sponsor's sops will provide more detail on safety reporting. during the entire duration of the study, all serious adverse events except the study outcomes as noted above will be collected and entered into the serious adverse event page of the ecrf. study duration encompasses the time from when the participant signs the informed consent until the last protocol-specific procedure has been completed (phone call at day ). an sae is defined as any untoward medical occurrence that at any dose results in • results in death, • is life-threatening, • requires participant hospitalization or prolongation of current hospitalization, • results in persistent or significant disability/incapacity, or • is a congenital anomaly/birth defect, • any important medical event and any event which, though not included in the above, may jeopardise the participant or may require intervention to prevent one of the outcomes listed above. any other medically important condition that may be not immediately life-threatening or results in death or hospitalization but may jeopardize the participant or may require intervention to prevent one of the outcomes listed above should also usually (i.e. based on medical and scientific judgment) be considered serious. an "unexpected" adverse drug reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable product information. a serious adverse reaction, the nature or severity of which is suspected to be not consistent with the applicable product information. all suspected new risks and relevant new aspects of known adverse reactions that require safety-related measures. clinical investigators and ultimately the principal investigator (pi) have the primary responsibility for sae identification, documentation, grading, and assignment of attribution to the investigational agent/intervention. information on all saes will be collected during phone follow-up. standard questionnaire (patient questionnaire, visits - ) will include key questions for sae screening, including the occurrence of the primary efficacy outcome (hospitalization, death), bleeding at potentially critical sites, or symptoms that may reflect an underlying and potentially severe condition of new onset. in the latter case, the severity of symptoms will be compared with the status at baseline. all saes will be fully documented in the appropriate ecrf. for each sae, the investigator will provide the onset, duration, intensity, treatment required, outcome and action taken with the investigational product. the investigator assesses the causal relationship of each sae according to the sae reporting form. an unexpected sae refers to any ae, the nature or severity of which is not consistent with the applicable product information. the investigator will promptly review saes to determine if the sae meets the criteria for a susar. the assessment by the investigator with regard to the study drug relation is done according to the following definitions:  the event started in no temporal relationship to medicinal product applied and  the event can be definitely explained by underlying diseases or other situations. related  the event started in a plausible temporal relationship to medicinal product applied and  the event cannot be definitely explained by underlying diseases or other situations. the investigator is responsible for reporting any saes to the sponsor immediately, i.e. within hours using the following email address: ovidstudie@usz.ch the investigator is responsible for sae reporting to the cec according to the following details:  reporting to cec any sae which resulted in death: -without delay, and no later than calendar days.  reporting to cec of fatal saes if evaluated as "suspected", "unexpected" and "drug related" (susar) -without delay and no later than calendar days following awareness that event meets criteria for an susar.  reporting to cec of non-fatal saes if evaluated as "suspected", "unexpected" and "drug related" (susar): -promptly and no later than calendar days following awareness that event meets criteria for a susar. the sponsor is responsible for sae reporting to swissmedic according to the following details: • compliance with the regulatory requirements of swissmedic regarding prompt reporting of unexpected saes for which a causal relationship with the study drug cannot be ruled out. reporting to swissmedic of fatal saes if evaluated as "suspected", "unexpected" and "drug related" (susar): -without delay and no later than calendar days following awareness that event meets criteria for a susar; • reporting to swissmedic of non-fatal saes if evaluated as "suspected", "unexpected" and "drug related" (susars): -promptly and no later than calendar days following awareness that event meets criteria for a susar. all other saes will be summed up in the annual safety report (asr), containing: -a summary of the safety profile of the drug studied as well as the safety issues that have arisen; the sponsor is responsible to prepare a dsmb charter, which will be submitted to the kek and swissmedic in due time and before the enrolment of the first patient. it is the role of the dsmb to advise the sponsor regarding the continuing safety of current participants and those yet to be recruited, as well as the continuing integrity, validity and scientific merit of the trial. a fundamental consideration is the safety of those who would be at potential risk due to their participation in the trial. the dsmb must be particularly alert to the risks inherent to anticoagulant therapy. in addition, the conduct of the study is subject to review in the context of its capability to ultimately address the scientific questions of interest, including recruitment rate, ineligibility, non-compliance, protocol violations, dropouts, completeness and timeliness of data. the dsmb may advise the sponsor and principal investigators to modify/improve specific aspects of the study conduct. the dsmb has a more circumspect role in recommending changes to the study protocol after having discussed these concerns with the sponsor and principal investigators. members of the dsmb have relevant expertise and experience in clinical trials and are aware of the responsibilities inherent in the operation of the dsmb. the dsmb includes a biostatistician knowledgeable in statistical methods used in clinical trials. all serious adverse events that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject's participation in the study, will be followed until any of the following occurs: -the event resolves, -the event stabilizes, -the event returns to baseline, if a baseline value/status is available, -the event can be attributed to agents other than the study drug or to factors unrelated to study conduct, -it becomes unlikely that any additional information can be obtained (subject or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts). two treatment arms are to be compared, experimental arm with enoxaparin versus control arm without any treatment. randomization will be : . objective is to demonstrate superiority of experimental treatment (enoxaparin). primary outcome of the study is any hospitalization or any-cause death within days of enrolment. sample size is fixed, one interim analysis is planned at time when the outcomes of % of the patients have been observed. we obtained official data on fatality and hospitalization rates observed in the swiss population until . . : a total of . patients aged years or older tested positive for sars-cov- , of whom ( . %) died and . ( . %) were hospitalized irrespective of whether this consisted of a primary hospitalization (after evaluation at the emergency department) or a secondary hospitalization for clinical deterioration after initial ambulatory treatment. assuming that two thirds of deaths and of any hospitalizations occurred in ambulatory patients, we estimated that the primary efficacy outcome rate would occur in % (any hospitalization %, case fatality rate %). as we anticipate that the a substantial number of the primary endpoint is due to venous or arterial thromboembolic complications, which would be prevented by the use of prophylacticdose enoxaparin, we estimated that enoxaparin will decrease the primary efficacy outcome to % (rr . ). the following studies were also considered for estimating the benefit of enoxaparin use in medical patients and sample size calculation: -prophylactic treatment with mg per day of enoxaparin subcutaneously (vs. placebo) safely reduced the risk of venous thromboembolism detected by bilateral venography or duplex ultrasonography in patients with acute medical illnesses ( -anticoagulant therapy, mainly with lmwh, appeared to be associated with better prognosis in severe covid- patients meeting sic criteria or with markedly elevated ddimer ( ). the sample size calculation is based on the parameters = . ( -sided), power = − = . , event rate in experimental group, = . and event rate in control group, = . . the resulting total sample size is . to account for potential drop-outs, the total sample size was fixed to . this will be the maximum sample size, no increase in sample size is planned. results will be reported in terms of risk ratios (rr) between experimental and control group, i.e. we anticipate that the estimated rr will be < . see details reported in the interim analysis ( . . ). a detailed statistical analysis plan will be written up upon ethics approval. the primary efficacy outcome analysis will be conducted in the intention-to-treat (itt) population, consisting of all randomized subjects who signed a valid informed consent. descriptive statistics of the patient characteristics at baseline will include mean and standard deviation for continuous variables, median and interquartile range for the ordinal or non-normal variables, as well as numbers and percentages of total for the categorical variables. for the primary outcome, the relative risk will be calculated for the experimental group as compared to control group, with % confidence interval. refined analyses include the stratification variables in order to reduce unexplained heterogeneity. for that, the mantel haenszel method as well as multiple logistic regression models will be used. a more detailed statistical analysis plan for interim analysis and final analysis will be written up while patients are being recruited. all analyses will be conducted with r (r core team ). rmarkdown will be used for dynamic reporting. r-packages used for sample size determination and study design: iabin . , gsdesign . . , and trialsize . .the corresponding reporting guideline for randomized superiority trials is consort guideline. heterogeneity analysis to study treatment effects of enoxaparin (versus no treatment) will be conducted in specific subgroups of patients categorized by sex, age-groups, renal function, and concomitant antiplatelet therapy. groups will be compared for all the secondary outcomes. results will be reported as relative risk and they will be calculated for the experimental group as compared to control group, with % confidence interval. a single interim analysis is planned. the aim of the interim analysis is to stop the trial early for efficacy (superiority) or futility. a group-sequential approach will be used, based on stopping boundaries with o'brian-fleming design (obf). obf is accepted by regulators and ich-e guidelines. design specifications: a symmetric -sided group sequential design with analyses and a total sample size of patients will be used, power will be %, -sided significance level will be . (type i error). bounds were derived using obf boundary. the following plot shows an illustration of the specification. the analysis of safety outcomes will be conducted in the safety population, including patients who received at least one dose of study drug (enoxaparin) or who were alive hours after randomization. the ovid study will be conducted as a national research initiative involving all the five university hospitals and two large cantonal hospitals in ticino under the coordination of a local covid commitee. at least one patient room is required for enrolment, ideally located outside main hospital facilities to avoid transmission of covid to staff and other patients ) ability to locally perform rapid blood cell count (hemoglobin, platelet count) and creatinine tests as some covid- outpatients may have no recent (< months) results of blood tests mandatory for enrolment. if point of care tests are used, these should ideally be performed outside the patient rooms. parking lot nearby the patient rooms because covid patients may not use public transport. signed contract with university hospital zurich (recruitment and study procedures must be in accordance with gcp standards and performed according with at least one of the aforementioned scenarios). each participating center has already received a contract examined by unitectra (clinical research agreement), which includes data on financing, results, data and liability, etc… the sponsor investigator is responsible for the implementation and maintenance of a quality management system, including the performance of quality controls in the form of monitoring and, if necessary, quality assurance audits. the sponsor investigator provides study-specific sops and wis to the participating centres. the investigator is responsible for ensuring that all persons involved in the trial are adequately trained for their tasks. this ensures that the test procedures are carried out in a standardized manner and that the applicable guidelines and laws are observed the study will strictly follow the protocol. if any changes become necessary, they must be laid down in an amendment to the protocol. all amendments of the protocol must be signed by the sponsor-investigator and will be submitted to cec and swissmedic. the investigators will use electronic case report forms (ecrf), one for each enrolled study participant, to be filled in with all relevant data pertaining to the participant during the study. all participants who signed the informed consent (pic ) have to be documented on a screening log. the investigator will document the participation of each study participant on the enrolment log. for data and query management, monitoring, reporting and coding an internet-based secure electronic data capture system redcap, which is hosted by the clinical trials centre (ctc) zurich will be used for this study. it is the responsibility of the investigator to assure that all data in the course of the study will be entered completely and correctly in the respective data base. corrections in the ecrf may only be done by the investigator or by other authorised persons. in case of corrections the original data entries will be archived in the system and can be made visible. for all data entries and corrections date, time of day and person who is performing the entries will be generated automatically. ecrfs must be kept current to reflect participant status at each phase during the course of study. participants must not to be identified in the ecrf by name. appropriate coded identification (e.g. participant number) must be used. it will be assured that any authorised person, who may perform data entries and changes in the ecrf, can be identified. a list with signatures and initials of all authorised persons will be filed in the study site file and the trial master file, respectively. the investigators assure to perform a complete and accurate documentation of the participant data in the ecrf. all data entered into the ecrf with exception of (for which data the ecrf will be source data to be specified for each study) must also be available in the individual participant file either as print-outs or as notes taken by either the investigator or another responsible person assigned by the investigator. the following documents are considered source data, including but not limited to:  ecrf (demographic and baseline characteristics, vital signs, comedications, laboratory parameters, sae, study outcomes),  nurse records, records of clinical coordinators, and  medical records from other department(s), or other hospital(s), or discharge letters and correspondence with other departments/hospitals. source data must be available at the site to document the existence of the study participants and substantiate the integrity of study data collected. source data must include the original documents relating to the study, as well as the medical treatment and medical history of the participant. study protocol. ongoing maintenance and use of this software is contractually agreed upon between the study sponsor and the data management department of the ctu zurich. appropriate coded identification (e.g. pseudonymisation) is used in order to enter subject data into the database. all data entered into ecrfs is transferred to a mysql database using encryption post filtering and sanitization to various relational database tables. the server hosting the edc system and the database is kept in an off-site locked serverroom. only system administrators have direct access to the server and back-up tapes. a role-based user concept with personal login and passwords (e.g. for site investigator, statistician, monitor, administrator etc.) regulates permission for each user to access the system and database when required. within each project, there are role-and user-based settings to control access to various functionality and modules, such as being able to export data, to enter data, export reports and view the logging records. another feature called data access groups, can be implemented to help segregate users so that the data they enter is only accessible by someone in their group, especially useful for multi-centric studies where the data entered by one institution should not be accessible or viewable by others within the same project. a current list with signatures and names of all authorized study personnel with access to the study records will be filed in the study site file and the trial master file, respectively. a built-in data logging tool (audit trail) ensures that any changes to the project or user activity (date and time stamp and user log), including contextual information (e.g. the project record being accessed), are continuously tracked in real-time and accessible online or via downloadable audit table. a multi-level back-up system is in place. whole system internal back-ups including the database are run several times per day and an additional external back-up onto tape once a day. the back-up tapes are stored in a secure place in a separate building. ecrfs are kept current to reflect subject status at each phase during the course of the study. for ad interim (if applicable) and final analyses, data files are extracted from the database in csv (case-delimited) format, typically supported by microsoft excel, sas, stata, r, or spss software systems. direct import into these statistical packages is advised for best data analyses. this study foresees the use of r for statistical analysis of study outcome. the study database will be securely stored by ctu zürich for at least years (after the regular end or a premature termination of the respective study). the edc system supports data checks completeness and plausibility. furthermore, selected data points are cross-checked for plausibility with previously entered data for that participant. additional central data validity checks against pre-determined parameters are run either automatically or ad hoc, to detect inconsistencies and identify missing data for source data verification. monitoring prior to the start and during the course of the study will help to follow up the progress of the clinical study, to assure utmost accuracy of the data and to detect possible errors at an early time point. the sponsor-investigator organises professional independent monitoring for the study and will collaborate with the clinical trials center (ctc) of the university hospital zurich. according to the ctc's monitoring sop the extent and nature of monitoring activities based on the objective and design of the study will be defined in a study specific monitoring plan. during the covid- pandemic monitoring will be performed by remote techniques as defined in the monitoring plan. see the attached monitoring plan. a quality assurance audit/inspection of this study may be conducted by the competent authority or cec, respectively. the quality assurance auditor/inspector will have access to all medical records, the investigator's study related files and correspondence, and the informed consent documentation that is relevant to this clinical study. the investigator will allow the persons being responsible for the audit or the inspection to have access to the source data/documents and to answer any questions arising. all involved parties will keep the patient data strictly confidential. direct access to source documents will be permitted for purposes of monitoring, audits and inspections. not applicable. by signing the clinical trial protocol, the investigator agrees on the use of the results of this clinical trial for publication and information for medical and industrial professionals. the findings of this clinical trial including the interim analysis will be published in a scientific journal or presented at a scientific meeting and may be used for pooled analyses with similar trials. publication of clinical trial results requires mutual agreement between the investigators and the sponsor. any publication of the clinical trial data by the sponsor or investigators will be wholly consistent with the integrated report in accordance with the ethical principles of the declaration of helsinki. all publications will follow the uniform requirements for manuscripts submitted to biomedical journals (www.icmje.org, october ). this investigator-initiated study will be funded by the clinic of angiology, usz and the clinic of cardiology, inselspital. various applications for public funding have been conducted, including university zurich, innovation pool usz, swiss red cross froundation, johanna dürmüller-bol foundation. additional public funding will be requested as needed. in case of involvement of centers from other countries, potential co-sponsors will apply for separate national public fundings. insurance is covered by "versicherung für klinische versuche und nichtklinische versuche" by zürich versicherungs-gesellschaft ag (policy no: . . ). any damage developed in relation to study participation is covered by this insurance. so as not to forfeit their insurance cover, the participants themselves must strictly follow the instructions of the study personnel. participants must not be involved in any other medical treatment without permission of the principal investigator (emergency excluded). medical emergency treatment must be reported immediately to the investigator. the investigator must also be informed instantly, in the event of health problems or other damages during or after the course of study treatment. the investigator will allow delegates of the insurance company to have access to the source data/documents as necessary to clarify a case of damage related to study participation. all involved parties will keep the patient data strictly confidential. a copy of the insurance certificate will be placed in the investigator's site file. . general study design and justification of the design unblinding procedures (code break) . administration of experimental and control interventions data collection and follow-up for withdrawn participants study flow chart/table of study procedures and . . pre-screening period (day - to day ) corriere dell sera -data analysis. «the real death toll for covid- is at least times the official numbers cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease (covid- ) pandemic clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy time to consider histologic pattern of lung injury to treat critically ill patients with covid- infection covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and followup prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars diagnosis potential effects of coronaviruses on the cardiovascular system: a review chest radiographic and ct findings in novel swine-origin influenza a (h n ) virus (s-oiv) infection autopsy findings in eight patients with fatal h n influenza h n -induced venous thromboembolic events? results of a single-institution case series acute pulmonary embolism and covid- pneumonia: a random association? venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in incidence of thrombotic complications in critically ill icu patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia high incidence of venous thromboembolic events in anticoagulated severe covid- patients thrombotic complications of patients admitted to intensive care with covid at a teaching hospital in the united kingdom is covid evolution due to occurrence of pulmonary vascular thrombosis? incidence of thrombotic complications in critically ill icu patients with covid- prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia covid- experience in high risk of thrombosis in patients in severe sars-cov- infection: a multicenter prospective cohort study pulmonary embolism in covid- patients: awareness of an increased prevalence acute infections and venous thromboembolism cytomegalovirus infection is associated with venous thromboembolism of immunocompetent adults--a case-control study thromboembolic events in patients with severe pandemic influenza a/h n a comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. prophylaxis in medical patients with enoxaparin study group rivaroxaban for thromboprophylaxis after hospitalization for medical illness external validation of the risk assessment model of the international medical prevention registry on venous thromboembolism (improve) for medical patients in a tertiary health system influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from years of autopsies in , subjects association of coronavirus disease (covid- ) with myocardial injury and mortality clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china covid- and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? jama endothelial cell infection and endotheliitis in covid- . lancet. . . isth interim guidance on recognition and management of coagulopathy in covid- the versatile heparin in covid- evaluation of the effects of low molecular weight heparin on inflammation and collagen deposition in chronic coxsackievirus b -induced myocarditis in a/j mice thrombosis-uk. practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- covid- and its implications for thrombosis and anticoagulation. blood. . rivaroxaban for extended thromboprophylaxis after hospitalization for medical illness: pooled analysis of mortality and major thromboembolic events in , patients from the magellan and mariner trials extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis thromboprophylaxis with enoxaparin and direct oral anticoagulants in major orthopedic surgery and acutely ill medical patients: a meta-analysis treatment of venous thromboembolism in patients with cancer: a network meta-analysis comparing efficacy and safety of anticoagulants critical appraisal of international guidelines for the prevention and treatment of pregnancy-associated venous thromboembolism: a systematic review american society of hematology guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients american society of hematology guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy american society of hematology guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in medical patients with enoxaparin (medenox) trial the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology (esc) rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty aspirin or rivaroxaban for vte prophylaxis after hip or knee arthroplasty rivaroxaban for thromboprophylaxis in acutely ill medical patients the incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study subcommittee on control of anticoagulation of the s, standardization committee of the international society on t, haemostasis. definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients lowmolecular-weight heparin and mortality in acutely ill medical patients extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial the following information (at least but not limited to) should be included in the source documents:• demographic data (age, sex) • inclusion and exclusion criteria details • participation in study and signed and dated informed consent forms • visit dates • medical history and physical examination details • key efficacy and safety data (as specified in the protocol) • aes and concomitant medication • results of relevant examinations • laboratory printouts • dispensing and return of study drugs • reason for premature discontinuation • assignment to treatment groupthe data collected during the phone calls (day , , , and ) will be entered directly in the ecrf. additionally, the site reports from the visits (in-hospital visit, as well as phone visits) will be imported into the electronic patient chart of the study centers. all study data must be archived for a minimum of years after study termination or premature termination of the clinical trial. any patient files must be archived for the longest possible period of time according to the feasibility of the investigational site, e.g. hospital, institution or private practice for the present clinical study, the electronic data capture (edc) software redcap (www.project---redcap.org) will be used for data processing and management. redcap was developed by an informatics core at vanderbilt university in , with ongoing support from us national center for research resources (ncrr) and us national institute of health (nih), grants nih/ncats ul tr . redcap was specifically developed around hipaa security guidelines and is gcp-compliant and fulfills the swiss regulatory requirements regarding the collection of patient data in clinical trials or noninterventional studies and patient registries and the swiss/eu data protections laws. operating requirements include a linux, unix, windows or mac interface. the system requires a smtp e-mail server, is accessed via php web-based front end (e.g. microsoft iis or apache) and runs on a mysql database server, hosted by the clinical trials center of the university hospital zurich, which holds a redcap end-user license agreement for this edc system. data collection occurs via electronic case report forms (ecrfs), which are generated via study-specific data dictionary defined in an iterative self-documenting process by members of the research team with planning support from the data management department of the clinical trials center, university hospital zurich, switzerland (ctu zurich). the iterative development and testing process results in a well-planned data collection strategy in keeping with the outcome parameters and procedures defined in the key: cord- -f w fw q authors: nan title: abstracts presented at the neurocritical care society (ncs) th annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: f w fw q nan external ventricular drain (evd) management after subarachnoid hemorrhage (sah) is thought to influence patient outcomes and complications. evidence from single center randomized controlled trials suggest that an early clamp trial is safe and associated with shorter icu stay and fewer evd complications. however, a recent survey revealed that most neuro icu's across the us still adopt a gradual wean and continuously draining evd strategy. therefore, we sought to determine the optimal approach at our institution. we reviewed consecutive patients admitted to our institution from to with nontraumatic sah requiring an evd. in , our neurocritical care unit revised our internal evd management guideline from a gradual wean to an early clamp trial approach. we performed a retrospective multivariate analysis to compare outcomes before and after our guideline change. patients that were gradually weaned after institution of the new guideline were also included in the early clamp trial group. we observed a significant reduction in ventriculoperitoneal shunt (vps) rates after changing to an early clamp trial approach ( % early clamp vs % gradual wean, p= . , or= . on multivariateanalysis). there was no increase in delayed vps placement at months ( . % vs . %, p= . ). an early clamp trial approach was also associated with a shorter mean evd duration ( . vs . days, p< . ), shorter icu length of stay ( . vs . days, p= . ), shorter hospital length of stay ( . vs . days, p< . ), lower rates of non-functioning evd ( % vs %, p= . ), and fewer ventriculostomyassociated infections ( . % vs . %, p= . ). we found no difference in symptomatic vasospasm rates between the groups ( . % vs . %, p= . ). an early clamp trial approach is associated with fewer complications and shorter length of stay compared to a gradual evd wean. prospective multicenter studies are needed to provide further insight into the best strategy. autoimmune encephalitis refers to rare sometimes paraneoplastic conditions in which the immune system attacks the brain, leading to altered function. delayed diagnosis and treatment potentially leads to permanent neurological injury or death. the primary objective of this study was to analyze the admission and discharge modified rankin scale (mrs) assessments among patients diagnosed with autoimmune encephalitis, and to identify any effectiveness of immunosuppressive therapy on a subset of these patients. through retrospective chart review we identified patients that met currently accepted clinical and serological criterion for autoimmune encephalitis. clinical data was obtained on these cases and a modified rankin score mrs was assessed on both hospital admission and discharge or subsequent 'best clinical' visit. assessment of "improvement" from initial therapy was based on any decrease in mrs score and clinical neurological functional improvement in accordance with physician and patient affirmation by the time of discharge. seventy-seven patients met criterion for clinical or serological autoimmune encephalitis. of these patients, had cancer and did not have known cancer. fifty-seven ( %) patients underwent immunosuppressive therapy with corticosteroids, ivig, and/or plasma exchange and patients experienced a decrease in mrs score. improvement from initial treatment was %, %, %, and % for admitting mrs scores or through respectively. the p-values for improvement from initial immune therapy based on an mrs of , , or compared to an mrs of were . , . , and . respectively. immunosuppressive therapies for patients with an initial mrs score of , or may have a higher yield than for those with an mrs of . these therapies are generally reserved for those with an mrs of or greater. further study is needed to assess functional improvement in those with autoimmune mediated encephalitis treated with immunosuppressive therapies. many patient, family and hospital factors have been associated with obtaining consent for organ donation after brain death (bd). we evaluated potential factors that played a role in the consent rate in a large tertiary hospital over a period of . years. we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation. we cross-matched the hospital electronic medical records with the records of the local organ procurement organization to identify this population. patients were included in the registry ( . % african american) and were approached for donation. there was a . % consent rate for organ donation. there was no significant relationship between sex, admission diagnosis, icu (neuro vs. medical vs. surgical), physician specialty (neurology vs. other), time from event to bd declaration or religion and decision to donate. families were more likely to consent to donation if the patient was non-aa ( % vs % for aa, p< . ), was younger ( . vs . , p= . ), had a lower creatinine at the time of death ( . ± . vs . ± . mg/dl, p= . ), and had an apnea test completed ( % vs %, p= . ). in a logistic regression model, only aa race and pao independently predicted refusal of donation (odds, %ci, . , p< . and . , p= . , respectively) . although the majority of bd patients in this large series were aa, their families were times less likely to consent for organ donation than non-aa families. there is an urgent need to explore the reasons for low donation rates in this population. post-anoxic myoclonus is seen in up to % of patients who remain comatose, and historically was felt to be a poor prognostic sign. little distinction has been made in the literature between epileptic (cortical) vs subcortical myoclonus. from consecutive cardiac arrest patients that did not return to baseline (may -may ) we identified % (n= ) patients with clinical myoclonus. basic demographics and characteristics of their arrest were collected and eeg reports were reviewed. raw eeg including video was reviewed by two epilepsy-trained neurologists, whenever available. myoclonus was subcategorized into subcortical and cortical based on the presence of a preceding eeg correlate. jerk-locked eeg back-averaging was performed on two representative patients. the average age of patients with myoclonus was +/- years, and % (n= ) survived to discharge. cortical myoclonus was twice as likely as subcortical myoclonus ( % vs %, respectively). compared with patients without myoclonus, patients with myoclonus were more likely to have longer, more severe arrests. patients with subcortical myoclonus were at risk for electrographic seizures, although at a lower rate than those with cortical myoclonus ( % vs %, respectively). mortality rates did not differ between patients with cortical and subcortical myoclonus ( % vs %). patients with cortical myoclonus were more likely to be discharged in a vegetative state compared to those with subcortical myoclonus ( % vs %, respectively (or . ; %ci . - . ). amongst survivors, good functional outcome at discharge did not differ between cortical vs subcortical myoclonus ( vs %, respectively). jerk-locked eeg back-averaging was useful in distinguishing subcortical from cortical myoclonus. myoclonus is seen in every sixth patient with cardiac arrest. cortical and subcortical myoclonus cannot be distinguished using clinical criteria. both may have good outcomes when managed with targeted temperature management and an aggressive antiepileptic regimen. intoxication by central nervous system (cns) depressant drugs can lead to anoxic brain injury by cardiac or respiratory arrest. we tested the hypothesis whether intoxication by these drugs contributes to mortality in acute anoxic brain injury we utilized healthcare cost and utilization project databases (nationwide inpatient sample and kids' inpatient database) to obtain patients admitted with diagnosis of anoxic brain injury. patients with drug intoxication (opioid, alcohol, sedative/hypnotic drugs) were identified. regression analysis was used to assess relationship between drug intoxication status to in-hospital mortality. the regression model was adjusted for age, gender, chronic medical comorbidities, presence of cardiac arrest and hospital characteristics. we analyzed a total of , patients with anoxic brain injury out of which ( . %) had drug intoxication and % were reported to have cardiac arrest. median age was years and % patients were males. in-hospital mortality was %. among the survivors, % underwent feeding tube placement and % had tracheostomy. drug intoxication was a significant positive predictor of inhospital mortality with adjusted odds ratio . ( . - . ), p= . . cns depressant drug intoxication is associated with higher in-hospital mortality in patients with acute anoxic brain injury. cardiac arrest affects approximately , individuals every year and is the third most common cause of mortality in the us. currently, there is no way of reliably risk stratifying survivors of cardiac arrest. identifying early predictors of outcome is vital for triaging and clinical trial enrollment. we proposed to identify key clinical and laboratory parameters that can reliably predict long-term outcomes among comatose survivors of cardiac arrest. this was a retrospective chart review of comatose survivors of cardiac arrest. we gathered data regarding several clinical (age, pre-arrest mrs, gcs on admission, and hours, presence/absence of shock and respiratory failure) and laboratory parameters (troponins, lactate, creatinine, and alt at admission, and peak values within the first and hours) as well as characteristics of the cardiac arrest (duration, arrest rhythm, location, and bystander cpr). we used a dichotomized gos ( - vs - ) at months as the primary outcome. we performed univariate and multivariable analysis to identify predictors of poor outcome. a total of patients were enrolled. on univariate analysis, higher age, higher pre-arrest mrs, lower gcs at hours, non vf/vt arrest rhythm, in-hospital arrest location, absence of bystander cpr, and shock were statistically significant (p < . ) for poor outcome. in multivariable analysis, only higher prearrest mrs and lower gcs at hours were independent predictors of poor outcome; no bystander cpr demonstrated a trend for being an independent predictor. none of the early laboratory data achieved statistical significance for predicting poor outcome. we identified several clinical predictors of poor outcome in our small cohort of comatose survivors of cardiac arrest. the above variables need to be analyzed among a larger cohort that includes all survivors of cardiac arrest in order to develop an injury severity score that can help risk stratify cardiac arrest survivors. after cardiac arrest, somatosensory evoked potentials (sseps), eeg characteristics, and mri are routinely used to evaluate comatose patients. the relationship between structural hypoxic injury, absent cortical potentials and the generation of background reactivity or epileptogenic potentials is unclear. here we evaluate a consecutive series of patients with cardiac arrest that were studied with sseps and evaluate clinical, eeg, and mri measures to study the dissociation between hypoxia-induced thalamic disconnection and spontaneous cortical activity. in this retrospective cohort study, all comatose patients post-cardiac arrest who received sseps were identified and reports were reviewed. patients were found; one patient with a high cervical cord injury was excluded. we recorded presence of cortical (n ) and subcortical evoked responses (p ), whenever available. based on the closest available eeg (maximum days from ssep recording) we determined reactivity, background characteristics (diffuse suppression or burst-suppression versus all other backgrounds), and presence of generalized periodic discharges (gpds) or seizures. diffusion weighted or t flair abnormalities in the thalamus were evaluated based on available mris. chi-square and fisher's exact test were applied as applicable. of patients with ssep, ( %) had absent n s, and % of those (n= ) had absent p . eeg reactivity was possible, albeit less common, in patients with absent n s ( % vs %, p< . ), but none of the patients with absent p s had a reactive eeg. those with absent n s were more likely to have diffusely suppressed or burst-suppressed background ( % vs %, p= . ) and to have abnormal thalamic signal on mri ( % vs %, p= . ). gpds, stimulus-induced gpds, and seizures were equally common in those with and without n s. the integrity of the somatosensory thalamo-cortical pathway does not appear to be necessary for presence of reactivity or generation of periodic epileptiform discharges. all families of patients who have become brain dead (bd) should be offered the choice of donation. this does not always happen and the factors that lead to approaching them or not are not known. our objective was to evaluate which factors influence the donation coordinators (dc) working for an organ procurement organization approach families after brain death we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation and cross-matched the hospital electronic medical records with the records of the local organ procurement organization. in order to refine neurologic prognosis in cardiac arrest patients we sought to incorporate heart rate variability into a multimodal prediction model. heart rate variability has been shown in animal studies to be preserved in survivors of cardiac arrest. in our preliminary study, we retrospectively analyzed patients admitted to the university of virginia who had undergone a cooling protocol following cardiac arrest. analysis of heart rate variability for each patient was done in the frequency domain using the fast fourier spectral transform with spectral bands at . - . hz for high frequency (hf) and low frequency (lf) power within the frequency band . - . hz. the unit-less lf/hf ratio was considered a measure of balance between sympathetic and parasympathetic tone. over a -year period, a total of patients were cooled. patients ( %) had ceeg, ( %) had routine eegs and ( %) had sseps performed. numerous patients ( , % of all arrests or % of all eegs performed) had malignant patterns, defined as burst suppression, severe suppression, or generalized periodic discharges. of the sseps, had an absent n (none survived to discharge) and had an n that was present ( survived to discharge). patients with absent n s and malignant eegs had lower lf/hf ratios when compared to survivors with present n s ( . vs. . ). the trend towards parasympathetic dominance following a severe neurologic injury and loss of normal sympathetic tone in those patients with absent n s and malignant eegs and may serve as an additional marker of poor prognosis following cardiac arrest. physicians often struggle with the intricacies of brain death determination and communication about end-of-life care. in an effort to remedy this situation, we introduced an educational initiative at our medical school to improve student comprehension and comfort dealing with brain death. beginning in july , students at our medical school were required to attend a -minute brain death didactic and simulation session during their neurology clerkship. students completed a test immediately before and after participating in the initiative. of the students who participated in this educational initiative between july and june , ( %) consented to have their data used for research purposes. students correctly answered a median of % of questions (iqr - %) on the pretest and % of questions (iqr - %) on the posttest (p< . ). comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative ( % of students were comfortable performing a brain death evaluation before the initiative and % were comfortable doing so after the initiative, p< . ; % were comfortable talking to a family about brain death before the initiative and % were comfortable doing so after the initiative, p< . ). incorporation of simulation in undergraduate medical education is high-yield. at our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was poor prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. this initiative was clearly a success and can serve as a model for brain death education at other medical schools. early withdrawal of life support (ewls) is a major factor in deaths following hypoxic ischemic injury after cardiac arrest (ca) in patients receiving targeted temperature management (ttm). appropriate timing of prognostication, and subsequent withdrawal of life support is recommended in recent guidelines, but is not always followed in clinical practice. we describe the impact of ewls in a multicenter registry database. using data from the international cardiac arrest registry (intcar), we defined ewls as withdrawal in the first three days of hospitalization. among all patients treated with targeted temperature management, we developed a logistic regression model to predict ewls. we then performed a propensity score and evaluated the incidence of good outcome between deciles of risk for ewls. patients entered into intcar from - from different hospitals were included. mean age was (± ) years, mean cpr duration was (± ) minutes, ( %) had a shockable rhythm, and ( %) received bystander cpr. support was withdrawn in , with ( %) events classified as ewls. ( % of total cohort). among patients with support withdrawal, older age (p= . ), nonshockable rhythm (p= . ), increased ischemic time (p= . ), and shock on admission (p< . ) were associated with ewls. among propensity matched patients grouped into deciles of probability for ewls, survival with good functional outcome occurred in % ( th decile), % ( th), % ( th), % ( th), and % ( th decile). early withdrawal of life support after cardiac arrest occurs frequently, and is associated with age, duration of cpr, a non-shockable rhythm, and shock at the time of admission. a cohort of patients propensity-matched to those with ewls had - % survival with favorable neurologic outcomes. these data support that in most patients receiving ttm, conservative and delayed prognostication after cardiac arrest is appropriate. brain herniation (bh) is a deadly event that requires immediate central venous access for infusion of hyperosmotic agents, especially . % nacl. traditional venous catheters, whether peripheral or central, takes several minutes to place, and requires skill for successful placement, thus delaying critical treatment. intraosseous (io) cannulation has been shown, at least during cardiac arrest, to be a secure and rapid means of central vascular access that requires limited training. however, limited data exists on the use of io in bh for administering . %. the aim of study of this study is to measure changes in serum sodium and bh reversal after administering . % via io. retrospective chart review of patients with acute neurologic injury requiring . % and io placement due to a lack of central access. demographics, diagnosis, gcs, sodium (na+), and pupillary reactivity, and immediate and delayed complications were collected. results patients included: males, age range - yo. diagnosis include intracerebral hemorrhage ( n= ), extra-axial hematoma (n= ) and sah (n= ). gcs ranged to . all patients were intubated. most patients were co-treated with hyperventilation, nabicarb, mannitol, and propofol. io was placed in tibia ( ) or humerus ( ); all placed correctly on first attempt. comparing hr post- . % nacl treatment to pretreatment: na+ level increased in of ; gcs improvement in of ; and returned pupillary reactivity in of . no adverse events reported, such as shock, cardiac arrest, tissue or limb injury. preliminary data suggest that during bh, io cannulation results in safe and timely . % administration in patients with no central access. additional safety data is needed, particularly with regards to the potential for myonecrosis. however, if safe, io cannulation should replace central line placement as the initial route of central venous access during bh. the pupillary light reflex is associated with outcome after cardiac arrest as a dichotomous variable (present/absent) at various time points following resuscitation (rosc). infrared pupillometry provides quantitative measures including pupil diameter (pd), and neurological pupil index (npi) which ranges from (nonreactive) to (brisk) and reflects velocity and degree of pupil constriction in response to a standardized light stimulus. these measures may provide early prognostic information to guide therapy. comatose adult survivors of cardiac arrest treated with targeted temperature management were monitored with the neuroptics npi- pupillometer. outcomes were defined as good (go) if discharge cerebral performance category score was - , and poor (po) if - . data are presented as median (iqr). groups were compared using non-parametric statistical tests. fifty-one patients were enrolled; the median age was ( . - . ), and ( %) were male. initial rhythm was vt/vf in %, asystole in %, and pea in %. outcome was good in ( %) patients. the initial pd did not differ between outcome groups [ . ( - . ) po vs . ( - . ) go]. the initial npi was lower in poor outcome patients [ . ( . - ) vs . ( . - . ) go, p= . ] measured . ( . - . ) hours after rosc. npi dropped below in more poor outcome patients [ ( %) vs ( . %) go, p= . ], and to zero in ( %) poor vs ( %) good outcome patients (p= . ). receiver operator characteristic curves confirmed that initial npi predicted poor outcome better than pupil diameter (auc . vs . , p= . ). a low neurological pupil index predicted poor outcome - hours after resuscitation from cardiac arrest, and dropped to abnormal levels (< ) and to zero (reflecting a non-reactive pupil) more often in patients with poor outcomes. additional research is needed to define potential confounders, optimal timing, and thresholds for different levels of neurological risk with pupillometry. prediction of death in a timely manner after withdrawal of life support (wls) is essential during organ donation after cardiac death (dcd). we aimed to develop a modified version of the recently develop dcd-n score to improve the specificity of prediction and test it in a specific group of patients with catastrophic brain injuries referred for dcd. we analyzed prospectively collected data by our local organ procurement agency on all consecutive adults with severe neurological injury evaluated for dcd across centers in the usa from march to may . we analyzed three variables used in the dcd-n score (corneal reflex, cough reflex and oxygenation index) and substituted the fourth variable for vasopressor support. a total of patients, mean age (sd± ) years were included in the final analysis. anoxic brain injury was the most common cause of death ( %) followed by stroke ( %). in multivariate logistic regression analysis adjusted for age and cause of death, absent corneal reflex (or . , % ci . to . , p = . , points), absent cough reflex (or . , % ci . to . , p = . , point), vasopressor support at high doses (or . , % ci . to . , p < . , points) and o ind ci . to . , p = . , points) were associated with the likelihood of death within minutes of specificity % and auc . . the modified dcd-n score has a greater specificity in predicting death within minutes of wls and is developed specifically from a cohort of patients evaluated for dcd. future prospective studies are needed for further validation of this scoring system. significant number of the patients with anoxic brain injury have poor neurological recovery. this created a significant anxiety in families who often request early prognostication. this study was conducted to evaluate possible ultra-early prediction of good neurological recovery in patients undergoing hypothermic protocol for anoxic brain injury retrospective chart review of the patients with anoxic brain injury was conducted. all patient underwent standard evaluation and management in the early stages of icu care, including initiating of hypothermic protocol with intravenous cooling device. all patients underwent evaluations with eeg and ssep within first day after admission during hypothermia phase and mri brain after re-warming. total of charts were reviewed. patient had normal ssep and normal mri. all patients had good neurological recovery, except for one patient who died secondary to severe cardiac failure eeg did not have any predictive value for the good neurological outcome when it was done during hypothermic protocol. normal ssep may a reliable predictor for good neurological recovery. apnea test is the essential component to confirm brain death by stimulation of respiratory center in brainstem. guidelines recommend that apnea testing should meet the criteria of disconnection from mechanical ventilator, and oxygen supplying by catheter. however, during the apnea test under this technique, disconnection from ventilator may induce hypoxia due to abrupt decruitment of alveoli and pulmonary barotrauma such as pneumothorax. there are some studies that suggest continuous positive airway pressure can be effective for patients with hemodynamically instability and respiratory impairment. we suggest a novel method of apnea test by using ambu bag with positive end-expiratory pressure (peep) valve to avoid abrupt change of peep during the apnea test. apnea testing was performed by using ambu bag with peep valve to adult brain death patients. ambu bag was not bagging during the testing and just connected to endotracheal tube with l/min of % oxygen. peep valve was applied the same peep of previous mechanical ventilator. on the apnea testing, vital signs and ekg were monitored. arterial blood gas analysis were measured and minutes after disconnection from mechanical ventilator. there were no significant differences in mean pao between before and after apnea test ( ± and ± , p= . ). mean arterial blood pressure were ± mmhg and ± mmhg before and after the test, respectively. during the intervention and following observation, arrhythmia or pulmonary complications had not occurred. we suggest a novel method of apnea testing which is a simple and easy technique by using ambu bag with peep valve to minimize decruitment of alveoli. this method shows vital signs and respiratory oxygenation of the patients remained stable during the test. declaration of brain death based on clinical exam has been plagued with challenges. as a result, ancillary testing such as nuclear scintigraphy cerebral blood flow (cbf) studies have been recommended. we present a case in which the apnea test could not be completed due to hemodynamic instability and where the nuclear scintigraphy cbf study resulted in a false declaration of brain death. a y/o male was admitted with bilateral hearing loss and confusion. on day two, the patient developed blurred vision, and an mri confirmed bilateral cerebellar and pontine infarctions. by day four, he had developed diffuse cerebral edema in the cerebellum, brainstem, and bilateral occipital lobes, and we proceeded with the clinical exam for brain death. all cranial reflexes were absent; however the apnea exam could not be completed due to blood pressure instability. a nuclear scintigraphy cbf study revealed the complete absence of radiotracer activity, and the patient was pronounced dead. two hours later, the patient regained a gag reflex. on the following day, the clinical exam, with the exception of apnea testing, was again consistent with brain death. a cerebral angiogram was performed and demonstrated normal blood flow to the anterior circulation. the patient was ultimately pronounced dead on day eight after two separate complete clinical brain death exams, including apnea testing, were performed. cerebral angiography showed essentially normal blood flow where nuclear scintigraphy showed no blood flow. nuclear scintigraphy cbf studies are commonly recommended when apnea testing cannot be completed. given the dramatic differences in the results observed between these modalities, a reevaluation of this practice should be considered. patients' perceptions of recovery moderate outcomes, however studies exploring the specific cognitive, functional, and psychological domains associated with subjective perceptions of recovery at hospital discharge after cardiac arrest (ca) are lacking. this is a prospective, observational cohort of patients admitted to columbia university medical center after ca, and survived to hospital discharge between / - / . patients with sufficient mental status to perform a neuropsychological exam and a questionnaire at discharge were included. subjective perceptions of recovery were assessed via responses to the forced-choice dichotomized question, "do you feel that you have made a complete recovery from the arrest?"objective outcome measures of recovery included: repeatable battery for neuropsychological status (rbans), modified lawton physical self-maintenance scale (l-adl), barthel index (bi), cerebral performance category scale (cpc), center for epidemiological studies-depression scale (ces-d), and post traumatic stress disorder-checklist (ptsd-c). chi-square, wilcoxon-rank sum, and logistic regression were used to compare the respondents, and determine factors associated with subjective perceptions of recovery. patients were included with mean age of ± years; % were men and % were white. % responded not having made a complete recovery. no significant differences were found between respondents in terms of demographics, charlson comorbidity index, arrest-related variables, rbans, l-adl, bi, pre-or post-arrest cpc scores. those responding that they had not made a full recovery had higher rates of ptsd-c ( % vs %, p< . ), and depression ( % vs %, p= . ). moreover, everyone that screened for ptsd (n= ) reported not having made a complete recovery. patients with higher ptsd scores were more likely to report not having made a complete recovery (or . ; p< . ) after adjusting for age, gender and depression scores. presence of post traumatic stress disorder symptomatology at discharge, and not neurocognitive or functional status, is highly associated with post-cardiac arrest patients' subjective perceptions of recovery. early eeg background reactivity is a strong predictor of neurological recovery after hypoxic-ischemic brain injury despite hypothermia and sedation. unfortunately, expert interrater-agreement on visual scoring of eeg background reactivity ranges from - %. recent studies indicate that machine-learning approaches using quantitative eeg (qeeg) might yield equivalent or superior performance to current eeg reactivity assessment practices, however its ability to predict outcomes has not been tested. we hypothesized that a qeeg reactivity method can predict long-term functional outcome in hypoxic ischemic brain injury. we retrospectively reviewed clinical and eeg data of cardiac arrest patients managed with hypothermia at two university hospitals. eeg reactivity was tested daily using a structured exam consisting of auditory, tactile, and visual stimulation. our quantitative eeg method evaluated changes in eeg spectra, entropy, and frequency features during seconds before and after each stimulation-step ( qeeg features used). only the first eeg reactivity assessment for each subject was used in the final analysis. good outcome was defined as cerebral performance category of - at six months. a penalized multinomial logistic regression was utilized for feature selection and a random-forest classifier was employed in the training and validation sets. model performance evaluation metric was the area under roc curve (auc). outcome and eeg data was available for a total subjects, and cases were excluded due to presence of burst-suppression, periodic epileptiform discharges, or eeg artifact. forty-seven subjects were included in the final analysis. mean age was . (standard deviation . ) years and . % had good outcome. the combination of four features provided best outcome prediction performance with an auc of . (kolmogorov-smirnov test, skewness, two-group test, and renyi entropy). early qeeg reactivity is predictive of good outcome at six months. a quantitative approach to eeg reactivity analysis might facilitate accurate and individualized prognostication in hypoxic-ischemic brain injury. hypoxic-ischemic brain injury is the leading cause of morbidity and mortality following cardiac arrest, and the ability to predict neurologic recovery in comatose cardiac arrest survivors is limited. functional mri measures brain network connectivity and resting-state network connectivity can be measured in comatose patients. the default mode network (dmn) is one resting state network that has been correlated with consciousness. we hypothesized the degree of connectivity in the dmn and other resting-state networks would correlate with consciousness recovery in post-cardiac arrest coma. consecutive patients with hypoxic-ischemic coma were enrolled. functional mri was obtained on all patients on post-arrest day - on an inpatient tesla mri. the connectivity in multiple resting-state networks was analyzed using pearson's correlations between component maps for each subject and previously defined standard network maps. connectivity in the default mode network and in additional resting-state networks was correlated with outcome. good outcome was defined as consciousness recovery at any point in the acute hospitalization. patients were included in this study. the mean age was ± years ( - ) and were male. patients survived with good outcome. the primary arrest rhythm and the duration of cardiac arrest did not differ between groups (primary rhythm as vt/vf: % vs %, good vs poor, p= . ; cardiac arrest duration: . ± . minutes vs . ± . minutes, good vs poor, p= . ). patients with good outcome had significantly higher mean network connectivity ( . ± . vs . ± . , good vs poor, p= . ). dmn connectivity showed a trend towards significance ( . ± . vs . ± . , good vs poor, p= . ). in comatose patients following cardiac arrest higher fmri measured resting state connectivity correlated with consciousness recovery. functional connectivity may be developed as a prognostic biomarker. sedative and analgesic infusions and neuromuscular blockade agents (nmba) are commonly used for comfort, suppression of shivering, and reduction of metabolic activity during targeted temperature management (ttm) after cardiac arrest. the optimal sedation and analgesia regimens are unknown. we sought to describe variability in sedation and shivering management practices at us and european cardiac arrest receiving centers. international cardiac arrest registry (intcar) centers were surveyed regarding sedation protocols for ttm after cardiac arrest. the survey was administered via redcap with a response rate of %. ten united states and european centers completed the survey. shivering is measured at ( %) of centers and recorded at ( %) centers. ten centers use nmb to control shivering prophylactically, centers use nmb only if shivering occurs, and centers increase opioids or sedatives when shivering occurs, but do not use nmb. the most common sedative was propofol ( / centers), followed by midazolam ( / ) and the most common analgesic was fentanyl ( / ) followed by remifentanyl ( / ). , , and centers report having a sedation target of light, moderate, or deep respectively. a sedation scale is used at ( %) centers, targeted to patient comfort at ( %) centers. daily sedation lightening is protocolized when rewarming starts at ( %) centers, when normothermia is reached at ( %) and not specified in the remainder of groups. of patients who awaken, centers report that they expect this to occur at ( centers), ( centers) and ( centers) hours respectively. among cardiac arrest receiving centers internationally, there is significant variability in ttm sedation and shivering management strategy. our hospital policy allows an optional sbd (with an apnea and a cerebral blood flow test) or a dbd (with an apnea test). we have evaluated the adoption of and reason for performing a single brain death exam (sbd) vs two (dual) brain death exams (dbd) and their impact on organ function and consent for organ donation. we evaluated our hospital's bd registry between january and june regarding sbd or dbd. we also cross-matched our electronic medical records with the records of the local organ procurement organization. of bd declarations, ( %) were sbd and ( %) dbd. during the st five years, % of all bd exams were sbd and during the second %. patients with sbd were older ( . ± . for sbd vs . ± . years for dbd, p= . ), had a primary neurologic diagnosis ( % vs %, p< . ) and were admitted to the neuro-icu ( % vs %, p< . ). during the nd exam, . % patients were on equal or higher dose of pressors. sbd patients had lower k+, bun, creatinine and heart rate, but higher peak na+ and apnea pao (for all p< . ), although apnea ph and paco were similar. the time between injury to bd pronouncement was shorter in sbd by . hours. there was no difference in consent rate between sbd and dbd ( % vs %, p= . ). at our institution, bd declaration was more often done by dbd exams, although the primary diagnosis and the unit of admission influenced the decision. an increased adoption of sbd exams was noted after the aan bd guidelines, supporting sbd exam, were published. although the number of exams did not affect rate of consent for donation, surrogate markers indicated better function of organs after sbd, while dbd patients stayed in the icus over a day longer. there are no data supporting better numbers or function of organs in donors after brain death (bd), if there is a shorter waiting period (as expected with single brain death exam [sbd] ) from the time that bd is declared to the time the patient arrives at the operating room (or). our goal was to find if the number of brain death exams, either sbd or dual (dbd), had any impact on the number of organs recovered and transplanted we evaluated our hospital's bd registry between january and june regarding sbd or dbd and cross-matched our electronic medical records with the records of the local organ procurement organization out of bd declarations, led to consent, of which ( . %) after sbd and ( . %) after dbd. there was a trend for longer consent to or time for dbd ( . ± . hours vs . ± . for sbd, p= . ). there was no difference in the number of organs recovered or transplanted based on the number of exams ( . ± . vs . ± . organs/patient recovered and . ± . vs . ± . transplanted for sbd vs dbd, respectively, p> . ). there was a trend for more lungs to be transplanted after sbd exam ( % vs %, p= . ), but this was not found with kidneys, heart, liver, pancreas or intestines. in multiple logistic regression models, adjusting for variables pertinent to each individual organ function (for example, bun or creatinine level for kidneys, blood gases for lungs etc), the number of exams was not an independent predictor for successful transplantation conclusions sbd exam led to similar numbers of organs transplanted compared to dbd exam in this single center registry analysis. more rapid brain death declaration, as with sbd, is not a factor that influences organ transplantation the glasgow coma scale (gcs) is a standardized and commonly used way of assessing important aspects of neurological condition for critically ill patients. while it is a validated tool for prognostication, it is unclear whether serial measurements add value to this prognosis. we used a large set of serially collected gcs measurements to assess the impact of gcs score on the trajectory of neurological recovery as well as factors affecting score variance. gcs total and subscores ( , time points from , patients) recorded hourly by registered nurses in the neurosurgical intensive care unit (nsicu) between january, and may, were analyzed retrospectively. k-means clustering provided groups with similar progression characteristics during nsicu stay. k-means clustering provided groups with similar progression characteristics during nsicu stay. descriptive features for each cluster were binned into histograms and evaluated for similarity using and kruskal-wallis tests. linear correlations of the sub-scores were very high (eye-verbal: . , eye-motor: . , verbal-motor: . ), while compositional variance was low for aggregate scores. hour-to-hour variance in gcs correlates to significant nsicu activities such as nursing shift changes. among patients with similar minimum gcs scores during their stay, those that recovered were significantly less likely to have deteriorated in the hospital ( , p<< . ). for patients with a minimum gcs<= , those that arrived at their minimum score (i.e., did not deteriorate in nsicu) were . % more likely to recover than those who deteriorated in-hospital (kw, p<< . ) . patients that experienced recovery show significantly greater improvement as early as hours after their minimum score (kw, p<< . ). the gcs is unnecessarily complex for most nsicu patients and can be represented by fewer variables. serial gcs measurements do provide value for prognosis and may be able to distinguish patients with potential to recover early in their hospital course. stroke is a major cause of death and disability, and common admission to neurological intensive care units. preferences for cardiopulmonary resuscitation (cpr) are often discussed, but there is limited understanding of cpr outcomes among stroke patients. systematic review and meta-analysis of published literature from to among stroke patients undergoing in-hospital cpr. preferred reporting items for systematic reviews and meta-analysis, metaanalysis of observational studies in epidemiology, and utstein guidelines were used to construct standardized reporting templates. detailed searches of pubmed and cochrane libraries were supplemented with hand-searched bibliographies. primary data from studies meeting inclusion criteria at two levels were extracted, i) survival to hospital discharge after cpr, and stroke as a primary admitting diagnosis, and the less restrictive, ii) survival to hospital discharge after cpr with stroke listed as a comorbidity, were meta-analyzed to generate weighted, pooled estimates of survival to hospital discharge. of articles screened, there were articles ( %) that underwent full review. three articles met primary inclusion criteria, specifically identifying patients with stroke as a primary admitting diagnosis. twenty additional articles met secondary inclusion criteria, listing stroke as a comorbidity. there was an % ( % confidence interval (ci) . , . ) rate of survival to hospital discharge rate from a combined sample of patients that received in-hospital cpr. among the more heterogenous population of inpatients with stroke listed as a comorbidity, there was % ( % ci . , . ) rate of survival to hospital discharge. adherence to utstein reporting guidelines was poor, and neurological outcomes were measured in ( %) of studies. survival to hospital discharge among stroke patients is lower relative to general hospital populations. these preliminary findings highlight the need for improving the quality of evidence to inform patient and provider discussions of cpr among stroke patients. there is often a tendency to treat patients with traumatic brain injury (tbi) and a glasgow coma scale (gcs) score of on presentation less aggressively because of low expectations for a good outcome. based on the crash trial database, a prognosis calculator has been developed for the prediction of outcome in tbi patients. our aim was to investigate whether the crash calculator can be used for prognostication in patients with tbi and gcs of on presentation. we performed a retrospective review of patients with tbi and a gcs score of from / to / . the crash calculator has been validated to estimate mortality at days and death and severe disability at six months (glasgow outcome scale-gos - ). the calculator uses country of origin (usa in our dataset), age, gcs, pupils reactivity to light, presence of major extracranial injury, and findings on ct scan of brain (petechial hemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated hematoma). the individual prognosis for mortality at days and unfavourable outcome at months was calculated and compared with the actual outcomes. a total of patients were included. a tend toward underestimation of the risk of mortality at days was found (estimated mortality was % compared to actual mortality of %; difference of %, p = . ). however, the estimation of outcome at months was accurate (estimated gos - was . % compared to actual of . %, p = . ). the crash prognosis calculator underestimated the risk of mortality, but accurately predicted unfavourable month outcome in patients with tbi and gcs of on presentation. pending larger studies to validate our findings, we believe that crash calculator can only support -not replace -clinical judgment. there are no nationally enforced standards regarding brain death. few data exist on how brain death is determined across the u.s. we used claims data from - from a nationally representative % sample of medicare defined as icd- -cm code . . the primary outcomes were evaluation by a neurologist or neurosurgeon, defined as a physician evaluation-and-management claim associated with the medicare provider specialty codes for neurology or neurosurgery, during the dates of the hospitalization. cpt codes were used to ascertain ancillary testing: brain radionuclide imaging, transcranial doppler ultrasound, or electroencephalography for brain death determination. exact binomial confidence intervals (cis) were used to report proportions. we identified patients with a brain death diagnosis. common associated neurological diagnoses were stroke ( patients; . %), cardiac arrest ( ; . %), and traumatic brain injury (tbi) ( ; . %). head ct or brain mri was performed in . %; this was true of . % of cases of stroke or tbi versus . % of cardiac arrests. neurologists were involved in the care of patients ( . %; % ci, . - . %). they were more commonly involved in the care of stroke ( . %) or cardiac arrest ( . %) than tbi ( . %) or other conditions ( . %). neurosurgeons were involved in cases ( . %; % ci, . - . %), mostly after tbi or stroke. two hundred patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon. twenty-nine patients ( . %; % ci, . - . %) underwent any ancillary testing. two hundred and nine patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon or underwent ancillary testing. in a nationally representative cohort of elderly patients, one-third of patients with a brain death diagnosis were not evaluated by a neurologist or neurosurgeon or by using ancillary tests. traumatic brain injury (tbi) is a major cause of death and disability in the us. recent advances in d illustration ( di) can precisely quantify intracranial pathology on computed tomography (ct). the current standard of measurement, abc/ , demonstrates variability in precision with bleed phenotype. the aim of this project is to assess accuracy automated di and compare it to standard abc/ measurements. baseline ct scans collected during the protectiii multicenter clinical trial (n= ) were retrospectively reviewed by a central neuroradiologist. subdural and epidural hematomas were identified (n ). the radiologist calculated abc/ score using osirix (mac) and radiant (pc) workstations. in a blinded fashion, research assistants concurrently generated di using the following methods: dicom data were resampled to . mm thickness slices and symmetrized using image analysis software (aquarius terarecon inc, ) . lesions were then compiled into single volumetric regions of interest ( d slicer v . , ) . hemorrhages were divided into two groups for analysis: group . volume of hemorrhage bland-altman analysis. this study was irb approved. there is a significant difference between the results of the di and abc/ methods. in group . the estimated relative bias between the two measurements (after transformation) is . (sd . ; pvalue . ; % ci . , . ). in group , the relative bias is - . , sd . , pvalue < . , % ci (- . , - . ). the di method calculates detailed surface area measurements in large and small volume hemorrhages, while abc/ averages cross-sectional area. the abc/ estimates vary by bleed phenotype and offer less topographical precision than di. this is particularly true in extra-axial hemorrhages, which are numerous studies have shown a significant association between hypotension and poor outcome in patients with head injuries. prior investigations have demonstrated that generation of negative intrathoracic pressure (itp) in ventilated patients with brain injury improves mean arterial pressure (map) and lowers intracranial pressure (icp). we hypothesized that augmentation of negative itp by breathing through an impedance threshold device (itd) with cmh o of inspiratory resistance would improve mean arterial pressure in a porcine model of intracranial hypertension. six spontaneously breathing female pigs ( . ± . kg), anesthetized with propofol, were subjected to focal brain injury through inflation of an french foley catheter placed in the epidural space. once a stable injury was obtained, baseline data were collected for minutes followed by minutes of itd use. results are reported as mean ± sd. the itp without the itd during inspiration was - . ± . mmhg, compared to - . ± . mmhg with the itd, p< . . following brain injury, map (mmhg) was significantly higher during itd use ( ± vs. ± ; p< . ). cerebral perfusion pressure (mmhg) was also significantly higher during itd use ( ± vs. ± ; p< . ). icp (mmhg) was not significantly different between groups ( . ± . vs. . ± . ; p= . ) although end tidal carbon dioxide levels (mmhg) were significantly higher during itd use ( ± vs. ± ; p< . ) presumably due to lower respiratory rates during itd use ( ± vs. ± ; p= . ). contralateral cerebral blood flow (ml/ gm/min) was similar between groups ( ± vs. ± ). in this porcine model of intracranial hypertension, spontaneous respirations through an itd significantly improved map and cpp. this approach could be utilized to prevent hypotensive episodes in the setting of brain injury. the impact of applying nanotechnology and biomedical engineering to improve the management of patients with spinal cord injuries (sci) is still not accurately described, nor understood. a systematic review of the literature was conducted, according to prisma criteria, to identify publications revolving around "sci+nanotechnology" and "sci+biomedical engineering" indexed on pubmed in the period - . furthermore, the database of clinicaltrials.gov was searched to highlight the stage of translation of this research into clinical practice through randomized clinical trials (rct). finally the uspto database was interrogated to identify the number of pertinent patents filed in northamerica in the same timeframe. the literature on bioengineering and nanotechnology contributions to sci is exponentially growing, with almost % of articles published between and . its quality and the interest of the scientific community are high, as confirmed by the average impact factor ( . ) and the average number of citations ( ) of articles published in the last two years. this field still represents a niche of sci research: the articles reviewed represent only . % of all articles on sci published in the same decade. this trend is confirmed on clinicaltrials.gov: out of rct on sci only few focus on the application of those technologies, furthermore out of articles spurring from the rct identified were published after , and % after . interestingly, with patents registered by the uspto, the interest in the commercial application of this research seems vivid. currently, the most promising areas of research are: nanofabrication/nanoscaffolding for structural repair, nanodrugs for regeneration, and design of neural interfaces for functional therapies. this review showed that both universities and independent research institutions (mostly from usa, china and european union) are driving this research race; the figures provided above suggest its potential to become a successful example of translational medicine. there are no neuroprotective and neuroregenerative treatments available for traumatic brain injury (tbi). clinical trials investigating potential treatments such as therapeutic hypothermia and progesterone have failed. pre-clinical studies indicate there may be a role of stem-cells in promoting neuroprotection/neuroregeneration in-vivo in animal models of tbi. we aim to provide a pre-clinical literature review into stem-cells as a potential therapeutic option in tbi-animal models. a literature search was conducted on pubmed and google scholar using the terms "traumatic brain injury", "stem-cell", "preclinical", and "animal studies". studies were included if there was an in-vivo animal model of tbi with either intravenous or intra-cortical stem-cell transplantation, along-with a control group, and investigated either motor or behavioral outcomes, or a combination. twenty-seven studies (n= animals) satisfied the criteria. / ( . %) animals were investigated for outcomes. studies harvested stem-cells from human-source, whereas harvested stem-cells from animal-source. bone-marrow stromal-cells (bmsc) were used in studies, neural stemcells (nsc) in , and miscellaneous in . / ( . %) animals received any stem-cell transplantation, whereas were controls. of animals receiving stem-cell transplantation ( ), ( . %) showed significantly better outcomes relative to control animals in each individual study, with exception of one study. amongst transplanted animals, functional outcomes did not differ significantly when grouped by stem-cell type (p= . ), transplantation route (p= . ), and source (p= . ). animals were followedup until week (n= studies), weeks (n= ), weeks (n= ), or > -weeks (n= ). this pre-clinical data demonstrates that stem-cell transplantation may have treatment potential in tbi as shown by improvement in functional outcome in as many as three-quarters of all animals that were treated with stem-cells. this data provides a foundation for the design of clinical translational studies. age of trauma patients including those with asdh is increasing as stated by national trauma registers. we were especially interested if age > years significantly influences outcome compared to younger patients and if other factors like initial gcs have an influence too. methods midline shift, if asdh was surgically removed, additional contusions, comorbidities and intake of anticoagulants. outcome was analyzed using the glasgow outcome scale (gos) at hospital discharge (gos ) and if possible months after discharge (gos ). uni-and multivariate analysis (cox regression model) was performed using the sigma stat softwar . . adverse outcome p= . . in addition, all patients > years with an initial gcs died whereas only % of younger patients with initial gcs died (p< . ). this was the only significant result in the multivariate analysis the monovariate analysis of our data showed a significantly higher risk for adverse outcome after asdh whe it should be considered if it is reasonable to transfer them from local hospitals to a specialized neurosurgical clinic, especially in times of limited resources. reported incidence of pulmonary edema in isolated head injury varies from - %. lung sonography is a potentially useful non invasive technique to detect extravascular lung water(evlw). this study aimed to identify the presence of evlw using lung ultrasound (b lines > per lung field) in chead injured patients admitted to icu . secondary objectives were to compare diagnostic accuracy and time to identification of evlw using chest x ray versus lung ultrasound. association of evlw with duration of mechanical ventilation (mv)and icu stay were observed after ethical clearance (iec no. int/iec/ / ), patients with head injury requiring mv and critical care were enrolled in the study. daily routine chest x ray and bedside lung ultrasound were done from the day of icu admission until the patient was on mechanical ventilator support. four inter costal spaces (ics) were scanned in semi recumbent position; third and sixth ics on either side of sternum till mid clavicular line. evlw was reprted as > b lines per lung field scan sonographically. details of mv and icu management were noted . evidence of evlw at the time of admission using sonography and cxr was recorded in and patients respectively. during icu stay . % patients showed evlw using lung usg (vs patients on cxr). mean delay in detection of evlw on cxr after detection on ultrasound was . ± . days. patients with low gcs, s. albumin, pao /fio ratio and greater apache ii and saps ii had significantly higher incidence of evlw. duration of weaning, mechanical ventilation and icu stay was significantly longer in patients with presence of evlw (p < . ) conclusions: lung ultrasound appears promising in detecting evlw earlier than chest x ray and may aid to minimize the duration of mechanical ventilation, weaning and icu stay . antiepileptic drugs (aeds) are recommended by guidelines for prophylaxis of early post-traumatic seizures (pts) associated with traumatic brain injury (tbi). there has been an increased use of both phenytoin and levetiracetam for this indication. the purpose of this study is to determine the incremental cost-effectiveness of phenytoin compared with levetiracetam for early pts prophylaxis in tbi patients. a cost-effectiveness study was conducted comparing phenytoin and levetiracetam for early pts prophylaxis during the days post-tbi. patients were included if they were years or older, received a study drug, and had a diagnosis of tbi. patients were excluded if they had a history of epilepsy, did not sustain a recent tbi, were initiated on both study drugs concurrently, or were switched to pentobarbital for elevated intracranial pressure. data was collected via retrospective chart review using electronic medical records and publically reported costs. effectiveness was measured as having a successful seizure prophylaxis regimen (sspr), which was defined as ) no clinical or electrographic seizure, ) no discontinuation of study aed, ) no cross-over of study aed to different aed, or ) no addition of aed during the days of therapy. the costs included costs of the study drugs, phenytoin level, and eeg. the data was used to calculate the primary endpoint, the incremental cost for the incremental change in sspr or the incremental cost effectiveness ratio (icer). the phenytoin regimen (n= ) cost $ . and had an sspr of . %. the levetiracetam regimen (n= ) cost $ . and had an sspr of . %. the icer was $ for each % increase in sspr with levetiracetam. the sspr of phenytoin and levetiracetam were similar. because patients who received phenytoin may differ from those who received levetiracetam, further analysis is needed prior to drawing any conclusions about the cost-effectiveness of levetiracetam relative to phenytoin. augmented renal clearance (arc) has been reported in up % of critically ill tbi patients and may impact therapeutic drug concentrations. improved predictors of arc are needed. serum cysc, a validated marker of glomerular filtration, has not been examined as a marker for arc in critically ill tbi patients. this pilot study tested the hypothesis that serum cysc concentrations are lower than reference values following tbi. adult tbi patients enrolled in the ukccts-unctracs prospective study of arc effects on drug clearance, were eligible. cysc serum concentrations (elisa -r & d cysc) were measured daily for up to days and compared to reference values. descriptive statistics and student t-test for continuous measures (patient vs. reference lower range cysc) were calculated. the first ten patients [ m/ f, mean age= . years ( - y/o), median gcs= (iqr - )] provided a total of serum cysc for analysis. each patient provided at least samples (range - ) for up to seven days. measured serum cysc concentrations were below the reference range in of samples. the overall mean cysc concentration was . + . mg/l vs expected mean of . + . . (ns) measured values fell below the lower reference range in patients ( m/ f) for the first study days (mean = . + . vs . + . p< . ). the mean difference between measured concentration and reference value was . + . mg/l. after days, four patients ( m/ f) remained below reference values with a mean difference of . + . mg/dl. preliminary results show cysc was not consistently below reference ranges in all tbi subjects. a subset of subjects showed significantly lower cysc within seven days of injury. the relationship between cysc and arc needs to be further examined as analysis continues. functional connectivity of the default mode network (dmn) is believed to be necessary for recovery of consciousness after coma. however, dmn connectivity has not been comprehensively studied in patients with acute severe tbi. we hypothesized that dmn connectivity in patients with acute severe tbi is associated with level of consciousness. we prospectively enrolled patients admitted to the intensive care unit for acute severe tbi and performed resting-state functional mri (rs-fmri) as soon as safely possible. dmn functional connectivity was assessed by rs-fmri analysis of the blood-oxygen level dependent (bold) signal using a seed-based approach. pearson's correlation coefficients were calculated between the mean bold time series within dmn nodes and all other regions in the brain. level of consciousness was assessed at the time of the scan using the coma recovery scale-revised (crs-r). two-sample t-tests were performed to identify brain regions with connectivity differences between conscious and unconscious subjects. we then tested for associations between level of consciousness and dmn connectivity within these regions. we enrolled patients ( male, mean+/-sd age +/- years) and matched controls ( male, age +/- years). rs-fmri was performed . +/- . days post-injury. at the time of rs-fmri, patients' levels of consciousness were coma (n= ), vegetative state (vs; n= ), minimally conscious state (mcs; n= ), and post-traumatic confusional state (ptcs; n= ). connectivity within the medial prefrontal cortex and posterior cingulate was selectively reduced in unconscious patients (coma and vs) compared to conscious patients (mcs and ptcs; false discovery rate-corrected p < . ). when these regions were further interrogated, connectivity correlated with crs-conclusions dmn functional connectivity correlates with level of consciousness after acute severe tbi. traumatic brain injury (tbi) is a substantial source of death, disability, and healthcare utilization. many older tbi patients present to community hospitals and are transferred to trauma centers for further care; however, little is known about the provision of care and patient outcomes at the final receiving hospital. we described trauma center care among geriatric transfer patients with tbi. we conducted a secondary analysis on a sub-cohort from a prospective multi-center study focusing on ambulance and emergency department (ed) care of injured older adults transported via ambulance. the current analysis focused on tbi patients transferred to the region's level i trauma center from another hospital. transfer paperwork from the originating hospital was reviewed and we conducted a detailed medical record abstraction, including computed tomography (ct) findings, procedures, length of stay (los), and ed disposition. data were collected on transfer patients. thirty had confirmed abnormalities on head ct ( . %). the mean age was years (range: - ), % female, and the most frequent mechanism of injury was falls ( %). average los was . days (range: - , median los . ), with patients staying one day or less. ct findings included subdural hematoma ( %), subarachnoid hemorrhage ( %), and intraparenchymal hemorrhage ( . %). five patients required neurosurgical intervention ( %), eight required icu admission ( %), two were discharged from the ed ( %), and two transitioned to inpatient hospice ( %). tbi is a frequent cause of transfers to trauma centers. in our sample, admission occurred in the majority of patients, but neurosurgical intervention was less common. however, for appropriately selected patients, strategies such as telemedicine may reduce transfers thus saving resources and improving continuity of care for patients and their families. this is an area in which future research is warranted. the prospects and timing of decannulation may affect surrogate decision making regarding tracheostomy for traumatic brain injury (tbi) patients, yet predictors of decannulation are unknown. methods tracheostomy admitted to an affiliated acute rehabilitation hospital between january and december . patients who had life-sustaining measures withdrawn were excluded. admission data, including injury characteristics and presence of lung injury on initial chest x-ray, and inpatient complications were compared. patients were followed throughout rehab and to the point of decannulation. patients lost to follow up were eliminated from analysis. time of decannulation was verified by inpatient physician notes. a cox proportional hazards model was created to determine factors associated with the time to decannulation and reported as hazard ratios (hr). there were tbi patients admitted to the icu during study period and ( % men, mean yearsold, median gcs ) underwent tracheostomy after ± days of intubation, of which were followed throughout rehabilitation. overall cannulation time was ( - ) days. ( %) patients had their trach removed prior to discharge from rehab after ( - ) days of cannulation. in a cox proportional model adjusting for sex, reintubation, aspiration pneumonitis, and presence of lung injury on admission chest x-ray; a higher hospital discharge gcs was associated with a shorter time to decannulation (hr, . ; % ci, . - . ; p =. ) while patients who required inpatient dialysis had a longer time to decannulation (hr: . ; % ci, . - . ; p = . ). the majority of tbi patients that require tracheostomy will be decannulated prior to discharge from rehab. longer durations of tracheostomy cannulatio hospital discharge and those that receive inpatient dialysis. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. poor outcome was defined via stratified dichotomy of the gos-e. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with outcome. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ) . parameters significant at alpha . are reported. prolonged duration of transgression was associated with poor outcome when: glucose> mg/dl (p= . ); hgb mg/dl (p= . ) and inversely associated with map mg/dl (p= . ) or and was inversely associated with map< mmhg (p= . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple significant associations between physiologic transgressions and patient outcome were found. the data suggest that reducing physiologic transgressions is important to minimizing patient morbidity after tbi. the measurement and management of intracranial pressure (icp) is a key component in the care of severe head injury. extracranial ventricular drains (evd) have remained the standard due to the ability to lower icp with the drainage of cerebrospinal fluid (csf). placement of an evd is a more invasive procedure than intraparenchymal icp monitors (ipm) and it is unclear if the use of an evd improves outcomes. we hypothesized that early placement of an evd, in adult patients with severe head injury, would not affect outcomes. utilizing data from the citicoline brain injury treatment (cobrit) trial, a prospective multicenter study, we identified patients who met the inclusion criteria; ) placement of an icp monitoring device, ) glasgow coma score (gcs) less than , ) evd placement prior to arrival or within hours of arrival at the study institution. primary outcome was glasgow outcome score-extended (gose) at days post injury. secondary outcomes included neuropsychological evaluations at days post injury, mortality, and length of icu stay. logistic regression with forward-stepwise predictor adjustment and propensity score adjustment was performed to assess the independent association between evd placement and outcomes. patients who received an evd prior to or within hours of arrival at the study institution had worse gose at days ( . ± . vs . ± . , p= . ), higher in hospital mortality ( % vs %, p = . ), and did worse on out of neuropsychological measures at days. there was no difference in icu length of stay ( . ± . vs . ± . , p= . ). early placement of evds in severe adult head injury is independently associated with worse outcomes and higher in hospital mortality. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with mortality. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ). parameters significant at alpha . are reported. mortality was . % and . % in the full and ticp cohorts. prolonged duration of transgression was associated with increased mortality for: hgb . (p mg/dl (p mg/dl (p= . ), and sbp . (p . (p= . ). covariates inversely related to mortality included single occurrence of map mmhg (p< . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple associations between physiologic transgressions and mortality were observed. the data suggest that maintaining physiologic measures within gdt guidelines may be important in preventing deaths. current outcome models in moderate-severe traumatic brain injury (mstbi) include only admission characteristics. yet, mstbi patients commonly have prolonged intensive-care-unit(icu)-stays with high risks to develop icu complications, lending to the hypothesis that these may be additionally associated with outcomes. the objective of this study was to examine the incidence rates of pre-specified medical and neurological icu complications, and their impact on post-traumatic in-hospital mortality and month functional outcomes. we analyzed mstbi patients consecutively enrolled in the prospective observational optimismstudy at a level- trauma center between / - / . poor outcome was defined as glasgow outcome scale - . multivariable logistic regression was employed to adjust for admission characteristics and icu-length-of-stay. the mean age was ± years, % were men, and median motor glasgow-coma-scale and injury-severity-scores were (iqr ; ) and (iqr ; ), respectively. the three most common medical and neurological icu complications were: hyperglycemia ( %), systemic inflammatory response syndrome ( %) and fever ( %); intracranial pressure crisis (icp; [ % of n= with icp-monitor]), brain edema requiring osmotherapy ( %), herniation ( %). multivariable models were adjusted for age, marshall-ct-classification, motor glasgow-coma-scale, pre-admission hypotension, icu-length-of-stay and injury-severity-score. after adjustment, in-hospital mortality was significantly associated with in-icu-cardiacarrest (or ; %ci . - . recent studies suggest benefits for early tracheostomy in patients with traumatic brain injury (tbi), yet data regarding who will require tracheostomy is lacking. ad lifesustaining measures withdrawn were excluded. admission and inpatient variables were compared. multivariable logistic regression analyses were used to assess admission and inpatient factors associated with receiving a tracheostomy and to develop models predictive of tracheostomy. there were patients ( % men, mean years-old, median gcs ) meeting study criteria with tracheostomy performed in ( %). admission predictors of tracheostomy included gcs, marshall score, injury mechanism, pao /fio ratio, and number of quadrants on chest x-ray with consolidation. inpatient factors associated with tracheostomy included the requirement for an external ventricular drain (evd), number of operations, pneumothorax, inpatient dialysis, aspiration, reintubation, and the presence of hospital acquired infections. multiple logistic regression analysis demonstrated that the development of hospital acquired infection (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ; p < . ), number of operations (aor, . ; % ci, . - . ; p < . ), pneumothorax (aor, . ; % ci, . - . ; p = . ), reintubation (aor, . ; % ci, . - . ; < . ), penetrating tbi (aor, . ; % ci, . - . ; p= . ) and placement of evd (aor, . ; % ci, . - . ; < . ) were independently associated with patients undergoing tracheostomy. a model of inpatient variables only was more strongly associated with tracheostomy than one with admission variables only (roc auc . vs. . , p< . ) and did not benefit from addition of admission variables (roc auc . vs . , p= . ). potentially modifiable inpatient factors have a stronger association with tracheostomy than do admission characteristics. existing traumatic brain injury (tbi) guidelines are designed primarily for the evaluation and management of tbi in tertiary care centers with advanced neuroscience capabilities. military special operations medical providers, however, are often required to treat and sustain patients in austere environments with limited resources for up to hours. tbi management guidelines directed specifically toward the care of these patients are needed. a review of recent operational experiences involving tbi and a survey of military special operations medics prompted a multidisciplinary expert panel to develop draft clinical practice guidelines/recommendations for prolonged field management of tbi. the panel conducted an in-depth review of literature on tbi and related topics and adapted existing and emerging therapies to address the unique challenges encountered in prolonged field care. tbi management while optimal management of pbto is not fully established. the objective of this -coeur arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). probes were localized in normal appearing white matter. we used a was calculated. a total of data sets were collected from patients (mean age . ± . , median gcs , mortality range from to ). mean pao for the group as a whole was mmhg (± ) and mean cpp was mmhg (± ). mean duration of pbto monitoring was . days (± . ). taking into account all determinants of pbto and using a protocolized approach to correct pbto , the mmhg for a few days. high pao values are possibly required due to the fact that oxygen delivery to the brain is rate-limited by diffusion and impaired by oedema or microvascular ischemia. it should be noted that pulse oximetry is not sensitive to detect pao below this level. traumatic brain injury (tbi) and stroke are extremely common causes of acute brain injury (abi), which cause long term disability and permanent neurological impairment. coma and stupor are common manifestations of abi, due to interruptions of the ascending reticular activating system (aras). neuro stimulants can improve functioning of the aras. despite decades of research there is a paucity of prospective high-level evidence utilizing neuro stimulants to help with earlier awakening from coma and stupor in abi. we reviewed the literature using the grade level of evidence (loe) methodology. we performed a preliminary literature search of the national library of medicine (nlm) using search terms abi and stimulants. within the literature we searched for timing of stimulant use among abi studies and included all forms of abi such as tbi, stroke, and anoxic injury. we retrieved total results, of which we excluded since they did not meet grade high loe criteria or were "n of " studies or aggregates. only high loe randomized studies or meta-analyses were found. among these various stimulants were investigated including methamphetamines such as methylphenidate and lisdexamfetamine, caffeine, armodafinil, galantamine, and amantadine. methylphenidate had randomized trials and a meta-analysis in subacute tbi but reported only attention as a main outcome. we were unable to draw broad-level recommendations about optimal timing, best stimulant, and patient centered outcomes from this data. there is insufficient data to recommend optimal stimulant, timing, and dosing among heterogeneous abi disease models. we propose conducting future homogenous abi neuro stimulant trials in for safety, tolerability, dose-finding, optimal timing, and outcomes based efficacy. neuro stimulants could play a role in earlier awakening and extubation in abi which could improve outcomes similar to sedation/vacation bundles in icu's currently if studied adequately. tbi remains the leading cause of death and disability in young adults in the us and europe. thus far, pharmacological and non-pharmacological intervention studies did not confirm benefits on functional outcomes. the inducible enzyme nitric oxide synthase (inos) is upregulated in response to brain injury, causing excessive production of no, a key driver of secondary injury after tbi. the antipterin vas is a structural analogue of the endogenous nos cofactor and a potent in-vivo selective inhibitor of inos. a randomized, placebo-controlled phase study examined dose levels of vas in patients with acute moderate or severe tbi. cerebral microdialysis showed pharmacologically relevant drug concentrations close to the injury and a tendency for vas to increase the arginine/citrulline ratio, an indirect marker of nos inhibition (stover et al., j neurotrauma ). vas conferred a significant benefit on the extended glasgow outcome scale interview (egos-i) at and months after injury. no changes in systemic blood pressure or partial brain oxygen pressure were noted. a recent pharmacokinetics and pharmacodynamics study further corroborated the selective inos inhibition by vas . the confirmatory nostra phase trial (eudract no. - - ; clinicaltrials.gov identifier nct ) was initiated in . adult patients with a nonrequiring intracranial pressure monitoring, are randomized : to vas or placebo, administered in addition to standard of care, as intravenous continuous infusion for hours, starting between and hours post tbi. the primary efficacy endpoint is egos-i at months post injury. additional endpoints include the daily therapy intensity level and tbi-specific quality of life measures. continuous safety monitoring is performed by an independent committee. nostra iii, the only ongoing registration study in acute moderate and severe tbi, is sponsored by vasopharm gmbh, and plans to recruit patients by q . a glasgow coma scale (gcs) score of on presentation in patients with traumatic brain injury (tbi) portends a poor prognosis. consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. we performed a retrospective review of patients with tbi and a gcs score of . demographics, apache iv scores , pupillary reactivity to light, intracranial pressure (icp), icp burden (the number of days with an icp spike > mm hg as a percentage of the total number of days monitored), and outcome (mortality and glasgow outcome scale-gos at months, with good outcome defined as gos of - ). patients were divided into groups: group (gos = - ) and group (gos = - ). a total of patients were included. the overall mortality rate was . %. at -month, patients ( . %) achieved a gos - . compared to group (n = ), group (n = ) had higher average apache iv score ( ± vs ± , p = . ), more patients with bilateral fixed pupils ( % vs %, p = . ), and higher icp burden ( ± vs ± , p = . ). gos score - was achieved in % of patients presenting with bilateral reactive pupils versus . % of patients presenting with bilateral fixed pupils (p = . ). . % of patients with tbi and a gcs of at presentation achieved a good outcome at months. apache iv scores, icp burden, and pupillary reactivity were significant predictors of outcome. we believe that patients with severe tbi who present with a gcs of should still be treated aggressively initially since a good outcome can be obtained in a significant proportion of patients. elevated circulating catecholamine levels are independently associated with functional outcome and mortality after isolated traumatic brain injury (tbi). we assessed the ability of peripheral catecholamine levels to improve the prognostic performance of the crash and impact-tbi models. prospective, observational, multicenter cohort study, conducted at three level trauma centers in canada and usa. epinephrine (epi) and norepinephrine (ne) concentrations were measured in the peripheral blood at admission (baseline), , and h after trauma. outcome was assessed at months and dichotomized into favorable [extended glasgow outcome scale (go -tbi models, which identified core prognostic markers of severe tbi. the baseline model (m ) included age, gcs and pupillary size/reactivity. the model (m ) included m + hypoxia, hypotension and marshall ct classification. model and included m + epi levels, and m + ne levels, respectively. the risk models performance was assessed by comparing receiver operating characteristic (roc) curves, and by the use of integrated discrimination improvement (idi) index. m had significantly higher roc and idi than the baseline model (m ), to predict mortality. m had a roc = . ( . - . , p = . ) and idi = . (p = . ). the prediction of mortality was not improved by including ne [m = roc = . ( . - . , p = . ) and idi = . (p= . )]. the integrated discrimination improvement index indicated the prediction of unfavourable outcome by the baseline model was improved by including epi (idi = . , p= . ), and ne (idi = . , p= . ) in the models. catecholamine levels improved risk models performance to predict mortality and unfavorable outcome after traumatic brain injury. following traumatic brain injury (tbi), depression is common and may influence recovery. small trials demonstrated that various drugs are beneficial in managing depression following tbi, but no large, definitive study has been conducted. we performed a meta-analysis to estimate the potential benefit of anti-depressant medications following tbi. multiple databases were searched using the terms "anti-depressant tbi," and "depression treatment tbi" to find prospective pharmacologic treatment studies of depression following tbi. studies were excluded if they did not measure depression as an outcome. effect sizes for anti-depressant medications in post-tbi patients were calculated for within-subjects designs that examined change from baseline after receiving medical treatment and treatment-placebo designs that examined the differences between anti-depressants and placebo groups. a random effects model was used for both analyses. of titles screened, studies were included, with total patients. medications evaluated included selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants. pooled estimates showed significant reduction in depression scores for individuals after pharmacotherapy (mean change [mc] - . , % confidence interval [ci]: - . to - . ) and significant difference in reduction of depression scores between medications and placebo in the pooled estimate (standardized mean difference of four trials [smd] - . , % ci: - . to - . ); however only one of the four treatment-placebo studies found medications significantly reduce depression scores more than placebo. this meta-analysis found a significant benefit of pharmacotherapy for treatment of depression in patients with tbi. however, there was a high degree of bias and heterogeneity regarding tbi severity, time since injury, depression severity, and demographics. larger prospective studies on the impact of anti-depressants on post-tbi depression are warranted to better understand treatment effects and the relationship of post-tbi depression and outcome more broadly. pleural effusion (pe) has been reported in % of medical icu. there is little published data on the prevalence and clinical significance of pe in mechanically ventilated patients with traumatic brain injury. head injury patients admitted to icu for mechanical ventilation (mv) within - hours and gcs > were assessed for eligibility. presence of pe was assessed by serial cxr on daily basis and volume of effusion was estimated and recorded. in case there was no evidence of pe on cxr, a bedside sonography in semi recumbent position was done within h of icu admission. pleural fluid volume was estimated based on -point classifications on sonography. details of mechanical ventilation and icu management were recorded. successful weaning was defined as ability to breath spontaneously for h. primary aim was to observe prevalence of pe in mv head injured patients. as secondary measure; impact of pe on duration of mv, weaning and length of icu stay were compared. study enrolled patients. three baseline cxr showed pe. total of ( %) patients developed pe in icu. patients had evidence of pe on both cxr and usg. patients had only sonographic evidence of pe, which were not detected on cxr. significantly more minimal effusions were detected on sonography ( / , p= . ). duration of mechanical ventilation and duration of icu stay were significantly more in patients with pe. (p= . , mann whitney rank sum test) there was no significance difference in duration of weaning in patients with and without effusion ( . ± . , . ± . , p= . ). chest ultrasonography increased the detection rate of pleural fluid. patients with pe had longer duration of mechanical ventilation. early detection may be associated with shorter period of mechanical ventilation and icu stay spine surgery can trigger a systemic inflammatory response syndrome and lead to hypotension requiring vasopressors. as sepsis is a major differential diagnosis in the post-operative period, the objective of this study is to understand the prevalence of a true systemic infection in this setting. retrospective review of all consecutive adults with post-operative shock requiring vasopressors following spine surgery in an academic tertiary medical center. a total of patients, median age years (iqr - ), were included in the final analysis. comorbidities included a median bmi of (iqr - ), coronary artery disease ( %) and diabetes mellitus ( %). median estimated blood loss was cc (iqr to cc). circulatory volume was adequately replaced in a total of % patients within hours post-op. all patients received crystalloids, and an additional % received multiple (> ) units of prbcs transfusion. adequate urine output was confirmed in ( %) of the patients. the maximum median rate and duration of each vasopressor infusion was as follows: phenylephrine mcg/min (iqr - , n = ), hours (iqr - ), norepinephrine mcg/min (iqr - , n = ), hours (iqr - ), epinephrine mcg/min (iqr - , n = ), hours (iqr - ) and vasopressin . units/min, hours ( - , n = ). of the patients, ( %) met at least sirs criteria. infection was confirmed in a total of patients; positive respiratory or blood cultures in ( %) patients and positive urinalysis or urine culture in ( %). two patients ( %) were diagnosed with myocardial infarction. no patients had pulmonary embolism. our study suggests that the risk of infection and sepsis in patients with persistent shock following spine surgery is small but not negligible. larger multicenter studies are needed to confirm our findings and to identify the predictive factors. ischemic and hyperemic injuries may occur unnoticed after severe traumatic brain injury (tbi) and contribute to additional brain damage. maintaining an adequate cerebral perfusion is considered crucial in preventing such injuries, as deviations from autoregulation-guided optimal cerebral perfusion pressure (cppopt) are associated with greater mortality and disability. this makes reliable estimation of cppopt an interesting diagnostic and treatment tool for monitoring. cppopt is defined as the cerebral perfusion pressure (cpp) at which the pressure reactivity index (prx) is minimal. the leading method for estimating cppopt automatically, by aries et al. ( ) , fits a parabola to pairs of prx and cpp data. the method uses preset heuristics to reject the fit as unreliable, namely when the parabola is too "shallow" or does not cover a certain cpp range. as a result, the cppopt estimates could be generated only about - % of the time. moreover, the manually set heuristics potentially restrict the generality of the model. here, we propose an alternative method based on bayesian inference. treating prx at each time as a function of cpp corrupted by noise serves as a "forward model" that can be inverted to yield, for a given data set, a temporally evolving posterior probability distribution over cppopt. the mean of this distribution is a bayesian estimate of cppopt; we find that these estimates are generally consistent with those obtained from the classic method. importantly, the width of the distribution at a given time serves as a metric of uncertainty about cppopt estimation. we find that this uncertainty tends to be large at time points where the classic method with preset heuristics rejects the fitted parabola. our method makes manually setting rejection criteria unnecessary. bayesian estimation of cppopt holds promise as a tool for providing additional decision support in the care of individual tbi patients. quantitative parameters derived from continuous eeg (ceeg) have been useful to understand evolution of traumatic brain injury (tbi) and the impact on regional networks. these parameters are often interrogated at a global level rather than region-specific. the regional evaluation of quantitative eeg parameters may provide an objective assessment of regional network function, and be of predictive value for prognostication continuous eeg was performed in patients with tbi, and mri imaging was obtained during acute and chronic time points post injury (within days and months, respectively). the extended glasgow outcome scale (gose) assessed clinical recovery at months, with good recovery defined as gose score - and poor as gose score - . volumetric measurements of selected brain regions, both cortical and subcortical, were obtained at acute and chronic time points. quantitative parameters derived from ceeg, such as percent alpha variability (pav) and hemispheric symmetry, were calculated continuously and anatomically (frontal, temporal, occipital) through the acute hospitalization course. we hypothesized that persistent regional variation in alpha power post injury would lead to brain regionspecific atrophy and may predict outcome at months acute pav within the first hours post injury was poor in patients with poor outcome. in addition, patients with poor outcome had significantly more atrophy in the thalamus, hippocampus, and temporal and occipital lobes. asymmetry of the hemisphere pav values correlated with both brain atrophy and clinical outcome regional asymmetry of pav within the first hours post injury correlates with chronic brain atrophy and clinical outcome after tbi after moderate and severe traumatic brain injuries (tbis), individuals are often admitted to an intensive care unit (icu), and later require intensive rehabilitation. many neuro-icus engage therapists and physiatrists for rehabilitation and therapy during a patient's icu admission. however, the optimal timing, intensity, and components of rehabilitation needed while in the icu are not known and practice patterns are highly variable. the goal of this study is to describe the rehabilitation practices to identify whether there is consensus on best practices. an electronic survey asking participants to describe tbi rehabilitation practices in their icu was distributed via redcap through the neurocritical care society (ncs) and american congress of rehabilitation medicine (acrm) websites. potential respondents were first asked if they cared for patients with tbi in the icu, and if they answered "yes," they were invited to complete the survey. two email reminders were sent to each group for completion. after weeks, the data were extracted and analysis completed. there were respondents who reported that they cared for patients with tbi in the icu ( attending physicians, advanced care practitioners, therapists, nurses, fellows, and other). of these, % recommended early rehabilitative care. the most common reasons to wait for the initiation of physical therapy and occupational therapy were normalization of intracranial pressure (icp) ( % and % respectively) and hemodynamic stability ( % and % respectively). speech therapy was typically recommended after extubation ( %) and normalization of icp ( %). the majority of clinicians caring for patients with tbi in the icu support early rehabilitation efforts, typically after a patient is extubated, intracranial pressure has normalized and the patient is hemodynamically stable. prospective studies evaluating the merits of these self-reported rehabilitation initiation criteria are warranted. high-dose methylprednisolone (hdmp) has been studied as a potential therapeutic option for acute sci, with mixed results regarding efficacy and consistent suggestion of complications. we conducted a retrospective cohort study of acute sci patients extracted from the medical information mart for intensive care iii (mimic-iii) database to evaluate the hypothesis that steroid-related adverse drug events (ades) occur less often than in published clinical trials using hdmp. three groups of patients coded for acute sci were identified from mimic-iii from june to october : hdmp recipients per nascis ii/iii protocols (hdmp, n = ), patients who received some steroids but not per nascis ii/iii protocols (non-hdmp, n = ), and patients who did not receive steroids (no steroids, n = ) . demographics and data on complications of steroid therapy were extracted. one-way anova or student's t test were used to evaluate continuous variables; chi-squared or fisher's exact test were used for nominal or categorical variables. there were no differences in steroid-related ades between the three groups. there were higher average blood glucose readings in recipients of any steroids compared with the no steroids group, and more variation in blood glucose readings in hdmp recipients compared with the other two groups. there was a higher icu los and ventilator time in the hdmp group compared with the other two groups. compared with three other trials examining similar use of hdmp in acute sci, there were higher rates of pneumonias overall, though lower rates of urinary tract infections, skin & soft tissue infections, pressure ulcers, and superficial thromboemboli/thrombophlebitis. the results of this study are consistent with previous works related to the potential for harm regarding the use of hdmp or any steroids in acute sci. changes in selected adverse event profiles may be due to standardization of icu supportive care over time. cervical spinal immobilization and clearance protocols are important steps in the minimization of secondary spinal cord injury. patients with primary neurologic diseases are frequently found down and placed in rigid cervical collars despite sustaining minimal-to-no cervical injury. in these patients, neurologic dysfunction can complicate and delay cervical clearance. decreasing time spent in cervical spinal immobilization could improve patient care by allowing greater access to / range-of-motion of the neck, increasing patient comfort, and decreasing skin breakdown. through retrospective chart review over a -month period, we collected the following: the rationale behind each mri, any mri evidence of cervical instability, the result of any ct imaging, and the basic mechanism of any trauma. for patients that were simply found down, any evidence of trauma either by history or physical exam was recorded. during the study period, there were instances where an mri of the cervical spine was performed. of those mris, ( %), were performed for cervical spinal clearance. sixty-one ( %) of mris were ordered without any ct imaging first. of the patients with a normal ct, six ( . %) were found to have mri evidence of cervical instability. notably, of the patients who were found down, there was only one instance where the mri demonstrated instability. that patient had extensive facial injuries suggestive of an unwitnessed fall. in the patients that were found down with no history or evidence on physical exam of trauma, there was no mri instability. for patients that are found down without any history or evidence on physical exam of trauma, a ct of the cervical spine is likely sufficient for cervical spinal clearance. acute subdural hematoma (asdh) represents a major clinical entity in severe traumatic brain (stbi), approximately % are accompanied by various extents of asdh. stbi has been reported to cause cerebral circulatory disturbances at an acute stage and had the worst circulatory disturbance among stbi. in this study, we focused on the cerebral circulation of asdh, evaluated the absolute left-right difference between cerebral hemispheres and compared the cerebral circulation between the favorable outcome group and the unfavorable group. we retrospectively reviewed patients with asdh. they were admitted to our hospital from to . in these patients, we simultaneously performed xenon-computed tomography (xe-ct) and perfusion ct to evaluate the cerebral circulation on post-injury days - . we measured cbf using xe-ct and mean transit time using perfusion ct and calculated the cerebral blood volume (cbv). a significant absolute difference in cerebral circulation between the hemispheres among different types of tbi was observed in mtt. there was no significant difference in these parameters between left-right hemispheres with asdh among the favorable outcome group and unfavorable group. although there was no significant difference in age, gcs at the onset of treatment, cbf and cbv, there was significant difference only in mtt between the favorable outcome group and unfavorable group. the circulatory disturbance in patients with asdh occurs diffusely despite the focal injury. additionally, in unfavorable patients, the circulatory disturbance is worse than in favorable patients. because asdh suffered ischemia more than other types of stbi, we had to perform not only removal of the occupying lesions, but also neurointensive care, including whole-body management and hypothermia therapy for the ischemic brain after surgery. we have to adopt a treatment strategy appropriate to the pathophysiology of the different tbi types. kcentra is -factor prothrombin complex concentrate that is fda approved for reversal of warfarin. there is limited research describing the use of kcentra for coagulopathy in the setting of traumatic intracranial hemorrhage. here, we show the largest ever retrospective review for the use of kcentra in the setting of traumatic intracranial hemorrhage. retrospective chart review was performed from - for patients with intracranial hemorrhage who presented to the r adams cowley shock trauma center. patients who received kcentra were identified. basic clinical information was obtained including cardiac/stroke history, blood pressure, glasgow coma score, medication history, and categorization of hemorrhage. pre and post inr level was assessed. hemorrhagic expansion was assessed with ct scan up to up to hours. disposition and thromboembolic events were recorded. forty-four patients were identified as receiving kcentra in the setting of traumatic intracranial hemorrhage. pre and post kcentra dosing inr was found to be significantly different (p< . ) across the two groups assessed (warfarin and tbi/noac coagulopathy). seventeen patients ( . %) had hemorrhagic expansion as determined on ct scan. disposition (home vs rehab vs death) was found to have three significant variables: history of stroke, hemorrhagic expansion, and admission glasgow coma score. eight patients ( . %) were found to have thromboembolic events. here, we show the largest retrospective review describing the clinical use of kcentra for coagulopathy reversal in the setting of intracranial hemorrhage. overall, kcentra is shown to be a safe and effective drug for the reversal inr. importantly, our reported hemorrhagic rate of . % is lower than established rates reported in the literature for warfarin/coagulopathic patients with intracerebral hemorrhage ( - %). the prognostic importance of hemorrhagic expansion was highlighted in the disposition analysis which showed that zero patients were discharge home if there was recorded expansion. despite the impact of post-traumatic amnesia (pta) duration on long-term functional outcome after traumatic brain injury (tbi), radiologic predictors of pta duration are lacking. we hypothesized that the number of traumatic microbleeds (tmbs) detected by gradient recalled echo (gre) magnetic resonance imaging (mri) in neuroanatomic regions that mediate memory correlates more strongly with pta duration than does the number of global tmbs. using a prospective outcome database of patients treated for mild-to-severe tbi at an inpatient rehabilitation hospital, we retrospectively identified patients who underwent acute mri with gre. pta duration was determined by the galveston orientation and amnesia test, orientation log or chart review. a rater blinded to pta duration identified tmbs on the gre datasets globally and in neuroanatomic regions that mediate memory, including the hippocampus, fornix, corpus callosum, thalamus, and the temporal lobe. associations between global and regional tmbs (in the mentioned locations) and pta duration were tested using spearman rank correlation coefficients. the cohort was comprised of % ( hippocampus and corpus callosum tmbs are associated with pta duration, and thus may have greater utility for predicting functional outcomes than global tmb number. validation of these findings in larger prospective studies is indicated. using a large two-center cohort of penetrating traumatic brain injury (ptbi) patients, we previously developed the survival after acute civilian penetrating brain injuries (spin) score, a logistic regressionbased parsimonious risk stratification scale for estimating survival after civilian ptbi. the objective of the present study was to externally validate the spin-score. our multicenter validation cohort comprised ptbi patients retrospectively identified from three u.s. level- trauma center registries. the spin score variables (motor gcs [mgcs], sex, pupillary reactivity, self-inflicted ptbi, transfer status, injury severity score [iss] and inr) were collected from the trauma registries supplemented by chart review. using the spin-score multivariable logistic regression model from the original study, receiver-operating-characteristic area-under-the-curve (roc-auc) analysis and hosmer-lemeshow goodness-of-fit testing was performed. the mean age was ± years, and patients were predominantly male ( %), with % white and % black. in-hospital mortality was %, and -month mortality of discharge survivors was . in this multicenter external validation study, the full spin-model predicts in-hospital survival after ptbi with excellent discrimination and calibration. after removing inr from the model, discrimination remained excellent, but model calibration diminished. the full spin-score may provide important information to guide families and physicians after civilian ptbi. limited data has described alterations in vancomycin pharmacokinetic (pk) parameters in traumatic brain injury (tbi) patients that have resulted in sub-therapeutic concentrations. the primary objective of this study is to evaluate the pk parameters of vancomycin in tbi patients to determine if using the common clinical practice of capping creatinine clearance (crcl) to ml/min in determining dosing impacts achievement of therapeutic concentrations. this was a single-center, retrospective study of patients at least years of age with tbi who received vancomycin and one reported steady-state vancomycin serum level from april to december . predicted pk parameters based on population data using actual and capped creatinine clearance (crcl) at ml/min were compared with calculated pk parameters based on serum trough concentrations at steady state. the difference was assessed using a two-sample wilcoxon rank-sum test where p < . was considered statistically significant. when using actual crcl [median ml/min patients with tbi experienced crcl that were greater than predicted. based on the results of this study, actual crcl is more accurate at predicting vancomycin pk than the common practice of capping crcl at ml/min. therefore, actual crcl should be used when determining vancomycin dosing regimens in patients with tbi to achieve desired therapeutic concentrations. neurocritical care is traditionally provided within institutions in urban centers while access in rural communities has been limited. transport to urban centers is not always favorable for a variety of reasons including critical patient condition, family wishes, weather, and geography. our hypothesis is that tele-neurocritical (tele-ncc) can extend access to this service with meaningful impact on icu outcomes. a tele-ncc pilot study was initiated within intermountain healthcare. starting / / , the study included all ischemic stroke patients admitted to the icu of one primary stroke center in utah. tele-ncc consultations were provided by ncc physicians at our flagship hospital located three hundred miles from the spoke site. tele-ncc consultations occurred via an existing telehealth platform developed inhouse. primary outcomes for this pilot study were icu and hospital lengths of stay (los). secondary outcomes include stroke complication rates and results on a provider satisfaction questionnaire. to date, tele-ncc consultations have been performed with median hospital los = days (iqr . - . ) and icu los = . days (iqr - ). in the months prior to the pilot, there were admissions to the icu for ischemic stroke with median los = days (iqr . - . ) and icu los = . (iqr - . ). for this small sample size, the p-values for comparison of hospital and icu lengths of stay before and after tele-ncc are . and . respectively. tele-ncc care can have significant impact on icu outcomes by expanding access to critical support from neurocritical care specialists. tele-ncc expands access to not only consultation on critical neurological emergencies, but also on when to de-escalate from the icu or in end of life discussions with which general icu teams may not be comfortable. these impacts could be measured as important decreases in hospital and icu los. hospital readmissions increase health care costs, increase patient exposure to nosocomial disease, and imply patients were not stable for discharge. because readmissions are a target for hospitals and payers, several centers have developed predictive readmission scores in order to identify high-risk patients. we contend that these general readmission scores are not suitable for neurocritically ill patients and that specific predictive score must be developed to identify high-risk patients. we conducted a retrospective chart review of consecutive patients admitted to our neuroscience critical care unit. we recorded the readmission scores, reason for admission, length of stay,and if they were readmitted. we then compared the median readmission scores between the two groups. after removing patients without readmission scores or died at the end of the original admission,we analyzed the records of patients. patients were more likely to be readmitted if they were initially emergently hospitalized or had malignancy. readmitted patients had a longer original hospital length of stay. we found no difference median readmission score between those who were readmitted, and those who were not. most readmitted patients ( . %) had an original "low-risk" readmission score. we found that our center's score was poor in predicting readmission for neurocritical care patients and that several components of the score do not apply to our patient population. we propose that to accurately predict readmission,centers should create their own unique readmission scores for more homogeneous admission populations. clinical evaluation of the level of consciousness in non-communicative patients can be very challenging. in this study, we aimed to evaluate the nurses and nursing assistants' (nas) perception of the consciousness on patients suffering from disorder of consciousness (doc). through their activities, nurses and nas have an extended observation time of patient's behavior, and make repeated implicit assessments of patients' clinical state of consciousness. we hypothesized that even in the absence of a structured and explicit evaluation of consciousness (in contrast for instance with the coma recovery scale revised -crs-r), nursing expertise could be a valuable measure to improve assessment of state of consciousness in doc patients. this was a prospective observational single-center study. our primary objective was to correlate the nurses and na's assessment of doc-patients' consciousness quantified through an analogic visual scale (the "doc-feeling score") with the results of the standard methods (including crs-r, fmri, electrophysiology). the secondary objective was to identify elements which correlate with this assessment and/or with the expert's diagnosis (such as visual pursuit, patient's participation to nursing, motor responses to verbal command or adapted reactions to painful care). . linear regression reveals a good correlation between the "doc-feeling score" and the crs-r gold standard (r = . , p-value < . , figure ). global assessment of the level of consciousness by all the caregivers interacting with the patient using the "doc-feeling score" is reliable and can improve assessment of state of consciousness in doc patients. investigating causes of deterioration in neurological patients is important to anticipate these complications and improve outcomes. this is a prospective observational study performed at an academic tertiary care trauma, stroke and neurorehabilitation center. data was collected over a year from rapid response system activations (rrsa). in one year, our center had admissions. rrsa were performed on patients. most common admission diagnosis was ischemic stroke ( %). most common rrsa organ system involvement was respiratory system (n= , . %). the only predictors of death or new limitation of care in those patients who had rrsa were age ( years vs years, p < . ) and history of cancer ( %) vs ( %) p= . . . % (n= ) of rrsa happened during day shift and . % (n= ) during night shift. . % (n= ) of rrsa happened around shift change and were more likely to result in an unplanned icu admission. . % (n= ) of rrsa happened within hours of admission and were more likely to result in unplanned icu admissions. the most common reasons for in hospital decompensation in neurological inpatients are nonneurological. most common organ system involvement responsible for rrsa is respiratory system. the only predictors of death or new limitation of care were history of cancer and age and older. rrsa activations were more frequent during day shift. however, there was no different in the outcomes we evaluated between day and night shifts. rrsa happening around shift change wew more likely to result in unplanned icu admission. rrsa within hours of admission showed an increased risk of unplanned icu admission when compared to rrsa happening after hours of admission. neurocritical care is a growing field with an increasing number of dedicated neuroscience intensive care units. in this dynamic context, it is unclear which types of physicians provide neurocritical care across the united states. we performed a retrospective cohort study using claims data from a nationally representative % within analyzed critical care procedures . the primary outcome was physician specialty, defined by medicare provider specialty codes. in a sensitivity analysis, we excluded claims for services on the day of admission and claims associated with a diagnosis of cardiac arrest, since these activities may often occur outside of neuroscience intensive care units. we identified between and , neurologists were responsible for approximately one-quarter of neurocritical care services among a nationally representative cohort of elderly patients. critically-ill patients on mechanical ventilation (mv) cannot verbally communicate. research suggests several phenomena occur in patients during mv because of impaired communication including anxiety, loss of control, loneliness, and compromised interaction (schou and egerod, ) . for neurocritical care patients, this can be especially profound when coupled with cognitive and motor/sensory deficits. currently, the blom® speaking valve (sv) is the only approved product available that allows phonation in ventilator-dependent patients with tracheostomy. sv trials are known to facilitate vent-weaning. the current standard of care (passy-muir speaking valve, minute trials), is contra-indicated in patients who cannot tolerate cuff deflation. as such, the blom® sv was evaluated for clinical and quality efficacy. we retrospectively evaluated clinical outcomes associated with blom® sv on mv during a trial in a neuroicu of a large tertiary center between / / and / / . baseline demographics, diagnoses, physiologic, sedation, delirium, mobility and swallowing parameters, length of stay, ventilator modes and settings, ventilator days, work of breathing and presence of pneumonia were abstracted along with patient, family and interdisciplinary staff satisfaction survey results. patients were recommended for blom® tracheostomy. patients received sv trials. of the trials were performed, % ( ) were optimal/completed ( + minutes); % ( ) were suboptimal/completed trials ( - minutes); % ( ) unable to complete. satisfaction results from patients/families were positive compared to the interdisciplinary team survey results. remaining parameters currently in analysis with results pending, to be completed by end of august, . impaired communication during mv is suboptimal for neurocritical care patients. our clinical experiences with blom® sv showed positive and negative outcomes. positive benefits were enhanced patient/family engagement and family satisfaction. unanticipated obstacles included significant increase in patient fatigue during sv trials, often delaying ventilator weaning. further study is needed to determine efficacy in this population. patients with clinical signs of cerebral herniation require immediate intervention known as a "brain code". in our neurosciences critical care unit (nccu), a rapid response program is in place to ensure the safety of . % hypertonic saline's use (high risk medication) and to expedite its delivery to the bedside given the emergent need for this medication when ordered. our institution, however, is lacking a more holistic and structured approach to cerebral herniation syndrome that include components of tiers zero to three emergency neurological life support elevated icp or herniation protocol. the neurocritical care communication council consists of bedside staff nurses, nursing leadership, advanced practice providers (nurse practitioners and clinical nurse specialist), pharmacists, respiratory therapists and physicians. the council identified processes during neurological brain codes that could be improved as a result of using a bedside debriefing tool. the unit leadership council of the nccu reviewed literature on hospital debriefing tools and referenced this organizations current resuscitation debriefing tool. from these sources, a brain code debriefing form was constructed. a clinical tool was developed with the expectation of standardizing the brain code process in this nccu. the brain code debriefing form will be piloted to determine unit and system wide value. pre-and postimplementation data will be collected to discover areas of improvement for optimized patient care. through the development of this debriefing tool, it was ascertained that a clinical practice guideline for impending cerebral herniation would be beneficial to further guide and direct evidence-based care. thus, a preliminary algorithm for identification and emergency treatment is in process. the americas medical center is a -bed tertiary hospital complex, located in the city of rio de janeiro. the center was elected by the international and the brazilian olympic committees as the referral hospital for the olympic family (of), comprised of athletes and their crews, support and technical personnel, credentialed media and credentialed governmental representatives from the participating countries. the neurology and neurocritical care teams were selected to head a comprehensive program of acute emergency neurology, including a -bed neurocritical care unit (nicu), and - emergency neurology service. we hereby describe our experience during the olympic games in rio de janeiro, brazil results neurological assessments were conducted in patients from the of, of these involving athletes from countries. the most common reason among athletes were traumatic brain injuries (tbi), with politraumas (all involving cycling), mild tbi ( of boxing, of field hockey, of rowing and of cycling) and moderate tbi (cycling and water polo). three patients were admitted to the nicu: ischemic strokes and politraumas with tbi. motor vehicle accidents with associated tbi involving the of were surprisingly frequent, with assessments, none requiring admissions. finally, ct scans of head, ct scans of the cervical spine and mri scans ( brain and spine mri) were performed to assess the patients. of note, cases of seizures, functional deficits, multiple sclerosis flare and psychiatric complaints were observed affecting the of. not only that multiple sports-related injuries were observed, cases of diverse acute neurological issues were reported involving members of the of. olympic games are complex events mobilizing thousands of people, and a comprehensive and detailed plan for neurological emergencies is of extreme importance the term "handoff" has been defined as the "transfer and acceptance of responsibility for patient care that is achieved through effective communication, passing patient-specific information from one caregiver or team of caregivers to another to ensure the continuity and safety of the patient's care" (patterson and wears, ) . the joint commission reported that two-thirds of sentinel events occur at the time of patient handoff, which led to a national patient safety goal, requiring standardized process for handoffs (the joint commission on accreditation of healthcare organizations, ) . to support this npsg, a nccu specific handoff tool and timeout process were created to support the transition from or to nccu. nccu postoperative handoffs were identified as an area to enhance staff satisfaction and patient safety. baseline data to evaluate the frequency of neurosurgery report was performed in may . using a qualtrics survey in june , staff satisfaction with current ns or report was obtained from nccu rns, nps, and fellows evaluating whether they felt they received: accurate medical history, accurate information about performed procedure, sufficient handoff for patient care, specific patient goals, recent pharmacological intervention, anticipated concerns regarding diagnosis/procedure, estimated blood loss, blood/fluid intake, airway concerns, complications and overall satisfaction with handoff. a taskforce of rns, nps, neurointensivists, and neurosurgeons was established, ending with the creation of a handoff tool and timeout process. the new tool and process were initiated and two months later, a repeat survey was sent to evaluate staff satisfaction and perceived effectiveness of the new process and handoff tool. currently being tabulated at time of submission. using standardized, open communication techniques including handoff tools and a timeout throughout the perioperative period is crucial to positive outcomes and can improve perioperative care in the nccu patient and increase satisfaction and collaboration of all team member during or handoff. in the age of the healthcare reform and rising costs, it is important for strategic service lines to explore cost saving and care efficiency strategies. beginning in september , physician and administrative leadership within the duke neurosciences intensive care unit (neuroicu) began investigating per patient cost to explore opportunities to decrease direct cost to the neuroicu, cost to the patient, and reduce redundancy of care. with assistance from health system finance, the team assessed the following data points within each cost group and compared these values to that of our peers within the us news and world report top honor roll: · number of units · direct cost per unit · total direct cost our performance according to our peers in the following cost areas was: .pharmacy-ranked th out of .laboratories-ranked th out of .radiology-ranked th out of .cardiovascular-ranked th out of . based on these performance metrics, neuroscience administrative and medical leadership developed a project grid of prospective initiatives and identified the following for each cost area: ·stakeholder-led teams inclusive of providers, nursing, and administration ·duration or impact of each initiative: short, medium, or long ·activity phases based on duration the stakeholder-led groups would propose and validate projects based on scope and duration. at each group's meeting, members reviewed charge level financial data by activity code for the group's respective cost area to develop applicable initiatives. multiple initiatives are currently underway including those within the cost areas of pharmacy, laboratories, and radiology. included among these initiatives is a change in routine resistant organism screening and cervical spine clearance. other initiatives will be target intravenous anti-hypertensive treatment and laboratory frequency. the total cost savings from these initiatives can only be estimated at this point but will likely be in excess of $ , for the calendar year. it is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. we examined the association between dedicated neurocritical care units and mortality, and the effects of standardized management protocols for severe traumatic brain injury. we surveyed trauma medical directors from centers participating in the american college of surgeons trauma quality improvement program (tqip) to obtain information about icu structure and processes of care. survey data were then linked to the tqip registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care (ncc) units, the presence of standardized management protocols and mortality. we performed three sensitivity analyses reclassifying ncc units by restricting to closed units, under ucns director leadership, and exclusion of neurotrauma units. data was analyzed from , adult patients with isolated severe traumatic brain injury admitted to tqip centers between to . fifty icus were dedicated neurocritical care units, whereas were general icus. rates of standardized management protocols were similar comparing dedicated neurocritical care units and general icus. care in a dedicated neurocritical care unit was not associated with improved risk-adjusted in-hospital survival (or . ; ( % ci . - . ; p= . ). the results from the model were robust in our sensitivity analyses. the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (or . ; % ci . - . ; p= . ). compared to dedicated ncc models, standardized management protocols for severe traumatic brain injured patients are low-cost process-targeted intervention strategies that may improve clinical outcomes. understanding the differences in processes of care within the context of icu structure is necessary to better understand mortality differences observed between centers, and may help in the design of future trials for severe tbi patients. complex multidisciplinary care of patients in the neurocritical care unit requires reliable and effective communication to minimize medical errors. we implemented a structured rounding process that incorporates ahrq-endorsed team strategies and tools to enhance performance and patient safety (team stepps) to improve interprofessional collaboration between team members. we convened a project team of physicians, advanced practice providers (apps), nurses, respiratory therapists, and pharmacists in a -bed nicu. we defined structured rounding processes and implemented team stepps strategies to promote closed-loop communication between team members during daily rounds. the assessment of interprofessional team collaboration scale (aitcs-ii) was administered to team members at baseline and months post-intervention. impact on overall team collaboration and subscale domains of team partnership, cooperation and coordination was assessed. the possible range of the overall collaboration score is to ; higher scores indicate better collaboration. the survey was completed by ( %) staff at baseline, and ( %) staff post-intervention. overall team collaboration scores improved significantly pre and post-intervention ( . ± vs . ± , p < . ), as did subdomain scores of team partnership ( . ± . vs . ± . , p < . ), collaboration ( . ± . vs . ± . ), and coordination ( . ± . vs . ± . ., p < . ). perceived shared understanding of patient daily goals between nurses and providers (physicians/apps) increased from % to % (chi-square . ; p < . ). % of staff reported that the intervention shortened or did not affect the duration of rounds. of those who reported longer duration of rounds, % responded that the intervention was worthwhile. interprofessional team collaboration can be enhanced by structured rounding and communication workflows. by promoting closed-loop communication during daily rounds, shared understanding of patient daily goals between team members is increased, and may optimize quality and safety of patient care. advanced practice providers (apps) are increasingly utilized to provide clinical care within neurocritical care units (nsicu) . despite the complex issues in this patient population, the specific educational and orientation needs of these providers have not been established. to meet the demands for rapidly and effectively training apps to provide advanced neurocritical care (ncc), a structured educational curriculum was developed and integrated within the standard orientation and on-boarding process for newly-hired app within our nsicu. this curriculum was designed with measurable learning goals, objective assessments of goal achievement, and opportunities for additional education and remediation at multiple steps within the program. the curriculum has three phases with distinct goals and assessments. phase i covers basic triage and resuscitation issues for the acutely-decompensating patient. phase ii covers general critical care principles in significantly greater depth. phase iii provides detailed experience and exposure to specific ncc issues. each phase incorporates relevant reading assignments with a tailored study guide, as well as a multiple-choice question post-test to demonstrate knowledge acquisition. phases ii and iii also include an oral exam incorporating hypothetical patient scenarios to allow the app to demonstrate comprehension and application of the goals for each phase. each phase lasts approximately to weeks with the expectation that the entire orientation curriculum will be completed within six months of employment. in addition to the educational curriculum, phases i and ii include working alongside a more senior app preceptor and providing bedside care for a progressively increasing number of patients. apps not meeting minimum established standards on any aspect of the curriculum are provided additional remediation and instruction by the preceptor and ncc faculty based on an individualized learning plan. a standardized educational curriculum provides a structured learning environment for new apps in the field of neurocritical care. reimbursement changes from the centers for medicare and medicaid services and value based purchasing systems have made quality improvement linked to clinical outcomes more crucial than ever. in one neuroscience icu, providers and nurses collaborate to address key infection parameters that impact patient outcomes. quality metric data in one neuroscience icu was collected over a period of fiscal years. outcome measures, consisting of glycemic and temperature control, and ventilator weaning strategies, were obtained after certain parameters were enforced over two years and then compared to the initial year. the urinary catheter utilization has decreased by over %, with catheter associated urinary tract infections decreased by % in years (p-value < . ). central line utilization decreased by %, with a % decrease in central line associated blood stream infections in years (p-value . ). new ventilator weaning strategies were put into place utilizing adaptive support ventilation mode, which decreased total ventilator days by days/year . successful weaning and extubations resulted in no recorded ventilator-associated pneumonia in the last years. this neuroscience icu maintains glucose below mg/dl more than % of the time. regarding temperature control data, a normothermia protocol was implemented that utilizes aggressive temperature control coupled with bromocriptine administration. as a result, % of patients had a temperature less than °c. all of the quality initiatives that have been implemented have improved the observed/expected mortality ratio by . %. this study shows that by optimizing infection control, temperature management, glycemic control and ventilation strategies, there is an overall positive impact on the patient's morbidity and mortality. as evidenced by these results, this institution is now a top performer when compared in a national clinical database. this presentation will share the pragmatic strategies to create a culture of quality improvement in any neurocritical care unit or patient care organization. health care records are not accessible universally at point of care delivery. in developing countries like thailand a large proportion of health care records are still paper based. patients may not able to convey relevant information about their own medical problems and medications during patient-physician encounters or in the event of emergency. our purpose was to create a simple platform for recording relevant basic healthcare information through a system that can be securely accessed even in countries like thailand. our vision is to improve healthcare communications and leverage social media in thailand and other developing countries, particularly for patients with lower levels of education or socioeconomic status. we created a cloud-based personal healthcare information platform 'meid' that uses a qr code scanned from wristbands and other products like stickers to access patient information. conventional methods require a treating team to request medical records from a patients' prior hospital visits including visits at different medical facilities. time lost during this process can potentially cause delay in treatment decisions. we also aim to improve health literacy in thailand. application name 'meidth' is available in both apple store and google play. we launched meid in thailand in april of . we have more than , active users and have sold more than wristbands. the meid thailand facebook page has received , likes. there are at least two patients that have already benefited from this product: one of these patients received intravenous tissue plasminogen and had a good outcome. timely access to his past medical history and medications via meid was a key in this case. our cloud based personal healthcare information platform using qr codes from wristbands and stickers can help increase health literacy, decrease times to appropriate treatment, improve patient safety and decrease healthcare costs. clinical pharmacists have become an integral part of multidisciplinary medical teams. expanding the role of pharmacists in the neurocritical care units has the potential to positively impact the quality of patient care and provide costs savings. this study examines these potential benefits at one neurocritical care unit. we reviewed patient medication profiles and had formal rounds with a pharmacist four times per week. for the purposes of this study, the focus was on minimization of a select number of high expense drugs. nine months of baseline data was compared to three months of post intervention data. interventions were performed at the time of rounding, which involved timely conversion to enteral formulas, changes to alternative medications or discontinuation of medications. we then performed a cost-benefit analysis to assess the net amount of money saved by reducing inappropriate pharmacy drug use following the interventions. average cost of nicardipine was $ , pre-intervention, compared to $ , post-intervention (pvalue . ). the cost of iv levetiracetam usage on average was $ , pre-intervention and $ , post-intervention (p-value . ), while the cost of iv dexmedetomidine was $ pre-intervention compared to $ post-intervention (p-value . ). average expense per month was reduced by approximately $ , per month compared to the average expense per month from the previous months (p-value . ). appropriate use of stress ulcer prophylaxis was also positively impacted; patient days/month on famotidine was reduced by approximately % from baseline, patient days (pre-intervention) vs days post-intervention. pharmacist interventions within a neurocritical care unit are known to be beneficial clinically for patients, however this study also shows that their interventions offer substantial cost benefits and should justify creating collaborations between pharmacists and neurointensivists. multi-disciplinary rounds have been shown to improve patient outcomes. the objective of this study is to observe the effect on patient care, team dynamic, and nursing satisfaction before and after the implementation of a nursing-led rounding model in the neurological icu. prior to the implementation of the nursing-led rounds quality initiative, nurses in the neurointensive care unit (nicu) were asked to answer a brief survey on basic demographics and perceptions of team dynamics and satisfaction in the nicu. a multidisciplinary systems-based rounding sheet inclusive of the abcdef bundle and previous nicu checklist was created and revised with extensive bedside and senior nursing educator input. while rounding, nurses presented and clinicians were to in real-time come up with an assessment and plan and relay these to the nurse and other team members. any questions, educational pearls or concerns by the clinician team or the bedside nurse were encouraged during these rounds. nurses completed a month post-implementation survey. of the full-time nicu nurses ( %) responded to both the pre-implementation and postimplementation surveys. a bimodal distribution of nursing experience was noted with % new nurses (< year) and % experienced nurses ( years+). more than half of the nurses ( %) reported doing both night and day shifts as opposed to being exclusive to only day or night. there was an increase in the nursing perceptions of participation during rounds as well as education during rounds. nurses felt significantly more involved with patient decision making and felt that they were able to give input into the patients care. the implementation of a nursing-led rounding structure may be beneficial to communication, education and overall patient care. as the project continues, we hope to further examine common icu objective measures as well as other subjective measures such as patient satisfaction scores and communication perceptions. with increased elective and non-elective volume, directing the flow of admissions has become essential to the efficient operation of inpatient strategic service lines. this is especially true in the neurosciences where widespread acute ischemic stroke intervention has placed an especially high demand on comprehensive stroke centers. as a result, an important collaboration was formed at duke between the health system, transfer center and neurosciences to create an algorithm-driven multi-hospital triage and pre-hospital care system called phast (pre-hospital acute services team). in this abstract, we present the formation and current state of this service. this effort was formally begun in the spring of with an initial focus on centralizing the admission process into the duke neurosciences intensive care unit (neuroicu) by an icu physician. after some initial success, it was clear that the service line would benefit from a more formalized process. as a result, a successful multidisciplinary collaboration with a core group of physicians and administrators was formed to develop algorithms and to overcome multiple administrative and legal hurdles. over a period of months, multiple algorithms were developed to systematize neuroscience admissions including acute ischemic stroke and vascular and non-vascular neuroscience emergencies. in an effort to decrease door-to-intervention times as well as effectively mitigate the impact of limited bed-space availability, this system now serves hospitals including with acute neurointerventional services and the rd with a burgeoning neurohospitalist program and incorporated rehabilitation services. in addition to systematizing the transfer and admission process, quality assurance, improvement, and educational processes are in a place. the current state of phast is that of a young but maturing and now essential service for duke neurosciences. extubation involves removal of an endotracheal tube (ett) and is a common intensive care unit (icu) procedure. extubation failure occurs in - % of icu patients and can be difficult to predict accurately. we hypothesized that a multivariate re-intubation scale calculation (risc) model could predict extubation failure better than a single variable like rapid shallow breathing index (rsbi). after irb approval, we conducted a retrospective review of data on mechanically ventilated icu patients above years of age who were not receiving mechanical ventilation through a tracheostomy tube from january , , through december , at mayo clinic rochester. various data points were gathered on these patients via electronic medical records search, and reintubations within hours of extubation were identified. univariate and multivariate logistic regression models were used to predict reintubation after extubation and construct a risc estimate. we included a total of patients which were randomly divided into a derivation set (n= ) and validation set (n= ). in the derivation set, patients had a mean age of ± years, and % were men. three hundred and ninety three extubation failures occurred within hours. predictors of extubation failure included underweight status, gcs score>= , mean airway pressure at minute= ml and total mechanical ventilation days>= in the final multivariable model. risc score was calculated using the validation set and ranged from to . logistic model result shows that, as risc increased by , the odds of having extubation failure was . fold higher (c-index= . ). roc analysis shows that the best cut off for risc was >= vs. < , which demonstrated a sensitivity of . , specificity of . and auc= . . the current risc model warrants further exploration in a prospective study to help critical care providers to decide when extubation can be done more safely. this report presents results of the nd nationwide survey concerning neurocritical care units (ncus) in china. this is an observational cross-sectional survey and close-ended self-reported questions were used. the questionnaire was sent to different provinces (autonomous regions and municipalities) across china from october st, to january st, . basic information, equipment and device information, and staffing and organization information were investigated. in total, questionnaires from ncus at hospitals in regions were received. most of the hospitals with ncus were large-scale (average hospital beds: ), teaching ( . %), and tertiary hospitals ( . %). the average number of ncu beds was , occupying . % of the total number of beds in their department. most of the equipment and devices ( / ) were available in over % of the ncus. however, some devices were centralized by hospital and operated with assistance from other departments. a total of full-time doctors and full-time nurses were employed at the ncus. a few of the ncus achieved a doctor-to-bed ratio of . : ( . %) and a nurse-to-bed ratio of : ( . %). and respiratory therapists, clinical dieticians, clinical pharmacists, and physiotherapists were present in . %, . %, . % and . % of the ncus. the number of ncus increased, the availability of ncu equipment became more sufficient, and the staffing of ncus improved. however, we should pay attention to the management of specialized ncu equipment, the shortage of ncu staff, and the need of ncu training. automated devices collecting quantitative measurements of pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the effect of ambient light conditions on pupil metrics. to address this issue, we we tested the range of pupil reactivity in healthy volunteers in both light and dark conditions. we measured quantitative pupil size and reactivity in seven healthy volunteers with the neuroptics- pupillometer in both bright and dark ambient lighting conditions. bright conditions were created by overhead led lighting in a room with ample natural light. dark conditions consisted of a windowless room with no overhead light source. the primary outcome was the neurologic pupil index (npi), a composite metric ranging from - in which > is considered normal. secondary outcomes included resting and constricted pupil size, change in pupil size, constriction velocity, dilation velocity and latency. results were analyzed with multi-level linear regression to account for both inter and intra-subject variability. seven subjects underwent ten pupil-readings in bright and dark conditions, yielding total measurements. mean resting pupil sizes were . v. [ . - . ], p< . ). all additional secondary outcomes except latency were also significantly different between conditions. we found that ambient light levels impact pupil parameters in healthy subjects. however, changes in npi are small and more consistent in varying lighting conditions than other metrics. further testing of patients with poor pupil reactivity is necessary to determine if ambient light conditions could influence clinical assessment in the critically ill. practitioners should standardize lighting conditions to maximize the reliability of their measurements. neural stem cells (nscs) are known to have anti-inflammatory effect in strokes in previous studies. however, the mechanism of anti-inflammatory effect in direct co-culture with nscs in hemorrhagic stroke remains unclear. the aim of this study was to investigate whether direct co-culture with nscs modulates hemolysate-induced inflammation in raw . cells. we stimulated raw . cells with hemolysate to induce hemorrhagic inflammation in vitro. hemolysate-activated raw . cells were co-cultured with hb .f directly for hours. following direct co-culture, the production of cycloxygenase- (cox- ), interleukin-signal regulated kinase (erk) were assessed by western blotting, and tumor necrosis factor (tnfevaluated by enzyme-linked immunosorbent assay (elisa). hemolysate generates an activation of inflammatory response in raw . cells. direct co-culture with hb .f significantly suppressed the phosphorylation of erk / in hemolysate-activated raw . cells. the expression of inflammatory mediators such as cox- , il-by direct co-culture with hb . f cell. in addition, the expression of cox- , il-attenuated by erk inhibitor (u ). our results demonstrated that direct co-culture with hb .f cells reduced the inflammatory responses in hemolysate-activated inflammation via suppressing erk / pathway. this suggests that nscs treatment can suppress the inflammatory response in hemorrhagic stroke. no pharmacological intervention improves outcomes after primary intracerebral hemorrhage (ich). we developed a novel therapeutic approach based on known biological function of endogenous apolipoprotein e (apoe). apoe is a key mediator of neuroinflammatory responses and modifies recovery from a variety of acute and chronic brain injuries. unfortunately, intact apoe holoprotein does not cross the blood brain barrier (bbb) and cannot be administered as a neurotherapeutic. we created apoemimetic peptides that cross the bbb and down-regulate neuroinflammatory responses in vitro and in vivo. cn- , our lead candidate, is a -amino acid apoe-mimetic peptide derived from apoe's receptorregion. cn- retains anti-inflammatory and neuroprotective effects of intact apoe, was well-tolerated in preclinical studies, readily crosses the bbb, and demonstrates excellent pharmacokinetic, safety, and tolerability profiles in phase studies. this is a multicenter, open-label phase a trial of cn- in patients with acute primary supratentorial ich. a total of participants between the ages and years across study centers, with a confirmed radiographic diagnosis of spontaneous, primary supratentorial ich. patients will be evaluated for eligibility within hours of symptom onset. eligible participants will receive cn- intravenously over --minute infusion every hours up to day maximum. participants will be monitored daily throughout the treatment phase and receive standard-of-care treatment for the duration of the study. primary: to assess safety of cn- administration in primary ich. secondary: to evaluate effects of cn- administration on --day mortality and functional outcomes. exploratory: to investigate feasibility of radiographic surrogates of clinical outcomes using perihematomal edema measurements on serial brain ct and mri, and investigate feasibility of serial biochemical markers of neuroinflammation as surrogate measure of perihematomal edema and clinical outcome. cn- represents a first-in-class agent now entering phase clinical trials in patients with acute ich. novel oral anticoagulant (noac) associated intracranial hemorrhage is a life-threatening condition for which activated prothrombin complex concentrate factor eight inhibitor bypassing activity (feiba) may be used for reversal. few studies report its use in spontaneous or traumatic intracranial hemorrhage. our institutional protocol is reversal with feiba units/kg and escalating doses as needed. the safety and efficacy of this protocol was assessed. we performed a retrospective review of adult patients presenting to a level trauma center between - with spontaneous or traumatic intracranial hemorrhage while on a noac . we evaluated the medication they presented on, indication for anticoagulation, location and size of the hemorrhage, presentation gcs, dosage of feiba recieved, change in size of hemorrhage on serial imaging as well as time between serial images, complications from reversal, and need for blood product transfusion. we identified patients with an acute intracranial hemorrhage while on noacs. patients underwent a baseline head ct documenting acute intracranial blood, were reversed with feiba ( u/kg), and underwent repeat imaging hours later per protocol. ten ( %, / ) patients had no increase in hematoma volume on repeat imaging. two underwent neurosurgical procedures (aneurysm coiling, sub-occipital craniectomy) without intra-operative bleeding complications. five ( % / ) patients had clinically insignificant increase in size of hemorrhage. of those, one underwent a subsequent neurosurgical procedure, which was already anticipated. two ( %, / ) patients had clinically significant hematoma enlargement. of those, one underwent urgent craniectomy (indicated based on initial presentation) and one required a ventriculostomy for hydrocephalus. two patients had no repeat imaging. adjusted dose feiba ( units/kg) may be an effective alternative to standard dose ( unit/kg) for reversal of noacs in acute intracranial hemorrhage. our experience showed clinically significant hematoma expansion in % of patients and no increase in unplanned neurosurgical procedures after reversal with feiba. here we sought to determine if there is an association between recanalization success and rate of hemorrhagic transformation amongst patients who have undergone intra-arterial thrombectomy for ischemic stroke secondary to anterior circulation large vessel occlusion (lvo), many treated at extended time from last seen well (lsw) after mri assessment. stroke patients with anterior circulation lvo treated with thrombectomy between april, to june, were studied. group-wise comparisons were made between patients with post thrombectomy hemorrhage (as confirmed by a single, blinded neuro-radiologist reviewer) and patients without hemorrhage. failed or incomplete recanalization was defined as mtici < b. symptomatic intracranial hemorrhage (sich) was defined as validated hemorrhagic conversion or parenchymal hematoma plus point decrease in nihsss. pertinent baseline characteristics were recorded and analyzed. sich was more prevalent amongst patients with tici< b recanalization (or . [ ci . - . ]). interestingly there was a low rate of sich amongst patients with tici= recanalization ( / [ . %]). although many patients were treated at advanced time lsw no excess rate of sich was observed. baseline characteristics including age, presentation nihss, and presentation aspects were similar among the two groups. rates of sich are low after successful mri seleted thrombectomy regardless ot time lsw. patients with poor recanalization show increased rates of sich in keeping with past literature. our data suggest that thrombectomy after mri selection may be safe and effective for patients at extended time lsw of tor patients with unknown lsw. cta spot sign is associated with hematoma growth, a common complication of intracerebral hemorrhage (ich) that portends worse outcomes. magnesium and calcium are cofactors in the clotting cascade and for platelet aggregation. we tested the hypothesis that magnesium and calcium levels are associated with the presence of the cta spot sign. patients with spontaneous ich presenting to northwestern memorial hospital were identified from a prospective observational registry. inclusion criteria included cta obtained within hours of symptoms onset and admission magnesium and calcium levels. cta spot sign (active contrast extravasation on ct angiography) was identified by a board-certified neurointensivist or neuroradiologist. variables suggesting association with spot sign at p< . were assessed for inclusion in a logistic regression model, and a parsimonious predictive model for ct spot sign was developed using backward stepwise variable selection. patients (age ± . years, % male, median ich score [iqr - ]) were included. seventeen ( . %) patients with cta spot sign were identified. admission magnesium was . +/- . and calcium was . +/- . . lower magnesium (or . , % ci . - . , p . ), lower calcium (or . , % ci . - . , p . ), and higher ich score (or . , % ci . - . , p . ) were independently associated with ct spot sign. magnesium and calcium level on admission are associated with the presence of a cta spot sign in patients with ich. magnesium and calcium supplementation may be attractive therapeutic targets for preventing harm from hematoma growth. cerebellar intraparenchymal hemorrhage (iph) is a rare and likely underreported complication of subdural hematoma (sdh) evacuation. we present two cases of post-operative iph and review the literature. case . an -year-old man underwent craniotomy for evacuation of a chronic right frontoparietal sdh. post-op ct showed pneumocephalus. the patient was extubated and clinically improved. three days post-operatively, he became lethargic and a ct brain revealed a cc right cerebellar iph. he was unable to safely swallow, declined a feeding tube and died under hospice care nine days later. case . a year-old man underwent craniotomy for evacuation for a left convexity sdh. routine post-op ct revealed an incidental left cerebellar iph. he returned to baseline one month later. only four such cases have been reported in the literature ( - ). two cases led to death within one week and two recovered, one with significant deficits. five more occurred following burr hole drainage of sdh and two others following drainage of subdural hygromas ( , - ). the incidence of cerebellar iph following supratentorial craniotomy has been reported in up to . % of cases with significant morbidity or mortality ( ). it occurs irrespective of age, pre-existing coagulopathy or arteriovenous malformations. size of insult and amount of csf loss do not correlate to iph, despite the fact that cerebral blood flow imaging shows over-drainage of cerebrospinal fluid (csf), causes intracranial hypotension and subsequent damage to dural veins ( , ). iph also occurs independently of operating room position, even though having the head turned is thought to compress venous drainage in the neck and cause congestion ( ). cerebellar vasculature may be more sensitive to changes in intracranial pressure, though why this does not lead to complications more routinely is not clear. cerebellar iph should be considered in cases of neurological decline after sdh evacuation. intracerebral hemorrhage (ich) location predicts outcome, but most studies have examined differences between deep, lobar, and infratentorial locations. this study aims to characterize specific deep ich locations in a diverse cohort. the ethnic/racial variations of intracerebral hemorrhage (erich) study is a multi-center, prospective, u.s.-based study. subjects with supratentorial deep ich, known ich volume, and three-month follow-up data were included. logistic regression was used to evaluate the association between location and poor outcome (mrs > ). receiver operating curve (roc) analysis was performed to identify ich volumes specific for poor outcome by location. thalamic, putaminal, and caudate ichs were included. median ich volume was largest in putamen ( ml), followed by thalamus ( ml) and caudate ( ml, p<. ). intraventricular hemorrhage (ivh) was most prevalent in caudate ( %), followed by thalamus ( %) and putamen ( %, p < . ). subjects with thalamic ich were older ( vs vs years, p < . ) and more likely hypertensive ( % vs % vs %, p= . ) than those with putaminal and caudate ich, respectively. compared to thalamic, putaminal ich had more ich expansion ( % vs %, p < . ) and surgery ( % vs % p = . ) but fewer external ventricular drains ( % vs %, p < . ). thalamic location predicted poor outcome (or . , % ci . - . ) at days after adjustment for age, sex, premorbid disability, ich volume, ich expansion, ivh, and admission gcs. roc analysis identified ml for thalamic and ml for putaminal ich without ivh as having % specificity for poor outcome. there are significant differences in characteristics and outcomes within deep ich. specificity estimates for the identified ich volume thresholds require external validation. these findings may have implications for prognostication and clinical trial design. racial differences in outcome after intracerebral hemorrhage (ich) among asians, native hawaiians and other pacific islanders (nhopi) have been inadequately studied since these racial groups have been historically aggregated into a single racial category. a multiracial prospective cohort study of ich patients was conducted from to at a tertiary center in honolulu, hi to assess racial disparities in come after ich. favorable outcome was defined as month modified rankin scale (mrs) score £ . patients with no available -month functional outcome, race other than asians and nhopi, and baseline mrs > were excluded. multivariable analyses using logistic regression were performed to assess the impact of race on favorable outcome after adjusting for the ich score, early do-not-resuscitate (dnr) order and dementia/cognitive impairment. a total of patients ( asians, nhopi) were studied. overall, ( . %) achieved favorable outcome at months. nhopi were younger than asians ( . ± . vs. . ± . years respectively, p< . ), and had higher prevalence of diabetes ( . % vs. . % respectively, p= . ), obesity ( . % vs. . respectively, p< . ), and lower prevalence of early dnr order ( . % vs. . % respectively, p= . ) and advance directive presence ( . % vs. . % respectively, p= . ). nhopi race was a predictor of favorable outcome in the unadjusted model (or . , % ci: . , . ) and after adjusting for the ich score (or . , % ci: . , . ) but not in the final model (or . , % ci: . , . ) . in the final model, the ich score remained as the only independent negative predictor of outcome (or . , % ci: . , . per point). nhopi are more likely to achieve favorable functional outcome after ich compared to asians even after controlling for ich severity. however, this association was attenuated after adjusting for dnr status and baseline cognitive factors. intracerebral hemorrhage (ich) patients often require continuous antihypertensive infusions. we sought to identify clinical and care process predictors of anti-hypertensive infusion duration, and tested whether infusion duration independently predicts intensive care unit length of stay (icu los) after adjusting for validated measures of ich illness severity. we identified spontaneous ich patients admitted / - / to a tertiary center, excluding those transitioned to comfort care within hours. we abstracted demographic and clinical variables from the medical record. we calculated the total duration each patient received continuous infusion of an antihypertensive medication. we categorized glasgow coma scale score as - ; - ; or < . two reviewers independently classified ich location and etiology. we determined univariate associations of clinical variables to anti-hypertensive infusion and performed regression analysis to determine the effect of continuous infusion on icu los. we identified spontaneous ich patients and excluded for early comfort care. in the remaining , mean age was [ - ] years, % were female, median ich score was [ - ], and % had lobar hemorrhages. continuous infusion included nicardipine, clevidipine, labetalol and diltiazem. a total of ( %) patients received anti-hypertensive infusions, mean hours. mean time to enteral antihypertensive administration medication was . hours, and mean icu length of stay was . days [ . - . ]. predictors of longer antihypertensive infusion duration were male gender (p= . ), non-lobar ich (p= . ), non-caucasian race (p< . ), younger age (p< . ), higher initial systolic (p= . ) and diastolic bp (p= . ), worse gcs category (p< . ), and longer time to first enteral medication (p< . ). anti-hypertensive infusion duration independently predicted icu los (p< . ) after adjusting for age, race, gcs category, time to enteral antihypertensives, and ich score. worse gcs category, younger age, non-lobar ich location, and race are significant independent predictors continuous iv antihypertensive infusion duration, which is significantly associated with longer icu stay. patients with sich have a high risk of vte. pharmacological prophylaxis such as unfractionated heparin(ufh) has been demonstrated to reduce vte. however, published datasets exclude patients with recent ich out of concern for hematoma enlargement. aha/asa guidelines recommend ufh - days after hematoma stabilization while the eso has no recommendations on timing of ufh. there are few data for patients who received ufh before hours. our institutional practice is to begin ufh following sich after hours of clinical and radiographic stability. we examine the impact of this practice on risk of hematoma expansion. we performed a retrospective cohort analysis of sich patients admitted in - to a single us university hospital. demographic and clinical characteristics were abstracted. ich was measured via d volumetrics for an admission ct, a hour follow-up, and a follow-up prior to discharge. percent hematoma growth between -hour ct and discharge ct was calculated. risk factors for expansion > %, including early heparin use, were analyzed via oneway t-test and chi-squared tests. results sich patients analyzed had a median ich score of (iqr - ) and median admission gcs of (iqr - ). %( / ) patients received early ufh. %( / ) suffered hematoma expansion > %. overall mean hematoma growth was higher with early ufh (ufh hr - %,p= . ). in multivariate analysis, ich score, gcs and initial hematoma size did not predict > % hematoma expansion. early vte prophylaxis at hours from sich had a statistically significant increase in hematoma size, but this increase is clinically insignificant. in this cohort, early ufh did not increase risk of significant hematoma expansion. further prospective trials are warranted, given the high risk of vte in this population. antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sich) may increase the risk of hemorrhage expansion and mortality. current guidelines recommend consideration of a single dose of desmopressin in sich associated with cyclooxygenase- inhibitors or adenosine diphosphate receptor inhibitors. this study sought to compare outcomes in patients that received desmopressin for antiplatelet reversal in the setting of sich to similar patients that did not receive desmopressin. this retrospective chart review of the electronic medical record included adult patients admitted for sich that were on antiplatelet agents at the time of diagnosis. patients that received desmopressin were compared to similar patients that did not receive desmopressin. exclusion criteria included traumatic brain injury, active coagulopathy and thrombocytopenia. the primary outcome was the incidence of hematoma expansion. additional outcomes included average increase in hematoma volume, in-hospital mortality and functional outcome at hospital discharge. overall, patients ( received desmopressin, did not receive desmopressin) were included for analysis. incidence of hematoma expansion was not different between groups ( % with desmopressin vs % without desmopressin, p= . ). average largest increase in hematoma volume on follow-up imaging from baseline was not different ( . ± . ml with desmopressin vs . ± . ml without desmopressin, p= . . in-hospital mortality was significantly higher in the desmopressin group ( % vs % without desmopressin, p= . ) as well as the incidence of a modified rankin score of - at discharge ( % vs % without desmopressin, p= . ). administration of desmopressin for antiplatelet reversal in sich does not appear to reduce the incidence of hematoma expansion. further studies assessing temporal relation of desmopressin administration and hematoma expansion are needed to confirm the results of this single-center retrospective study. clinical outcome after intracerebral hemorrhage (ich) remains poor. definitive phase- trials in ich have failed to demonstrate improved outcomes with intensive systolic blood pressure (bp) lowering.we sought to determine whether other bp parameters-diastolic bp, pulse pressure (pp), and mean arterial pressure (map)-showed an association with clinical outcome in ich. we retrospectively analyzed a prospective cohort of patients with spontaneous ich and documented demographic characteristics, stroke severity, and neuroimaging parameters. consecutive hourlybp recordings allowed for computation of systolic bp, diastolic bp, pp, and map. threshold bp values that transitioned patients from survival to death were determined from roc curves. using inhospital mortality as outcome, bp parameters were evaluated with multivariable logistic regression analysis. patients who died during hospitalization had higher mean pp compared to survivors ( . ± . mmhg vs. . ± . mmhg; p= . ). the following admission variables were associated with significantly higher in-hospital mortality (p < . ): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. roc analysis showed that mean pp dichotomized at . mmhg, provided a transition point that maximized sensitivity and specific for mortality. the association of this increased dichotomized pp with higher in-hospital mortality was maintained in multivariable logistic regression analysis (or . ; %ci . - . ; p < . ) adjusting for potential confounders. widened pp may be an independent predictor for higher mortality in ich. this association requires further study. a national confidential enquiry into patient outcome and death (ncepod) report concerning management of aneurysmal subarachnoid haemorrhages in the uk suggested up to half of patients received suboptimal consideration for organ donation. as demand for organs continues to increase, so does the need to pursue all potential sources of donor organs. subarachnoid haemorrhages have an estimated mortality of % and can potentially provide younger donor organs with less chronic pathology. this is a comprehensive picture of donation rates within a tertiary centre. retrospective data regarding all deceased patients on the neuro-intensive care unit during with aneurysmal subarachnoid haemorrhage as the cause of death was obtained from the nhs blood and transfusion team. the local audit committee provided ethical approval. data regarding organ donation was extracted and compared to national data, then analysed using fisher's exact test. referral rates were %. this is greater than the national average of . % (p= . ), yet only . % of referred patients proceeded to organ donation. consent was withheld in . % of potential donors. nationally . % of donors are lost due to non-consent (p= . ). . % of consented patients were unable to donate organs, similar to national figures (p= . ). referral rates within this centre are excellent; consent remains the main obstacle. consent rates can be improved using a long contact model where specialist nurses in organ donation establish relationships with relatives prior to any discussion of donation. the ideal discussion is a pre-planned collaboration involving a senior doctor and a specialist nurse. early brain stem testing may facilitate earlier acceptance of death by relatives whilst reducing the duration of the multi-systemic effects of the associated hyperresponsive cascade on donor organs. neurosurgeons should be encouraged to suggest organ donation when declining referrals. further work is needed to assess the barriers to instituting these measures and inspiring change. spontaneous brainstem hemorrhage has been historically associated with high mortality. however, updated data on the frequency and outcome of spontaneous brainstem hemorrhage is scarce vis-a-vis advances in neuro-critical care. the purpose of this study was to investigate the frequency and outcome of spontaneous brainstem hemorrhage. records of consecutive intracerebral hemorrhage (ich) patients presenting to an urban academic medical center from january though december were reviewed. cases with brainstem hematomas were isolated for analysis. data on demographics and outcomes were collected and analyzed. sub-group analysis was also done to look at outcomes based on location of hemorrhage in the brainstem. of consecutive spontaneous ich patients, ( . %) presented with brainstem hemorrhage; ( . %) were pontine, ( . %) mesencephalic, and ( . %) were located in both the pons and the midbrain. the average age was . years and ( . %) were men. median glasgow coma scale on presentation was . . thirty-day mortality rate was . %, with in-hospital deaths and deaths post discharge. two and patients were discharged home or a rehabilitation facility, respectively. in subgroup analysis, thirty-day mortality for midbrain, pons and combined pons/midbrain hemorrhage was %, % and %, respectively. spontaneous brainstem hemorrhage remains an uncommon but highly fatal clinical entity. more than one-half die within days. only a minority are discharged to rehabilitation or home. in sub-group analysis, location of brainstem hemorrhage was shown to influence outcome, with % mortality in case of combined pons/midbrain hemorrhage, and more than % mortality with pontine hemorrhage. midbrain hemorrhage was associated with good outcome with % survival. patients with intracerebral hemorrhage (ich) frequently present with hypertension. it is unclear whether this is due to preexisting hypertension (prhtn) causing the bleed, an effect of the bleed, or both. we retrospectively analyzed a single-institution cohort of ich patients presenting between and . data included home antihypertensive use; asbp; tte, and ekg and imaging results; and nicardipine administration. the primary objective was to assess the relationship between prhtn and asbp, while the secondary objectives were to assess the relationship between prhtn, imaging and acute antihypertensive requirements. ich patients met inclusion criteria. in our assessment for prhtn, we found that % of patients were on antihypertensives, % had lvh on ekg, and % had lvh on tte. there was a significant relationship between lvh on tte and lvh on ekg (p< . ), but not between home antihypertensive use and presence of lvh using either modality. asbp was higher for all patients with markers of phtn, but this was only significant for patients with lvh on tte ( mmhg, iqr - vs. mmhg, iqr - , p < . ) and patients with lvh on ekg ( mm hg, iqr - vs. mm hg, iqr - , p< . ). all patients with markers of prhtn were more likely to require nicardipine, but this was only significant for patients with lvh on tte ( % vs. %, p= . ) and patients with lvh on ekg ( % vs. %, p= . ). all patients with markers of prhtn were more likely to have deep bleeds (p= . for patients with lvh on ekg vs. those without lvh on ekg). there was no relationship between any markers of prhtn and the presence of a spot sign. in patients with ich, prhtn is related to higher asbp, deep bleed location, and increased acute antihypertensive requirements. all spontaneous intracerebral hemorrhage (sich) patients, including those with low severity are uniformly admitted to the intensive care unit (icu) at our institution. many may not benefit from this high-intensity observation and leave the icu within hours without experiencing any complications. identifying low-risk characteristics could aid in triaging such patients to stroke units instead. retrospective data collection of all sich patients admitted to our institution from june , -june , included ich score, need for surgical interventions, medical complications, and icu/hospital los. we analyzed variables predicting short (< hour) icu los among low severity (ls-ich) patients (defined as those with ich score - ). ( %) of sich patients had ich scores of - , of which just under half ( ) had icu los hr. they also spent significantly fewer days in hospital ( vs . , p< . ). we could not identify a clear ich score cutoff that was sensitive enough to predict short icu los. however, requirement for antihypertensive infusion and early clinical deterioration correlated strongly with longer icu los p< . . there appears to be a subset of mild ich patients (ich score - ) who do not require icu observation. a risk assessment score incorporating gcs and ich volume may be able to delineate this low-risk population who could instead be admitted to a stroke unit, with the potential for significant cost saving and hospital efficiency. obesity has been linked with relative longevity in several disease conditions. this relationship has been termed the "obesity paradox." in this study we sought to evaluate the impact of obesity on short-term outcomes in patients with intracerebral hemorrhage (ich). patients admitted with a diagnosis of ich were selected from the - nationwide inpatient sample (nis) database, using icd- codes. patients with ich were dichotomized based on the presence of obesity as a coexisting diagnosis based on icd- codes and diagnosis related groups. the primary outcome measure was in-hospital mortality. length of stay and total charges were also examined as resource utilization measures. of obesity is a major health care burden as evidenced by higher resources utilization. counterintuitively, obesity appears to be associated with lower in-hospital mortality in ich patients. one possible physiological basis for this could be that the higher ldl levels on presentation result in a lower likelihood of hematoma expansion. recent short-term outcome analysis indicates association of spontaneous intraventricular hemorrhage (ivh) related hydrocephalus with incontinence and gait dysfunction. we explore the association of hydrocephalus scores, intraventricular alteplase and clinical variables with these outcomes at long term follow up in survivors from the clear iii trial. clear iii, a randomized, multi-center, double-blinded, placebo-controlled trial was conducted to determine if pragmatically employed external ventricular drainage (evd) plus intraventricular alteplase improved outcome, in comparison to evd plus saline in patients with ivh causing obstructive hydrocephalus. we assessed hydrocephalus scores on survivors at diagnosis, days and . incontinence and dysmobility were defined using -month barthel index subscores (< for bladder and < for mobility, respectively). outcome measures were predictors of incontinence and gait dysmobility at year after ich. this prospective observational study analyzed consecutive ich-patients (n= ) treated at the neurological and neurosurgical departments of the university-hospital erlangen, germany over a month inclusion period ( / - / ). we analyzed the influence of patient characteristics, inhospital measures and functional status on treatment recommendations and on oac initiation during -month follow-up. clear treatment recommendations by attending stroke physicians seem necessary to ensure oac initiation after ich. oac showed beneficial associations; however data here suggests the presence of an indication bias introduced by treatment recommendations and outpatient care during follow-up. therefore, observed association with age and functional status might affect unadjusted analyses. although recently, non-vitamin k antagonist oral anticoagulants (noacs) therapy in patients with non valvular atrial fibrillation have half the incidence of intracerebral hemorrhage (ich) compared to warfarin. however, it would be still controversial subject that outcome of noac-associated ich (nich) might be worse or better than warfarin-associated ich (wich). in this study, we investigated clinical outcome and radiological finding of ich between two different anticoagulation treatments. retrospective review of medical records was performed for , patients who admitted with ich from to in seoul national university bundang hospital. clinical characteristics, functional outcome, location and volume of ich, and all-cause mortality within days were analyzed. among those patients, patients with wich and patients with nich were included. lesion location was common in supratentorial deep area ( . %, . %), lobar area ( . %, . %) and brainstem and cerebellum ( . %, . %) in the nich and wich group, respectively. no significant difference found in initial nihss ( . vs ), discharge nihss ( . vs ), mrs ( to ) at discharge ( . % vs . %), mrs ( to ) at discharge ( . % vs . ), mrs ( to ) at days ( . % vs . ) and mrs ( to ) at days ( . % vs . ) in nich and wich group. we did not find any difference between nich and wich for allcause mortality at discharge ( % vs %), days ( . % vs %), and year ( % vs %). median baseline ich volume was not significant difference in two groups ( . vs . ). in our study, functional outcome, mortality, and baseline ich volume were similar following nich and wich. because of low statistical power due to small sample size in our study, further studies with prospective larger patient cohorts will need to be conducted. novel oral anticoagulants (noac) are increasingly used as an alternative to vitamin-k antagonists (vka) such as warfarin for anticoagulation and have shown lower rates of intracranial hemorrhage in several randomized clinical trials. it has been suggested that noac-iphs might be particularly dangerous, yet the literature regarding hematoma characteristics and outcomes between noac-iphs and vka-iphs is inconclusive. given the lack of standardized reversal strategies and lack of information on outcomes following noac-associated iph, the aim of this meta-analysis was to compare ) mortality; ) hematoma volume, and ) risk of hematoma expansion in patients who developed an iph on noacs versus vka. a meta-analysis of the literature through december was conducted using pubmed, embase and cochrane databases in accordance with prisma guidelines. pooled risk ratios (rr) were calculated for mortality and hematoma expansion and pooled mean difference (md) was calculated for hematoma volume (ml) using random-effect (re) and fixed-effect (fe) models. noac-iph was not associated with increased mortality (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) and hematoma expansion (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) compared to vka-iph. the hematoma volume of noac-iph was smaller than vka-iph (re: md: - . ml; %-ci: - . ; - . , fe: md: - . ml; %-ci: - . ; - . ; studies), but with considerable heterogeneity that could not be alleviated (i = . %, p-heterogeneity . ). noac-iph was not associated with increased mortality or hematoma expansion compared to vka-iph and may be associated with a smaller hematoma volume. controversy exists regarding blood pressure (bp) reduction and perihematomal ischemia (phi). we investigated the association of acute bp reduction and presence of qualitative and quantitative phi in a large prospective cohort of intracerebral hemorrhage (ich). consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. the association of clinical, radiographic factors and bp at baseline and hours with qualitative perihematomal and/or remote ischemia (i.e. dwi bright adc dark) and quantitative ce on adc were determined. patients ( % female) with mean age ± , and nihss (iqr , ) were included. mri time was . hours (iqr , ). % had lobar ich. ich volume was cc (iqr , ). % had perihematomal ( %) or remote ischemia ( %). % of patients had areas of perihematomal adc cc) was associated with higher absolute ( ± mm hg, p= . ) and relative ( % ± % vs % ± %, p= . ) map reduction, younger age (p= . ), h/o tia/stroke (p= . ) and larger ich volumes ( vs cc) (p< . ). in multivariate analysis, map reduction was not significantly associated with ce whereas ich volume was (p= . ). perihematomal and remote ischemia is frequently seen after ich, but the severity of phi is small and of unclear significance. bp reduction may be associated with phi but this was not an independent predictor. introduction: patients with left ventricular assist devices (lvads) receive anticoagulation and antiplatelet therapy to prevent pump thrombosis. consequently, neurological events including intracranial hemorrhage (ich) are one of the most feared causes of morbidity and mortality in these patients. there is little evidence to guide initiation of anticoagulation after such ich events. methods: this is a retrospective, single academic center analysis of lvad patients from - . the electronic medical record was reviewed after irb approval for the physiologic, laboratory, and radiographic data of these patients as well as survival or cause of death by days or by discharge. results: during the analysis, patients were reviewed, of which ( . %) had intracranial hemorrhage. one patient was excluded from analysis after care was transitioned to hospice, thus follow-up scans were not obtained. the remaining patients were receiving both aspirin ( - mg daily) and warfarin ( - mg daily) with an inr of . - . (mean= . ) at the time of ich. aspirin ( - mg daily) was resumed within - (mean= . ) days post ich. warfarin was resumed - (mean= . ) days post ich at - mg (mean= mg) with goal inr ( . - )-( - ) depending on device. there was death due to withdrawal of life support in setting of multiple comorbidities, though follow-up scan days post warfarin resumption revealed no evidence of rebleed. the remaining patients showed no evidence of rebleed on ct scans at months post warfarin resumption and were subsequently discharged to rehab facilities or home with modified rankin scores - (mean= . ). conclusion: in this review of lvad patients, about % suffered ich, and of those survivors aspirin was safely resumed within days and warfarin was safely resumed as early as days post-event. further studies are needed in order to establish safe practice guidelines and risk factors to prevent ich. intracerebral hemorrhage (ich) remains a devastating form of stroke, and perihematomal edema worsen outcomes after ich. recent studies have demonstrated the safety of minimally invasive surgery (mis) for hematoma removal, but the efficacy of mis in the treatment of ich is controversial. this study aimed to evaluate the effect of mis compared with medical treatment for basal ganglia ich. we retrospectively analyzed the clinical outcomes of prospectively collected data from two stroke centers. the treatment strategies of the two stroke centers for basal ganglia ich are different; one stroke center underwent mis and the other stroke center medically treated according to the current guidelines. we hypothesized that mis could reduce perihematomal edema and improve functional outcomes compared to medical treatment. primary outcome of this study was a modified rankin scale (mrs) at months after ich occurrence. a total of patients with basal ganglia ich were treated with different treatment strategies; patients underwent mis and patients received medical treatment. no statistically significant differences were found in age, sex, hematoma volume, and glasgow coma scale scores between the groups. a better functional recovery (mrs < ) at months was found in the medical treatment group than the mis group ( . % vs . %, p < . ). no significant differences were observed between groups in terms of mortality. our findings suggest that the best medical treatment improves functional recovery after basal ganglia ich compared to mis. these results are contrary to other studies of ich, and further randomized trials are required. perihematomal edema (phe) after intracerebral hemorrhage (ich) is thought to be predominantly vasogenic. the presence and extent of cytotoxic edema (ce) is controversial. we investigated phe diffusivity (phed) and factors associated with ce. consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. clinical and radiographic factors associated with ce were determined. cytotoxic edema is detected in the perihematomal area, early after ich and is associated with younger age, larger ich and prior h/o tia/stroke. its clinical significance needs to be studied further. hemorrhagic stroke carries a high mortality rate and determining prognostic factors during initial presentation can aid redirecting intensive care unit (icu) management. we described the physiological profile and clinical outcomes of hemorrhagic stroke patients in a colombian icu. we retrospectively reviewed all hemorrhagic stroke patients admitted to our icu from - . clinical characteristics, outcomes, available laboratory values and hourly vital signs from the first hours in the icu were retrieved and analyzed. our primary stroke center admitted patients, ( %) were hemorrhagic. out of these, required icu management, representing % of the total icu admissions during this time frame. intracerebral hemorrhage (ich) was present in patients while subarachnoid hemorrhage (sah) was seen in . the latter had a median fisher score of . for all patients, the most common risk factors were hypertension ( . %), dyslipidemia ( . %) and smoking ( . %). icu mortality was . % ( . % with ich and . % with sah). mean sequential organ failure assessment (sofa) score was significantly greater in patients who died ( . vs. . , p< . ) and mean glasgow coma scale was significantly lower ( . vs. . , p< . ). vasopressors were required in patients ( . %), mechanical ventilation in ( . %), and half of the patients requiring either support therapy died. only patients ( . %) had fever in the first hours and all died. mean coefficient of variation for systolic, diastolic and mean blood pressure was significantly lower in patients who survived. mortality cases were more likely to have hypokalemia and hypomagnesemia than surviving patients ( . % vs. . % and . % vs. %, respectively). icu-admitted hemorrhagic stroke patients have a poor prognosis. sofa and gcs are accurate predictors of mortality. certain electrolyte disturbances, fever and a higher variation of blood pressure during the first hours were associated with a worse outcome. the association between worsening cerebral edema and unfavorable outcome in ich patients has been described in rcts. the objective of this analysis was to compare hospitalized spontaneous ich patients with and without perihematomal edema (phe) expansion and to evaluate relationships between hypertonic saline (hts) use, peak serum na, phe expansion, and short-term outcomes. we conducted a cross-sectional study of consecutive spontaneous ich patients admitted to a single center from / - / . head cts during the first week of admission, use of hts, and phe (using abc/ method) were evaluated. phe expansion of % or more was considered worsening edema. outcomes of interest included time to peak na, poor disposition (not home or inpatient rehabilitation), discharge mrs - , and in-hospital death. of ich patients, % experienced worsening phe. there was no difference in age, race, sex, arrival bp arrival, or vascular risk factors in patients with or without worsening phe. however, for each mm of midline shift (mls) present on initial head ct, odds of phe expansion was decreased by % (or . , %ci . - . , p= . ). mls on initial head ct was the best discriminator of phe expansion (auc . ( %ci . - . ). although hampered by small sample size, our data indicates that finding that ich patients with degree of mls on initial head ct is the best radiographic predictor of had lower odds of phe expansion. those without mls at presentation may be at risk of phe expansion, and counterintuitively may be those most in need of aggressive medical management. may suggest a role for intensive osmotherapy in patients with favorable imaging at presentation. intracerebral hemorrhage (ich) is a devastating stroke with high mortality rates. previous studies have shown a potential role of immune cells as a prognostication method. a high neutrophil to lymphocyte ratio was associated with poor outcomes after ich. we sought to determine whether absolute lymphocyte count(alc) at admission was predictive of outcomes in patients with ich. we performed a retrospective chart review of all patients admitted to our hospital with a diagnosis of ich from january to december .we collected baseline demographic characteristics, medical history, ich scores, differential leucocyte, platelet and total leucocyte(tlc) counts at admission. the functional outcomes after ich were measured using modified rankin scale (mrs) at discharge. mrs of and were considered poor outcomes. statistical analysis was done after grouping lab values into higher and lower groups with respect to the normal reference ranges a total of patients with ich were admitted to our center during the study period. patients were included in the study and the rest were excluded due to lack of differential leucocyte counts at admission. % ( of ) had poor outcomes. univariate analysis using fisher's exact test showed significant association between low alc levels ( . ) were also found to be significantly associated with worse outcomes (p = . , . , . , respectively). however, after multivariate analysis, only low absolute lymphocyte counts retained significant association (p = . ). intracerebral hemorrhage patients with low absolute lymphocyte counts at admission have a higher probability of poor outcomes at discharge. further studies are required to confirm our results. intraventricular hemorrhage (ivh) is a significant predictor of poor outcome after intracerebral hemorrhage (ich), and may differentially predict hydrocephalus and mortality among blacks vs. nonblacks. we aimed to confirm these findings in a separate cohort of spontaneous ich patients with severe ivh. the cleariii-ivh trial was a randomized, multi-center placebo controlled trial examining the effect of intraventricular alteplase versus saline, on outcomes in patients with spontaneous ivh. we retrospectively analyzed data on all patients, including self-reported race/ethnicity, medical comorbidities, presentation characteristics and functional outcomes. represented race/ethnic groups with > subjects per group were ( . %) white/non-hispanic (wnh), ( . %) white/hispanic (wh), ( . %) black/african american/non-hispanic (bnh), and ( . %) asian. bnh were significantly younger than rest of the cohort with median age [interquartile range] [ , ] years, had more hypertension( %, p= . ), and significantly higher rates of antihypertensive medication non-compliance ( . %, p= . ). wnh had more frequent coronary artery disease ( . %, p< . ), use of vitamin k antagonists ( . %, p= . ) and elevated inr on presentation ( . %, p= . ). bnh had significantly more frequent hydrocephalus on presentation ( . %, p= . ), and a higher rate of ventriculoperitoneal shunt placement ( %, p= . ). neither ich nor ivh volume at enrollment, nor ivh remaining at end of treatment differed significantly between race/ethnic groups. however, bnh patients were more likely to have greater than % ivh reduction, a recognized endpoint for better functional outcomes in cleariii ( . % vs. %-wh; . %-wnh; . %-asian; p= . ), and this difference persisted in those who received intraventricular alteplase (p= . ) and after adjustment for diagnostic ivh volume (p= . ). race/ethnicity was not an independent predictor of mortality or poor outcome at or days on multivariable logistic regression. although functional outcomes did not differ significantly among race/ethnic groups, differences in risk factors, hydrocephalus/shunting post ivh and response to thrombolytic therapy warrant further exploration. investigators from the randomized trial of unruptured brain arteriovenous malformations (avm) trial (aruba) reported in that interventions to obliterate unruptured avms resulted in greater morbidity and mortality compared to medical management. we investigated whether patterns of avm treatment changed after aruba's publication. we used inpatient and outpatient claims data from - from a nationally representative % sample of medicare beneficiaries. unruptured brain avms were identified using icd- -cm code . . the date of first avm diagnosis was coded as occurring before or on november , (online publication of aruba) versus after. outcomes were referral to a neurologist or neurosurgeon, and interventional treatment. interventional treatments were identified using cpt codes - , - , , , or - . the likelihood of outcomes after versus before aruba was compared using survival analysis with log-rank tests and cox proportional hazards models adjusted for age, sex, race, and the charlson comorbidity index. we censored patients at diagnosis of intracranial hemorrhage. we identified , patients with a mean . (± . ) years of follow-up after diagnosis of unruptured brain avm. diagnosis was most often by neurologists ( . %), neurosurgeons ( . %), and internal medicine specialists ( . %). after aruba publication, there were no changes in -year cumulative rates of referral to a neurosurgeon ( . % after, . % before; p = . ) or neurologist ( . % after, . % before; p = . ), but there was an increase in avm treatment ( . % after, . % before; p = . ). after adjustment for demographics and comorbidities, there was an increased likelihood of interventional management (hr . ; % ci, . - . ) after aruba's publication. in a nationally representative cohort of elderly patients, we found an increase in interventional avm management after publication of aruba. this is notable given that our data pertain to older patients who are generally seen as less suitable surgical candidates. elderly patients with severe intracerebral hemorrhage (ich) are often projected to have future functional dependence but unclear degree of cognitive recovery. surrogates for such patients frequently weigh multiple concerns when facing the difficult decision of whether to prolong life with tracheostomy and gastrostomy tube insertion versus pursue comfort care. we aimed to characterize distinct groups of surrogates in these situations, based solely on how they prioritize their concerns. subjects recruited from a probability-based us population sample completed an online best-worst survey that presented the above scenario and asked the respondent to prioritize concerns as the patient's surrogate. clusters were identified with latent class analysis after weighting data to match the us census demographic distribution. class solutions were replicated times from random starting seeds, with the solution chosen after factoring in akaike's information criterion. we identified distinct decisional groups among respondents (response rate = . %). all groups reported multiple concerns as important, but group ( . %) was more concerned than any other that the patient was too old to live with disability. group ( . %) focused on ensuring agreement among other family members. group ( . %) was concerned that the patient might suffer if tube feeding and iv fluids were stopped and that the prognosis could be incorrect. group ( . %) had numerous considerations that were comparably important but prioritized paying for long-term care. groups varied in whether they would actually request prolonging care for the patient (group = . %, g = . %, g = . %, g = . %, p< . ). in a multivariate model, religious affiliation and frequency of attending religious services were the only variables independently predicting group membership. we identified distinct profiles of decisional patterns for surrogates of severe ich patients with uncertain prognosis. these data will inform development of strategically tailored decision aids. cerebral venous sinus thrombosis (cvst) represents an important cause of both ischemic and hemorrhagic strokes in young people. while recent guidelines recommend management in a stroke unit, the impact of neurocritical care in this condition has not been studied. we aimed to assess whether the introduction of a neurocritical care program influenced clinical outcomes in cvst patients. we retrospectively reviewed electronic medical records of adult patients admitted to yale new haven hospital's neuroscience icu (nicu) between and with a diagnosis of cvst. demographics, vascular risk factors, comorbidities, length of stay and discharge modified rankin scale (mrs) were collected. patients were excluded for age hours of presentation. we compared two time periods, before (epoch , - ) and after (epoch , - ) the introduction of continuous staffing of cvst cases by neurointensivists in the nicu. univariable and multivariable logistic regression were utilized to model the odds of poor outcome (dichotomized mrs - vs - ). fifty-three patients with cvst met the inclusion criteria during the study period (mean age (+/- ) years, % female). patients were identified for epoch and patients for epoch . overall, patients ( %) had a good (mrs - ) outcome. for epochs and , good outcomes were observed in ( %) and ( %) patients, respectively (p= . ). in both univariable and multivariable regression analysis (adjusted for age and sex), admission during epoch was associated with a significantly reduced odds of a poor outcome (or . , ci . - . ; p = . ) and (or . , ci . - ; p= . ), respectively. in this small, single-center cohort of patients with cvst, most patients experienced a good outcome. the institution of continuous neurointensivist coverage was independently associated with better outcomes. further validation in prospective, multicenter cohort studies is needed. thrombelastography (teg) provides a dynamic assessment of clot formation, strength, and stability. we examined relationships between teg parameters and outcomes from intracerebral hemorrhage (ich). we prospectively enrolled patients with spontaneous ich between to . teg was performed at the time of admission. we divided patients into two groups based on the presence or absence of hematoma expansion (he). clinical characteristics, baseline teg values, and outcomes were compared between the two groups. multivariable regression analysis was conducted to compare the differences of teg components between the two groups after adjusting for potential confounding effects. we included patients, ( %) with he and ( %) without he. patients with he were more often male and had higher rates of aspirin use, lower incidence of intraventricular hemorrhage, and larger baseline hematoma volumes. after controlling for potential confounders, mean r time was independently associated with he ( . ± . vs. . ± . mi significantly higher risk of he with or . ( % ci: . , . ), p=< . . patients with hematoma expansion were more likely to have poor neurological outcome (mrs - ) at discharge ( % vs. %, p= . ) and had higher mortality rates ( % vs. %, p= . ). overall, patients ( %) died in the hospital. following multivariable analysis, patients who died had significantly lower mean delta ( . ± . vs. . ± . mins.; p= . ) and smaller angle ( . ± . vs. . ± . degrees; p= . ) than those who lived. hematoma expansion and mortality from ich are independently associated with slower clot formation on teg. baseline teg identifies significant coagulation disturbances which may predict poor outcome and represent potential targets for therapeutic intervention. intracerebral hemorrhage (ich) patients often present with acute hypertension requiring intravenous and enteral antihypertensive medications. we performed a cohort study to determine clinical predictors of time to enteral antihypertensive medication and its effect on icu length of stay (icu los). we identified consecutive spontaneous ich patients admitted from / to / to a tertiary center, and excluded those transitioned to comfort care (cmo) within hours of admission. we calculated time from hospital admission to first enteral (oral or feeding tube) antihypertensive. we abstracted demographic and clinical variables. two reviewers examined medical records and classified ich location and etiology. we determined univariate and adjusted associations of clinical variables to time to enteral antihypertensive medication and performed regression analysis to determine effect on icu los. we identified patients and excluded for early transition to cmo. endotracheal intubation (p= . ), higher ich score (p< . ), no outpatient antihypertensive use (p= . ), and non-lobar ich location (p= . ) predicted longer time to starting enteral antihypertensive in adjusted analysis. presenting systolic or diastolic bp, time of icu admission (day vs. night), sex, and race were not significant predictors of time to enteral antihypertensive. time to enteral anti-hypertensive is the strongest predictor of icu los (p< . ) after adjustment for age, gcs, ich score, sex, race, and duration of iv antihypertensive infusion. patients with higher ich scores, intubation, no prior antihypertensive use, and non-lobar ich are at risk for increased time to enteral antihypertensive administration. timely enteral antihypertensive administration is an important and potentially modifiable predictor of icu los in acute ich. overall mortality from intracerebral hemorrhage (ich) represents a combination mortality from a potentially fatal disease as well as practice variation around treatment withdrawal of care. early do-not-resuscitate (dnr) rates are independently associated with in-hospital mortality and may serve as a proxy for withholding aggressive care. the american heart association (aha) guidelines recommended that dnr orders should not be applied before hours out of a concern that less aggressive care would lead to a self-fulfilling prophecy and excess mortality. we performed a retrospective analysis of temporal trends among primary ich patients presenting to all nonfederal emergency departments in california from to using data from the office of statewide health planning and development (oshpd). demographic information, clinical covariates (such as mechanical ventilation, craniotomy), and early dnr status within hours were collected and analyzed using segmented regression to evaluate for differences in linear trends from - compared with - . over a use of early dnr orders for ich patients has steadily decreased over the last years, even after adjusting for age and disease severity. the pace of this downward trend did not significantly change around the time when recommendations on early dnr use for ich in aha guidelines were revised in . spontaneous intracerebral hemorrhage (ich) is a common form of stroke that often results in severe morbidity or death. for most ich, there are no proven therapies for acute management. evidence suggests minimally invasive surgical evacuation of ich may result in improved patient outcomes. the enrich clinical trial is designed to determine the efficacy and economic impact of early ich evacuation using minimally invasive, transulcal, parafascicular surgery (mips) compared to standard guideline-based management. in this abstract we present the trial design and rationale at the foundation of the enrich clinical trial. enrich is an adaptive, prospective, multi-center clinical trial designed to enroll up to patients with acute ich. patients are block-randomized based on hemorrhage location (lobar vs basal ganglia) : to mips or standard management. included patients are - years, gcs - , baseline mrs , presenting within hours from last known well and found to have a spontaneous, cta-negative, supratentorial ich ( - ml). primary efficacy will be determined by demonstrating significant improvement in the mean utility-weighted mrs at days after enrollment. economic effect of mips will be determined by quantifying the cost per quality-adjusted life-years gained at pre-determined time points. the rationale for early intervention is to interrupt the time-dependent ich related pathophysiology caused by mechanical pressures and the pro-inflammatory secondary cascade that leads to worsened cellular injury and edema formation. the planned enrichment strategy acknowledges that hemorrhages in varied locations may have a differential response to mips. study adaptation, in the form of enrichment, may occur if pre-determined futility rules are met for the primary outcome in either of the two locations. enrich is designed to establish the clinical and economic value of early mips in the treatment of ich. enrollment was initiated in december . early seizures (< days) after intracerebral hemorrhage (ich) may be associated with the presence and degree of perihematomal cytotoxic injury. we explored the association between perihematomal diffusivity (phd) and early seizures after ich. consecutive patients from the prospective nih funded dash study (> years, spontaneous ich) were included. all patients had multimodal mri within weeks. perihematomal edema (phe) volume was outlined on t /flair and ich volume on gre; these and adc were coregistered to analyze phd. eeg monitoring was performed for clinical suspicion of seizure. mean adc values of phe and the percentage of phe volume were compared between the seizure and no-seizure groups, with adc values as vasogenic edema. results ( %) of a total of patients had early seizures at a median of day post ich. mean adc in the phe region was higher in the seizure group (mean: +/- vs +/- , p= . ). ich, absolute, and relative phe volumes were not different between groups. the phe of the seizure group had a lower percentage of cytotoxic edema ( % vs %, p= . ) and a higher percentage of vasogenic edema ( % vs %, p was the most predictive of seizure with auc = . , though adc thresholds between - had largely similar auc's. phe volume of > % (of adc > ) identified patients with seizure with sensitivity of . , specificity of . , and remained significant in multivariable analysis. patients with early post-ich seizures have higher mean perihematomal adc and a larger percentage of vasogenic edema in the perihematomal region. vasogenic edema due to bbb breakdown and perihematomal inflammation rather than cytotoxic injury is associated with early post ich seizures. novel neuroprotective treatments hold the promise to improve patient outcomes by broadening time windows of intervention and reducing hypoperfusion and reperfusion injury in the era of mechanical thrombectomy for acute ischemic stroke. hibernating species, such as arctic ground squirrels (ags), demonstrate remarkable resilience to ischemic and reperfusion injuries. bioinformatic analyses of genomes of hibernating species reveals signatures of convergent evolution in genes regulating stability and formation of mitochondrial respirasomes. hypoxia pre-conditioning (hpc) also leads to improved survival upon subsequent exposure to hypoxia, and is associated with increased stabilization of respirasomes. the respirasome is a macromolecule consisting of oligomers of complex i, iii, and iv. cox a l is a key mediator of respirasome stability via interactions with complex i and iii. in this study, we explored the role of cox a l in mediating respirasome stabilization in ags neural stem and progenitor cells (nsc/npcs) as well as mouse nsc/npcs exposed to hpc. respirasome stability was assessed using blue native gel electrophoresis and mitochondrial metabolism assessed by measuring oxygen consumption in vitro (seahorse metabolic analyzer). exposure to mild hypoxia and induction of hif leads to stabilization of respirasomes, upregulation of hif, and modulation of mitochondrial metabolism. interestingly, overexpression of the ags isoform of cox a l, which has amino acid substitutions in residues mediating respirasome stability, recapitulates the effects of hypoxia on respirasome stability and mitochondrial metabolism without altering hif expression. targeting respirasome stability by modulating cox a l is a potentially novel neuroprotective target for treatment of ischemic injuries. testing of these hypotheses in pre-clinical models of stroke is on-going. acute stroke symptoms need timely diagnostics in order to ensure best outcomes. as a non-academic, community-based center located in rural western nc, where we are the regions only comprehensive stroke center, we developed a process to intake stroke patients quickly directly from ct to interventional radiology when applicable. a smooth transition reduces the quantity of time from imaging to interventional suite, ultimately reducing the time it takes to prepare to actively treat a patient. interventional radiology value stream mapping started in june . multidisciplinary team worked in multiple work groups to design and create "code ir stroke now". flow chart created to show multiple moving parts simultaneously, to streamline transition from er (sometimes this includes triage from the region also) to ir. an ir "ready" criteria was made, er and ir checklists, followed by post procedure debrief and treatment plans/order set to standardize care and documentation. first mock code ir was done / / , this was critiqued/perfected. "go live" date: / / . we continue process improvement today. in first three months, patients have gone through this process. average compliance for goal door to puncture < min went from . % to %. door to groin times reduced from minutes to minutes. our performance is minutes quicker than other comprehensive stroke centers ( m avg gwtg database). saved an average of million neurons per patient. total of million neurons saved on average since / / ! door to groin times can be reduced with streamline approach to care. multidisciplinary team approach, including house supervisors, anesthesia, switch-board in addition to the bedside staff and providers can make a smooth transition from the time a large vessel occlusion is identified to getting the patient to the interventional suite. activation of "code ir stroke now" page activates this team / . it is unknown whether antithrombotics for secondary stroke prevention in patients with acute ischemic stroke (ais) due to infective endocarditis (ie) reduce the rate of secondary ais or increase major bleeding. we conducted a multi-center, retrospective cohort study from - of patients with ais secondary to left-sided ie, separated into two groups (antithrombotic vs no antithrombotic). antithrombotics included antiplatelets and/or therapeutic anticoagulation. the primary outcome was a composite of recurrent ais and major bleeding. secondary outcomes included ais and major bleeding individually. a binary logistic regression model adjusted for age and native vs prosthetic valve involvement was used for outcome evaluation. the final analysis included patients ( antithrombotic vs no antithrombotic). median age was years and ( %) patients had prosthetic valve infections. infecting organisms were mostly methicillin sensitive s. aureus ( %) or streptococcus spp. ( %). valve repair/replacement occurred in ( %) patients. aspirin with or without another antithrombotic ( %) was the most common antithrombotic treatment. the primary outcome occurred in . % vs . % of patients with antithrombotics vs no antithrombotics, respectively (or . ; % ci . to . ). ais ( . % vs . %; or . ; % ci . to ) and major bleeding ( . % vs . %; or . ; % ci . to . ) were similar between groups. a subgroup analysis of aspirin monotherapy vs no antithrombotic yielded similar results for the primary outcome ( . % vs . %; or . ; % ci . to . ) and ais ( . % vs . %; or . ; % ci . to . ). major bleeding was increased, however ( . % vs . %; or . ; % ci . to . ; p= . ). antithrombotics after ais secondary to ie were not associated with a decrease in recurrent ais or an increase in major bleeding. aspirin monotherapy was associated with an increase in major bleeding without any reduction in ais. malignant hemispheric stroke (mhs) represents between - % of all hospitalized ischemic stroke in the united states. pooled analysis of european studies has demonstrated that decompressive hemicraniectomy (dchc) for mhs reduces mortality compared with conservative medical management and may also improve functional outcomes. these trials however, excluded patients with major medical comorbidities that might confound clinical outcomes. apache ii and sofa scores are validated icu scoring systems to help characterize disease severity and estimated hospital mortality. this study aims to evaluate apache ii and sofa scores in predicting outcomes for patients undergoing dchc for mhs. this is a single center retrospective analysis of patients who underwent early dchc for mhs between may through january at unc chapel hill. apache ii and sofa scores were calculated for the date of admission or date of first presentation to neurologic care. outcomes included mortality at discharge, mortality at day, and functional outcome at last follow up, up to one year. multivariate analysis included timing of surgery, age, laterality, presence of midline shift, hemorrhage or multiple territory infarction. we identified patients who met inclusion and exclusion criteria. the median age was ( to ), -nine percent of patients received surgery by hospital day . full statistical analysis is pending. our hypothesis is a positive correlation between icu severity scores and mortality. given apache ii and sofa scores capture the effects of acute and chronic disease that would affect patient recovery, we hope to provide a more comprehensive prognostication of outcomes following surgery to help guide physicians and family members of these patients in their decision-making process. we conducted this study to investigate the effects of decompressive craniectomy (dc) combined with hypothermia on mortality and neurological outcomes in patients with large hemispheric infarction. within hours of symptom onset, patients were randomized to one of the following three groups: dc group, dc plus head-surface cooling (dcsc) group and dc plus endovascular hypothermia (dceh) group. we combined the data of the dcsc and dceh group to dch group during analysis. the primary endpoints were mortality and modified rankin scale (mrs) score at months. there were patients in the dc group, patients in the dcsc group and patients in the dceh group. for all patients, the mortality at discharge and after months was . % ( / ) and . % ( / ), respectively. the dch group had lower mortality, but the difference was not statistically significant (at discharge, . % vs. . %, p= . ; months, . % vs. . %, p= . ). after months, patients survived, and . % of the surviving patients had good neurological outcomes (mrs score of - ). the dch group had better neurological outcomes, but this difference was also not statistically significant ( / , . % vs. / , . %; p= . ). the total number of patients experiencing complications in the dc group and the dch group was ( . %) and ( . %), respectively. treatment with hypothermia led to decreased mortality and improved neurological outcomes in lhi patients who received dc. a multi-center rct is needed to confirm these results. destiny ii investigated hemicraniectomy in patients -years and older for the treatment of malignant cerebral edema. we sought to describe the treatment effect of early hemicraniectomy in destiny ii, using number needed to treat to benefit (nntb) and benefit per hundred (bph) treated at and months. as an mrs of is generally undesirable, we also present nntb and bph excluding this outcome. for all possible dichotomizations of the mrs, net nntb was derived by taking the inverse of absolute risk difference, and net bph by multiplying absolute risk difference by . for benefits simultaneously across all disability transitions on the mrs, nntb, and bph, estimates were derived using joint outcome tables: ) algorithmic minimum and maximum and ) four independent experts. the expert data is presented as geometric mean. the algorithmic nntb was . (range . - . ) at -months and . ( . - . ) at -months, while bph was . ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months and . ( . - . ) at -months, and the bph was . ( - ), and . ( - ) respectively. excluding mrs the algorithmic nntb was . (range - . ) at -months and . ( . - . ) at -months, while bph was ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months, and . ( . - . ) at -months, and bph was . ( - ) and . ( - ) respectively. early systematic hemicraniectomy improves outcome (including mrs ) for every - patients treated. excluding patients with mrs , hemicraniectomy improves outcome for every . patients treated. the algorithmic range provides bounds to the data, while the expert geometric mean provides the most accurate point estimate. these data provide a powerful tool to describe the potential treatment outcomes to families during the first day following a malignant middle cerebral artery infarction. background cerebral bypass surgery is performed to restore, or revascularize blood flow to the brain. previous studies have not shown whether emergency surgical reperfusion therapy may be effective in acute ischemic stroke patients with large artery occlusion and hemodynamic deterioration. objective to evaluate the effect of emergency sta-mca bypass surgery on the outcome of hemodynamic compromised patients who had progressive or fluctuating stroke despite best medical treatments. we retrospectively reviewed the clinical and radiological data of consecutive patients treated by both emergency bypass surgery ( cases, . %) and elective bypass surgery ( cases, . %) due to large artery occlusion at a single center. the effect of surgical therapy was measured with the modified rankin scale (mrs) at months. clinical severity was evaluated by the national institutes of health stroke scale (nihss) between pre-and post-operative state. major perioperative complications were defined as any hemorrhagic stroke, myocardial infarction and death. results occlusive sites were the cervical internal carotid artery in ( . %) patients and the middle patients in emergency surgery group and ( . %) patients in elective surgery group. emergency bypass surgery improved nihss (preoperatively, [ - ] ; weeks postoperatively, [ - ]). major perioperative complications in days were happened in three patients ( . %) after emergency bypass surgery, and four patients ( . %) after elective bypass surgery. emergency revascularization surgery may be effective alternative treatment for acute ischemic stroke patients with hemodynamic deterioration refractory to maximal medical treatments without significant complications. larger randomized clinical study is needed to evaluate the effect of emergency revascularization surgery in acute hemodynamic deterioration. multiple studies have reported lower mortality rates in obese patients with various cardiovascular disorders, a phenomenon called as the 'obesity paradox'. such relationship has been largely unreported in patients with neurological pathologies especially stroke. this study reports the effect of obesity on prognosis in patients with ischemic stroke. analysis of national inpatient sample data ( - ) showed a total of , , patients discharged with primary diagnosis of is, icd- code .xx and .xx. patients with obesity were identified using agency of healthcare research and quality (ahrq) criteria. we used binary regression to compare inhospital mortality between obese and non-obese patients with ischemic stroke. from - , , , patients with ischemic stroke were identified of which . % were found to be obese. obese patients with ischemic stroke were more often younger, female, and african american as compared to caucasian. after risk adjustment for demographics, and baseline comorbidities, obese patients with ischemic stroke had lower observed in hospital mortality as compared with non-obese patients with ischemic stroke ( . % vs %, or: . ci= . - . p< . ). from an eleven year nationwide cohort of patients with ischemic strokes, we observed a significant protective effect of obesity and better prognosis including a lower mortality rate. more prospective studies are warranted to further analyze this counter-intuitive trend. very early mobilization of critical care patients improves outcome, length of stay, and patient satisfaction. data for efficacy of very early mobilization for stroke patients have been mixed, and there is limited outcomes data for patients mobilized within hours of receiving intravenous alteplase (iv tpa). the objective of this retrospective observational study was to determine if patients receiving iv tpa who were mobilized earlier were more likely to discharge home. medical records of ischemic stroke patients who received iv tpa between and at two urban facilities were reviewed for mobility protocol activities. patients who received endovascular treatment, were placed on comfort care day zero or one, mobilized after the first hours, and transferred out or left against medical advice were excluded. multinomial regression was used to determine if there were significant differences in patients' discharge status by time first mobilized, adjusting for stroke severity using the national institutes of health stroke scale (nihss), age and gender. of the patients included, . % (n= ) were female, mean age was . (± . ), and the median admit nihss was . [iqr: . , . ]. the median time first mobilized was . hours [iqr: . , . ], . % (n= ) of patients were discharged to home, . % (n= ), a skilled nursing facility (snf), . % (n= ), an inpatient rehab facility (irf), and . % (n= ) hospice or expired. there was suggestive, but inconclusive evidence for a relationship between time first mobilized and discharged to snf versus home (p=. ). for every one hour increase in time mobilized, patients were . ( % ci= . - . ) times more likely to be discharged to snf than home. this study reveals very early mobility is potentially efficacious after iv tpa. longer time to first mobility was associated with discharge to skilled nursing facility, although this was not statistically significant. medical management of cerebral edema after large volume stroke varies greatly across institutions. hypertonic saline has emerged as a common treatment strategy to attempt to reduce edema and theoretically prevent the need for decompressive hemicraniectomy. there is no established protocol for hypertonic saline administration and there have been concerns regarding safety. in a single-center, retrospective analysis we identified patients who received hypertonic saline for malignant edema after an ischemic stroke involving the entire hemisphere or diffuse middle cerebral artery (mca) territory. we compared patients who received continuous infusions of % or % hypertonic saline to those who received continuous infusions with boluses of . %. the primary endpoint was time to goal sodium ( ). secondary endpoints included the need for surgical decompression and adverse events. we included patients who received only continuous infusions of hypertonic saline and patients who received a combination of continuous infusions and bolus doses. we found no significant difference between number of patients who reached goal sodium ( vs respectively, p= . ) or time to goal sodium ( hours vs . hours, p= . ). there was a significant difference in the number of patients who underwent surgical decompression ( vs , p= . ). there was not a significant difference in the rate of acute kidney injury or development of acidosis between groups ( vs. , p= . ). both hypertonic strategies appear to be safe. bolus dosing, on review, was more often instituted during clinical deterioration, accounting for the higher rate of surgical intervention. we feel we can safely be more aggressive earlier in the clinical course to potentially avoid surgical decompression. furthermore, we may need to look more closely at our target sodium, evaluating whether it should be based on the patient's baseline sodium or a universal value. even though recanalization is strongly associated with improved functional outcomes and reduced mortality, clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. in the recent study, endovascular treatment(evt) has been demonstrated to improve functional outcome in patients with acute ischemic stroke (ais) within the time window of onset to or hours. however, beyond usual thrombolysis time window, early neurologic deterioration(end) related with proximal artery occlusion is not uncommon in ais. with this, we report ais case series treated with evt because of end related proximal artery occlusion. from january through march , all patients underwent iat for ais with anterior circulation stroke. among them, twenty-four patients underwent evt due to end. at admission, all twenty-four patients showed near to complete occlusion of a proximal artery and had diffusion-perfusion mismatch. mean age was . initial median initial national institutes of health stroke scale (nihss) was and nihss after end was . all patients had diffusion-perfusion mismatch over %. seven patients treated with iv-tpa before evt. good recanalization (tici b/ ) was achieved in . %. the hemorrhagic complication was seen in the follow-up computed tomography scan in of cases: three were hemorrhagic transformation, another was the subarachnoid hemorrhage. the thromboembolic mortality case. in our report, evt in ais with end achieved safe and successful recanalization. and successful recanalization was associated with good clinical outcome. we think evt could be a useful method in case of end in ais patients with proximal artery near to complete occlusion, even beyond usual to hours time window for evt. jugular bulb venous monitoring can provide information about cerebral hemodynamics and metabolism. we investigated the feasibility and clinical application of jugular bulb venous monitoring in acute ischemic stroke patients at neurocritical care unit. from march to june , we conducted jugular bulb venous monitoring in patients in a tertiary referral hospital. five patients were excluded; without ventilator care and other diseases than stroke. jugular venous catheters were placed in internal jugular vein by ultrasound-guided method. lactate, venous oxygen saturation (sjvo ), and arteriovenous oxygen saturation differnece (avdo ) were monitored every hours. metabolic derangement was defined when lactate level was more than . mmol/l. patients were divided according to presence of clinical deterioration. for long-term prognosis, modified rankin scale - at months were defined as poor outcome. twelve patients ( . %) showed metabolic derangement and they experienced more frequent clinical deteriorations compared to patients without metabolic derangement (n= , . % vs. n= , . %, p= . ). clinical deterioration was noted in patients, and lactate level was significantly higher in the presence of clinical deterioration group ( . ± . vs. . ± . mmol/l, p= . ). adjusting other potential variables (age, baseline stroke severity, sjvo , and avdo ), metabolic derangement was an independent factor associated with clinical deterioration (or . , % ci . - . , p= . ). meanwhile, poor outcome group (n= ) showed no difference on lactate level, but avdo were higher in poor outcome group ( . ± . v. . ± . , p= . ). avdo remained an independent factor for poor outcome after multivariable logistic regression analysis (or . , % ci . - . , p= . ). this study showed that lactate was associated with clinical deterioration during neurocritical care, whereas venous desaturation contributed to long-term prognosis. jugular bulb venous monitoring is a feasible tool in patients with acute ischemic stroke at neurocritical care unit. swift recognition of stroke symptoms, immediate access to testing and timely treatment plays a vital role in functional outcomes (middleton et al., ) . delays can postpone treatment and complicate recovery. delays at this facility included registration, order entry times, and imaging. pi included evaluating and eliminating interruptions, with a goal of reducing the time to treatment. process improvement (pi) utilized an evidence-based algorithm to improve performance metrics and treatment of acute strokes. setting was a suburban, ancc magnet recognized primary stroke center with beds in the ed that experiences , ed visits and , admissions per year. patients included in the acute stroke protocol presented with signs and symptoms of stroke and last known well within hours of symptom onset. participation included ed staff, and staff working in areas impacted by stroke care. code stroke was initiated for patients who fit the criteria. an overhead page was implemented notifying the team throughout the hospital. radiology would prioritize ct and call the ed as soon as ct was ready. in the meantime, ed team continued assessments. with ct resulted, the physician would determine whether the patient was eligible for tpa. the acute stroke protocol included a list of inclusion/exclusion criteria for tpa administration. other treatment requirements included reminders for frequency of vital signs, neuro checks and assessments. implementation began in may and the team began to see a significant decrease in ct times and better compliance of dysphagia screening and nih assessments. ct tat completed within minutes increased from % to %. nih stroke scale completion rose from % to %. compliance with completing dysphasia screening increased from % to %. results stem from a commitment to excellence from the entire team. pi continues to further improve care for stroke patients. induced hypertensive therapy (iht) has used to enhance cerebral perfusion pressure in subarachnoid hemorrhage and stroke, but there is no established indication for iht in ischemic stroke. we report the usage of iht in acute ischemic patients with hemodynamic instability caused by steno-occlusive disease of a main cerebral artery. we reviewed acute ischemic stroke patients with cerebral perfusion deficit due to intracranial and extracranial steno-occlusive disease. iht was applied for early neurological deterioration and maintained until hemodynamic instability was stabilized over hours or neurointervention including angioplasty and extracranial intracranial arterial bypass surgery were performed. patients were analyzed. territories of stroke were of anterior circulation of intracranial vessels, of posterior vessels, and of extracranial vessels. mean duration of ih therapy was . minutes. pre and post nihss score of ih therapy was . and . , respectively. patients ( . %) were showed improvement and patients ( %) were stabilized without further aggravation. patients revealed bradycardia. there was no fatal complication of therapy. patients were performed further treatment include bypass surgery, angioplasty, and stenting after ih therapy. at months follow up, patients showed good outcomes (modified rankin scale , , and ). iht may be safe and effective for the neurologic deterioration or progression of acute ischemic stroke with hemodynamic instability due to severe steno-occlusive disease of major cerebral artery. large randomized trials are needed to confirm this result. most patients with progressive stroke have a poor prognosis. the aim of our study was investigate the factors related with progressive neurologic deficit (pnd) in the patients receiving recanalization therapy for acute ischemic stroke. -month period, were enrolled. blood pressures (bps) at , , and hours after admission and bp variation (bpv) for the first hours were collected. variables associated with pnd were analyzed. among enrolled patients, patients showed pnd. the patients with pnd had higher systolic bps at , , and hours after admission and higher bpv than the others (p < . ). posterior circulation stroke was more prevalent in the patients with pnd (p < . ). in logistic regression analysis, pnd was independently associated with posterior circulation stroke [odds ratio (or) = . , p < . ] and systolic bp at hours after admission (or = . , p = . ). pnd may be associated with elevated systolic bp for the first hours after admission in the patients receiving recanalization therapy for acute ischemic stroke. telestroke has revolutionized stroke care delivery in the modern era. massachusetts general hospital (mgh) uses the most common model, the hub and spoke. the demonstration of superiority of endovascular therapy (et) with intravenous tpa over tpa alone for acute stroke patients with large vessel occlusions prompts a thorough assessment of telestroke's role in the delivery of et, particularly in terms of transferring patients to hubs capable of et. our primary objective was to examine associations between transfer time and clinical outcomes. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct who had nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate the primary predictor, transfer time (defined as the mgh arrival time minus the telestroke consult answered time, n= ). several clinical outcomes were explored by linear and logistic regression to determine association with transfer time. of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and ( %) underwent et at mgh. median transfer time was min, and median aspects decrease was during transfer. longer transfer time was associated with decreased likelihood of undergoing et (p= . ). however, transfer time was not significantly associated with aspects decrease during transfer. for those patients undergoing et, transfer times bore no association to day mrs. this study identifies an association between longer transfer time and decreased likelihood of undergoing et. reasons are varied, and are not clearly related to imaging progression alone. only % of transferred patients underwent et. more efficient spoke triage and transfer may improve the ratio of patients treated with et. these data provide an important perspective during this period of stroke triage evolution. intra-arterial thrombectomy (iat) has been approved for acute treatment of ischemic strokes (is). with the advent of several new devices for iat, this procedure has become more widely utilized with better outcomes. we performed this analysis to evaluate trends and predictors of utilization of iat over an year period. analysis of nationwide inpatient sample data ( to ) showed a total of , patients discharged with a primary diagnosis of is, icd- code .xx, and .xx. iat was ascertained by icd- procedure code . . independent predictors of iat were studied using binary logistic regression. the predictors included in the model were age, sex, race, teaching status, and insurance type. results or . % of is patients received iat. mean age of patients receiving thrombolysis was . years. percentage of is patients receiving iat has consistently increased from . % in to % in . we also observed significant year to year decrease in mortality among patients receiving iat. in , . % of iat patients died as compared to . % in . using binary logistic regression, the statistically significant independent predictors of iat utilization were age (or= . , p= . ), female gender (or= . , p= . ), insurance type as compared to medicare (private insurance or= . p= . , and self-pay or= . p= . ). as compared to caucasians, african americans were less likely to receive treatment (or= . p= . ). also, a teaching hospital was found to be more likely to administer iat as compared to a non-teaching hospital (or = . , p= . ). is patients with younger age, female gender, private insurance and patients admitted to teaching hospitals are more likely and african americans are less likely to receive iat. this study showed that iat utilization has increased significantly since with a steep decline in the in-hospital mortality. this may point to improved iat devices and better patients' selection. telestroke plays an integral role in stroke care. nationally the most common model is the hub and spoke, which is used at our institution. understanding telestroke's role in the transfer of candidate patients for endovascular therapy (et) is critical to minimizing delays. our primary objective was to evaluate predictors of transfer delay. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct with nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate transfer time (the mgh arrival time minus the telestroke consult answered time, n= ). ideal time was calculated using google maps incorporating date/time information for ground transfers and straight line distance at mph for helicopter transfers. ideal time was subtracted from actual time to calculate delay, accounting for distance, mode of transport, weather, and traffic. analysis of covariance was used to explore possible predictors of delay (night vs. day, weekend vs. weekday, tpa delivery at spoke). of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and underwent et. a significant proportion of the variation in delay was explained by the predictors (f= . , p< . ). nocturnal transfer ( - hrs) was associated with significantly longer delay ( . additional minutes relative to daytime transfers, p< . ). weekend vs. weekday transfer and tpa delivery at spoke hospital did not contribute significantly to model variance. our findings highlight the importance of refining protocol approaches. nocturnal transfers were associated with substantial delay relative to daytime transfers. in contrast, delivery of tpa was not associated with delays, underscoring the impact of effective protocols that are in place. metrics and protocols for transfer, especially at night, may have a positive impact on transfer times. the use of anticoagulant therapy in the acute stage of ischemic stroke is controversial. novel oral anticoagulant (noac) is effective in preventing recurrent embolism in patients with non-valvular atrial fibrillation (nvaf), but the risk of hemorrhagic transformation is the major concern for its early use in ischemic stroke. we aimed to study the use of noac in patients with acute ischemic stroke and nvaf. patients with acute ischemic stroke and nvaf, who were admitted to our acute stroke unit from to , were recruited in this single-centre cohort study. the timing of initiation of noac is at the discretion of the treating physician based on the stroke severity and infarct size. nvaf attributed to . % ( / ) of all ischemic stroke cases. the early recurrent embolism rates were . %, . % and . % at one week, two weeks and one month respectively. noacs were prescribed in patients. noacs were initiated within one week in patients ( . %). the median time to noac initiation were five days (iqr . - . ), nine days (iqr . - . ) and days (iqr . - . ) for patients with no/small-sized infarct, moderate-sized infarct, and large-sized infarct respectively. at one month, two patients had recurrent ischemic stroke despite treated with noac. only one patient, who had a large-sized infarct, developed symptomatic hemorrhagic transformation. early use of noac in ischemic stroke appears to be safe. further large prospective studies are required to evaluate the risk and benefit of noac use in acute ischemic stroke. osmotherapy (hypertonic saline or mannitol) is the mainstay of available therapy to counter cerebral edema that can develop after large hemispheric infarction. in a post-hoc analysis of the games-rp trial, we hypothesized that patients with large infarction, treated with intravenous glyburide, might require less osmotherapy than placebo treated patients. games-rp was a multi-center prospective, double blind, randomized, placebo controlled study which enrolled patients with large anterior circulation infarction. patients were randomized to iv glyburide administration (biib ; n= ) or placebo (n= ) with target time from symptom onset to drug infusion decompressive craniectomy (dc), or both. total bolus osmotherapy dosing was quantified by an "osmolar load" (volume in l * osmolarity in mosm/l). of the subjects, the percentage of patients who received bolus osmotherapy did not differ between the glyburide and placebo treated subjects ( % v. %; p= . ). there was no difference in mean total osmolar load received (mosm) or hours from drug bolus to osmotherapy administration. overall, subjects received osmotherapy. the baseline dwi lesion volume (ml) was significantly larger in the osmotherapy treated group ( . ± . v. . ± . ; p= . ). the presence of adjudicated malignant edema on imaging was more common in the osmotherapy group ( % v. %, p= . ), as was dc ( % v. %; p< . ). among patients with adjudicated clinical neurologic deterioration from edema, % (n= ) did not receive osmotherapy. treatment with iv glyburide was not associated with less osmotherapy, possibly due to a ceiling effect resulting from the large infarct volumes. however, osmotherapy use was associated with larger infarct volumes, malignant edema, and higher incidence of dc. use of osmotherapy did not always follow the appearance of clinical or radiographic malignant edema. acute ischemic stroke patients receiving intravenous alteplase (iv-tpa) are placed on bedrest for hours or longer due to provider fear of worsening stroke symptoms from decreased cerebral perfusion. this is based on medical uncertainty and lack of robust studies, despite american stroke association (asa) recommendations for mobilization when hemodynamically stable. this retrospective observational study evaluates very early mobility in acute ischemic stroke patients post iv-tpa while evaluating for change in nihss. medical records of ischemic stroke patients who received iv-tpa between and at two urban hospitals were reviewed for mobility protocol activities. patients who were given endovascular treatment, placed on comfort care on day zero or one, mobilized after the first hours, transferred out or left against medical advice were excluded from the analysis. multiple linear regression was used to determine if those patients mobilized earlier saw a greater change between nihss at admit and hours post iv-tpa administration, adjusting for age and gender. of the patients included in the final analysis, . % (n= ) were female, mean age was . the multiple linear regression results showed no significant relationship between change in nihss from admit to hours post iv-tpa and earlier mobilization, after adjusting for age and gender (ß= - . change in nihss points per hour; p= . ). this study reveals early mobility does not worsen stroke symptoms or severity based on nihss. this suggests that very early mobility of patients after iv-tpa is safe as recommended by asa. interhospital transfers to a stroke center following iv-tpa administration are increasingly common. however, no studies have evaluated icu needs in these transfer patients and such understanding may have a significant impact on resource utilization. the aim of this study is to compare the frequency, timing, and nature of icu-level needs in post-iv-tpa patients that were transferred versus those who present directly to the admitting hospital. retrospective chart review of consecutive, tpa-treated ischemic stroke patients admitted to the icu at a comprehensive stroke center servicing a large telestroke referral network from / to / was performed. we evaluated patient demographics, stroke characteristics, and icu needs between transfer and non-transfer patients before and after icu admission. results patients were admitted to the icu post-tpa. patients ( . %) were transferred from an outside hospital, of which patients had icu needs ( . %). this frequency of icu needs was no different when compared to the non-transfer patients ( / , . %, p = . ). similar icu needs were observed for each specific icu intervention between transfer and non-transfer patients (iv antihypertensive, vasopressor requirement, iv rate control, respiratory support, ia therapy, icp monitoring, hypertonic therapy, and neurosurgical intervention, all p > association with icu needs (or . in transfer patients, or . in non-transfer; both p < . ). transferring post-iv-tpa patients is not associated with increased icu needs. about one-half of post-tpa patients do not have icu needs, and these patients typically have milder stroke severity. our data supports the safety of transferring post-tpa patients, and to potentially monitor a subgroup of these patients in a non-icu setting. the ability to appropriately triage post-tpa patients may lead to more efficient and cost-effective stroke care. stroke patients requiring decompressive craniectomy remain at high risk of prolonged mechanical ventilation as well as ventilator associated pneumonia (vap). early tracheostomy placement may provide a reduction in the duration of mechanical ventilation however prediction of those who ultimately require a tracheostomy remains a clinical challenge. a preoperative assessment of tracheostomy dependence may help to guide decision making. the authors compare key outcome data after early versus late tracheostomy and develop a preoperative decision-making tool to predict postoperative tracheostomy dependence. a subsequent validation utilizing a decision tree analysis applied prospectively is ongoing and will be presented. we performed a retrospective analysis of prospectively collected registry data and developed a propensity weighted decision tree analysis to predict tracheostomy requirement utilizing factors present prior to surgical decompression. outcomes include probability functions for icu los, hospital los, and mortality based on data for early ( day) tracheostomy. a subsequent validation of the decision tree is being applied prospectively to evaluate its predictive value. a total of surgical decompressions were performed on patients with acute ischemic or spontaneous hemorrhagic stroke between - . forty eight patients ( . %) required a tracheostomy, whereas ( . %) developed vap, and ( %) survived hospitalization. mean icu and hospital los were . and . days respectively. utilizing gcs, sofa score and hydrocephalus presence, our decision tree analysis provided a % sensitivity and % specificity for tracheostomy prediction. early tracheostomy conferred significantly fewer ventilator days (p< . ) and shorter hospital los (p= . ) with similar vap and mortality rates between groups. early tracheostomy shortens duration of mechanical ventilation and length of stay following surgical decompression for stroke, however without a demonstrable impact in mortality or vap rates. a preoperative decision tree awards a practical tool that may provide insight to guide preoperative decision-making with patient families. patients suspected acute stroke are critical in time delay of endovascular or intravenous thrombolytic therapy. prehospital notification from emergency medical services (ems) may shorten the door to recanalization time. the 'brain saver', web-based prehospital notification system could reduce the time interval from symptom onset to recanalization. beginning in march , stroke team consisted of stroke specialized doctors, nurses and radiologists of multi departments received direct alarms via smart phone application from paramedics of ems about transport information of patients with suspected stroke. we compared baseline characteristics and prehospital/ in-hospital delay time in stroke patients treated with intravenous thrombolysis or endovascular treatment for months with and without ems use brain saver protocol. patients ( patients with protocol and patients without protocol) were enrolled in this program. the patients who used brain saver had shorter median onset-to-arrival times ( minutes versus minutes, p < . ) and in in-hospital delay time ( minutes versus minutes, p<. ). prehospital notification by brain saver was associated with shorter median door-to-imaging time ( minutes versus minutes, p<. ), door-to-needle time ( minutes versus minutes, p <. ), door to puncture time ( minutes versus minutes, p < . ) we found that prehospital notification was associated with faster door-to-imaging time, door-to-needle time and door-to-puncture time in patients presenting within hours of symptom onset. close collaboration between stroke team in hospitals and the ems system gives stroke suspected patients an in-time emergency care system. infection is a common complication in the acute phase after ischemic stroke. furthermore, malnutrition is associated with unfavorable outcome in patients with stroke. therefore, we investigated that premorbid undernutrition identified by objective and quantitative method, nutritional risk index (nri) was related to the risk of infection after ischemic stroke. a consecutive patients who were admitted within days after ischemic stroke onset between october and october were included. we assessed initial nutritional status using nri, and nri formula as follows: nri = ( . × serum albumin, g/dl) + { . × present weight (kg)/ideal body weight (kg)}. the patients were categorized into three groups on the basis of nri [no risk (nri > . ), moderate risk (nri . - . ), and severe risk (nri < . )]. we compared the clinical characteristics and nri according to the presence of infection. among the included patients (mean age, . years, male, . %), ( . %) patients experienced infection during hospitalization. the rate of pneumonia was . % (n= ), and the rate of urinary tract infection was . % (n= ) among total infection. the proportion of lower nri patients (moderate risk and severe risk) was significantly greater in the infection group ( . % vs. . % and . % vs. . %, p < . ). moreover, higher nri patients were less likely to be admitted to the intensive care unit ( . % vs. . % vs. . %, p = . ). a multivariate analysis revealed that lower nri groups had a higher risk of infection [odds ratio ( % confidence interval); moderate risk . ( . - . ); severe risk . ( . - . ), p for trend = . ]. our study demonstrated that the lower nris predicted infection complications and severe infections after ischemic stroke. this suggests that assessment of nutrition depletion could be a useful predictor and a modifiable risk factor for infection following stroke. cyp c plays a major role in the metabolism of the clop[idogrel. cyp c generates an active oxidized metabolite of clopidogrel that exerts antipl;atelet activity by inhibiting p y reeceptor. the major alleles of the cyp c gene are * , * , * and * and approximately % of caucasians and % of asians have one or more loss of function alleles in this study, patients with at least two * or * allels were classified as poor metabolizer(pm), those with one * or * allele were classified as intermediate metabolizer(im), and those without a * , * or * alleles were classified as extensive metabolizer. in addition. those with (* /* or * /* ) were classified as unknown metabolizer. stroke patients were enrolled for this trial. the mean age was years, and % were women. % had a history of hypertension, % of dm and % of dyslipidemia. of the participants, % were classifies as em, % as um, % as im, % as pm and % as unknown metabolizer. % had good genotype for clopidogrel metabolism and % had poor genotype. there were no significant diffirences in the demographic and clinical findings between the good and poor genotype groups the prevalence of cyp c polymorphisms is different according to the ethnicity. the racial difference in platelet function may lead to diffrerences in the treatment as well as new targets for antiplatelet therapy the social brain hypothesis is an evolutionary theory proposing that the number of contacts in a primate's social network is proportional to neocortical volume. we tested the hypothesis in a patient population with social network data before and after vascular events. we studied whether social network indices would decrease after stroke, but not after myocardial infarction (mi), as anticipated by the theory. we examined trajectories of the lubben social network scale score (range - , higher values indicating larger network) before and after vascular events in participants from the cardiovascular health study. we used a repeated measures design with linear mixed models to compare the change in social network score before and after events in persons with ischemic stroke and with mi. over a mean of . years of follow-up for stroke and . years for mi, we examined an average of social network scores for each participant. we controlled for socio-demographics, baseline cognitive function, and comorbidities. social network scores declined significantly after stroke (an additional - . points every year, % ci - . , - . , p= . ), but not after mi (- . , % ci - . , . , p= . ) compared to the baseline slope in fully adjusted models. social network score declined more steeply after stroke than after mi, even after adjusting for potential confounders. these findings support the social brain hypothesis but do not address mechanism. shrinkage of the social networks may be a specific target for interventions to optimize recovery in vascular diseases, particularly stroke. emergency neurological life support (enls) protocols are an essential component to assessment and management of patients within the first hours of the neurological emergency. with increasing focus on emergent endovascular treatment for large vessel occlusion (lvo) in acute ischemic stroke our institution incorporated stroke van assessment as part of the enls acute stroke initial assessment protocol. stroke van screening tool was taught to all nurses in the emergency department (ed) who triage stroke. all patients who presented to the ed with suspected stroke had a van assessment completed prior to ed physician evaluation and ct imaging. patients with weakness in addition to visual changes, aphasia, or neglect were considered van + and triaged immediately to ct angiogram head/neck with immediate notification to the neurointerventionalist. a sample of patients presenting to the ed as a stroke alert over an month time period were utilized. using the stroke van assessment tool was found to improve time to identification of lvo by reducing time from arrival to cta for van positive patients from minutes pre-intervention (n= ) to minutes post-intervention (n= ). this was a significant decrease in time to identification of patients presenting with lvo (p< . ), improving time to endovascular treatment. incorporating stroke van as part of the acute stroke assessment protocol improved identification of patients presenting with lvo, decreased time to cta imaging and improved time to endovascular treatment which is well documented with improved neurological prognosis. time is essential in neurological emergencies. the van assessment is quick and easy to perform, requires no scoring or calculations, and is the only lvo screening tool tested in the ed by ed nurse and physicians. we suggest incorporating stroke van to the enls acute stroke protocol as a way to improve identification of lvo and improve time to endovascular treatment. elevated blood pressure (bp) is known to be related to hemorrhagic transformation (ht) after ischemic stroke. however, the effect of bp variation on the ht remains unclear, especially in patients with successful recanalization after mechanical thrombectomy. therefore, we investigated the relationship between bp and ht after mechanical thrombectomy following ischemic stroke. a consecutive patients with acute ischemic stroke and successful recanalization (tici b or tici ) were included for the analysis between january and november . the information on bp was obtained over the first hours using various parameters including mean, maximum (max), minimum (cv), and successive variations (sv) for systolic, diastolic bp, and mean bp. we defined major ht as a parenchymal hematoma type (ph ). among the included patients (age, . ; and male, . %), patients ( . %) developed major ht over the first hours after successful recanalization. systolic bp max-min was significantly increased in patients with major ht compared to those without major ht ( . mmhg vs. . mmhg, p = . ) while other bp parameters were not. in addition, systolic bp max-min was significantly associated with symptomatic ht (n= , . %, p = . ). after adjusting for confounders, systolic bp max-min was independently associated with major ht (odds ratio, . ; % confidence interval, . - . ). our results demonstrated that absolute change of systemic bp over the first hours was associated with major and symptomatic ht after successful mechanical thrombectomy after acute ischemic stroke. this suggests that maintaining stable systolic bp is an important factor in possibly preventing major ht after successful recanalization. the benefits of intravenous tissue-plasminogen activator in acute ischemic stroke are highly timedependent. however, there are so many cross-departmental tasks to eligible patent that many stroke centers have difficulty achieving the guideline recommended -hour door-to-needle (dtn) time. we have developed web based visual task management system called "task calc. stroke" (tcs) by using information and communication technology. herein, we performed a trial installation and preliminary evaluation of tcs. the application software of tcs was designed to run on the google cloud platform. tcs alerts the relevant hospital staff to the patient's arrival condition and time, and displayed tasks to be performed and its treatment status by changing color in real time on networked wall-mounted smart devices in the several relevant departments. we started a trial installation of tcs during the daytime from august . we compared lead times before (august to july ) and after (august to july ) trial installation of tcs. trial installation of tcs in our hospital showed successful information sharing. a total of patients included (pre: , post: ) . after the installation, significant reductions occurred in the median time from door to complete blood count time [ . vs. . min, p < . ] and a trend toward a reduction from door to needle time [ . vs. . min, p = . ]. tcs may be useful tool to reduce the lead times of acute stroke patients. tcs is a new approach that has the potential to promote efficiency for acute stroke care. prior history of intracranial hemorrhage (ich) has been considered a contraindication to administration of intravenous recombinant tissue plasminogen activator in acute ischemic stroke, per the original activase fda label and aha/asa guidelines. however, limited data are available on the risks of lysis in patients with prior ich. we performed a cross-sectional study of adult patients who received thrombolysis, using administrative claims data on admissions to acute care hospitals in california between - . diagnosis codes were used to identify patients who received thrombolysis, and to ascertain ( ) a prior diagnosis of ich, including intraparenchymal hemorrhage (iph), subarachnoid hemorrhage (sah), subdural hematoma (sdh), or epidural hematoma (edh); and ( ) relevant comorbidities, including hypertension, smoking, diabetes, heart failure, atrial fibrillation, renal disease, malignancy, and demographic data. we used univariable and multivariable logistic regression to model the odds of in-hospital mortality as a function of prior ich, after adjusting for potential confounders. , patients received thrombolysis during the study period (mean age [sd ], female count , [ %]). of these, patients ( . %) had a documented diagnosis of prior ich on admission. inhospital mortality was % overall, . % for patients without prior ich, and . % for patients with prior ich. in multivariable analysis, all prior ich subtypes remained independently associated with in-hospital mortality, including iph (or . , ci . - . , p < e- ); sah (or . , ci . - . , p < e- ); and sdh (or . , ci . - . , p= . ). only patients had edh and testing was not possible. . % of patients who received thrombolysis during the study period had prior diagnosis of ich. prior ich was found to be significantly associated with in-hospital mortality regardless of ich subtype. we evaluated the association between early neurological improvement (eni) after ert and time spent from symptom onset to recanalization, according to the degree of collateral circulation measured using multiphase cta. patients with anterior circulation occlusion who underwent ert based on a non-contrast brain ct and multiphase cta were evaluated. collateral status was evaluated using a pial arterial filling score, which was developed into a six-point scale. eni was defined as equal to more than %, or as an -point decrement in nihss from baseline. neurological statuses at day and at day (or discharge) were determined by a certified neurologist using nihss. the collateral circulation degree measured by multiphase cta was inversely correlated with baseline stroke severity (p= . ). the proportion of eni at day was significantly lower in patients with poor collateral status (score ~ ) according to the time from symptom onset to recanalization ( - , . %; - , . %; > , . %; p= . ). however, the proportion was similar in patients with a good - , . %; - , . %; - , . %; > , . %; p= . , day or discharge; - , . %; - , . %; - , . %; > , . %; p= . ). collateral status was the best predictor for eni after ert. eni was achieved in only ( . %) patients with poor collateral status, and their time from symptom onset to recanalization was more than minutes. the time window for ert might differ according to baseline collateral status measured by multiphase cta. the current time window for ert within hours from symptom onset to groin puncture could be atrial fibrillation (af) is the most common cardiac arrhythmia among adults. despite of the proven advantage in primary and secondary stroke prevention in patients with af, antithrombotic therapy has been reported to be still underused in many countries. however, there is a little data about the incidence of af and any changing pattern of antithrombotic therapy among patients with af over the past decade in korea. data source for this study were obtained from the nationwide sample cohort comprising , , individuals ( % of entire population in korea) which were established by nationwide health insurance system. during a -year follow-up period, there was , developed af ( . %). the incidence of patients with af remained relatively constant during study period ( . % in vs . % in ). the proportion of patients with antithrombotic therapy increased from . % in to . % in significantly (p for trends < . ). however, the proportion of patients with antiplatelet agents was higher than with oral anticoagulation. af steadily increased over recent years in korea. however, only . % of af patients were receiving antithrombotic therapy. our study demonstrated that there was huge gap between the clinical practice and treatment guideline in antithrombotic medication for af patients in korea over the past decade. ohiohealth (oh) possesses one of the nation's largest neuroscience programs and is the leading volume provider of stroke care in ohio. oh is comprised of hospital-based sites, primary stroke centers, comprehensive stroke center, and a virtual health (vh) stroke network that serves hospitals throughout the state. in august , stroke services at ohiohealth were restructured to enable dedicated clinical time for vh providers, require expertise, training, and quality review participation for stroke responders, streamline activation algorithms to limit hand-offs, and eliminate identified barriers to vh consultation. a month interim analysis was planned to assess the impact of these changes (termed "stroke . "). comparative analyses were performed between the first months of stroke . and the similar time period of the year prior to restructuring. pre-defined metrics included consultation volume, vh response time, iv-tpa time to treatment, research enrollment volume, endovascular referral rate and time to treatment, ischemic stroke (is) observed : expected (o:e) mortality data, and patient retention rate at associate vh sites. during the first months of stroke . , encounters were seen (historical ) with a mean activation to vh log in of . minutes. both volume of patients treated with iv-tpa ( vs. , p< . ) and mean treatment times ( vs. minutes; p< . ) were significantly reduced. mean time to endovascular intervention was less during stroke . ( vs. minutes, p < . ). system-wide o: e mortality was reduced after restructuring ( . vs. . , p< . ), accounting for additional lives saved. acute stroke research enrollment doubled ( vs. ) during this same period. transfer rates to vh hub were unchanged ( vs. %, p = . ). strategic changes in staffing, expertise, vh structure, and access can have profound and positive changes on a well-functioning stroke system. strokes due to cns fungal infections (scfi) are often misdiagnosed. retrospective study of electronically-extracted records in patients with strokes & positive fungal studies, from cerebrospinal fluid (csf) or brain biopsy. other stroke etiologies were excluded. thirteen patients had scfi by a priori exclusion & inclusion criteria. nine were males. mean age was + years. symptoms were mild [nihss ( , . ) (median and iqr)]. focal deficits & headaches (both . %) were common. seventy-percent were immuno-compromised (medications, malignancy, transplant recipients). clinical course was indolent in . %. seventy-percent had poor outcome ( -ltac, -snf, -dead). ninety-two percent had csf pleocytosis (range: - ) while % had csf glucose less than mg/dl (range: - ). seventy-five percent had lymphocytic predominance. seven strokes were from yeasts ( -cryptococcus, -coccidiomycosis, -histoplasma, -candida) and from molds ( -zygomycetes, -aspergillus). sixty-two percent had posterior circulation involvement ( . % yeast vs % molds). there was lepto-meningeal enhancement in % of yeast vs. % of molds infections (p= . ). the basal ganglia (bg) was involved in % of intravenous-drug users (ivdu) vs. % of non-ivdu (p= . ). one had abnormal cns vessel imaging directly attributed to the ischemic lesions. in this series, patients were young, immunocompromised or ivdu. stroke sizes & clinical deficits were modest with no angiographic evidence of vasculitis. majority had csf pleocytosis & hypoglycorrhachia. posterior circulation involvement was typical. lepto-meningeal meningitis was only seen in yeast infections. the bg was spared in non-ivdu but common in ivdu. mechanism of stroke in yeast infections is probably from meningitis & secondary involvement of small perforating branches. mechanism in mold infections in immuno-competent ivdu is probably direct angio-invasiveness in small vessels of the bg. outcomes are poor in spite of therapy. scfi should be considered in selected cases of cryptogenic (recurrent or progressive) strokes with clinical, csf and mri features described. life-threatening bleeding requires prompt reversal of factor xa (fxa) inhibitors. their anticoagulant effects can be reversed with the antidote andexanet alfa. the efficacy of andexanet to reverse bleeding in an apixaban anticoagulated porcine trauma model was investigated. after ethical approval, male pigs (n= ) were given apixaban for days ( mg daily); the sham group (n= ) received placebo. standardized polytrauma by blunt liver injury and bilateral femur fractures were inflicted. minutes post-trauma, animals were randomized (n= per group) to a single andexanet bolus ( , mg), a bolus ( , mg) + infusion ( , mg over hours) regimen, or vehicle (control). blood loss (bl) and hemodynamics were monitored over hours or until death and analyzed by anova (mean±sem). apixaban anti-fxa levels were ± ng/ml with no differences between anticoagulated groups prior to injury. bl in the sham animals was ± ml minutes after injury (total bl ± ml at "x" hours; % survival). anticoagulation with apixaban significantly increased bl minutes after injury ( ± ml; p< . ). controls exhibited a total bl of , ± ml with % mortality (mean survival time = minutes). treatment with a bolus or bolus+infusion of andexanet was associated with a significant reduction in bl versus sham (p< . ) and % survival. two hours after injury, apixaban anti-fxa levels in bolus animals were ± ng/ml, whereas the bolus+infusion regimen resulted in levels of ± ng/ml (p< . ). hemodynamic parameters (e.g., cardiac output) and markers of shock (e.g., lactate) recovered to pre-trauma levels in andexanet-treated groups. clinically and macroscopically, no adverse events were observed. in this study, andexanet effectively and safely reversed apixaban anticoagulation and reduced bl induced by severe trauma under anticoagulation. the bolus alone had a similar impact on survival and bl as the bolus+infusion regimen in this lethal porcine model. current guidelines for management of pain, agitation, and delirium in mechanically ventilated patients in the intensive care unit (icu) recommend an analgesia-first approach to sedation management. however, these guidelines are derived from non-neurologic patient populations leaving uncertainty in their generalization to this population. the purpose of this study was to evaluate implementation of an analgesia-first sedation clinical pathway in the neuroscience icu. a single-center cohort study was performed within the neuroscience icu including patients mechanically ventilated for greater than hours over a time period of three months before and after clinical pathway implementation. providers were educated on the pathway with emphasis on frequent assessment of richmond agitation-sedation scales (rass), critical care pain observation tool (cpot), and confusion assessment method-icu (cam-icu) scores and systematic de-escalation of sedatives through adequate pain and delirium management. outcome measures included frequency and magnitude of rass, cpot, and cam-icu scores, analgesic and sedative medication prescription/administration per day of mechanical ventilation (mv). a total of patients met inclusion criteria ( pre-pathway and post-pathway). there was no statistically significant difference in the median frequency of rass ( . vs. . ) and cpot ( . vs. . ) assessments per day of mv or in median rass (- vs. - ) and cpot ( vs. ) scores. mean acetaminophen usage increased from . % to % (p< . ) post-pathway implementation. there was no statistically significant difference in mean opioid or propofol usage, however a trend toward increased morphine and decreased propofol usage was observed post-pathway. analgesia-first sedation pathway implementation trended towards increased opioid analgesic and decreased sedative use, however only increased acetaminophen usage was significant. this highlights challenges in changing unit-based practices and future directions include focus on the frequency and reliability of pain, agitation and delirium assessment. interdisciplinary coordination and communication remains necessary for effective unit-based practice changes. andexanet alfa (andexanet), a modified, recombinant human factor xa (fxa) molecule, binds and sequesters fxa inhibitors. in a phase study of apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, andexanet rapidly reversed pharmacodynamic markers of anticoagulation. here, the ability of andexanet to reverse the anticoagulant activity of betrixaban was investigated. in a randomized, double-blind, phase study in healthy subjects, andexanet (n= ) or placebo (n= ) was administered intravenously following mg po qd betrixaban to steady state ( days). in cohort (andexanet bolus only), subjects (n= ) received a -mg andexanet bolus hours after the last betrixaban dose (day ) or placebo (n= ). in cohort (andexanet bolus plus -hour infusion), subjects (n= ) received a mg andexanet bolus hours after the last betrixaban dose, followed by a -hour infusion of andexanet ( mg/min) or placebo (n= ). endpoints included safety and pharmacodynamic markers of anticoagulation reversal. following treatment with betrixaban in cohort , andexanet rapidly decreased anti-fxa activity from . ± . to . ± . ng/ml, while the anti-fxa levels following placebo were largely unchanged ( . ± . to . ± . ng/ml). unbound betrixaban plasma concentration decreased from . ± . to . ± . ng/ml with andexanet, but remained constant following placebo administration ( . ± . to . ± . ng/ml). similar results were observed in cohort following andexanet bolus ( minutes after bolus), and the effects were maintained during the -hour infusion of andexanet. for cohort , thrombin generation was restored in / ( %) and / ( . %) of andexanet-administered and placebo subjects, respectively. for cohort , thrombin generation was restored in / ( . %) of andexanet subjects versus / ( . %) of placebo subjects. andexanet was well tolerated; there were no thrombotic events or serious/severe adverse events. andexanet was well tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. these and other studies indicate that andexanet could be a universal antidote for fxa inhibitors. andexanet alfa (anxa), a recombinant human fxa molecule, reverses the anticoagulant activity of fxa inhibitors. in studies of healthy volunteers, anxa showed dose-dependent reversal of direct and indirect fxa inhibitors in tissue factor (tf)-initiated thrombin generation (tg). we compared rivaroxabaninduced inhibition of tg initiated via the extrinsic pathway (tf) versus intrinsic pathway (non-tf). tf-initiated tg was measured using a calibrated automated thrombogram (cat) and ppp-reagent. non-tf-initiated tg was measured using cat and actin fs. anti-fxa activity was measured using an anti-fxa chromogenic assay. pooled plasma was spiked with rivaroxaban or rivaroxaban+anxa; tg, anti-fxa activity, and clot formation were measured. for low tf-initiated clot formation, thromboelastography profiles were measured. anxa alone had minimal effect on endogenous thrombin potential (etp). anxa fully reversed rivaroxaban-induced anticoagulation in the actin fs assay, independent of anxa-tfpi interaction. modulation of tf activity was assessed by correlating etp versus anti-fxa activity with rivaroxaban or rivaroxaban+anxa. rivaroxaban dose-dependently inhibited tf-initiated tg as anti-fxa activity increased. at similar anti-fxa levels, rivaroxaban+anxa had higher etp than rivaroxaban alone, but not in the actin fs assay. clot formation was studied in plasma using thromboelastography without rivaroxaban. anxa did not affect thromboelastography parameters, with/without recombinant tissue plasminogen activator (rtpa). when low tf initiated clot formation without rtpa, anxa reduced the thromboelastography-r parameter, but not maximum amplitude. the fibrin clot was lysed at low rtpa, resulting in well-segregated coagulation and fibrinolysis. with the optimal rtpa, fibrin clots formed at each tf concentration were compensated by the fibrinolytic activity of rtpa. without a fxa inhibitor, anxa had minimal effect on tf or actin fs-initiated tg with no direct effect on rtpa function. anxa dose-dependently and completely reversed rivaroxaban-induced inhibition of tg initiated by intrinsic or extrinsic pathways, but had different effects on etp due to the anxa-tfpi interaction. there is a growing body of evidence relating poor outcomes to off-hour management. studies investigating the effect of overnight extubation (oe) have produced mixed results, and limited data is available for brain-injured patients. there may also be tendency to limit oe due to decreased staffing levels at night. we sought to determine the safety of oe and risk factor profiles associated with extubation failure (ef) in this cohort. we conducted a retrospective review of mechanically ventilated patients admitted to a single-center in-house database. exclusion criteria included limitations in care, tracheostomy placement, selfextubation, and death prior to extubation. the primary outcome was ef defined as non-elective endotracheal intubation within hours. ef rates were compared between daytime ( am - : pm) and overnight ( pm - : am) extubation cohorts. in-hospital mortality served as a secondary outcome. amongst identified patients, ( . %) underwent daytime extubation (de) and ( . %) oe. ef was indifferent between de and oe ( . % and . % respectively; p= . ). however, multivariable adjustment for clinical severity indicators suggests higher ef for oe (or: . , ci: . - . ; p= . ). compared to de, oe was more likely performed in elective post-operative patients ( . % vs . %; p= . ) with lower apache-ii scores (median vs ; p= . ), and shorter durations of mv (median . vs . days; < . ). higher apache-ii score, longer duration of mv, and admission diagnoses of acute vascular injury or neuromuscular disease were associated with ef. there was no difference in mortality (p= . ). in our cohort, oe was not associated with increased ef or mortality. our results suggest that oe can be performed safely if standard extubation criteria are met in low-risk patients. these data provide a basis for subsequent more robust studies. case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or takotsubo cardiomyopathy, in the setting of acute neurological diseases such as subarachnoid hemorrhage. the nature of the association between various neurological diseases and takotsubo remains incompletely understood. we performed a cross-sectional study of all adults in the national inpatient sample, a nationally representative sample of u.s. hospitalizations, from - . our exposures of interest were primary diagnoses of acute neurological disease, defined by icd- -cm diagnosis codes. our outcome was a diagnosis of takotsubo cardiomyopathy. binary logistic regression models were used to examine the associations between our prespecified neurological diagnoses and takotsubo cardiomyopathy after adjustment for demographics. we identified , , adults with a primary acute neurological diagnosis and , , patients admitted to the hospital without a primary acute neurological diagnosis. among neurological diagnoses, subarachnoid hemorrhage (odds ratio [or], . ; %ci, , status epilepticus (or, . ; % ci, . - . ), transient global amnesia (or, . ; % ci, . - . ), and meningoencephalitis (or, . ; % ci, . - . ) were most strongly associated with takotsubo cardiomyopathy. weaker associations were present for ischemic stroke (or, . ; % ci, . - . ) and migraine headache (or, . ; % ci, . - . ). intracerebral hemorrhage and guillaine-barre syndrome were not significantly associated with takotsubo cardiomyopathy. in our multivariable model, female sex was significantly associated with takotsubo (or, . ; % ci, . - . ). we found associations with takotsubo cardiomyopathy for several acute neurological diseases besides subarachnoid hemorrhage. gram-negative meningoventriculitis (gnmv) causes significant morbidity and mortality. in addition to intravenous antibiotics, intra-thecal (it) or intraventricular (iv) antibiotics may be used to treat central nervous system (cns) gram-negative infections, including multi-drug resistant gnmv. there are limited studies on the effect of direct cns administration on cerebrospinal fluid (csf) cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it or iv antibiotics for gnmv since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gnmv during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: gentamicin ( ), colistimethate sodium ( ), amikacin ( ), and tobramycin ( ). the most common pathogens were p. aeruginosa ( ), k. pneumoniae ( ), enterobacter sp. ( ) and e. coli ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p<. ) between the first and last dose of iv/it antibiotics. twenty-five ( . %) patients survived to discharge, ( . %) were confirmed alive at months. patients who survived to discharge went to rehabilitation ( ), home ( ), long-term acute-care ( ) and skilled nursing facility ( ). it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gnmv. it and iv administration may provide additional benefit to systemic therapy. gram-positive organisms are the most common cause of meningo-ventriculitis. systemic antimicrobial therapy may fail to achieve adequate cerebrospinal fluid (csf) concentrations, particularly against organisms with higher minimum inhibitory concentrations, such as mrsa and vre. direct intraventricular (iv) or intra-thecal (it) administration may be beneficial as they can facilitate high csf levels at the site of infection. there are limited studies on the effect of direct central nervous system (cns) administration of antibiotics on csf cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it/iv antibiotics for grampositive meningo-ventriculitis since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gram-positive meningoventriculitis during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: vancomycin ( ) and daptomycin ( ). the most common pathogens were staphylococcus sp. ( ), enterococcus sp ( ), and streptococcus sp ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p=. ) between the first and last dose of iv/it antibiotics. twenty-nine ( . %) patients survived to discharge, ( . %) were confirmed alive at months. it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gram-positive meningo-ventriculitis. it and iv administration may provide additional benefit to systemic therapy. use of prothrombin complex concentrate (pcc) for urgent reversal of anticoagulant associated coagulopathy is increasing, and at the university of illinois hospital (uih), an anti-thrombotic reversal guideline was developed in may in order to assist licensed practitioners in choosing the appropriate reversal agent, optimal dosing, and improve timely administration pcc. the current study examined the safety and efficacy of pcc used for the urgent reversal of anticoagulant associated coagulopathy before and after the development of the anti-thrombotic reversal guideline. this was a retrospective chart review of adult patients who received pcc as the only hemostatic agent at the uih from jan to april . the primary endpoint was hemostasis and secondary endpoints included thromboembolic events and time to pcc administration. there were and patients who received pcc before and after the anti-thrombotic reversal guideline, respectively. frequent cause of coagulopathy was warfarin ( % and %, respectively), and frequent indication for pcc was acute intracranial hemorrhage ( % and %, respectively). -factor pcc was more frequently used before the guideline and -factor pcc was more frequently used after the guideline. in patients presenting with warfarin induced major bleeding, target inr < . was achieved in % and % of these patients before and after the guideline, respectively. clinical assessment of bleeding cessation from direct oral anticoagulant (doac) therapy was difficult to assess. thromboembolic event was observed in % and % of the patients, respectively. median time to pcc administration from its initial order was minutes and minutes, respectively. hemostasis was similarly observed in the warfarin group before and after the development of reversal guideline, but more thromboembolic events were observed before the reversal guideline. in order to further reduce the pcc administration time, a change in workflow has been made to administer pcc in timely manner. dexmedetomidine, a selective alpha- adrenoreceptor agonist inhibiting sympathetic neuronal activity, is a mild sedation agent. two recent case reports showed reduced norepinephrine (ne) requirement in septic shock with clonidine, a less selective alpha- agonist. increased vasopressor responsiveness (vr) was also observed with dexmedetomidine in cardiovascular surgical settings. sympatholytic effects of the alpha- agonists reverse vascular desensitization due to high levels of sympathetic activity in sepsis. depletion of intra-neuronal catecholamines with reserpine has shown to increase vr. in septic sheep infused with escherichia coli, clonidine reduced renal sympathetic tone and restored vr. additionally, alpha- agonists have shown to decrease pro-inflammatory cytokines and reduce mortality, improve capillary perfusion deficit, and lower arterial lactate in animal sepsis models. a prospective trial in human septic shock is in the pipeline. we report decreases in vasopressor requirement with initiation of dexmedetomidine in two patients with brain injury. a -year-old woman presented with a high-grade subarachnoid hemorrhage and concomitant reverse takatsubo cardiomyopathy. her clinical course was complicated by septic shock secondary to aspiration pneumonia at admission. when dexmedetomidine was started after hours of ne infusion, a steady decrease in ne dosage was observed until its discontinuation. increased vr was also observed in a year-old man being treated for new onset refractory status epilepticus. on hospital day , the patient continued to have stimulus-induced seizures on ketamine, midazolam and pentobarbital infusions and required ne to maintain an adequate mean arterial pressure. when dexmedetomidine was added, a decrease in ne infusion was observed within an hour and continued for six hours until the patient no longer required vasopressor therapy. these findings are consistent with aforementioned reports of restored vr by alpha- agonists in septic shock, and warrant further investigation of possible beneficial effects of attenuated hyperadrenergic state conferred by alpha- agonists in various neurocritical care settings. decreasing the amount of time a patient remains intubated has been shown to reduce multiple negative outcomes. by extubating these patients earlier, risk of infection, prolonged immobility, and delirium are reduced. in early , this nsicu was chosen to participate in the society of critical care medicine's icu liberation collaborative. the collaborative was focused on implementation of the abcdef bundle or icu liberation. the successful implementation of the bundle led to a decrease in the amount of time neurocritically ill patients were intubated. the bundle elements began to be rolled out in june (end of st quarter). included in the bundle's roll out was the creation of a respiratory clinical specialist role to help the interprofessional team with the respiratory components of the bundle. this role was a full time respiratory care practitioner who was dedicated to the nsicu and helped to ensure standards were being met. additionally, as a part of the bundle's implementation, a spontaneous awakening trial and spontaneous breathing trial algorithm was developed and initiated. this algorithm relied on interprofessional collaboration between nursing and respiratory therapy with communication to the provider and was rolled out in september (end of rd quarter). ventilator o/e for : st quarter- . , nd quarter- . , rd quarter- . , th quarter- . ventilator o/e for : st quarter- . , nd quarter- . the bulk of the research conducted that proved the benefits of the bundle elements has been completed in medical and/surgical patient populations. the neurocritical care patient population is very specialized and has several nuances that may impact the way the various elements need to be implemented. through this process, we have found that the techniques suggested within each element can positively impact the neurocritical care patient population. the cognitive reserve hypothesis refers to inter-individual differences in the ability of patients to cope with brain pathology. cognitive reserve can be measured by surrogate markers such as education and occupation and has shown to be an important predictor of outcomes in alzheimer disease, multiple sclerosis and traumatic brain injury. in this prospective longitudinal cohort study we determined whether cognitive reserve measured as number of years of education and employment status predicted -month functional outcome of ncc patients. demographic and clinical data, including number of years of education and occupational status, were collected. at three months after discharge, glasgow outcome scales (gos) were collected via telephone from patients or surrogate respondents. gos scores were categorized into 'good' or 'poor' outcome (gos - ). from march to july , / patients with -month follow-up data were included. mean age was ± years, ( %) were male, with stroke as the predominant admitting diagnosis.the two groups with good vs poor outcomes did not differ in age, gender or race in univariate analysis although employment status was statistically different in the two groups. in multivariate logistic regression neither employment nor education was a significant predictor of good vs poor outcome (p = . , p = . ). prognostication in neurocritical care patients is difficult. the effect of cognitive reserve needs to be studied further. our current sample size is small and as enrollment continues, we will determine the relationship between cognitive reserve and -month functional outcome. fever commonly occurs in patients with spontaneous intracerebral hemorrhage (sich). however, it is non-infectious in the majority of cases. blood cultures (bcx) are often obtained as part of a fever workup, yet their utility may be limited and false-positive results may potentially compromise patient care. we hypothesized blood cultures in the first hours would more likely be false-positive. we performed a retrospective chart review of patients admitted to a tertiary medical center with a diagnosis of spontaneous intracerebral hemorrhage. patients with secondary causes of ich as well as institution of comfort measures only were excluded. data obtained included demographics, clinical parameters of ich and blood culture results. blood culture results and charts were reviewed for adjudication of false-positive and true-positive cultures. of included patients with sich, patients ( %) had blood cultures obtained. cultures were positive, of which were classified as false-positive and as true positive. false positive results were more common in the first days ( vs. ), while true positive results were more common after the first hours ( vs. ) (p= . ). early blood cultures in patients with sich are more commonly non-infectious. in line with prior published data, our results demonstrate the high cost and limited yield for blood cultures within the first hours. predictive energy expenditure (pee) equations are commonly used in lieu of indirect calorimetry (ic) due to cost and limited resources; however, these equations may not be as accurate as ic in estimating resting energy expenditure (ree) in critically ill patients. the purpose of this study is to compare pee and measured energy expenditure (mee) in critically ill adults with acute brain injury. this was a retrospective review of adult patients admitted with acute brain injury between may st, and april st, who had ic performed. three predictive equations (pe), harris benedict (hbe), penn state university, and mifflin st jeor (msj), were used in comparison to ic results. subgroup analyses included a modified aspen weight-based equation, stratifying patients based on bmi and type of acute brain injury. patients met inclusion criteria. comparing the pee estimated by the three predictive equations to the mee from ic found no significant difference. high degrees of interpatient variability were discovered in each anova analysis, with standard deviations ranging from - %. despite no difference found among pee and mee, pearson's correlations indicated weak associations when hbe, penn state, and msj were individually compared to mee (r-values = . , . , and . , respectively). in patients with a bmi < kg/m , a significant difference was found (p-value= . ) with pee underestimating the ree. additionally, in aneurysmal subarachnoid hemorrhage a significant difference was observed between pee and mee( p-value= . ). the results of this study highlight the importance of using ic whenever feasible due to the interpatient variability of the ree of critically ill patients with acute brain injury. although predicative equations appear to have similar estimations as ic, interpatient variability warrants more accurate measurement with ic to optimize nutrition in patients with acute brain injury. introduction -factor prothrombin complex concentrate (pcc) should be administered as soon as possible for reversal of anticoagulation in the setting of life-threatening bleeding or urgent procedures. limited information is available on the safety, efficacy, and time to administration of pcc when administered at high infusion rates. on march , grady health system implemented a rapid pcc administration strategy while attempting to reduce times from order entry to administration as a quality improvement initiative. this irb-approved, retrospective evaluation includes pcc administrations days pre-and post-protocol implementation. after protocol implementation, pcc doses were prepared in up to four, -ml syringes, dependent on the ordered dose. each syringe was administered over minutes, not exceeding a rate of iu/minute. the primary objective of this study is to evaluate the safety of a rapid administration strategy for pcc. secondary objectives include turn-around times and effectiveness of inr reversal in patients previously on warfarin. results unique pcc administrations were identified: administrations in the pre-cohort and in the postimplementation cohort. most pcc administrations were in the setting of spontaneous or traumatic intracranial hemorrhage. there were no infusion-related adverse events documented with the exception of a possible pcc infiltration post-implementation which resolved with supportive care only. the median order entry to administration time was higher in the post-implementation group ( vs. minutes). administrations in the pre-cohort and administrations in the post-cohort were for warfarin reversal. a greater percent of patients previously on warfarin reversed to an inr < . in the post-cohort compared to the pre-cohort, . % vs . %, respectively. this retrospective evaluation suggests that rapid intravenous push administration of -factor pcc is safe and effective. time to administration was longer after implementation of rapid pcc administration and may have been due to operational limitations. icu readmission is defined as a return to the icu during the same hospital admission. there are multiple studies related to medical and general surgical recidivism, however there is limited data on icu readmissions following spine surgery. the aim of this study was to evaluate factors associated with icu readmissions following spine surgery. patients requiring icu admission following spine surgery from june to june were studied. variables included age, gender, icu and hospital disposition, icu and hospital length of stay, bmi, comorbidities, surgical location, number of previous surgeries and vertebra manipulated, estimated blood loss, post op blood transfusions, and cause of readmission. a : matched control group based on age, bmi and location of surgery was identified. thirty-two patients required readmission following spine surgery during the study period. there was a higher prevalence of preoperative atrial fibrillation in the readmission group ( % vs. %, p= . ). ebl ( vs ml, p= . ) and lowest maps ( vs . mmhg, p= . ) were not significantly different in the two groups. we found a higher mortality rate ( % vs %, p= . ), longer icu ( . vs . hours, p= . ) and hospital los ( . vs . days, p= . ) in the readmission group. respiratory distress ( %) was the most common reason for readmission followed by cardiovascular instability ( %). discharge rates to inpatient rehabilitation and nursing facilities were similar for both groups; however % of the control group went directly home as opposed to % of the readmission group. complex spine patients who experience icu recidivism have a longer hospital stay and incidence of death within years of their index procedure. they are less likely to be discharged home. preoperative a-fib correlates with increased incidence of readmission to icu post-operatively. further studies are needed looking at post operative fluid and pain management. to demonstrate the feasibility of exenatide infusion for hyperglycemia following acute brain injury. adult patients with acute brain injury and having two blood glucose concentrations > mg/dl and was administered within hours of admission and continued per protocol for a maximum duration of hours. the primary endpoint was feasibility (< % of subjects experiencing severe hypoglycemia (< - mg/dl). descriptive endpoints were also collected. data is presented as medians [interquartile range] or percentages. a total of eight patients received exenatide (age . years [ . , . ], . % male, . % caucasian, . % history of diabetes, a c . % [ . , . ]). admitting diagnoses were intracerebral hemorrhage (n= ), acute ischemic stroke (n= ), subarachnoid hemorrhage (n= ), and subdural hematoma (n= ). glascow coma score was . [ . , . ] and sequential organ failure assessment was . [ . , . ]. based upon predefined criteria, feasibility was met with % of subjects experiencing severe hypoglycemia, . % achieving the blood glucose goal, and % experiencing nausea requiring discontinuation. blood glucose was controlled during the -hour exenatide infusion ( intravenous exenatide infusion is feasible for the treatment of hyperglycemia following acute brain injury. extubation failure remains a common complication in critical care patients, and is associated with increased intensive care unit and hospital length of stays, hospital costs, morbidity and mortality. the most common cause of reintubation is laryngeal edema, often identified by the presence of a high pitched inspiratory whistling sound known as post-extubation stridor (pes). providers in the neurocritical care unit (nccu) at a large urban academic medical center noted higher than normal rates of pes. to reduce the rates of pes and reintubation without delaying extubation, a clinical pathway was created by an interdisciplinary team. the purpose of the pathway was to aid in the identification of patients expected to develop pes and guide prophylactic treatment. prior to project implementation, all providers in the nccu completed hands on training with practice in completing the pathway in the form of a checklist. during the week implementation phase, checklists were completed on all intubated patients daily during rounds. during the week trial, there were a total of ventilator days. there were completed checklists, yielding an . % compliance rate for utilization of the clinical pathway. of the patients who were extubated during the trial, had a checklist completed, generating . % compliance on the day of extubation. a chi-square analysis was performed to evaluate outcomes following all non-palliative extubations during the week pre-implementation (n = ) and post-implementation (n = ) periods. implementation of the pathway was associated with a statistically significant reduction in rates of pes ( , n = ) = . , p< . , reintubation ( , n = ) = . , p< . and reintubation due to pes, ( , n = ) = . , p< . . the clinical pathway implemented in our nccu was safe and effective in reducing rates of pes, reintubation and reintubation due to pes. agency for healthcare research and quality (ahrq) identified postoperative deep vein thrombosis (dvt) or pulmonary embolism (pe), also commonly referred to as venous thromboembolism (vte), as one of the complications acquired in the hospital and thus developed a mechanism to report its rate using administrative data. postoperative vte rate reduction became top priority for the university of illinois (uih) due to its high yearly rate, especially among patients in the neurosciences intensive care unit (nsicu). therefore, a quality improvement team in the nsicu implemented vte bundle and analyzed its effect on the vte rate. the vte bundle was initiated on all neurosurgery and neurology patients admitted to the nsicu since march . vte bundle included lower extremity doppler ultrasound within hours of admission, vte education provided to patient or family member within hours of admission, and daily surveillance on proper use of mechanical sleeves and the mechanical device, low-dose heparin initiation and maintenance therapy, and documentation of activity status. the nursing staff were encouraged to follow the early mobilization protocol. mean vte rate was . per cases approximately -year before and . per cases approximately -year after the implementation of vte bundle. the rate of compliance was high on all aspects of vte bundle, especially on correct placement of ipc sleeve > %; functioning ipc device > %; low-dose heparin > %; documentation of activity status > %. no adverse effects were noted (i.e., skin breakdown, major bleeding) during the study period. this was the first time in years at uih, the postoperative vte rate was reduced among nsicu patients based on the ahrq reports. the reduction may partly be attributed to the implementation of vte bundle; however further evaluation need to be performed to determine the effect size of vte bundle. increasing evidence suggests that large volume infusions of . % sodium chloride (nacl) for resuscitation are associated with hyperchloremic metabolic acidosis and renal vasoconstriction leading to an increased risk of acute kidney injury (aki). in patients with neurologic injury, hypertonic ( . % or %) nacl or sodium acetate (naacetate) may be required for therapeutic hypernatremia, treatment of cerebral salt wasting or elevated intracranial pressure. the primary aim of this study was to determine the incidence of aki in neurologically injured patients receiving intravenous hypertonic nacl and in those who were switched to hypertonic naacetate based on provider preference. this single-center, retrospective study compared patients that received only hypertonic nacl to patients that were switched to naacetate. data was collected to assess renal function, hyperchloremia, and metabolic acidosis. a total of patients were screened and of those were included. the patients who were switched from nacl to naacetate (n= ) had a greater incidence of aki ( % vs. %, p< . ) and hyperchloremia ( % vs. %, p = . ) compared to patients who received only nacl (n= ). the incidence of metabolic acidosis was increased but not statistically significant ( % vs. %, p = . ). on average, hypertonic nacl was switched to hypertonic naacetate on day of treatment with a mean chloride of . meq/l at the time of the switch. there was no statistical difference in the administration of nephrotoxic antibiotics, mannitol, vasopressors, or contrast dye between the two groups. the receiver operating characteristic (roc) analysis demonstrated that if a patient received greater than meq of chloride over days they were more likely to develop aki (sensitivity %, specificity %, p= . , auc . ). neurologically injured patients receiving hypertonic sodium therapy requiring a switch to hypertonic naacetate had an increased incidence of hyperchloremia and aki. in-hospital complications following acute neurological injury has been a topic of extensive research to help reduce the morbidity and mortality among the patients. however, the incidence and prevalence of in-hospital infections following an acute neurological injury at the national level has never been studied. the aim of our study is to determine the frequency and prevalence of in-hospital complications among different patient groups admitted following acute neurological injury. we identified patients with primary diagnosis of ischemic stroke (is), subarachnoid stroke (sah), intracerebral hemorrhage (ich), status epilepticus (se), meningitis, encephalitis and traumatic brain injury (tbi) from nationwide inpatient database ( - ) through using the respective icd- codes. common in-hospital complications among the above-mentioned diagnoses through using their respective icd- codes patients with primary diagnoses of is (n= ), sah (n= ), ich (n= ), se (n= ), meningitis (n= ), encephalitis (n= ), tbi (n= ) were identified. in-hospital events such as myocardial infarction (mi), sepsis, pneumonia, deep venous thrombosis (dvt), pulmonary embolism (pe), urinary tract infections (uti), and gi bleed were identified and compared among different patient groups. patients with se were noted to experience higher systemic complications, mi ( . %), sepsis ( . %), pneumonia ( . %), dvt ( . %), uti ( . %), gi bleed ( . %). patients admitted with meningitis had a higher incidence of sepsis ( . %), pneumonia ( . %), dvt ( . %), pe ( . %) and uti ( . %) compared to the other groups. uti was the most common in-hospital complication observed. based on our analysis, we report a higher incidence of urinary tract infections among all patients admitted following acute neurological injuries. patients with primary diagnosis of status epilepticus experienced more systemic complications compared to the other diagnoses. macroglossia is a phenomenon that has been documented in association with prolonged neurosurgical procedures, brainstem injury, phenobarbital administration, and venous/lymphatic congestion of the tongue. however, exact causation of this condition in the neurocritical care population remains unclear. patients with macroglossia face significant risk for airway compromise. no interdisciplinary patient safety and management protocol exists. patients admitted to two neuro icu's within a single health system between - were reviewed. twenty-five patients with macroglossia were identified. an interdisciplinary patient management protocol was created, instituting airway safety standards, oral care directives, and interventions to promote symptom resolution. early consultation to oral and maxillofacial surgery and consideration of early tracheostomy was recommended. seventeen patients ( %) were women. age ranged from - years. the majority ( / ) of patients were african american. primary diagnoses included status epilepticus ( / ) and stroke ( sah, ais, ich). nineteen patients received antiepileptic medications before diagnosis. average gcs at symptom onset was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and at time of discharge was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . median symptom onset was hospital day [ - ]. twenty patients ( %) required tracheostomy. nine ( %) experienced symptom resolution by hospital discharge. two patients received botulinum toxin injection; both experienced symptom resolution. lingual massage was performed in two patients; in both patients, tongue swelling resolved. tongue lacerations occurred in / patients ( %), although most were observed following macroglossia onset, ruling out trauma as an inciting event. chlorhexidine oral rinse was discontinued for all except five patients due to concern for angioedema. endotracheal tube was dislodged in two patients, complicating reintubation, although successful. no trend in pre-existing allergies or antibiotic regimen was apparent. macroglossia is a relatively uncommon but high-risk condition in the neuro icu that warrants further study. care of patients with macroglossia should be standardized in order to ensure airway safety. an interdisciplinary approach is recommended. one of the biggest challenges of magnetic resonance imaging (mri) examination is the acquisition of high-quality diagnostic images, as it requires the neurological intensive care unit (nicu) patients to keep still for a significant time. in situations with poor patient cooperation, unplanned sedation is inevitable, which can lead to complications such as desaturation and hypotension. we investigated the incidence and factors related to complicated mri examinations (mri-c) in patients admitted to the nicu. we designed a retrospective study to review the data of patients who had an attempt to undergo brain mri during stay in the nicu between july and august . the mri-c group was defined when a patient met one of following criteria: ) required sedation for mri examination due to irritability mmhg or required inotropic agents, ) developed cardiac or respiratory arrest. of patients, ( . %) developed mri-c. the most common cause of mri-c was unexpected irritability at the mri room. among patients with mri-c, ( . %) patients required unplanned sedation; , desaturation; , hypotension; none, cardiac or respiratory arrest. higher apache ii scores (p = . ) and lower gcs scores (p = . ) on admission and use of sedative agents during critical care in the nicu were associated with mri-c (p < . ). in addition, patients with mri-c had longer mri scan time than those without mri-c (p = . ). many of neuro-critically ill patients undergo unsafe mri scans. our findings suggest that severity of illness and use of sedative agents during management in the nicu were factors related to mri-c. introduction: fulminant hepatic encephalopathy (fhe) with diffuse cerebral edema has dismal prognosis if transplantation is not performed. novel therapeutic interventions may change this outcome. we reviewed all cases with fhe admitted to our hospital since . in , we developed a multidisciplinary management protocol, mandating transfer of patients entering grade from other icus to the neurosciences-icu (nicu) for intracranial pressure (icp) management. multiple interventions were utilized including coagulopathy reversal with factor vii and prothrombin complex concentrate (pcc, kcentra), icp device placement, osmotherapy, aggressive ammonia lowering regimen with lactulose and rifaximin, early renal replacement therapy, mild hypothermia for refractory icp, in conjunction with liver transplantation candidacy investigation. results: twenty-four patients ( women, mean age of all patients years) were admitted; seven were managed in the micu/sicu and in the nicu. the etiology of fhe was acetaminophen toxicity in % of patients. the model for end-stage liver disease (meld) admission scores and liver enzymes between the micu/sicu and the nicu were not different (mann-whitney test). although the nicu admission ammonia level was higher than the micu/sicu ( . vs . , p = . ), the lowest achieved ammonia was lower in the nicu ( . vs . , p = . , mann-whitney). patients received icp monitoring (all in the nicu plus in the sicu) and the highest icp recorded was mm hg. the preand post-coagulation reversal inr were . and . , p= . , wilcoxon test). seven patients in the nicu received hypothermic treatment. mortality in the micu/sicu was . % ( / ) and in the nicu . % ( / ), p = . (chi square test). conclusion: a multidisciplinary approach centered around anti-cerebral edema protocol-driven management based on novel interventions may improve the outcome of patients with fhe. catheter-associated urinary tract infections (cauti) are among the most common health-care associated infections (hcais), (gould, ) . neurological patients in the critical care setting are particularly at risk for cauti due to cognitive, motor, and sensory deficits. in the neuro intensive care unit, despite following recommended cauti reduction bundle guidelines, cauti rates continued to rise over the last five years with rates reaching . per catheter days. in january of , the unit implemented a cauti taskforce to perform a literature review of best practices and subsequent : peer training and education targeting cauti reduction. in an analysis of organisms causing the infections, e. coli and enterococcus bacteria accounted for more than % of cautis on the unit. the taskforce (comprised of staff nurses) focused on fecal management, proper cleaning technique, and proper indications of indwelling urinary catheter necessity. using training videos, indwelling urinary catheter care checklists, and real-time feedback on technique, the taskforce performed : training with bedside staff over four weeks. to ensure undivided attention, the taskforce worked in pairs enabling one trainer to teach and observe the staff member receiving training while the second trainer provided the necessary clinical duties for the trainee's patients. after implementation, the cauti rate decreased to . for january-march and . for april-june , lowering total cauti events to for fy compared to for fy . implementing a : training program focused on fecal management, cleaning techniques, and appropriately timed catheter removal can reduce cauti rates in the neuro critical care setting. brain aneurysms can be treated with coil embolization or flow-diverting devices. thromboembolism is a major complication of aneurysmal coil embolization, with an incidence as high as % . new flowdiverting devices have been designed to have a mesh with high coverage area and high flexibility to facilitate the redirection of blood flow. these features can induce blood stagnation and thrombosis. to reduce the risk of thrombosis, the common but unproven practice of dual antiplatelet therapy with aspirin and clopidogrel has been implemented from the cardiac literature. despite some favorable outcomes, clopidogrel, "non-responsiveness" has been reported to be present in as low as % to as high as % making this agent not optimal. this will leave practitioners with other oral p y alternatives such as prasugrel and ticagrelor that have not been studied widely in this setting. it is therefore likely that controversy exists among practitioners regarding the use of optimal antiplatelet agents in neurointerventional procedures. we hypothesized that practices in regards with the use of oral antiplatelets in neurointerventional procedures are likely heterogeneous and different from state to state. by using an electronic survey, we would like to identify different practices surrounding the use of oral anti-platelets in neuro-endovascular centers in the united states. an electronic survey will be distributed via the web using survey monkey (seattle, wa). the survey will be posted on the neuro-critical care society (ncs) web page. all practicing neuro icu or stroke physicians, pharmacists, physician assistants, or nurse practitioners are eligible to respond to this survey. this survey is approved by the johns hopkins hospital irb and the ncs research committee. centers have completed the survey at this point. the results will be analyzed after the closing date of survey ( / / ). to be completed myasthenia gravis (mg) crisis and guillain-barre syndrome (gbs) are immune mediated diseases that may require mechanical ventilation as part of their management if severe. comparative analysis of outcomes in terms of length of stay, disability, and mortality between these two disease entities at national level is not reported mechanically ventilated patients with primary diagnosis of guillain-barre syndrome and myasthenia gravis were identified from the nationwide in-patient sample (nis) database for the years to mechanically ventilated mg patients (n= , mean= +/- . years) were older compared to gbs patients (n= , mean= . +/- . years, p= . ). medical co-morbidities were significantly higher in mg patients (diabetes mellitus, congestive heart failure, coagulopathy, chronic lung disease and dyslipidemia) whereas significantly higher nicotine dependence and alcohol abuse were noted in gbs. significantly higher in hospital complications of pneumonia and urinary tract infection were noted in gbs. disease severity measured by apdrg severity index and rate of treatment with intravenous immunoglobulin and plasma exchange was comparable. length of stay ( . ± . days , p < . ); hospital charges ( $ . ± . vs . ± . p = . ) ; moderate to severe disability ( . % vs . % p < . ) were significantly higher for gbs patient compared to mg. inhospital mortality was comparable ( . % gbs vs . % mg, p = . ). in multivariate analysis after adjusting for confounders including treatment, myasthenia gravis patients had significantly less disability (or . ( % ci . - . ) and shorter length of stay (or . , % ci . - . ). mechanically ventilated gbs patients have higher in-hospital complications, length-of-stay, and disability compared to mg. this may reflect a delay in diagnosis of gbs at admission and poor response to immunotherapy in certain gbs variants. betrixaban is an inhibitor of factor xa (fxa) for prophylaxis of venous thromboembolism (vte) in at-risk patients hospitalized for acute medical illness. a phase trial (apex) compared extended-duration anticoagulation with betrixaban to enoxaparin in acute medically ill patients; the effect of patient characteristics on population pharmacokinetics and exposure-response relationships is analyzed here. patients received betrixaban ( - days; n= , ) or enoxaparin ( ± days; n= , ). the primary efficacy and safety endpoints were composite occurrence of vte events and incidence of major bleeding, respectively. betrixaban dose was mg po qd ( mg po qd for patients with severe renal insufficiency/requiring concomitant p-glycoprotein inhibitor). pharmacokinetic samples were collected - hours or - hours after the most recent dose of study medication. patient characteristics included age, sex, race, region, body weight, crcl category, and specific p-glycoprotein inhibitor. , pharmacokinetic samples were analyzed. at mg, the projected concentration was . ng/ml at hours post-dose and . ng/ml at hours post-dose, showing a stable daily concentration. coadministration of p-glycoprotein inhibitors on the day of sampling more than doubled betrixaban concentration to ~ ng/ml at hours post-dose. at mg, the projected concentration was . ng/ml at hours post-dose, indicating a greater-than-dose-proportional exposure relationship. patient age, sex, weight, crcl category, p-glycoprotein inhibitors, and region were significant covariates affecting betrixaban pharmacokinetics. the exposure-response relationship for the primary efficacy endpoint was not significant, but the relationship between betrixaban concentration and major/clinically relevant nonmajor bleeding was significant in multivariate testing (p= . ). the betrixaban pharmacokinetic profile exhibited stable serum concentrations with qd dosing. several covariates had a %- % effect on betrixaban concentration, but no effect on efficacy/safety. betrixaban dose should be adjusted to mg for patients taking amiodarone or clarithromycin, but not other p-glycoprotein inhibitors. andexanet alfa is being investigated for reversal of anticoagulation by factor xa (fxa) inhibitors. a pharmacokinetic/pharmacodynamics model, developed in healthy subjects, predicted the andexanet regimen required to reverse anticoagulation by fxa inhibitors. the current analysis validated the pharmacokinetic/pharmacodynamic model using interim data from the annexa- study in patients with acute major bleeding. in annexa- , an ongoing prospective, open-label study, bleeding anticoagulated patients received iv andexanet bolus ( or mg) followed by -minute infusion ( or mg/min). anti-fxa activity was measured before andexanet administration (baseline), at end of bolus (eob), at end of infusion, and at , , and hours after infusion. the relationship between baseline anti-fxa activity and reversal in healthy subjects was derived from the pharmacokinetic/pharmacodynamic model and used to predict percent reversal for patients with acute major bleeding. from the first interim analysis of annexa- , patients (apixaban, n= ; rivaroxaban, n= ) had plasma levels available for model qualification, although did not meet criteria for inclusion into safety and did not meet criteria for efficacy analysis. the mean observed percent reversal of anti-fxa activity for rivaroxaban and apixaban was well predicted by the healthy subject pharmacokinetic/pharmacodynamic model; the point estimates fell within the % confidence intervals of predicted values. the percent reversal at eob for rivaroxaban and apixaban were . [ . - . ] and . [ . - . ], compared with . and . predicted by the model. the predicted reversal closely fit the observed confidence intervals through the first hours for rivaroxaban and apixaban, and extended through all evaluated time points for rivaroxaban and slightly outside of post- -hour time points for apixaban, possibly due to higher baseline anti-fxa activity levels for apixaban. the pharmacokinetic/pharmacodynamic model in healthy subjects closely predicted the extent of reversal of anti-fxa activity for apixaban and rivaroxaban in patients with major bleeding. risk factors and methods to predict extubation failure are well established for patients in medical icus and surgical icus. literature on patients who fail extubations in neurological icus is limited. the intention of this study was to collect descriptive information from patients with neurological injuries who failed liberation from mechanical ventilation. retrospective review of all patients with acute neurological injury who were admitted to our neuro icu and who required reintubation within hours of discontinuation of mechanical ventilation between january -february . we identified patients intubated primarily due to neurological pathology who required reintubation within hours after initial extubation over a -year study period. the majority of reintubated patients (n= ; . %,) had a positive fluid balance prior to failed extubation. twenty-six of the reintubated patients had a concurrent underlying chronic cardiac and/or pulmonary disease. five patients were placed on noninvasive ventilation post extubation. low glascow coma scale and absence of basic brainstem functions (gag and cough reflexes) was only minimally predictive of extubation failure. most of our reintubated patients did not have significant supratentorial midline shift nor an insult to the posterior circulation or dominant hemisphere. in patients with primary brain injury who required reintubation, a positive fluid balance prior to extubation may confer a lower rate of successful extubation. lesion location and supratentorial midline shift may not be tightly associated with extubation success. overall, our reintubation rate is quite low. early tracheostomy may play a small but significant role in the low rate of reintubation. further studies may be useful in creating a scoring system to identify the likelihood of extubation success in patients with neurological injury. surgical prophylaxis guidelines for evd insertion recommend peri-procedural antibiotics rather than prolonged antibiotic administration for the duration of evd placement. several small studies have shown that prolonged systemic antibiotic use does not reduce the incidence of catheter related ventriculitis. prolonged use is also associated with a higher rate of multi-drug resistant (mdr) infections. this study aims to show that prolonged antibiotic administration following evd insertion is potentially harmful. this is a single center, retrospective, chart review. all patients admitted to our hospital who had an evd placed from january to march were identified. patients with preceding infections, incomplete data or uncertain infection diagnosis were excluded. sixty-nine patients were analyzed. documented variables included demographics, comorbidities, indications for evd, duration of antibiotic therapy, infections and organisms' sensitivities. eight patients ( %) did not receive any antibiotic therapy; the rest received cefazolin following evd insertion. infections occurred in of ( %) patients; of ( %) were mdr bacteria. ventriculitis occurred in ( %) patients, and of these were resistant to cefazolin (mdr). ventriculitis was not associated with the use or duration of antibiotic therapy. graphical analysis showed that the probability of any infection decreased during the first days of antibiotic prophylaxis. after days, the longer patients remained on prophylactic cefazolin, the higher the probability of infection (spearman rank correlati patients who received antibiotics for > days were . times as likely to develop mdr infections ( % ci, . to . ; p= . ). cefazolin may prevent infections for the first days after evd insertion. however, prolonged administration increased the risk of mdr bacterial infections. a randomized study comparing periprocedural ( hrs) antibiotic use is needed to resolve this controversy. each year more than , deaths are associated with urinary tract infections. eighty percent of all utis are associated with an indwelling catheter. neuroscience intensive care (neuro-icu) units have the highest rates of catheter associated urinary tract infections. catheter associated urinary tract infection (cauti) increases morbidity rates, length of stay, and costs among hospitalized patients. at an urban academic medical center, our neuro-icu had the highest cauti cases among our icus. the purpose of this project was to reduce our cauti cases by %. this quality improvement project used several strategies: ( ) formed a multidisciplinary cauti task force that included nurses, physicians, infection control, management and supply chain personnel; ( ) developed an action plan to update standard of practice by conducting a review of the literature and pilot testing new products; and, ( ) educated staff using huddles, a bedside guide, and email blasts with cauti facts starting in august . additionally, cauti prevention was discussed during patient handoffs among nurses and physicians. data were collected for all neuro-icu patients from fiscal year (fy) - . cauti cases are determined by utilizing cdc's national healthcare safety network. analysis included evaluation of trends across time. we reduced our number of cauti cases from in fy to in fy . as of the beginning of fy , we have not had a cauti for days. a comprehensive approach with a strong commitment by clinicians is critical for sustaining a reduction in cauti. we reduced our cases and exceeded our goal. our efforts to provide evidence-based care are ongoing as we continue to monitor the research and upcoming supplies aimed at making hospitalacquired cauti a never event. isophane insulin (nph) is a commonly prescribed basal insulin to manage hyperglycemia in critically ill patients on continuous tube feeding due to its intermediate duration of action. however, the incidence of hypoglycemia may be higher given the duration of nph can last between - hours and because of the potential for unexpected interruption in feeding. using scheduled regular insulin (ri) instead of nph may reduce this risk given its shorter duration of action. it may also improve glycemic control due to more frequent titration. this was a single-center, retrospective, observational, cohort study from december to may . patients on continuous tube feeding who were prescribed scheduled ri were compared to those prescribed nph. all patients continued to receive an insulin sliding scale. choice of agent was determined by the bedside team. the primary endpoint was incidence of hypoglycemia while secondary endpoint assessed efficacy. in our patient population, a higher incidence of hypoglycemia was seen in those that received nph. hypertonic saline bolus (hsb) is a proven intervention for neurological emergencies arising from cerebral edema and increased intracranial pressure. safety of hsb administered via central venous catheters is well established. however, infusion of hsb through peripheral intravenous access raises concern for complications related to caustic nature of the solution. we aim to assess the safety of peripherally administered boluses of hypertonic saline ( % sodium chloride) at a regional level trauma and comprehensive stroke center. we performed retrospective chart review of patients who received hsbs from january , to january , as part of a quality improvement project. we identified instances of hsb administration. the cases were individually reviewed for iv gauge, location of the iv, whether central access was present at the time of administration, documentation of iv removal, and volume of boluses. patients were excluded if there was concurrent central venous access catheter present at the time of hsb administration or unrelated death within hours after administration of hsb. adverse events were defined as line infiltration, erythema, or swelling at the site of hsb administration. charts were excluded from the study because of presumed administration of hsb through central venous access, not peripheral iv. two patients had adverse events ( . %). none of the patients progressed toward limb threatening complications. the majority of patients ( / ) did not experience erythema or infiltration of the iv. hsb administered through peripheral intravenous access does not pose significant risk of severe complications and may be safely used in emergency situations in the absence of central line access. routine screening of high risk asymptomatic trauma or surgical patients for venous thromboembolism(vte) is controversial. studies suggest against screening while others recognize that some patients at high risk may benefit. the purpose of this pilot study is to evaluate the outcome of routine screening in patients who underwent neuro-surgical interventions. all adult patients admitted to a neuro-intensive care unit with a primary diagnosis of brain injury requiring surgical interventions were included. data from april-june, were retrospectively collected on all subjects who had either spine or cranial surgery. data collected include: incidence of vte, number of times duplex ultrasonography and computed tomography of the chest was performed. on july st, prospective data collection began by screening for presence of deep vein thrombosis(dvt) on day , and from admission or surgery day. all patients received pharmacologic and mechanical vte prophylaxis within - hours post-operatively. a total of (pre-pilot, n= and post-pilot, n= ) subjects were included in the study. in the pre-pilot group, the ages ranged from - and most were male. majority, / ( %) had either craniotomy/craniectomy while / ( %) had spine surgery. about / ( %) were admitted with primary diagnosis of traumatic brain injury. of the subjects, had duplex screening for dvt and had screening for pulmonary embolism(pe). the incidence of vte was confirmed in / ( %); (dvt- % and pe- %). median hospital length of stay was (iqr - ) days. / ( %) were discharged home and / ( %) death rate was attributed to pe. in the post-pilot group, one incidence of pe was identified on day post surgery screening. the rest of the results are still pending. in this preliminary report, post surgical patients have a higher incidence of vte. routine screening might benefit to lower the incidence of mortality caused by pe. epsilon aminocaproic acid (eaca) is an antifibrinolytic agent that crosses the blood-brain barrier and has shown benefit in decreasing bleeding in patients acutely. its use in intracranial hemorrhage has uncertain benefit. we aimed to describe the administration and impact of eaca in a single-center neurosciences intensive care unit (neuroicu) over one year. we performed a single-center retrospective study of neuroicu patients undergoing intravenous eaca administration over a one-year time period. inclusion criteria included eaca administration over hours for a diagnosis of acute traumatic hematoma. the dose and duration of eaca infusion was collected. we additionally collected and compared pre-administration and post-administration prolonged thromboplastin time (ptt) hematology assays and neuroimaging. clinical outcomes were reviewed for survival at hospital discharge. over a -month period (april -may ), patients each received a -hour infusion of eaca. the most common indication for eaca was to prevent worsening of intracranial hemorrhage in patients in traumatic coma (gcs < ). % of patients underwent neurosurgical management. ptt assay values showed a significant difference before and after eaca administration. (ptt . +/-sd vs. . +/-sd; student's t test p< . , n= ). stability of the intracranial hematoma burden was evident following eaca in % of patients. % of patients who received eaca survived to discharge. patients receiving eaca showed a significant reduction in ptt assay values hours after completing their dose. ct neuroimaging demonstrated stable intracranial hemorrhage burden in most patients receiving eaca despite a high prevalence of acute operative neurosurgical management. however, only a modest number of patients receiving eaca survived to discharge. these results suggest that eaca may acutely reverse hematologic abnormalities and enable emergent neurosurgical management in patients with severe, acute traumatic hemorrhage, despite a limited role in affecting survival outcomes in these patients. prognostication is difficult for patients admitted to a neurocritical care unit (nccu). can serum biomarkers obtained as part of routine admission lab work help predict outcomes among patients in this prospective cohort study, the following biomarkers were measured at admission: c-reactive protein (crp), arterial lactate, neuron specific enolase (nse), lactate dehydrogenase (ldh), albumin, and brain natriuretic peptide (bnp). we collected information about demographics, comorbidities, hospital procedures and complications and -day mortality. we compared these serological biomarkers in patients who were alive versus those who had died at days. a total of patients were enrolled over months from june to september , of which whom ( . %) died within days of admission. there were no statistically significant differences in age or gender between the two groups. the -day mortality group had a higher mean charlson comorbidity index (cci) ( . vs . , p= . ) as well as mean nse ( . vs . ug/l, p= . ) and bnp levels ( . vs . pg/ml, p= . ). mean crp, lactate, and ldh were also higher in the -day mortality group ( . vs . mg/l, . vs . mmol/l, and . vs . u/l) while mean albumin was lower ( . vs . g/dl), although these differences were not statistically significant (p< . ). cci and serological biomarkers may have utility in predicting -day mortality among patients admitted to the nccu. as we continue enrollment, we plan to develop a predictive model for -day mortality on admission for patients admitted to the nccu using serological biomarkers, cci and admission characteristics. among hospitalized acutely ill medical patients, the risk for venous thromboembolism (vte) is high. the goal was to examine vte prophylaxis of at-risk patients and vte risk during hospitalization and in the outpatient continuum of care. acutely ill medical patients were identified from the marketscan commercial and medicare databases from / / to / / . inclusion criteria were hospitalization for heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases; months of continuous insurance coverage prior to (baseline period) and after (follow-up period) the index hospitalization. outcomes included the proportions of patients receiving inpatient and/or outpatient vte prophylaxis, and the risk for vte events. years, and . % were female. patients were hospitalized for infectious diseases ( . %), respiratory diseases ( . %), cancer ( . %), heart failure ( . %), ischemic stroke ( . %), and rheumatic diseases ( . %). mean hospital length of stay was . days. in total, . % (n= , ) of patients did not receive any vte prophylaxis, and . % (n= , ) received both inpatient and outpatient vte prophylaxis. during hospitalization, . % (n= , ) received vte prophylaxis (enoxaparin, . %; warfarin, . %; enoxaparin and warfarin, . %; a direct oral anticoagulant (doac), ~ %). following discharge, . % (n= , ) received outpatient vte prophylaxis (warfarin, . %; doac, . %; enoxaparin, . %; enoxaparin and warfarin, . %). among the entire study population, the vte event risk remained elevated up to - days after hospital admission. among hospitalized acutely ill medical patients, the risk for vte was present in both the inpatient and outpatient settings, with significant vte risk extending into the post-hospitalization period. only a small portion of at-risk patients ( . %) received vte prophylaxis in both the inpatient and outpatient continuum of care, suggesting an unmet medical need for vte prophylaxis in the post-hospitalization. brain edema is a good research target in various forms of neurologic injury. a real time measurement of brain edema is possible using thermal conductivity methods. however, this technique might be hard to apply in small rodents, which are commonly used as experimental brain edema models. we developed a new approach method for applying thermal conductivity methods in rodent brain edema model. a -week-old spraque-dawley rats were used for brain edema model. qflow probe was inserted through a suboccipital burr hole, located mm left from the midline, then was advanced anteriorly mm from the occipital bone margin until probe place assistance value indicates valid values (ranging from to . ). probe was fixated using adhesive glues and tagging suture. in vivo brain water content was continuously calculated using thermal conductivity values. for validation, calculated brain edema was compared with standard methods (dry/wet brain weight ratio) in water intoxication models (intraperitoneal injection of distilled water, % of body weight) and drying effect of mannitol was validated in streptokinase induced intracerebral hemorrhage (ich) models. calculated brain water content was . ± . % in thermal conductivity method and . ± . % using dry/wet weight ratio methods (p= . ). in water intoxication model, brain water content started to increase minutes after injection and reached up to . ± . % at hours post injection. on wet/dry weight method, edema was measured as . ± . % (p= . ). in ich model, brain water content started to drop minutes after administration of mannitol ( . mg/kg) and drifted back hours after injection of mannitol. thermal conductivity method in assessing brain edema is applicable in rodents using suboccipital approach through burr hole. this method may better reflect dynamic changes of brain edema. in patients with critical brain injury, alterations of brain physiology with dialysis initiation are poorly understood. from a consecutive series of brain-injured patients undergoing invasive multimodality monitoring between and , patients that underwent continuous veno-venous hemodialysis (cvvh-d) and patients that underwent intermittent hemodialysis (ihd) were identified. changes in mean arterial pressure (map), intracranial pressure (icp), and brain tissue oxygenation (pbto ), and microdialysis lactate-pyruvate ratio (lpr) were compared six hours prior to and twelve hours following dialysis initiation. high-resolution data was collected every seconds, with the exception of lpr collected hourly. data were normalized to patient maximum values, analyzed by fitted segmented regression, and checked for slope change-points by davies' test. values prior to dialysis initiation were averaged as a baseline for comparison. median values for patients undergoing cvvh-d were map +/- . , icp . +/- . , pbto . +/- . mmhg (n= ), and lpr . +/- . (n= ). normalized median values for patients undergoing ihd were map +/- . , icp +/- . . for the cvvh patient segmented regressions with normalized data, there was no change in map (slope . ) during the twelve hours. however, we found a change-point in icp at . hours (ci . - . , slope change . to . ) and pbto at . hours , slope change . to - . ). lpr increased through cvvh (slope . +/- . ). median values for patients undergoing ihd were map +/- . , icp +/- . . there was no identified change-points in map or icp in ihd patients, further parameters were limited by small sample size. initiation of cvvh in patients with neurologic multimodality monitoring showed change-points in icp and pbto in setting of stable map, with slight decrease in icp and pbto . initiation of hd in showed no change-points in icp. data on the cerebral effects of antihypertensive agents are limited but potentially important in patients requiring blood pressure reduction in neurological emergencies. our objective was to measure the effect of rapid-acting antihypertensive agents on cerebral blood flow (cbf) in patients with acute hypertension we conducted a prospective, quasi-experimental study of patients with a sbp > mmhg and planned rapid-acting antihypertensive treatment in the emergency department. patients < years or pregnant were excluded. non-invasive hemodynamic and transcranial doppler measurements of the middle cerebral artery mean flow velocity (mfv) were obtained prior to and post treatment. analysis included descriptive statistics and generalized linear modeling to test the effect of four categories of antihypertensive agents on mfv. categories included clonidine, iv labetalol, iv hydralazine and combination therapy. we enrolled patients ( % female) with a mean age of ± years. eight ( %) patients received clonidine, ( %) iv labetalol, ( %) iv hydralazine and ( %) combined therapy. the mean baseline sbp was ± mmhg and mfv ± cm/sec. the mean percentage fall in sbp by medication was: clonidine - ± %, labetalol - ± %, hydralazine - ± %, and combination - ± %. the overall change in mfv was - ± %, and by medication was: clonidine - % ( %ci - to - %), labetalol - % ( %ci - to - %), hydralazine + % ( %ci - to + %), and combination - % ( %ci - to - %). adjusting for baseline bp, hydralazine caused less change in mfv compared to other medications (difference between means + %, %ci - to + %, p= . ). in this study with modest bp reductions, rapid-acting antihypertensive medications had comparable effects on cerebral blood flow. these results hint that cerebral blood flow may be more stable with hydralazine administration, but further testing of hydralazine and infusions such as nicardipine is required. studies exploring correlations between non-invasive (oscillometric) blood pressure (nibp) and intraarterial blood pressure (abp) have excluded neurocritically ill patients with continuous infusion of vasoactive medications. compared to abp, nibp monitors generally tend to over-read at low values and under-read at high values. this study examines the relationship between simultaneously measured nibp and abp recordings in these patients. following informed consent, prospective observation of patients (n= ) admitted to a neurosciences icu, with simultaneous abp and nibp monitoring and continuous vasopressor (n= ) or antihypertensive (n= ) infusion. paired nibp/abp observations along with covariate and demographic data were abstracted via chart audit. analysis was performed using sas v . . , paired nibp/abp observations from subjects ( % male, % white, mean age years) receiving vasopressors (n= ) or antihypertensive agents (n= ). t-tests show significant difference between paired readings: ([sbp: m= vs mmhg respectively; p<. ], [dbp: m= vs mmhg respectively, p<. ], [map: m= vs m= mmhg respectively, p<. ]). the paired differences for specific medications were tabulated, with - % of the differences < mmhg, and - % of the values with < mmhg difference. bland-altman plots for map, sbp, and dbp demonstrate good intermethod agreement between paired measures (excluding outliers) and demonstrated marked nibp-abp sbp differences at higher blood pressures. pearson correlation coefficients for paired measurements show strong positive correlation for map (+ . ), sbp (+ . ), and dbp (+ . ). despite a statistically significant difference between nibp and abp readings for patients on vasoactive medications, there may be no clinical significance. the relatively positive and linear correlation between paired values guide providers towards not being forced to use one over the other. the final manuscript will aim to detail whether there is a clinical significance in particular vasoactive medications. pathological activity in continuous electroencephalogram (ceeg) data of icu patients is conventionally categorized into a small number of named rhythmic and periodic patterns. we aimed to develop a valid method to automatically discover a small number of homogeneous pattern clusters, to facilitate efficient interactive labeling by ceeg experts. we extracted time and frequency domain features from + hour ceeg recordings from different icu patients. after removing artifacts, we applied principal component analysis ( % variance retained), then separated the data into clusters (k-means). from each cluster we took random samples plus the most central one, rendering samples in total. three expert electroencephalographers independently categorized all samples into one of standard pattern categories (seizures, gpds, lpds, lrda, grda, burst suppression, other). we compared two methods for labeling clusters: ( ) "labor intensive labeling" (lil): assign the most frequent of expert-provided labels; ( ) "labor efficient labeling " (lel): assign the most frequent of the expert labels for the central sample. we compared interrater agreement (ira) among experts vs. between each expert and consensus labels using lil vs. lel. finally, we used laplacian eigenmaps (le) to visualize the data. this research suggests that large ceeg datasets can be automatically clustered into a small number of patterns described by standard icu eeg pattern labels. we demonstrated efficient cluster labeling by inspecting only the central-most representative of each cluster. furthermore, le visualizations support the hypothesis of an interictal-ictal continuum. real time measurement of cerebral oxyhemoglobin (oxyhb) and deoxyhemoglobin (deoxyhb) using near infrared spectroscopy (nirs) may help us better understand the status of cerebral oxygenation and possibly cerebral blood flow (cbf) in patients with acute brain injury. we developed multichannel functional nirs (fnirs) system and evaluated its role in patients with acute brain injury. a channel fnirs system (nirsittm) was used for measuring cerebral oxyhb and deoxyhb in patients with brain injury. measurement protocols were as follows; baseline measurement for minutes with activation stimuli (nipple pinching for seconds). patients groups were categorized as follows; ) global cerebral ischemia with profound cerebral injury (n= ), ) large ischemic stroke or decrease in cbf in the frontal lobe due to severe stenosis in the middle cerebral artery (mca) or internal carotid artery (ica) (n= ), ) high grade subarachnoid hemorrhage with a risk of vasospasm (n= ), control groups did not have either cerebral lesion or cbf abnormality (n= ). global ischemia with good functional outcome group had better oxyhb level (rso ) compared to those with poor outcome ( . % vs. . %, respectively, p = . ). patients with poor perfusion in the mca territory had low oxyhb level compared to mirror lead in the contralateral hemisphere. oxyhb level in patients with decreased vasomotor reactivity on diamox spect had improved after carotid stenting. three patients who underwent superficial temporal artery-middle cerebral artery bypass surgery had transient hyperperfusion syndrome. oxyhb and total hb were elevated in the affected area. patients with sah and vasospasm had blunted oscillation pattern of oxyhb compared to those without vasospasm. bedside multichannel measurement of oxyhb and deoxyhb using fnirs might be useful in understanding hemodynamic changes occurring in patients with acute brain damage at the real time. multimodality monitoring (mmm), brain tissue oxygenation (pbto ) and microdialysis (md) in sah may be important to the treatment of delayed cerebral ischemia (dci). our hypothesis was that concordance between pbto and md occurs in the tissue bed displaying angiographic vasospasm. this retrospective observational study includes patients with sah. the extent of angiographic vasospasm for each vessel was graded on angiography by the on call neuro-interventionalist and quantified as (no spasm) to (severe spasm). pbto and md probes were placed in the frontal lobe white matter. the severity of vasospasm was estimated by the weighted average of ( x aca + x mca + x ica) / . cases with score of or more were considered to have clinically relevant vasospasm. using a within-subjects design, epochs of baseline mmm were compared with during spasm using daily mean for pbto , lpr, glucose, icp and cpp. given the limited number of observations the simplifying assumption was made that the observations from all epochs are independent. the measurements from all patients were divided in the two groups with and without spasm and were compared using a twotailed non-paired student t-test. sixteen sets of baseline and vasospasm epochs were evaluated for pbto and for md. compared with baseline values, the average pbto was significantly lower ( . vs . mmhg, p= . ), lpr was non-significantly higher ( . vs . , p= . ), and glucose was similar ( . vs . mmol/l, p= . ) during vasospasm epochs. there was no difference in icp ( . vs . mmhg, p= . ). these differences were unaffected by induced hypertension, when cpp was augmented for treatment of dci ( . vs . mmhg, p= . ). mmm during angiographic vasospasm after sah suggests discordant changes in brain oxygenation and metabolism. these data suggests that dci may be related to metabolic factors other than tissue oxygenation. multimodal monitoring including brain tissue oxygenation (pbto ) is increasingly used for the management of acute tbi patients. the optimal management of pbto is not fully established. increasing fio is efficacious to correct pbto but may mask other oxygen delivery mechanisms which may be deficient. the objective of this study was to explore the clinical utility of a pbto /pao ratio to detect overtreatment by fio . retrospective cohort stud were collected simultaneously whenever an arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). causes of cerebral hypoxia (pbto < mmhg) were noted. pbto /pao ratio < . was considered abnormal and plotted over time for each patient individually. data sets were collected from patients (mean age . ± . , median gcs , mortality %). . % of the time and associated with a mean pao of mmhg. measures within the low pbto -low ratio category had significantly lower cpp ( vs mmhg), higher pao ( vs mmhg) than patients with normal pbto or normal ratio respectively. various causes of hypoxic pbto were reported when the ratio was abnormal: hypocapnia, low cpp, low cardiac index, long equilibration time... four patterns of evolution of the ratio over time were identified and associated with different mortality rate: . %, . %, . % and %. conclusions associated with increased pao and decreased cpp. this suggests clinicians often used fio to compensate for deficient cerebral oxygen delivery. indeed, various causes of hypoxia besides low pao were identified and corrected. pattern of temporal evolution of the ratio seems to correlate with mortality. pupillary light response (plr) evaluates cranial nerves ii, iii, and midbrain function. bedside quantitative infrared pupillometry provides reproducible assessment of the plr, reported as the neurological pupillary index (npi). increased intracranial pressure results in decreases in npi. intracranial hypotension (ih) can also cause brainstem distortion. we therefore hypothesized that similar changes in npi could be seen with ih. here, we describe sequential changes in npi in ih before and after treatment. we identified four patients monitored with pupillometry for clinical care during ih diagnosis and treatment. ih was diagnosed with a compatible history, exam, and characteristic neuroimaging findings. patients' npi at baseline, during symptomatic ih, and after treatment were compared using related samples friedman's two-way anova and wilcoxon signed ranks tests. two patients were male; causes of ih were csf leak following lumbar instrumentation (n= ) and basilar skull fracture (n= ). mean baseline npi was normal (defined as > ) and declined in one or both eyes concurrent with clinical deterioration in the - hours preceding definitive diagnosis. all patients underwent treatment for csf leak with epidural blood patch or fracture repair, with return of npi > within hours of treatment. the baseline, symptomatic and post treatment npi's differed significantly ( . ± . vs . ± . vs . ± . , mean +/-sd, pre-treatment vs nadir vs post-treatment, p= . ). both baseline and post treatment npi's differed from the npi nadir (p= . ) but there was no difference between baseline and post-treatment npi (p = . ). impairment of the plr, as measured by npi, occurred during symptomatic ih and resolved after treatment. because management of intracranial hyper-and hypotension differ markedly, our results emphasize the importance of evaluating the clinical context before attributing pupillary/npi changes to increased icp. automated pupillometry provides a non-invasive, bedside tool for monitoring progression and treatment of intracranial hypotension the correlation of optic nerve sheath diameter (onsd) as seen on ultrasonography (us) and directly measured intracranial pressure (icp) has been well described. nevertheless, differences in ethnicity and type of icp monitor used are obstacles to the interpretation. therefore, we investigated the direct correlation between onsd and ventricular icp and defined an optimal cut-off point for identifying increased icp (iicp) in korean adults with brain lesions. this prospective study included patients who required an external ventricular drainage (evd) catheter for icp control. iicp was defined as an opening pressure over mmhg. onsd was measured using a mhz us probe before the procedure. linear regression analysis and receiver operator characteristic (roc) curve were used to assess the association between onsd and icp. optimal cut-off value for identifying iicp was defined. a total of patients who underwent onsd measurement with simultaneous evd catheter placement were enrolled in this study. thirty-two patients ( . %) were found to have iicp. onsd in patients with iicp ( . ± . mm) was significantly higher than in those without iicp ( . ± . mm) (p . mm disclosed a sensitivity of . % and a specificity of . % for identifying iicp. onsd as seen on bedside us correlated well with directly measured icp in korean adults with brain lesions. the optimal cut-off point of onsd for detecting iicp was . mm. impaired cerebral autoregulation following neurological insult has been established as a strong predictor of clinical outcome. hypothermia may offer autoregulatory protection in these patients, although the effect of body temperature on autoregulatory status is unclear. retrospective analysis of data from an ongoing prospective study to evaluate multimodal monitoring using near infrared spectroscopy (nirs) for bedside measurement of autoregulation. ninety-one comatose patients (gcs < ) were continuously monitored for up to three days. nirs derived cerebral oximetry index (cox) was used as a marker of autoregulation. cox was calculated as a moving, linear correlation coefficient between regional cerebral oxygenation saturation and map. autoregulation improves as cox values approach , and is impaired as values approach . patients were grouped by trend in temperature seen over the monitoring period: no change (< oc temperature change, n= ), increase (n= ), decrease (n= ), increase followed by decrease (n= ), decrease followed by increase (n= ), and fluctuating (n= ). we performed multivariable logistic regression analysis to assess the association between temperature and outcomes. the association between hourly temperature and cox was assessed using mixed random effects models with random intercept. in patients showing a sustained increase or decrease in temperature, a linear relationship between temperature and cox was seen; for every oc increase or decrease in temperature, cox changed by . ± . (p< . ) and - . ± . (p= . ), respectively, after adjusting for pco , haemoglobin, map and temperature probe location. mean temperature changes over the monitoring period for these groups were . ± . oc and - . ± . oc, respectively. cox did not change significantly in other groups. there was no significant difference in mortality or poor outcome (mrs - ) at discharge and , , or months between patients in each group. in acute coma patients in the neurocritical care unit, increasing body temperature is associated with worsening cerebral autoregulation as measured by cox. the historical tradition of examining the pupillary light reflex (plr) required the examiner to score the size and reactivity of the pupil. a change in the plr from brisk to sluggish or fixed may be a marker of a pathological process and a need for intervention. the plr has been difficult to quantify and has poor inter-rater reliability. handheld pupillometry provides several novel measures, such as the neurological pupillary index™ (npi) and constriction velocity (cv) that may be more quantifiable than the plr. the purpose of this analysis is to examine the relationship between cv and npi in neurologically injured patients. the end-panic registry is a prospective registry of pupillometer values and variables associated with intracranial dynamics (e.g., icp). this analysis from adult (over years) patients from hospitals includes , pupillometer readings; left eye ( , ), and right eye ( , ). subjects had a mean age of . yrs and . % were male. the primary admission diagnosis included neoplasm ( ), ischemic stroke ( ), sah ( ), ich ( ), tbi ( ), and other ( ). the left eye mean/s.d. cv ( . / . ) npi ( . / . ) and size ( . / . ) were similar to the right eye cv ( . / . ) npi ( . / . ) and size ( . / . ); statistically significant difference related to large sample size. the correlation between left eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). the correlation between right eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). constriction velocity is highly dependent on size of the pupil. further studies need to be undertaken to determine the sensitivity and specificity of abnormal npi and cv in detecting pathological processes such as midline shift or rd nerve compression that effect pupillary reactivity. cerebral injury is increasingly described in adult recipients of extracorporeal membrane oxygenation (ecmo) therapy. we describe the association between regional brain tissue oxygenation (rso ) measured by near infrared spectroscopy (nirs), survival, and cerebral injury on neuroimaging. a single-center retrospective chart review was conducted of adult patients who underwent veno-arterial (va) ecmo from april to october . all patients had received nirs monitoring during ecmo therapy. baseline demographics, in-hospital complications, and mortality were recorded. desaturations of rso , defined as decline > % below baseline or absolute value < , were recorded and analyzed. desaturation burden was calculated by area under the curve analysis and measured by rso *seconds. eighteen va ecmo patients ( females) underwent nirs monitoring during the study period. eleven patients experienced desaturations, while did not. patients with desaturations tended to be younger ( . vs. . years old), more likely female ( vs. ), had lower ejection fraction ( . % vs. . %) and experienced liver dysfunction ( patients vs. ). patients with desaturations were more likely to have abnormalities on ct scan ( vs. ). eleven of the patients survived to discharge. survivors tended to be younger ( . vs. . years old) and had lower initial ecmo sweep ( . vs. . ). survivors had lower baseline rso values at the beginning of nirs monitoring (right - vs. , left - vs. ), fewer desaturation events ( vs. ), lower desaturation burden, and spent less overall time desaturating ( : vs. : hours). desaturation on nirs may be correlated with cerebral injury in the adult va ecmo population and may have utility in triggering clinical investigation or determining prognosis. further studies in larger patient populations are needed to determine its reliability and accuracy. pressure reactivity index (prx) is the most validated index to measure cerebrovascular reactivity in patients after traumatic brain injury. the aim of this study is to identify the natural history of cerebral autoregulation measured by prx in various forms of brain injury to monitor restoration or not of cerebral vasomotor reactivity in the acute phase. retrospective analysis of data from ongoing prospective study to evaluate multimodal monitoring using prx for the measurement of cerebral autoregulation at the bedside. thirty comatose patients (glasgow coma scal used as a marker of autoregulation. prx was calculated as a moving, linear correlation coefficient between icp and map. impaired cerebral autoregulation has been pre standard maximal medical therapy was implemented to treat elevated icp, cerebral edema, etc. patients with withdrawal of care in the first hours or brain death on neurological exam were excluded. thirty comatose patients from acute brain injuries ( intracerebral hemorrhage, tbi, aneurysmal subarachnoid hemorrhage, intraventricular hemorrhage, hypoxic ischemic encephalopathy) were studied. the average prx upon starting neuromonitoring using prx was . ± . (impaired), whereas the average prx at the end of day of neuromonitoring was ± . (restored). one third of the patients had icp crisis during monitoring. the average opening icp= . , average highest recorded icp= . . impaired cerebral autoregulation has been implicated as a predictor of clinical outcome. aggressive medical therapy instituted by the neurocritical care team (icp and cerebral edema management, blood pressure control, etc.) may result in restoration of cerebral vasomotor reactivity measured by prx by intensive care day - . restoration of cerebral vascular reactivity may be a necessary but not sufficient for favorable outcome. elevated intracranial pressure (icp) is an important cause of death following acute liver failure (alf). while invasive icp monitoring (iicpm) remains the gold standard, the presence of coagulopathy increases the risk of bleeding in alf. measurement of optic nerve sheath diameter (onsd) using optic nerve ultrasound (onus) may accurately detect elevated icp. our goal was to study the ability of onus to detect sustained intracranial hypertension following alf, and to predict death and therapeutic intensity level (til), a quantitative measure of the intensity of treatment required to control icp. consecutive patients with alf admitted to our institution in a -year period underwent onus. blinded measurement of onsd was performed from deidentified onus videos. patients underwent iicpm on the basis of an institutional protocol for selection of appropriate candidates, coagulopathy reversal and insertion of an intraparenchymal monitor. the til-basic for management of icp during the icu stay was recorded. the ability of highest onsd to predict concurrent icp> mmhg at the time of measurement, sustained icp elevation > mmhg at any time and til-basic> was assessed in patients who underwent iicpm, while prediction of death was assessed in all patients. receiver operating characteristic (roc) curves were constructed for the outcomes of interest. thirty-nine patients with alf were admitted during the study period, / ( %) underwent onus, / ( %) underwent iicpm and ( %) died. of patients who underwent iicpm, ( %) developed sustained icp elevation and ( %) had a til-basic> . the roc area under the curve (auc) of onsd for prediction of concurrent icp> mmhg was . ( % confidence-interval . - . , p= . for null hypothesis of auc= . ), sustained icp elevation at any time was . ( . - . ,p= . ), death was . ( . - . ,p= . ) and til> was . ( . - . ,p= . ). in patients with alf, onsd measurement performed poorly for detection of icp elevation, and was a poor predictor of til and death. limited literature exists regarding the neurochemical and physiologic events that occur as brain death develops. using intracranial multi-modality monitoring, we identify physiological changes that signal the onset of brain death. we measured intracranial pressure (icp), brain partial oxygen tension (pbto ), cerebral blood flow (cbf), and biochemical correlates of cerebral metabolism in patients with diffuse hypoxic ischemic brain injury after cardiac arrest during the development of brain death. monitoring probes were inserted into cerebral white matter through a burr hole using a ct compatible multi-lumen bolt. brain tissue energy-related metabolites (lactate, pyruvate, glutamate, glucose, glycerol) were measured using a bedside microdialysis analyzer. pbto and temperature were measured via a licox catheter. cerebral perfusion was measured with a hemedex bowman perfusion monitor. brain death was confirmed in accordance with institutional guidelines. a characteristic pattern of physiologic and neurochemical findings emerged as brain death occurred. absolute loss of cerebral autoregulation, with a near perfect correlation between icp and map was followed by equalization of map and icp resulting in progressive drop in cpp to zero, followed by a progressive decline in pbto that became unresponsive to a % fio challenge. cerebral perfusion decreased in tandem with pbto . lactate/pyruvate ratio (lpr), glutamate, and glycerol all increased precipitously, with lpr consistently > . brain temperature decreased despite maintenance of a normal core temperature. finally, intracranial compliance, while initially very low (evidenced by marked increase in the p component of the icp waveform), appeared to paradoxically re-normalize as the recording continued. continuous neuromonitoring reveals a characteristic pattern of cerebrovascular physiologic changes that accompany brain death. these changes are consistent with a progressive cessation of cerebral perfusion caused by diffuse cerebral edema. although not currently a part of the formal brain death determination process, such monitoring could be helpful to identify when brain death has truly occurred. automated devices that collect objective quantitative data on pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the normative range of pupillary reactivity in the critically ill, and the relationship between reactivity and traditional monitoring metrics. to determine pupil characteristics in this population, we prospectively collected quantitative pupillometry data in patients admitted to the neuro icu with an expected stay of at least hours. trained nursing staff measured pupillary reactivity with the neuroptics- pupillometer device every -hours. measurements included the neurologic pupil index, (npi) a composite metric ranging from - in which > is considered normal, resting and constricted pupil size, constriction velocity, dilation velocity and latency. these recordings were compared with averaged intracranial pressure (icp) and glasgow coma scale (gcs) assessments within the same hour. we used univariate and spearman's rank tests to explore associations between pupil characteristics and clinical variables, followed by multi-level linear regression to account for intra-and inter-subject variability. one-hundred patients underwent paired observations. fifty-five patients had at least one recorded episode of anisocoria, had low npis in more than % of recordings, and had normal pupil reactivity. average and minimum npi was correlated with average and minimum recorded hourly glasgow coma score (gcs) (p values < . ). increased asymmetry in both pupil size (p= . ) and dilation velocity (p= . ) was associated with increased intracranial pressure (icp). anisocoria was associated with hyperosmolar therapy (p= . ). the presence of low npis in more than % of total pupil measurements was associated with death at discharge (p= . ). the range of pupillary metrics varies among critically ill neurologic patients and correlates with gcs and icp. further study is needed to establish whether change in pupil metrics predict specific clinical events. near infrared spectroscopy (nirs) provides a non-invasive measurement of regional cerebral oxygen saturation (rso ) that may be able to detect seizure activity. in this study, we explored the hypothesis that rso is lower ipsilateral to seizures or epileptiform activity compared to the contralateral side in comatose patients. five patients ( men and women; mean age ) underwent continuous electroencephalography (ceeg) monitoring and nirs recording. ceeg data were classified as baseline, epileptiform activity or seizure, slowing, or burst suppression at hourly intervals over the course of the recoding period (mean duration . hours, range to hours). three patients had idiopathic status epilepticus, two had intracranial hemorrhage, and one had a temporal meningioma. the relationship between rso and epileptiform discharges was explored using scatterplots. the association was assessed using mixed random effects models with a random intercept. an independent within-subject residual structure was used. there were measurements with ceeg and nirs from patients. one patient was excluded as the nirs sensors were potentially reversed. epileptiform activity or seizures were observed in a median of % of the measurements (iqr - %). rso was significantly lower on the side ipsilateral to seizures - . , p < . ) after adjusting for map. all patients only had partial seizures with no generalization. partial seizures and/or epileptiform discharges were not associated with impaired autoregulation. we found a significant lower cerebral oxygen saturation ipsilateral to seizures and/or epileptiform activity. the association was observed in patients with various etiologies of coma, and with either convulsive and non-convulsive seizures. decreases of regional cerebral oxygen saturation at the bedside may alert the clinician of ipsilateral seizures. elevated intracranial pressure (icp) and cerebral edema are common causes of mortality in neurocritical-care patients. key monitoring techniques for icp-elevation include neuroimaging and invasive icp-measurement. examination of the pupils is routinely performed to determine disturbances within cerebral physiology but shows high inter-rater variability. portable infrared pupillometry is increasingly used for accurate measurements. the benefit of these technique remains to be established in patients with elevated icp. aim of this study was identify pupillary parameters associated with icpcrisis in neurocritical-care patients. we prospectively enrolled critically-ill patients (subarachnoid hemorrhage/intracerebral hemorrhage/stroke/bacterial meningitis) admitted to our neurointensive care unit( / - / ) who required placement of external ventricular drains. we recorded serial pupillometer readings [i.e. maximum/minimum apertures(mm), constriction/dilation velocities(mm/sec.), latency period(sec.)] and corresponding icp values every hours after admission. neurological pupil index(npi), an algorithm that compares above mentioned pupillary parameters to a normative model of pupil reaction to light, grades pupil-function on a scale of (nonreactive) to (normal). receiver operating characteristic(roc) curve analysis was performed to investigate associations between pupillary parameters and presence of icpcrisis(icp> mmhg). in our data suggest a relationship between non-invasively detected changes in npi, cv or mcv and icpcrisis. yet, clinical benefit of these parameters is subject to future studies. lung injury is frequently observed in patients with severe, acute brain injury. while these patients often require mechanical ventilation, a lung protective ventilation strategy has not been extensively studied. this may be due, in part, to concerns that elevated positive end-expiratory pressure (peep) could adversely affect intracranial pressure (icp) or cerebral perfusion pressure (cpp). we were interested in exploring this relationship as a first step towards understanding whether mechanical ventilation resulted in a transmission of pressure to the brain. ) and received both mechanical ventilation and icp monitoring were enrolled in this pilot study. an esophageal balloon was inserted to measure their transpulmonary pressure (ptp). fluid responsiveness was assessed prior to the intervention. subjects underwent a step-wise increase in peep (increments of five) from to cmh o. airway pressure, ptp and icp were measured at each peep interval. of the planned twenty, three patients have been enrolled to date. primary diagnoses included aneurysmal subarachnoid hemorrhage and intraparenchymal hemorrhage with a median gcs of . patients were ventilated using either volume control or pressure support ventilation; median fio was . . two patients were on vasopressors and the same two patients were determined to be fluid responsive. at baseline (peep ), mean icp, cpp, and ptp were mmhg, mmhg, and - . cmh o, respectively. when peep was increased to cmh o, the average change from baseline in icp and cpp was - . % and - . %, respectively. when increased to cmh o the change from baseline in icp and cpp was . % and . %. during the intervention icp did not exceed mmhg, nor did any patient experience hypotension. preliminary data suggests that intrathoracic pressure is not directly transmitted to the intracranial compartment. continued enrollment is needed to confirm these findings. neurocritical care after severe traumatic brain injury (stbi) is focused on detecting and preventing secondary brain injuries. in addition to intracranial pressure (icp), measures of brain tissue oxygen (pbto ), regional cerebral blood flow (rcbf), and electrocorticography (deeg) may provide critical clinical data. few studies have assessed the safety of such an approach and the reliability of data that is gathered. we describe here the placement, complications, and reliability of multimodality monitoring (mmm) data from a novel, single burr hole approach using a four-lumen bolt at our institution. we included consecutive adult stbi patients admitted to the neuroscience intensive care unit at the university of cincinnati from april to march who underwent mmm as part of standard clinical management per institutional protocol. data was obtained regarding device placement and complications. all data was visually inspected for errors and gaps in data. patients were included. the mean age was +/- and % were men. bolts were placed a median of . (iqr . - . ) hours from injury. no clinically significant complications occurred, although . % had minor complications (e.g. small tract hemorrhage or pneumocephalus). suboptimal placement of probes was noted in %. we monitored patients a median . (iqr . - . ) hours. icp data was the most reliable, with data available . % of the total monitoring time and only . % error time. pbto and deeg data were reliable for > % of total monitoring time with < % error time. rcbf provided data for % of total monitoring time and had . % error time. mmm in stbi may be carried out via a single burr hole without significant clinical complications and reliably yields continuous data to facilitate clinical decision making. this supports the feasibility of our approach as an alternative to icp monitoring alone. intracranial hemorrhage patients with non-compliant ventricles may have high intracranial pressure (icp) despite normal ventricle size. we aimed to assess the incidence of elevated icp among those with no radiographic evidence of intracranial hypertension. prospectively enrolled primary intracranial hemorrhage patients (sah, sdh and iph) admitted to two tertiary-care centers between / - / were retrospectively reviewed. among patients with external ventricular drainage (evd), admission head ct (hct) scans within h prior to evd placement were reviewed for evidence of elevated intracranial pressure (icp) including: ventricle size (bicaudate index, temporal horn size), basal cistern effacement, midline shift and global cerebral edema. when all of these features were absent, patients were classified as having normal-icp hct. the incidence of elevated icp (> mmhg) at the time of evd placement and during hospital stay were recorded. of intracranial hemorrhage patients enrolled, ( %) had evd. / ( %) had a normal-icp hct. of these, / ( %) had elevated opening pressure at the time of evd placement, and / ( %) had elevated icp during their hospital stay. among normal-icp hct patients with icp> mmhg, % had sah, and the median gcs and hunt-hess scores were (range - ) and (range - ). the positive and negative predictive values of normal-re % %, respectively (auc . , p= . ) the only radiographic feature that was associated with elevated icp was global cerebral edema (or . , % ci . - . , p< . ). approximately half of intracranial hemorrhage patients without radiographic features of elevated icp had icp> mmhg at the time of evd placement and additional patients had elevated icp during their hospital stay. radiographic findings should not be relied upon to exclude the possibility of elevated icp. the measurement of intracranial pressure (icp) is a cornerstone of intensive care management following severe traumatic brain injury (stbi). it has been only recently that the time integral of icp has been quantified in relation to outcome; the time integral of brain tissue oxygen (pbto ) has not been studied. we gathered time-locked intracranial monitoring data on s tbi patients at the university of cincinnati over years. clinical management of all patients followed national standards. raumedic pto probe was used to measure icp and pbto ; accuracy was verified by visual inspection with automated data cleaning. normalized data was mapped based on correlation with glasgow outcome scale scores at - months. we studied patients aged +/- years (mean+/-sd); % were male. initial post-resuscitation glasgow coma scale score was median (interquartile range: . - ). / underwent craniectomy prior to monitoring. among those with good (gos - ) and poor (gos - ) outcome, the average icp was . +/- . mmhg and . +/- . mmhg (p= . ); the average pbto was . +/- . mmhg and . +/- . mmhg (both n.s.). the correlation with outcome was dependent on both icp and time: an icp > mmhg for > minutes was associated with poor outcome, whereas an icp < mmhg was associated with poor outcome only after hours. in contrast, the pbto level, but not the duration, correlated with poor outcome in those without craniectomy at a pbto < mmhg, and particularly below mmhg. pbto burden was less reliable in those following craniectomy. we replicated the effects of icp/time in a cohort of patients with severe tbi, both with and without craniectomy and subsequently demonstrated the burden of brain tissue hypoxia in those without craniectomy. the time integral of multimodality monitoring data may provide more accurate measures of secondary insult burden with implications for clinical care and prognosis. neurologists who work in neurocritical care (ncc) as neurointensivists may have critical care (cc) charges rejected for payment unless they are classified per centers for medicare services (cms) taxonomy codes in their systems as critical care providers. the neurocritical care society and cms created a new ncc code a x to fix this issue. we polled the aan ccen section members for awareness of this problem. we conducted a six question google forms survey using the aan ccen synapse community website to assess knowledge of the ncc taxonomy code: we received anonymous responses by the time we closed the poll on / / . question (q ) and (answers, a ): are you a neurology or neurosurgery back grounded intensivist who does neurocritical care at your hospital? y/n (yes/no). a : % reported being neurologists. q : were you aware of the new cms neurocritical care taxonomy code a x ? y/n a : % were aware of the taxonomy code. q : are you aware why the ncc taxonomy code was created? y/n a : % of respondents were unaware why this code was created. q : what is your primary department for revenue collection? a : % reported neurology, % neurosurgery, % critical care, and % blend. q : are you aware that medicare can reject critical care charges ( and ) can be rejected unless you are listed as a cms 'critical care provider' or as a neurocritical care provider? a : % reported rejected charges at their centers. q : are you aware of rejection of critical care charges happening at your own institution due to this misclassification? y/n a : % of respondents reported rejected charges at their center. although limited in sample size, this survey revealed almost half of the respondents were unaware of the ncc code. we believe a larger study is warranted. arterial subdural hemorrhage (sdh) is a rare but potentially devastating neurologic entity. it has been associated with ruptured aneurysms. we report a case-series of five patients with arterial sdh and their outcomes. a retrospective chart review of our institute's vascular database was conducted using a pre-defined search strategy including the terms "aneurysm", "arterio-venous malformation", "subdural hemorrhage", and "dural arterio-venous fistula" (dural-avf). amongst patients in the database, five cases were identified with ages ranging from to (four females). four had sdh due to aneurysm (two internal-carotid, one middle-cerebral, and one posteriorcerebral artery; one had parieto-occipital dural av-fistula. no patient had preceding head-trauma or anticoagulation. of aneurysmal patients, one had no sah. on admission ct-head imaging, the mean-sdh size was . mm (sd . ; range . - mm), and mean midline-shift (mls) was . mm (sd . ; range - mm). the mean ratio between sdh-size and mls was . (sd . ). in a historic cohort of acute subdural hemorrhage of non-arterial etiology ; the mean size of sdh was . mm and the mean mls was . mm. ratio of mls: sdh size was . . in our series, three patients with aneurysms had decompressive-craniectomy, one had mini-craniotomy for sdh evacuation; the patient with dural-avf had coiling and mini-craniotomy for sdh evacuation. four patients had died during hospitalization, whereas patient with dural-avf recovered to baseline functional-status at -month follow-up. arterial sdh is a rare entity and may present without subarachnoid hemorrhage and any preceding head-trauma. the degree of midline-shift is usually out of proportion to sdh size. there should be a low threshold to obtain vessel imaging in cases of sdh with no clear trauma history. mls: sdh ratio may be a useful screening tool for possibility of arterial sdh especially in absence of trauma and may reflect rate of bleeding. neurostimulant medications (amantadine and modafinil) are sometimes prescribed after acute nontraumatic brain injury to facilitate wakening and rehabilitation participation; the safety and effectiveness of this practice is unknown. following a retrospective evaluation of our experiences, we characterized anticipated challenges to designing a prospective randomized trial of neurostimulant medications to promote rehabilitation participation after acute non-traumatic brain injury. retrospective chart review of patients over with subarachnoid hemorrhage (n= ), intracerebral hemorrhage (n= ) and ischemic stroke (n= ) who received neurostimulant medications over a period of months. data regarding clinical course and potential confounders to assessing response were collected. continuous data are reported as median and interquartile range. neurostimulant medications were initiated in patients at a median of ( - ) days after hospital admission, for hypersomnolence ( %), not following commands ( %), lack of eye opening ( %), and/or low gcs ( %). thirty-nine ( %) patients were receiving sedatives or opioids at the time of neurostimulant(s) initiation. twenty-two ( %) patients received newly prescribed sedatives or opioids after neurostimulant(s) initiation. potentially sedating antiepileptic medications were prescribed to ( %) of patients. twenty-two ( %) patients were intubated at the time of neurostimulant initiation confounding the gcs-v. potentially confounding clinical factors included hydrocephalus ( %), vasospasm ( %), and seizures ( %). twenty-eight ( %) of patients had temporary cerebrospinal fluid diversion in place at the time of neurostimulant initiation. initiation and titration of neurostimulant medications after acute non-traumatic brain injury was common, but timing and indications varied widely. confounders to assessing effectiveness included concomitant sedating medications, variable pathophysiology related to the type and location of the stroke, and clinical factors like seizures, vasospasm, and hydrocephalus. these confounders are likely to make prospective evaluation of neurostimulant medication effectiveness difficult in the period of initial therapy following acute non-traumatic brain injury. brain small vessel disease can cause cognitive impairment via ischemic or hemorrhagic mechanisms. current imaging modalities, specifically magnetic resonance imaging allow for easier detection of different intracranial pathological processes including cerebral microhemorrhages (cms). research demonstrated that the number and location of cms correlate with the type of cognitive impairment (memory, processing speed, executive function, and motor speed). a retrospective analysis of patients (age to ) seen at our neurology outpatient clinic from to who were identified by linguamatics software to have "microhemorrhage" in their radiology mri report. additional information included age, sex, cognitive examination, presence of cardiovascular risk factors, mri, and the number and location of cms. cognitive function was determined by mini mental state examination (mmse) score and diagnosis by a cognitive neurologist. patients were grouped by presence of cm or greater ( to ) and regression was used to determine a relationship with mmse and vascular risk factors. the number of microhemorrhages per patient were ( patients), ( patients), ( patients), ( patients), ( patients), ( patients) and ( patients). vascular risk factors included hypertension ( patients), diabetes mellitus ( patients) and smoking history ( patients). regression analyses indicated that the presence of more than cm correctly predicted mmse lower than at % (p= . ). age was the only factor that influences this finding and increased this prediction to %. this study provides novel evidence that the presence of multiple cms on brain images predicts the presence of cognitive impairment. this study raises the need for more investigations. point-of-care ultrasound is a valuable tool in critical care, allowing timely and frequent beside assessment of clinical questions. neurocritical care has long utilized transcranial doppler but is still early in the adoption of other critical care ultrasounds. this study looked at the comfort level and competency of the participants at the point-of-care ultrasound workshop at the neurocritical care society annual meeting. the workshop comprised of didactics and hands-on small group practice using live models. topics covered included ultrasound physics, lung, cardiac, optic nerve sheath ultrasounds, as well as case studies in neurocritical care. participants were asked to complete an anonymous pre-and postworkshop assessment on a volunteer basis. a total pre-workshop and post-workshop assessments were completed. the mean age of the participants was . ± . years. there were ( . %) attending physicians, ( . %) advance practice practitioners, ( . %) fellows, ( . %) residents, and ( . %) research scientist. participants had limited ultrasound experience prior to the workshop, with ( . %) reported none, ( . %) reported < year, and ( . %) reported to years. on a - scale on comfort using ultrasound with being very uncomfortable and being very comfortable, participants reported a median score of (iqr - ) pre-workshop with an improvement to (iqr - ) post-workshop. for matched pre-and post-tests, all participants had an improvement in their ultrasound knowledge. while the majority of the participants at this workshop had prior ultrasound experience, many are still uncomfortable with their ultrasound competency. the format of didactics and hands-on small group practice improved the comfort level as well as overall ultrasound knowledge of these participants. additional opportunities for point-of-care ultrasound training should be considered in neurocritical care fellowships and meetings. event related potentials (erps) allow assessment of cognitive processing in unconscious brain-injured patients. here we explored the diagnostic and prognostic value of erps obtained shortly after brain injury. we prospectively collected a comprehensive erp paradigm labeled "local global paradigm" from a consecutive series of unconscious patients with acute brain injury. this auditory paradigm allows the assessment of: ) cortical responses, ) unconscious cognitive processing, ) unconscious focusing of attention, and ) conscious processing of sounds. levels of consciousness assessed with the coma recovery scale-revised (crs-r) at the time of recording were correlated with the presence/absence of each erps component and functional connectivity/complexity measures. we tested the prognostic value of each measure for recovery of consciousness prior to discharge. we analyzed recordings from patients (median recordings per patients [iqr , ]). recordings were made [iqr . , . ] days after brain injury and all patients were unconscious at the time of the initial recording. underlying etiologies included ich(n= ), sah(n= ), tbi( ) and other (n= ). there were trends for higher crs-r scores in patients with preserved erp components. crs-r scores correlated with the functional connectivity indexed (rho= . ; p= . ) but not with complexity measures. five ( %) patients regained consciousness (within to days from brain injury). one of these patients had to be excluded due to poor quality recording. all the ( %) remaining patients had the three type of non-conscious responses preserved on at least one recording in comparison to only ( %) among patient who did not recover consciousness (fischer p-value = . ). similarly, connectivity was greater in patients who regained consciousness ( . vs . ; p= . ) but the complexity was similar. simple bedside erp responses indexing cognitive processing during the local global paradigm obtained shortly after brain injury correlate with the level of consciousness but, more importantly, the probability to recover consciousness. over a decade ago, the institute of medicine introduced family-centered care (fcc) as a vital aspect of quality health care by strongly recommending that family members of intensive care unit (icu) patients be actively involved in decision-making. while there are many resources to help icu staff conduct meetings and provide information to families, the latest society of critical care medicine guidelines for fcc recommend the implementation of communication and decision support tools for family members to use. electronic decision support tools such as my icu guide have been effective in pilot studies at allowing family members to customize information delivery and communicate their preferences to icu staff. we sought to integrate a decision support and communication tool for families into an electronic patient portal. we developed an electronic patient and family engagement checklist for the neurointensive care unit (nicu) using doctella (patient doctor technologies, sunnyvale, ca), an existing patient engagement application. checklist components included: identifying a spokesperson, developing an advance directive, understanding diagnosis and prognosis, access to helpful resources, and a family meeting guide and planner. we presented the checklist to our hospital's patient and family engagement steering committee for the icus and received useful feedback. the checklist will also be vetted by the hospital's patient and family advisory council. usability testing will also be conducted. a family engagement checklist using an electronic patient portal is a novel strategy to enhance communication in the nicu. further validation of the tool is needed. applying painful stimuli to brain injured patients is a time-honored practice assumed to provide valuable clinical information for diagnosis, prognosis, and potential guidance for therapeutic interventions. however, there is limited literature that has evaluated and discussed the benefits and potential adverse effects related to repeated painful stimulation during bedside neurological examinations. though providers intend to do no harm, the practice of repetitive painful stimulation can unintentionally damage patient's skin, muscle, and bone, as well as inflict emotional duress. in conjunction with basic ethical principles used to justify painful stimulation during patient examinations, we propose a revisiting of the practice of routine repetitive painful stimulation in neurologic bedside assessments. . discuss the current literature regarding the use of painful stimulation and its beneficial and damaging effects, . describe alternative strategies for neurologic assessments, . propose guidelines to optimize accurate neurologic assessments while avoiding unnecessary repeated painful stimulation, . propose the development of a graded methodology for delivering painful stimulation when necessary for neurologic assessments. a summary of the literature will be outlined and discussed focusing on the ethical considerations and justification for the use of painful stimulation in the neurologic patient and the perception of pain in coma and minimally unconscious patients, . alternative strategies will be presented to minimize bodily and emotional injury, . a proposed outline with a companion flow diagram "easing the pain guidelines" implemented in a tertiary care neurocritical care unit will be presented. there has been little attention paid to the burden of painful stimulation inflicted on patients in the neurocritical care unit. the guiding principle of nonmaleficence (do no harm) morally obligates clinicians to evaluate current practice standards using repetitive painful stimulation in routine neurologic assessments. implementing standardized guidelines will limit unintended harm to patients without compromising accurate neurologic assessments. plasmapheresis is utilized in anti-n-methyl-d-aspartate receptor (nmdar) encephalitis to remove autoantibodies. antiepileptic drugs (aed), such as valproate, are often used to control seizures which may complicate anti-nmdar encephalitis. it is important to prevent rapid reductions of aed levels to ensure proper seizure management in this setting. we obtained total and free (active drug, unbound to plasma proteins) valproate levels intermittently throughout two -day courses of daily plasmapheresis. during the first course, trough levels were obtained. during the second course, levels were obtained before, during, and after plasmapheresis. the patient was a year old female, weighing kg. albumin was . g/dl. her valproate regimen ranged from mg to mg every hours ( to mg/kg/day), given intravenously or enterally. prior to the first plasmapheresis, valproate dose was mg every hours, resulting in a total level of mcg/ml (reference range: - mcg/ml). free valproate was mcg/ml (reference range: - mcg/ml); free fraction was % (reference range: - %). four days later, prior to the th plasmapheresis, the total valproate level was . mcg/ml. two days after the th plasmapheresis the total level was unchanged at mcg/ml; free valproate was mcg/ml and free fraction was %. during the second course of plasmapheresis, valproate total levels, free levels, and free fractions were mcg/ml, mcg/ml, and % before, mcg/ml, mcg/ml, and % during (valproate dose given upon initiation of plasmapheresis), and mcg/ml, mcg/ml, and % after plasmapheresis, respectively. valproate serum levels were not markedly influenced by plasmapheresis. free valproate levels and the free fraction were highly elevated throughout the patient's hospital course, however. future studies should evaluate critically ill patients' clinical response and toxicity correlations as the free fraction of valproate appears to be elevated in this setting. the purpose of this study is to assess knowledge retention of emergency neurological life support (enls) after participation in the course via a prospective observational study. study subjects seeking enls certification consented for study participation (enls-vs) from the ncs website then took a closed-book, multiple-choice question pre-test within hours of enls course participation. after completion of the enls course, participants took the same closed-book, multiplechoice question test (post-test). these tests consisted of novel questions from material presented in the course. questions were not repeated from the enls certification exams. thirty participants enrolled in the study with completing both the pre-test and immediate post-test. all participants' scores improved on the post-test as compared to the pre-test. the mean percent correct on the pre-test was . % with a median of . % (range . - . %). of the participants who have completed both pre-and immediate post-test, the mean pre-test score was . % with a median of . % (range . %- . %). the mean post-test score was . % with a median of . % (range . %- . %). the improvement of scores was statistically significant on the post-test compared to the pre-test ( . % vs. . % %, p< . ). all participants in the emergency neurological life support course showed improved test scores immediately after participation in the standard enls course. this study will assess knowledge retention at -months following training, and is actively enrolling new participants. augmented renal clearance (arc, defined as a creatinine clearance of > ml/min) has been demonstrated in neurocritical care disease states such as traumatic brain injury, intracranial hemorrhage, and subarachnoid hemorrhage. arc may result in increased elimination of renallyeliminated medications, thereby reducing drug exposure with standard doses. the overall prevalence of arc is not well described. the purpose of this study was to estimate the overall prevalence of arc in a neurocritical care population. this was a retrospective cohort study of adults > years of age admitted to the intensive care unit on the neurosurgery service. demographic and pertinent laboratory data were collected for patients admitted from january , thru december , . an arctic score was calculated for each patient ( or greater suggests arc). parametric data was compared using one-sample student's t-test, nominal data was compared using fisher's exact test (alpha = . ). statistical analysis was conducted using ibm spss version . present in a total of . % of patients. a broad spectrum of neurocritical care diagnoses was present. the mean age in years was significantly lower in patients with arc [ . ( sd)] than without arc [ ( sd), p = . ], as was the serum creatinine [with arc . mg/dl ( . sd) vs without arc mg/dl ( . sd), p < . ]. mean hospital length of stay was greater in patients with arc than without [ . ( sd) vs . ( sd), p < . ]. arc occurs commonly in neurocritical care patients and likely merits proactive screening or direct measurement of creatinine clearance in select patients. pharmacokinetic studies of commonly used renally-eliminated medications may be needed to establish population parameters in the neurocritical care population. education surveys demonstrate gaps in resident neurocritical care education and training. we assessed junior residents' baseline knowledge of neurologic emergencies, procedural competency, knowledge of available resources, and the impact of pre-rotation orientations. junior residents (neurosurgery pgy s and neurology pgy s) who had not previously rotated in the neuroicu were surveyed. a three-part survey was administered: part i, knowledge of icu structure and personnel; part ii, procedural competency; part iii, comfort with common neurocritical care emergencies. the survey was comprised of selection responses. after the survey but prior to starting the rotation, each resident was oriented to the unit by a neuroicu attending and nursing director. this orientation reviewed rotation goals, icu structure, personnel and rounding expectations. a survey was repeated to evaluate the orientation. of residents who had not rotated in the icu, ( . %) responded. none of the residents understood their specific role within the icu team. % did not understand the role of the resource nurse and were unaware of where to find procedure equipment. % of residents were not comfortable placing an a-line; % were not comfortable performing a lumbar puncture. over half of respondents said they "didn't know and could not easily find" the indications for hemicraniectomy after malignant mca ischemia, the indications for icp monitoring, or the initial workup of autoimmune encephalitis. residents responded to post orientation surveys. % felt the orientation was helpful in explaining the roles of team members. % felt it was at least "somewhat helpful" in understanding the role of the resource nurse. % felt the orientation was "helpful" and % felt it was "somewhat helpful" in identifying the goals of the rotation. these baseline measures underscore the importance of structured interventions, both before and during the neuroicu rotation, to improve junior resident comfort and preparedness in managing neurologic emergencies. physician-staffed helicopter emergency medical services (hems) are a well-established component of prehospital care in japan. however, there has been no report on hems and neurocritical care patients. we studied characteristics of neurocritical care patients who were transported by hems. we retrospectively evaluated neurocritical care patients who were brought to our emergency and critical care medical center (eccmc) by hems between january, and march, . we excluded patients in whom the outcome was unknown, those who were transported to other hospitals or between facilities. of the most important role of hems is rapid transportation of a flight medical team to the scene to provide immediate, lifesaving medical treatment. we found that half of patients admitted to our hospital by hems were neurocritical care patients. as proposed in the enls of neurocritical care society, hems is considered useful to allow neuro-emergency patients to receive the best care in the first hour. optic nerve sheath diameter (onsd) measurement using ocular ultrasound has been shown to accurately detect elevated intracranial pressure (icp), but does require specialized training. variations in the optimal onsd threshold for detection of elevated icp in the literature limits clinical utility, and may reflect heterogeneity in manual measurement techniques. our objective was to develop, and validate against expert measurement, an image-analysis algorithm for onsd measurement to facilitate standardization and ease of use of this technique. consecutive patients with acute brain injury admitted to the neurointensive care unit underwent ocular ultrasound with a multipurpose point-of-care ultrasound machine. a -second video was recorded from each eye in the axial plane and downloaded in dicom format. the onsd measurement algorithm was as follows. an average of images was calculated using non-overlapped segments of the image sequence. a line integral was performed to estimate the border of the region of interest (roi), the globe. the roi orientation and globe point of the segmented region were established, then a point mm posterior to the globe point identified. the onsd was measured at this point. manual onsd measurement was performed separately from the dicom videos by an expert blinded to the algorithm measurement. an intraclass coefficient (icc) was calculated for absolute agreement between highest onsd measured by the algorithm and expert manual measurement. a total of patients with acute brain injury underwent ocular ultrasound. the icc for absolute agreement between algorithm (median . , interquartile range . - . ) and manual expert (median . , . - . ) highest onsd measurement was . ( % confidence interval . - . ). an algorithm for automated measurement of onsd was developed and demonstrated good inter-rater agreement with expert measurement, although further refinement is required. automated measurement may help standardize and simplify a promising noninvasive bedside tool for the detection of elevated icp. after transition to electronic health record (ehr), transition to inpatient hospice required a separate encounter to account for change in insurance payer in our neuroicu. this negatively affected completed transitions and hence patient-centered care. the focus of this quality improvement project was to define the new process, improve outcomes, and identify further opportunities. the quality improvement method "plan-do-study-act" was employed for this work within a -bed neuro-icu at a large academic medical center. we assessed the current state (not enabling transition to inpatient hospice) and the desired state (enrollment in hospice during inpatient stay). a new process was created using an ehr discharge navigator, coordinating all relevant stakeholder groups (patient/caregiver, nurse, pharmacist, bed control, physician,). in addition, standard methodology for unit-based education, in-service, just-in-time training, and booster education was employed to identify process, outcome, and improvement opportunities. after rollout of the new discharge navigator, % of all patient-facing staff successfully completed the inpatient hospice training. process improvements lead to increase in palliative care consults by % ( to annually) and inpatient hospice discharges up to % ( to annually). furthermore, there was a statistically significant improvement in the vizient mortality index r = . , f( , ) = . , p < . and length of stay index r = . , f( , ) = . , p < . within the study population and period. ability to transfer patients to inpatient hospice is often limited and complicated. this study shows how employing standard quality improvement as well as education and implementation methods can result in improved process and outcome measures with sustainable success. opportunities remain in further analyzing and optimizing 'time to palliative care consult', 'time to admission to hospice and withdrawal of artificial support'. arnp and pa's are a rapidly growing part of the critical care workforce. proper selection among a pool of app candidates for the job is necessary to ensure the "right fit" and optimize patient safety. conventional interview techniques may not be adequate when selecting critical care app's. we hypothesized that use of a simulation center could be used to help select app candidates based on their critical thinking skills in conjunction with contemporary interviewing skills. from to , we performed conventional interviews for app's to staff critical care and neurocritical care patients. in we changed to an interview process consisting of the conventional interaction with the interviewee followed by simulation. after narrowing down the initial candidate pool, each was taken to the simulation center where they participated in a simulation of a decompensating patient. proctors were able to view the simulation in a separate room and direct the simulation mannequin. during this time proctors were able to evaluate the interviewee's patient interaction, assessment and interventions. an evaluation tool was to grade app candidates for their decision making skills, communication and thought. from to , we screened candidates before selecting for interviews and finally of those for simulation. over this timeframe, our center hired app's. comparing the ratio of screen applicants to employment was . and ratio of interviewed to hired candidates was . . these ratios show the competitive process and potential use of simulation in selecting apps. compared to the time period of applicants prior to simulation to after, retention went from to %, and disciplinary action for practice deficiencies went from % to %. the use of simulation based interviews for critical care app's in our institution improved retention and decreased the number of disciplinary actions compared to conventional interview methods. the contraindications for lumbar puncture (lp) in the setting of cerebral mass effect remain debatable. limited retrospective data advocate its potential safety. yet, high-quality guidelines specifically addressing this topic are not available. specific patient populations (post-instrumentation & immunosuppressed) may benefit from csf studies. we reviewed consecutive patients who underwent lp and cerebral imaging a week before or after lp from - . all individuals with evidence of brain herniation, a component of midline shift, or mass effect were included. all subjects received a low volume lp ( - cc of csf). there were patients with radiological increased icp. midline shift (average = mm) was present in patients. we also observed herniation: uncal (n= ), subfalcine (n= ), and a combination of both (n= ) , ventricular effacement (n= ) and cisternal compression with partial occlusion: quadrigeminal cistern (n= ), cerebellar-pontine-angle cistern (n= ), ambient cistern (n= ), crural cistern (n= ), prepontine cistern (n= ), suprasellar cistern (n= ), basal cistern (n= ), suprachiasmatic cistern (n= ), cisterna magna (n= ), interpeduncular cistern (n= ), medullary cistern (n= ). all patients tolerated the lp without complications. most survived a week after the procedure (n= , %). notably, four individuals deteriorated for reasons unrelated to the lp and expired within a week because of withdrawal of care. as brain compliance cannot yet be accurately determined radiologically, we believe anatomical involvement should drive decision-making regarding lp safety. our data suggest that a low volume lp ( - cc) might be safe in individuals with subfalcine herniation, midline mass effect < mm at foramen of monro level, and partial cisternal effacement. we believe that while lps might be safer in patients with supratentorial mass effect, individuals with posterior fossa involvement may tolerate it as well. these promising findings need further verification in larger sample populations. the importance of neurocritical care has recently been recognized in japan. however, to date, there has been no neurocritical care training program. we developed the neurocritical care hands-on seminar as a proposed training module, and here we report the satisfaction of participants. we prepared a post-course questionnaire about participants' degree of satisfaction. the main concept of our seminar was "how to maintain cerebral oxygen demand and supply balance." beginning with a short lecture about this concept, participants joined four hands-on scenarios: post-cardiac arrest syndrome (pcas), subarachnoid hemorrhage (sah), traumatic brain injury (tbi), and states epilepticus (se). in the pcas scenario, participants learned how to trouble shoot regarding targeted temperature management, especially in regard to the management of shivering. in the sah scenario, they learned about perioperative management, including delayed cerebral ischemia. in the tbi scenario, starting with actual insertion of an intracranial pressure (icp) monitor in the simulator, they learned about icp management through a scenario-based simulation. in the se scenario, they learned about se management, with actual continuous electroencephalogram monitoring. this seminar was held twice in . most participants were middle-aged intensivists; % were in their twenties ( / ), . % were in their thirties ( / ), . % were in their forties ( / ), and . % were in their fifties ( / ). most of the participating physicians were specialists in emergency or intensive care medicine ( . %; / ); nurses ( . %; / ) and a clinical engineer ( . %: / ) also participated. most participants ( . %; / ) were satisfied with the seminar, and almost all ( . %; / ) improved their self-confidence in the ability to carry out clinical practice in neurocritical care. we received positive, satisfied reactions from the japanese intensivists who participated in our seminar. for further improvement, we need to collect objective data to assess the utility of our neurocritical care hands-on seminar. lumbar puncture in the presence of mass effect? ciro ramos-estebanez uhcmc, case western reserve university/neurology, cleveland, ohio, usa introduction ) we propose an international consortium that would prospectively confirm the safety of low volume lumbar puncture (lp) in the presence of mass effect in selected scenarios. ) welcome peers and advisors to join the effort. lp may be clinically necessary in the presence of cerebral mass effect. while empirical antibiotic therapy is generally successful, specific groups such as post-instrumentation patients and immunosuppressed individuals may benefit from cerebrospinal fluid (csf) studies. in the absence of high-quality clinical recommendations, uncontrolled retrospective literature suggests that a small volume lp ( - cc) might be without complications in specific situations. nevertheless, the ethical principle of non-maleficence and the liability risk prevent clinicians from performing lps. in this scenario, an extended length of stay, poor outcomes, or a higher cost of care are legitimate concerns. synthesize an external peer reviewed methodology to maintain rigour and transparency. . seek appraisal, approval and endorsement of national and international quality improvement committees. . generate and assimilate the most current clinical evidence through: a. systematic review and meta-analysis. b. prospective randomized controlled clinical trial. . construct a protocol to inform decision making amongst healthcare and non-healthcare personnel. . dissemination and implementation. . schedule updates and/or revision. centers across the globe (north america = , south america= , europe= , and asia= ) have agreed to establish an lp consortium so far. retrospective analyses suggest low-volume lp's relative safety in the presence of increased icp. thereby, an expert consortium trusted with prospective verification would potentially benefit specific patient populations. patient centered decision making in the nccu requires family members understanding of their loved one's preferences and values as well as the complexities of their medical condition and treatments. family-centered care (fcc) is essential so that family members are actively involved in decision-making. stakeholders have reported their preference to receive prognostic information in smaller packets and recapitulated in different venues including rounds, bedside and care conferences. we examine implementation of a multimodal communication strategy on clinician utilization, family engagement and satisfaction in the nccu. an interdisciplinary team convened to develop a plan implementing a multimodal communication strategy. pre-implementation survey of clinicians (mds, nps, rns, etc.) and patient families was completed to determine the level of family engagement already in place in the nccu. four interventions were implemented: family communication boards were installed in patient rooms; family engagement pamphlets developed; a script and schedule for family care rounds was developed; nursing and provider staff were educated on inviting families to participate in patient care team rounds. family involvement on patient care rounds and family conferences was compared before and after the implementation of the best practice initiatives. additionally, pre and post implementation patient satisfaction survey results were also compared to evaluate the project's success. pre-implementation data was collected from october -november . sixty-one clinician surveys and forty family surveys found that family more consistently participated on daily rounds. baseline and postimplementation surveys demonstrated families feeling supported during the decision-making process. the implementation of a multimodal communication framework to achieve consistent family engagement and communication has led to an appreciable change in utilization by clinicians. its use is supported by consistent positive family attitudes towards communication and availability of information in the nccu. neurocritical care society undertook initiatives to integrate social media in member engagement activities and initiated a twitter journal club (#ncstjc) in with the first journal club conducted in february . articles were chosen by a subgroup of the communications committee in consultation with dr. eelco wijdicks, chief editor, neurocritical care journal. these articles were chosen based on their overall importance and the interest bound to generate amongst the journal club attendees. the journal club occurs bimonthy over an hour and is unique in the participation of the authors. the journal club is registered with healthcare hashtag project. each article chosen for #ncstjc is made available free to download weeks before and after the scheduled date for the journal club courts springer. analytics data on usage on article discussed in #ncstjc was obtained from sean beppler, editor, clinical medicine. between feb and apr , sessions were held with data available from . the ncc articles discussed had higher than average altmetric scores (measuring social media activity). these articles represented % of all ncc articles discussed on twitter since feb but . % of all tweets. total usage (number of times an article html page is accessed, or a pdf is downloaded ) was , ( mean , n= ) representing . % usage of all neurocritical care articles, a total of citations and downloads ( mean ) . the upper bound of the audience as assessed by the publisher was total of , for all articles (mean , per article) twitter is becoming an emerging platform for dissemination of information in medical education and academic activities. while the exact impact of the initiative on member engagement or outreach in enhancing journal impact or citations is hard to determine, we saw trends in enhanced engagement. neurostimulant medications have been studied in patients with traumatic brain injury, but few studies describe their use in patients with acute non-traumatic brain injury. our objective was to describe neurostimulant medication prescribing patterns, clinical response, and potential adverse effects in this patient population. retrospective database review of patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage who received amantadine or modafinil from december through june . neurostimulant selection, dosing regimen, and indication were recorded. patients were classified as responders if they met two of the following three criteria within days of neurostimulant initiation: ) increase in average daily gcs of greater than points, ) neurological improvement documented in provider progress notes, or ) increased participation in rehabilitation therapies documented in physical or occupational therapist progress notes. safety data included need for a new anxiolytic or sleep aid or seizure. continuous data are reported as median with interquartile range. eighty-eight patients received neurostimulants: intracerebral hemorrhage (n= ), ischemic stroke (n= ), subarachnoid hemorrhage (n= ). median age was ( - ) years and ( %) were male. amantadine (n= ), modafinil (n= ), or both (n= ) were initiated a median of ( - ) days after hospital admission. the median initial daily dose of amantadine and modafinil were mg and mg, respectively. reasons for initiation included somnolence ( %), not following commands ( %), lack of eye opening ( %), and low gcs ( %). forty ( %) patients were responders, occurring at a median of ( - ) days after neurostimulant initiation. twenty-three ( %) patients required new prescription of an anxiolytic or sleep aid. four ( %) patients developed seizure. neurostimulant medications may increase wakefulness and participation in rehabilitation therapies in patients with acute non-traumatic brain injury, with tolerable adverse effects. the role of neurostimulants in this population should be defined in prospective studies. difficulty in obtaining peripheral intravenous (piv) access often necessitates central venous access placement in many critically ill patients. central line placement exposes patients to potential complications such as pneumothorax, hemorrhage, catheter-related infection or deep venous thrombosis. ultrasound-guided piv placement has become common practice in emergency departments, but there is no systematic program to train and support routine use of ultrasound-guided piv access in icus. we have developed a systematic program to train and support icu nurses in becoming experts and clinical leaders in ultrasound-guided piv placement. we hypothesize that implementation of this program will increase nurse confidence and chances of successful piv placement subsequently decrease central line-related complications in -bed neurocritical care icus. we have developed a video didactic training program for the neurocritical care nursing staff. the program discusses use and maintenance of the ultrasound machine and guided-technique for piv placement including the short-and long-axis approaches. the training video is followed by a hands-on simulation session using mannequins. standardized-surveys are administered to nurses before training and then at and months post training. we are prospectively collecting data on nurse comfort level with ultrasound-guided piv placement, total iv attempts, patient central line associated bacteremia (clab) rates and total number of patient central line days. we will compare this data for months pre-and post program implementation. comparisons will be made using t-test and chi-square analyses or non-parametric equivalents depending on data distribution. central-line related complications are an important clinical problem in all icus. we have developed and implemented a systematic training program to support nursing-led ultrasound-guided piv placement. we will determine if this program reduces the overall number of central lines placed, duration of indwelling central lines, and clab rates in a neurocritical care, and subsequently expand to additional icus and beyond. ultrasound measurement of optic nerve sheath diameter (onsd) is a sensitive and specific non-invasive ultrasonographers. despite clinical applications in the icu, er and outpatient settings, neurology residents lack experience and training. the aim of our project was to provide neurology residents with foundational skills in ocular ultrasound and onsd measurement. we designed a two-part workshop for neurology residents covering ultrasound basics, measurement of onsd, and ultrasound appearance of papilledema. workshop was a minute lecture and demonstration followed by minutes of hands-on practice. two weeks later, workshop included additional minutes of practice to consolidate learning. the practical portions were facilitated by emergency medicine attendings and residents with experience in performing ocular ultrasounds. neurology residents tracked the number of practice ultrasounds performed. they also completed anonymous pre-and posttests to assess their knowledge of ocular ultrasound and their comfort level and likelihood to perform future procedures using a -point likert scale. prior to the workshop, the majority ( / ) of neurology trainees had never performed an ocular ultrasound. one ( / ) was able to answer two basic questions about the procedure correctly, which increased to % on the posttest (n= ). trainees performed an average of ultrasounds total during the workshops. resident self-assessment of comfort performing the procedure increased from a median of "very uncomfortable" to "moderately comfortable" on the -point likert scale (p= . ). resident likelihood to perform the procedure in the future increased from a median of "very unlikely" to "moderately likely" on the -point likert scale (p= . ). this session successfully increased basic knowledge, comfort, and likelihood to perform ocular ultrasound among neurology residents. future directions include follow-up to gauge magnitude of practice changes and accuracy of procedural skills. reaching patients by telephone is a common method of assessing functional outcome, cognitive function, and quality of life after hospital discharge. however, when patients do not answer the phone, missing data creates bias and warrants strategies to increase follow-up rates. we hypothesized that we would have less follow up with patients discharged to long-term care facilities and sought to examine other potential sources of lost data. between / and / , we identified all patients admitted to the university of cincinnati neuroscience intensive care unit (nsicu). we excluded those with recurrent admissions, boarders, and those admitted < hours or for uncomplicated post-op care. telephone follow-up was attempted for each patient. univariate analysis was used to identify associations with patients who did not answer the phone. critically-ill patients were included. average age was . +/- . and % were men. the average hospital length-of-stay was . +/- . days. major diagnoses were: ischemic stroke ( %), intracerebral hemorrhage ( %), traumatic brain injury ( %), seizures/status epilepticus ( %) and subarachnoid hemorrhage ( %). ( %) died in the hospital; ( %) died by follow-up. survivors were assessed . +/- . days following admission. calls were answered, were not. there were no associations between rate of answered calls and age, gender, race, hospital length-of-stay, diagnosis, or hospital disposition. there were no differences in between morning vs. afternoon calls. only the number of attempts differed: the probability of an answered call was % on the first attempt but declined to % by the third attempt (or . ; p< . ). our outcome assessment strategy captured data on % of neurocritically ill patients. those who answer the phone are most likely to answer with the first call; the probability of a patient answering after a second phone call may not justify resources needed to continue calling these patients. posterior reversible encephalopathy syndrome (pres) typically presents with vasogenic edema on neuroimaging. a subset of patient, however, can have "atypical findings" including restricted diffusion and intracranial hemorrhage. these atypical findings all suggest acute vascular injury, and may mark a distinct pathophysiological subtype of pres. however, it is unknown whether atypical imaging findings are associated with differences in precipitating factors or outcome. patients with evidence of restricted diffusion, frank hematoma, microhemorrhage, or subarachnoid hemorrhage were classified as having atypical imaging findings. the demographics, risk factors, clinical outcomes, and degree of vasogenic edema for patients with typical (n = ) vs atypical pres findings of vascular injury (n = ) were analyzed. patients with atypical pres had a longer hospital stay ( . vs . days; p = . ) and were less likely to be discharged home ( . % vs . %; p = . ). severity of vasogenic edema (graded using a standardized radiologic scale) was also higher in patients with atypical imaging findings (severe edema: . % vs . %; p = . ). restricted diffusion and hemorrhage are features of acute vascular injury that may mark a unique pathophysiological subtype of pres. pres patients with these atypical imaging features had longer hospital stays, greater degree of vasogenic edema, and were less likely to be discharged home. this may be due to the fact that bleeding and infarction lead to irreversible brain injury, prolonging hospital stay and contributing to overall disability. in , deaths occurred in the neuro-oncologic critical care unit (nccu). the impact of this event is significant for patients, families, and the staff that care for them. brain and spinal pathology can be incredibly debilitating causing a rapid and impromptu decline of the patient's status. in order to better support patients, family, and staff throughout the dying process, the nccu staff created formalized endof-life care interventions. these interventions include educational pieces and supportive approaches to aid all involved through the dying process. several interventions were created to help transition the family members during the dying process. these include the creation of: dnr-cc closet, homemade blankets, condolence cards, hygiene bags, educational packets, word clouds, and aromatherapies and massage items. once the patient's code status is changed to comfort care, a blanket is given to the patient. family members are provided with a bag of toiletries for those that remain at bedside. education on the dying process are given to family members. multidisciplinary resources are provided, such as religious support focused on patient/family beliefs, palliative care for symptom management, and dietary provision of light snacks to the family. education for the physicians, nurse practitioners, nurses, and patient care associates was provided for those who wished to attend to further understand this end of life care program. a item tool was created to collect before and after data on staff satisfaction and comfort with the end of life process. results from this process are currently in process. creating specific end-of-life care interventions for the nccu have enabled staff to better care for patients and families. through the creation of the interventions and utilization of the dnr-cc closet, this unit has been able to better provide comprehensive education and supportive pieces to patients and family members during such a difficult time. delirium is a neuropsychiatric syndrome, characterized by disturbance in awareness, with reduced ability to sustain attention, impaired cognition, perception, tends to fluctuate in severity during the day; in critical care is associated with longer stay and increase mortality. this study aimed to determine the incidence, prevalence, predictors, risk factors and outcomes of delirium in critically ill adult. a historical cohort study was conducted in adult patients hospitalized in a polyvalent icu from january until december . delirium was diagnosed using cam-icu. a bivariate and multivariable risk were analyzed and presented as odds ratio (or) and % confidence interval (ci). a total of patients were enroll. delirium developed in patients.the incidence was . %. three independent predictors for delirium were identified, sedation (or ( % ci, p < , ); alcohol dependence (or , ; %ci, p < , ) and glasgow coma scale < (or , ; % ci, p < , ). delirious patients had a significantly apache ii ( ( - ) vs ( - ), p < . ), higher sofa, ( ( - ) vs ( - ), p< . ) and higher saps iii ( ( - ) vs ( - ), p< . ). other risk factors were hyperlactatemia ( p< . ), and hypotension (map< mmhg),(p< . ). patients required prolonged mechanical ventilation, p< . ), and prolonged icu-hospital stay. the incidence of delirium in the period from january to december , was . % in a polyvalent intensive care unit. exposure to sedative medications, alcohol dependence, and decrease glasgow coma scale minor are independent predictors for the development of delirium. similarly, the icu stay was longer in the group that developed delirium; however, mortality was not affected by the presence of this condition. it has been previously reported that the course of hsv- in the cns is significantly more benign that hsv- , and that it rarely causes encephalitis or significant morbidity in immunocompetent adults. the aim of our study was to investigate the claim that hsv- cns infections are typically benign, and to assess for predictors of poor outcome in those patients who do suffer significant morbidity from hsv- cns infections. restrospective chart reviews were completed on patients with a positive hsv pcr at our institution from july until july . patients with a hsv pcr positive for hsv- were selected in our analysis. multiple clinical variables were evaluated in these patients and we assessed outcome in the patient population, dichotomizing outcome into two categories at the time of discharge: good outcome defined as home or inpatient rehabilitation versus those with poor outcome defined as death, hospice, or placement in a long term acute care facility. patients with hsv- positive pcrs were identified. their charts were evaluated for demographics, laboratory values (serum and csf), imaging results, and outcome. there were patients with poor outcomes. it was noted that they were all female, their mean age was . (vs . in the good outcome group) and two of the three were immunocompromised ( % vs % in the good outcome group). statistical analysis was performed however due to the small sample size no statistical significance was found. however, age, sex, clinical presentation consistent with encephalitis and immune status seemed to have a trend towards poor outcome in this pilot study. future study with larger sample size is warrented to further assess this trend, as hsv- may not be as benign as previously reported. there is a high prevalence of non-traumatic illness in patients presenting to emergency departments as trauma team activations (tta). we sought to determine the prevalence of neurologic emergencies within a population of patients receiving a tta. this was a retrospective review of prospectively-collected registry data capturing all ttas in a highvolume, urban, academic level i trauma center. records from june through june were reviewed to identify patients found to have a diagnosis of ischemic stroke, intracerebral hemorrhage (ich), subarachnoid hemorrhage (sah) or status epilepticus. further demographic, clinical, and outcomes data was then abstracted from the electronic medical record. a proportion of abstracted charts were reviewed by an independent reviewer to ensure data quality. there were , trauma activations in the registry during the study period. patients ( . %) were found to have a nontraumatic neurologic emergency and were included in the analysis. of these patients, there were ischemic stroke ( %), ich ( %), sah ( %), and status epilepticus ( %) patients. the mean age was , and patients ( %) were male. the mean gcs on presentation was . about half of these patients ( %) were intubated in the emergency department. all patients received a head ct scan. patients ( %) received intravenous thrombolysis. neurologic emergencies such as ischemic stroke, ich, sah or status epilepticus were common diagnoses in this population of trauma activation patients. clinicians caring for patients in these settings must maintain a high index of suspicion for non-traumatic illnesses, and act quickly to mobilize appropriate resources when a diagnosis is made to avoid delays in care. further research is needed to examine ways to improve both time to diagnosis and quality of care in this patient population. formalized communication strategies decrease post-traumatic stress disorder (ptsd) symptoms in caregivers in the intensive care unit (icu). in one study, only % of family meetings met all shared decision-making criteria. however, much of the research has focused on family meetings, ignoring less formalized communication. the decision maker (patient or caregiver) was interviewed for all patients admitted to the medical (micu), neurosciences (nsicu), surgical (sicu), and cardiothoracic icu (cticu) for greater than hours. subjects who stated significant decisions had been made were asked to report on aspects of shared decision making on a -point scale. they identified the lead provider, who was subsequently approached to complete the same questionnaire. overall, eligible decision makers were identified, ( %) in the micu, ( %) in the nsicu, ( %) in the sicu, and ( %) in the cticu. of these, ( %) were unable to be contacted, ( %) had insufficient english, and ( %) reported no decisions made, with ( %) enrolled. nineteen ( %) provider interviews were completed. topics most reported covered "well" or "thoroughly" by caregivers were assessment of understanding ( , %) and the nature of the decision ( , %), while those least covered were need for input from others ( , %) and the context of the decision ( , %). topics reported most covered by providers were the nature of the decision ( , %) and opinions about the treatment decision ( , %), while those least covered were patient's values and preferences ( , %) and their preferred role in decision making ( , %). eighteen ( %) caregivers and ( %) providers described all topics covered "well" or "thoroughly." these results demonstrate differences in perception of shared decision making by decision makers and providers. further qualitative investigation is underway to elucidate the nature of these inconsistencies. organ donation is a life-saving medical intervention. the effect of race, insurance and economic status on organ donation and recipients has not been studied at a national level. in our study, we analyzed nationwide in-patient (nis) database of years - to select donors and recipients. baseline demographics (i.e., age, gender, race), insurance status and socio-economic status was compared between two groups. we identified donors (n= ) and recipients (n= ) from - . recipients were significantly older (mean age ± sd, . ± . vs . ± . , p< . ). donors had higher ( . % vs . %, p< . ) proportion of women compared to recipients. both groups had a higher proportion of whites compared to other races ( % and . % respectively). insured patients were largely represented in both groups with private insurance predominating in donors ( %) and medicare in recipients ( . %). interestingly, self pay represented . % of donors but only . % of recipients. race, insurance and socioeconomic status seem to be evenly similarly represented in donors and recipients. interestingly self pay insurance has a higher distribution among donors than recipients. central line-associated bloodstream infections (clabsis) are a common health care associated infection accounting for , infections annually in the intensive care and acute care areas (cdc, ). according to the center for disease control, clabsis result in thousands of deaths yearly and upwards of billions of health care dollars spent on preventable hospital acquired infections. intensive care patients, especially the neurocritical care population, have an increased need for centrally placed catheters related to inadequacy of peripheral access, need for caustic iv medications, and fluid resuscitation. our neuroicu's goal was to decrease utilization and subsequently reduce number of clabsis. in february , we initiated a patient-centered quality improvement effort with this goal in mind. the neuroicu clinical nurse leaders conducted rounds daily to evaluate the necessity and management of central lines. the neurocritical care team and clinical nurse leaders collaborated in exploring alternatives if central lines were present. in addition to daily rounding, clabsi bundles based on cdc guidelines for clabsi prevention were initiated. our neuroicu developed checklist "buster cards" in september of , prompting staff to the bundle interventions. the intent of the cards was to enhance nurse to nurse dialogue of bundle elements. the cards were evaluated monthly for trends in care. from august -june , there was a % reduction in neuroicu utilization of central lines. in addition, the mean number of clabsis per month decreased from . to . . trending of unit buster cards did not show care variances during this time period. implementing daily clinical nurse leader rounds with enhanced team communication significantly reduced the neuroicu's utilization of central lines and thereby decreased the rate of clabsis. percutaneous dilatational tracheostomy (pdt) is one of the most commonly performed procedures on critically ill patients. many studies showed the safety and feasibility of pdt, but there is limited data of pdt in neurocritical care units. we have described our experience of pdt performed by neurointensivist. pdts were performed by neurointensivists at bedside using the griggs guide wire dilating forceps technique. to confirm a secure puncture site, pdt was done under fiberoptic bronchoscopic guidance. from september to may , procedural data were prospectively collected. the patients' demographic and clinical characteristics were retrospectively reviewed. we analyzed immediate complications of pdt as the primary outcome. pdts were performed for patients; the mean age was . years, ( . %) were male, and mean acute physiology and chronic health evaluation ii score was . ± . . overall, the procedural success rate was % and the mean procedural time was . ± . min. periprocedural complications occurred in patients; had minor bleeding and had tracheal ring fracture. there were no serious periprocedural complications of pdt. from our experience, pdt performed by neurointensivist was safe and feasible and was implemented without serious complications. the neurocritical care unit (nccu) is a fast paced setting with a multitude of providers and team members requiring optimal communication. it is also a high cost/high utilization environment, dictating the need for patients to be moved thru appropriate levels of care efficiently. all of this must be accomplished while providing support and opportunity for collaboration and decision making on the part of the patient/ family unit. there is great discussion in the case management world about the benefits of a unit based verses service based case management model. we looked at outcomes following the implementation of a unit based case manager in the nccu. a dedicated case manager (cm) was implemented in the nccu to maximize assessment, advocacy, communication, education, identification of resources, and facilitation of services. processes to support maximal contributions were created.interventions included use of a discharge planning worksheet, implementation of a morning huddle, and space for the case manager to be physically available on the unit. los of patients discharged from nccu decreased from . to . . alos for patients that passed thru the nccu during their hospitalization decreased from . days to . . there was a % increase in discharges from nccu from to . average time from admission to cm assessment decreased from hours to . hours. progress notes indicating intervention and/or communication of the plan increased from to . staff questionnaire indicated increased awareness of los and dc plan needs. in this midwestern, academic medical center, integrating a dedicated, unit based cm resulted in improved los, increased discharges and improved staff awareness of dc plans. high throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. open data access is the final barrier to be overcome to capitalize fully on the opportunities currently available in stroke genetics research. the international stroke genetics consortium (isgc) has created the cerebrovascular disease knowledge portal (cdkp), a comprehensive web-based resource to explore and freely access genetic data related to cerebrovascular diseases. funded by the nih, the cdkp has been jointly developed by the isgc and the american heart association (aha) institute for precision cardiovascular medicine. the cdkp seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on stroke. within the cdkp, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. the cdkp houses two types of data, each meeting different regulatory and analytical needs: summary level data and individual level data. the cdkp offers three main features: ( ) a web-based graphical user interphase that allows the exploration of stroke genomics information through a wide menu of integrated tools for analysis and data visualization; ( ) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field, available with a single mouse click ; and ( ) a repository of individual level data, accessible through a secure cloud working space provided by the aha platform for precision medicine. the cdkp can be accessed at www.cerebrovascularportal.org. the cdkp advances the isgc's goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. in the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well. hyperosmolar therapy using hypertonic saline is common in patients admitted to the neurocritical care unit (nccu) for the management of different type of cytogenic cerebral edema or increased intracranial pressure (icp). vancomycin is commonly prescribed in nccu as empiric antimicrobial therapy. the purpose of the study is to evaluate the effects of hypertonic saline therapy on the pharmacokinetic parameters of vancomycin in critically ill patients with generalized or compartmental icp. this was a retrospective, observational study of adult patient consecutively admitted in the nccu between february and february who received hypertonic saline ( % sodium chloride) and vancomycin dosing protocol managed by the pharmacist. patients with serum creatinine > . mg/dl were excluded from the study. the estimation of vancomycin trough levels was done by using published pharmacokinetic equations and then compared to the measured trough levels with the paired t test. the study protocol was approved by our institutional review board. of forty-four patients who met the inclusion criteria, twenty-one patients ( . %) were diagnosed with intracerebral hemorrhage, nine ( . %) ischemic stroke, seven ( . %) subarachnoid hemorrhage, four ( %) subdural hemorrhage, two with brain tumors, and one patient with chiari malformation. the mean dosing regimen was . ± . mg/kg every ( - ) h. the mean measured trough level was lower than the predicted trough level ( ± . vs. . ± . mcg/ml; p < . ). the mean serum sodium level was ± meq/l and the mean serum osmolality was ± mosm/kg. critically ill patients with cerebral edema or high icp who were treated with hypertonic saline achieved a subtherapeutic vancomycin level that may lead to lower through level and possibly poor clinical response. further research is warranted to evaluate the clinical response of vancomycin in this patient population. unnecessary telestroke activations are costly to emergency departments (ed), telestroke providers, and patients. therefore it is important that ed nurses are well trained to effectively recognize stroke symptoms, and decrease the rate of false-positive stroke code activations. the nursing-driven acute stroke care (nas-care) study aims to determine if implementing a standardized ed stroke program decreases door-to-needle times in emergency departments utilizing telemedicine. the nas-care intervention consists of ed nursing education including mock codes, nihss certification, and implementation of a standardized flow sheet. in this interim analysis from the first (of ) nas-care study hospitals, we examined ed admission and discharge diagnoses at each site for months of blinded baseline data collection ("control") and months after standardized training ("intervention"). false-positive encounters were defined as stroke code activations for which the patient diagnosis on leaving the ed was not stroke. although hospitals trended toward a reduction in false-positive stroke code activations after implementation of the standardized stroke education, mock stroke codes, and flow sheet, none of the values were statistically significant. further research is needed to determine whether intensive ed nursing education can improve telestroke resource utilization. pharmacist-driven intravenous (iv) to oral (po) conversion protocols result in greater compliance, improved cost-savings, and better patient outcomes related to length of stay, re-admission, and duration of intravenous therapy. this study aims to determine the cost-savings and patient impacts of such a conversion protocol for anti-epileptic drugs (aeds) including lacosamide, levetiracetam, phenytoin, and valproic acid. a retrospective, observational phase was conducted to determine usual practice patterns concerning conversion to oral therapy between / / and / / . the conversion protocol was approved in december and implemented in january . a second retrospective phase observed conversion practices beginning / / and ending / / . length of intravenous and oral therapy, date eligible for conversion, and date of conversion were recorded. hospital acquisition costs were utilized for medication expenditure calculations. this information was used to determine financial impact of the protocol and is presented as descriptive endpoints. adverse drug events were collected via an institutional incident reporting system. a total of encounters were identified, resulting in encounters in the pre-cohort and postcohort encounters. looking at the pre and post cohorts respectively, both cohorts had similar median lengths of stay ( days vs. days), -day readmission rates ( . % vs . %), and rates of conversion from oral back to intravenous therapy ( . % vs . %). the median length of intravenous therapy was days prior to protocol implementation and decreased to days in the post-cohort. the average cost per day of aed therapy was $ . in the pre-cohort but decreased to $ . in the post-cohort. median missed opportunity costs, defined as the cost savings if conversion occurred at the earliest possible date, also decreased between the cohorts from $ . to $ . . pharmacist involvement in aed conversion had a positive financial impact without compromising patient care. the national institute of neurological disorders and stroke (ninds) established the nih strokenet to facilitate the rapid initiation and efficient implementation of multi-center exploratory and confirmatory clinical trials focused on promising interventions in stroke prevention, treatment, and recovery. strokenet was initiated in the fall , and involves over hospitals across the us. the network is anchored by regional coordinating centers (rccs), along with the national coordinating center (ncc) at the university of cincinnati and national data management center (ndmc) at the medical university of south carolina, as well as active participation by the ninds. one of the primary goals of the strokenet is to serve as the primary infrastructure for conducting stroke clinical trials and pipeline for new potential treatments. to maximize the impact of nih strokenet, it is important for the larger community of stroke researchers and clinicians, including the neurocritical care specialists, to know its structure and the process and timeline by which stroke trials are developed and implemented. since the inception of the network, * proposal concepts have been submitted to the strokenet and are in different development stages. among those evaluated to obtain ninds permission to submit a grant application, have submitted and are in the process. every application has been prepared and submitted for peer review within months of the ninds permission. two* funded strokenet trials are now underway with brisk enrollment rates, and another is awaiting study initiation. (*as of abstract submission date) the nih strokenet has become a stable infrastructure and offers several distinct advantages to developing competitive clinical trial proposals, including scientific input from the strokenet working groups, comprehensive feasibility assessments (including site enthusiasm and patient availability), assistance with grant budgeting, and other requirements for grant submission that are likely to help refine and improve the application. the modified early warning score (mews) is a physiological scoring system, validated in adult medicalsought to determine the value of mews to identify clinical deterioration or occurrence of sepsis in neuroicu patients. we retrospectively reviewed all patients admitted to the neurological intermediate care unit (imc) or neuroicu of a large tertiary care center from / presentation/during admission. baseline characteristics, diagnoses, physiologic parameters, infections, treatment with antibiotics, neurological worsening and mortality were abstracted from the electronic medical record. outcomes were defined as escalation of care and discovery of a new infection or sepsis. of p were male. % were intubated, and in-hospital mortality was % (versus % for all admissions). ( %) were already treated with antibiotics for a known infec diagnosed in %. in reaction to the elevated mews score, antibiotics were added or broadened in %, and level of care was escalated in . % from imc to icu. in . %, there was neurological worsening, most frequently associated with increasing cerebral edema ( %) and midline shift/herniation ( %). the mews score is not a valuable screening tool in the neuroicu population. it preferentially was triggered in known high acuity patients with ongoing or present infections with no change of management in the majority of patients. while associated with high mortality, its ability to indicate new infections or sepsis was poor. in out of patients, the mews score was associated with neurological worsening known at that time of the score. other screening tools should be explored for early warning in the neuroicu. introduction: it is challenging to maintain neurosciences critical care nursing expertise in an environment of a rapidly expanding knowledge, changing evidence-based practices and technological advancements. to address the needs for neuroscience nursing expertise in a mixed critical care unit, our institution developed a core group of nurses, known as "neuro champions", who have additional training and expertise in neurocritical care. methods: nursing participation was voluntary and recruitment was via unit-wide announcements. the goal was to improve patient care by developing a core group of nurses who serve as resources and educators for all things neurosciences related. to develop content expertise, the nurses initially completed a set curriculum including: neuro anatomy and pathophysiology, cerebral hemodynamics and multimodal monitoring, pupillometry, eeg interpretation, temperature management, evds, and quality indicators. bi-monthly meetings continued ongoing education, with content including clinical case studies and review of processes and protocols. additionally, beds staffed by neuro champions were designated as critical neurological care unit ("cncu") beds to co-localize the highest acuity neurosciences patients. the neuro champions are responsible for educating and sharing neuro related practices with the entire icu nursing staff. results: as a result of the implementation of the neuro champion role, our icu has benefited from: ) dedicated co-localized beds for the highest acuity neuro patients; ) increased number of enls certified nurses; ) improved collaboration between the medical team and nurses; ) promoting care uniformity to maintain comprehensive stroke center certification; ) integration of multimodal monitoring advancements, all of which supports advances in patient care and research. conclusions: the neuro champion role has provided a platform for neurosciences-specific nursing expertise in a mixed critical care unit and has facilitated education dissemination to the entire staff via a core group of nurses. this expanded knowledge has improved the care of the neurologically critically ill patients. the rate of cerebrovascular complications in patients treated with extracorporeal membrane oxygenation (ecmo) is about %. transcranial doppler (tcd) can be used to noninvasively monitor cerebral blood flow velocities (cbfvs) in patients undergoing ecmo. the aim of this study is to describe tcd-cbfv patterns in patients undergoing venovenous (vv) and venoarterial (va) ecmo. a neuro-surveillance protocol among ecmo patients was initiated as part of a quality improvement project at our institution. daily neurological exam, daily tcd, brain-ct on days one and three and -hr continuous eeg were performed in all patients undergoing vv and va-ecmo. demographics, clinical and imaging data were collected for the duration of ecmo support. cbfvs, lindegaard ratios (lr), pulsatility index (pi) and resistance index (ri) on tcd were collected. total of patients were included in the study [ female ( %); caucasians ( %)]. mean age was years. ( %) patients received va-ecmo; ( %) vv-ecmo; ( . %) received both va and vv-ecmo. median days on ecmo was days. median number of tcd studies performed was (mean, . we observed an overall pattern of low-normal flow cbfvs and reduced pulsatility in patients on va-ecmo. nurse practitioner (np) and physician assistant (pa) roles continue to expand in the critical care setting. single and multisite studies have examined various aspects of app practice, but none have focused on role implementation within the neurologic critical care unit (nccu). the purpose of this study was to obtain foundational knowledge about how nccu apps are implementing the role nationally this was a voluntary, cross-sectional, descriptive study of nurse practitioners (np) and physician assistant (pa) practicing in the us. apps were invited to participate in this voluntary, item survey. distribution occurred initially through email inquiry via multidisciplinary, professional organization listservs (ncs, aacn, aann) followed by snowball effect circulation. enrollment occurred from march to june . data was collected in redcap and analyzed using spss with descriptive statistics for demographic, institutional, practice, role characteristics of the sample and for each survey data element app participants completed the survey: % np, % pa, % other. the majority of respondents were master's prepared ( . %) acute care trained, ( . %) and hospital employed ( . %). participants were either early in their career ( . % - years as app) or experienced ( . % > years). % work in a direct care role with % providing total care for their patients with an average daily caseload of . + . patients. % of providers believed - patients was a reasonable caseload for total care. in addition to the nccu, % of participants care for patients in step-down or emergency department ( %) with % routinely bilingl for their work. this study is the first to provide information regarding how ncc apps are implementing the role in the united states. this study provides benchmarking data which may guide future research with this population as well as serve as a template for evaluation of other app specialty roles. despite advances in treatment, the median survival for high grade gliomas (hgg) remains poor. there is a growing body of research showing that palliative care improves quality of life and survival in patients with advanced malignancies. we sought to examine our own practices in the neurologic intensive care unit (nicu) regarding palliative care consultation in this population. we hypothesized that the incidence of palliative care consultation is low and associated with a clarification of patient's wishes, measured by a change in code status. we conducted a retrospective cohort review of patients with previously diagnosed hgg admitted to the nicu from - with a length of stay (los) greater than hours. the primary outcome was the incidence of patients with an advanced directive or inpatient palliative care consult (pcc). secondary outcomes included intensive care unit los, change in code status and location of death. patients were identified with hgg. the mean age was . years ( - years), % were male, % were white. zero patients were admitted with an advanced directive on admission. pcc was obtained in patients ( %). pcc was associated with increased nicu stay ( hrs vs hrs p= . ), a change in code status to do not resuscitate ( % vs % p= . ), and an increased likelihood to not die in the hospital ( % vs % p= . ). at our large academic tertiary care facility intensivists underutilize palliative care services for hgg patients. patients with fatal brain tumors are not having end of life discussions prior to admission, indicating a need for early palliative care intervention. patients are six times more likely to change their code status and there is a trend towards dying outside of the hospital if they receive a palliative care consult. hypertonic saline (hts), a hyperosmolar solution, is typically administered using a central venous catheter (cvc) due to concerns of extravasation, but a cvc is rarely readily available. in emergent situations, intraosseous (io) access is used when peripheral intravenous access is not available. existing literature does not address the administration of hypertonic saline using io access for adult patients with brain injury. the administration of hts is often delayed due to the time taken to obtain a central venous access. insertion of an io needle is typically much faster than a cvc. we report the safety and tolerability of hts using io route. a prospective pilot study on the safety and tolerability of % hts via io is currently underway. data on local complications at the site of injection, pain during insertion and during infusion, and serial serum sodium levels were collected. additionally, we report a case of successful administration of . % hts using the io route. preliminary data demonstrated that % hts was well-tolerated, with no reports of severe pain, infections, extravasation, soft tissue injury or local infectious complications in our sample of patients with brain injury. indications for use of hypertonic saline included patients with cerebral edema and mass effect from intracerebral hemorrhage. an appropriate rise of serum sodium levels by approximately mmol/l/hr in was observed. in the case where ml of . % hts, no local complications were observed and serum sodium levels rose appropriately. administration of hts using io route appears to be safe and feasible. utilizing io access for urgent administration of hts may reduce the lag time to administration of the initial bolus, reduce the need for emergent placement or eliminate the placement of cvc in certain cases. optic nerve sheath diameter (onsd) measurement is an emerging bedside tool to assess intracranial pressure (icp) non-invasively in brain injury patients. multiple studies demonstrate onsd width from . mm to . mm correspond to an external ventricular device (evd)-measured icp > mmhg. we sought to create a low cost, -d constructed, re-usable osnd teaching model to train neurology, neurosurgery, and critical care advanced practice providers and physicians. we searched the national library of medicine using terms "optic nerve sheath diameter ultrasound" with combinations of "simulation" and "model." the literature was used in conjunction with a human non-contrast head ct head model to make an eye ball model which was then tested in our simulation center and compared to a live human model. we identified articles, of which were associated with models and two with simulation. one gelatin model was reported, upon which we based our initial design. we could not validate the visual findings of this model. however, following construction of multiple beta models, the design most representative of human eye anatomy was a globe made of ballistics gel with either a mm, mm or mm -d printed "optic nerve" attached to a platform composed of ballistics gel and psyllium powder with a hollowed out core for ultrasound gel the globe rests upon. this model was taught to learners at a continuing medical education event prior to teaching osnd on a live human model. a -d printed skull from ct head data is being created to incorporate this model. a simple -d ballistic onsd model allows learners to learn proper hand placement, basic landmarks, onsd measurement, and practice proper pressure on human eyes. this model can be replicated and utilized in a sustainable fashion given that the globe and platform are composed of ballistics gel. pressure measurements using pressure guide wires is an invaluable diagnostic tool in the management of many endovascular revascularization therapies. its role is well established in coronary artery disease management such as use of fractional flow reserve (ffr) as a standard diagnostic tool to determine need for stenting, angioplasty or bypass. renal fractional flow reserve remains an integral physiologic parameter used in endovascular revascularization therapy of renal artery stenosis. despite the wide spread use of pressure wires in endovascular therapies, its application in the management of cerebral venous diseases remains vastly unexplored. we sought to evaluate the safety and applicability of pressure guide wires in several cerebral venous diseases. patients undergoing diagnostic angiography for possible venous outflow obstruction had pressures measured by pressure guide wires (volcano verrata® or prestige primewire®) across the following vessels: superior sagittal sinus, torcula, right and left transverse sinus, right and left sigmoid sinus, and right and left internal jugular vein. venous pressures were also collected from patients undergoing venous thrombectomy, stenting, or an arteriovenous malformation embolization (avm). five patients who underwent diagnostic angiography for pseudotumor cerebri showed no major variability in their pressures across the cerebral venous architecture which was confirmed by lack of stenosis or thrombi on intravascular ultrasound (ivus). four patients had a pressure difference above which was suggestive of a stenosis and later confirmed by ivus. patients undergoing pressure measurements that had evidence of stenosis or thrombosis by ivus showed improvement in pressure gradients post stenting or thrombectomy. no variability in pressure gradients were noted in a patient that underwent avm embolization. pressure measurements using pressure guide wires can improve diagnostic accuracy and guide management of several diseases of the cerebral venous system. further studies are necessary to understand the applicability of this approach in the management of venous disease. monitoring metrics is imperative for quality assurance and ongoing improvement in a developing clinical unit. a new neurocritical care unit (nccu), specializing in the treatment of critically ill, neurologicallyinjured patients opened in july . this study examined quality metrics that correlate with the development and growth of a neurocritical care program. data from patients with principle diagnoses of ischemic stroke (isc), subarachnoid (sah) or intracerebral (ich) hemorrhage, seizure, or brain tumor, admitted to nccu in and were used in the analyses. quality metrics included overall and individual complication rates per , patient days of pneumonia, venous thromboembolism, pulmonary embolism, sepsis, septic shock, pulmonary edema, gastrointestinal bleeding, and catheter associated urinary tract infection, as well as hospital mortality and length of stay (los). chi-squared and mann-whitney tests and poisson regression were used to compare metrics between and . patient volumes increased by . % ( to ) from to . the overall complication rate declined significantly from . to . per , patient days (p= . ). the highest complication rate in and was pneumonia ( . and . per , patient days, respectively). the proportion of patients who expired decreased from . % (n= ) in to . % (n= ) in , though not significantly (p= . ). there were no significant differences in los among patients with isc, brain tumor or seizure. however, those with sah or ich had significantly shorter stays in (median [interquartile range] = . [ . , . ]) versus ( . [ . , . ]) (p= . ). data suggest that over the initial -year period, complication rates among patients in the nccu improved. los did increase for hemorrhage patients; however, this may be related to greater severity of illness in the patient population over time. further analyses will be conducted to account for severity and other factors. delirium is a frequently seen but underestimated problem in critical care settings. delirium screening is considered time consuming, which is one of the factors leading to under diagnosis. the cam-icu screening tool for delirium has been validated in medical and surgical icus. among neurological patients, it has been validated in stroke patients but not in general neurocritical care population. this study was designed to validate cam-icu flow sheet in neurointensive care unit. a prospective cohort study was conducted in a bed neurointensive care unit of a university hospital. patients meeting the inclusion criteria (all nicu patients) and exclusion criteria (comatosed, aphasic, psychotic, prior diagnosis of neurocognitive disease, persistently vegetative state, sedated) were screened for delirium by ( ) a nurse practitioner using confusion assessment method (cam-icu) and ( ) a physician reference rator using delirium screening criteria in diagnostic and statistical manual of mental disorders- . assessments were done daily monday through friday for the icu stay. paired assessments were done less than hours apart. the study enrolled patients ( male, female). daily assessments were done. mean age of the patients was . and mean sap score was . admitting diagnoses were ich ( ), sah ( ), ischemic stroke ( ), tumor ( ), spinal surgery( ), neurological infections( ), seizures( ),elective angiograms( ), hydrocephalus( ), transverse myelitis( ) and av dural fistula( ). using dsm- criteria, the reference rator identified delirium in out of ( %) patients during the icu stay. out of assessments were positive for delirium according to dsm- and according to cam-icu. cam-icu flow sheet had sensitivity of . % ( %ci . % - . %) and specificity of . % ( %ci . %- . %). cam-icu has high sensitivity and specificity for diagnosing delirium in critically ill neurological population. it is a valid tool for diagnosing delirium. a value stream mapping event (vsm) for general neurology inpatients, revealed multiple barriers related to videofluoroscopy swallow studies. there was a high volume of patients requiring instrumental swallow assessments, a limited number of radiology appointments, and transportation delays that were delaying feeding plans, discharge recommendations and goals of care discussions. an operations engineer involved in the vsm event started the process by collecting observational data regariing timing. after meeting with the chief operating officer, director of patient transport, director of radiology, speech pathology manager, neuro intensive care unit manager and the operations engineer, a pilot program was agreed upon. the results for the three week pilot program were successful, and resulted in a permanent change in procedure. the pilot data showed a decrease in test time by minutes, a decrease in transport delays by minutes, and a decrease in length of stay by . days. the number of patients waiting for the study dropped from . to . per week. by annualizing this data, the change has created new available bed days, additional patient encounters and an incremental annual contribution margin of $ , . with the appointment time consistent, the nurse is able to plan patient care around the study, and ensure the patient is prepared and not delayed for the study. it has also allowed, if deemed safe for the patient to swallow, medications to be changed from the intravenous route to the oral route earlier, and earlier determination of safe feeding and diet restrictions. we previously reported outcome for children with refractory and super-refractory status epilepticus in a cohort of patients. mortality was %. % of survivors required new tracheostomy and/or gastrostomy tubes. the majority of surviving patients experienced some degree of disability at discharge as determined by the pediatric cerebral performance category scale (pcpc). here, we aimed to identify patient factors in this cohort that were associated with a decline in functional neurologic outcome at discharge. retrospective chart review of children age - years who received pentobarbital infusion for status epilepticus in the pediatric intensive care unit of a large tertiary children's hospital from - . outcome was defined using pcpc at admission and discharge. potential factors associated with outcome were evaluated using fisher's exact test and wilcoxon rank sum test. children were included. pcpc score at admission (p= . ), etiology of status epilepticus (p= . ), new tracheostomy (p= . ), and new gastrostomy tube (p= . ) were all significantly associated with children were more likely to have normal baseline neurologic function and more likely to have febrile encephalitis, stroke/trauma, or hypoxic ischemic encephalopathy as the etiology of status epilepticus. duration of pentobarbital infusion (median = days vs. days) (p= . ) and duration of hospital admission (median = . months vs. . months) (p= . ) were both longer in patients who had an admission pcpc score, etiology of status epilepticus, new tracheostomy and gastrostomy tube as well as longer duration of pentobarbital infusion and longer hospital stay were significantly associated with a decline in functional neurologic outcome at hospital discharge in children with refractory and superrefractory status epilepticus. status epilepticus (se) is the most common pediatric neurological, and super-refractory se is a lifethreatening form of se that continues or recurs for more than hours despite multiple therapeutic interventions. this population-based study investigated pediatric se and srse admissions in germany. pediatric (age - years) admissions between - were identified in the arvato health analytics database. se, epilepsy, and febrile seizure cases were identified using a modification of a previouslypublished algorithm based on icd- diagnosis codes (g , g , and r ) and coding for ventilator and intensive care unit use. based on primary diagnosis, prior epilepsy status, and ventilation se was subclassified as non-refractory, refractory (rse), and super-refractory (srse). inpatient mortality, costs, length-of-stay (los), and discharge disposition were assessed overall and for rse and srse. the algorithm identified , seizure-related admissions and classified % as se, of which . % were rse and . % were srse. the rse frequency was highest among ages - . the incidence of cases classified as srse peaked among newborns (age< year), decreasing between ages - years. cases classified as se accounted for . % of total costs associated with seizure-related hospitalizations. srse exhibited the highest per case cost (mean € , ), amounting to . % of all se costs, and these costs correlated with the highest los (median . days). srse was associated with greater mortality ( . %) cases classified as srse accounted for . % of all pediatric seizure-related costs, despite representing only . % of admissions. srse was associated with the highest los and mortality rate. these results highlight the burden of illness associated with srse and suggest that optimization of srse management has the potential to improve outcomes and reduce costs. despite its more routine use and the recognition that mri provides superior detection of traumatic brain injuries, there has been little written about how mri might affect the acute management of trauma patients. we sought to describe mri findings in a cohort of children admitted to the picu with tbi and to extend comparisons between ct and mri in acute trauma. a secondary aim was to quantify in what ways mri findings influenced clinical management in this cohort. we retrospectively identified patients admitted to the picu with an acute head injury between september and may who underwent head mri within the first hrs. we compared mri with ct findings, using the nih common data elements definitions of injury type. we determined by chart review the indication for mri and if there was documentation that mri led to a change in management, defined as either an escalation or a de-escalation of care. seven patients had mri only, and mri identified additional lesions in of the patients who had first undergone head ct. of these, patients had new intra-parenchymal lesions, had new extra-axial lesions, and had both a new intra-parenchymal and a new extra-parenchymal lesion identified. the most frequent new lesions were contusions and traumatic or diffuse axonal injury. acute management was influenced by mri in a majority of patients, leading to an escalation of medical or surgical management in nearly one third and a de-escalation of care in half. early mri may have a beneficial role in the acute management of pediatric traumatic brain injury. mri frequently identified clinically important lesions not appreciated on ct, and findings influenced management decisions. future studies will assess whether early mri improves patient outcomes or provides cost/benefit by reducing length of stay. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. we identified patients who received dh, of whom underwent reconstructive cranioplasty at our institution. the post-cranioplasty complication rate was %, which was due in part to hemorrhage, infectious complications, or csf compartment disturbances. patients receiving early cranioplasty developed an increased rate of hemorrhagic complication ( % vs %; p = . ), increased median hospital length of stay (los) ( vs days; p = . ) and increased median icu los ( vs days; p = . ). of the patients who received dh surgery related to malignant cerebral edema from an acute ischemic stroke, total complication rates trended down for early compared to late cranioplasty surgery ( % vs %; p = . ). patients receiving dh surgery for any cause who underwent early reconstructive cranioplasty, experienced higher rates of hemorrhagic complications and increased hospital and icu los. however, among those patients receiving dh surgery for the specific indication of malignant cerebral edema from acute ischemic stroke, significant differences did not exist between the early and late cranioplasty groups. the total complication rates in these patients trended lower in the early group. another important and mainly unpublished finding is that a majority of dh patients are lost to surgical follow up and may therefore impact the complication rate of this not so benign surgery. postoperative antibiotics (pa) are often administered to patients after instrumented spinal surgery until all drains are removed to prevent surgical site infections (ssi). this practice is discouraged by numerous medical society guidelines, so our institutional neurosurgery quality improvement committee decided to discontinue use of pa for this population. we retrospectively reviewed data for patients who had instrumented spinal surgery at our institution for seven months before and after this policy change and compared the frequency of ssi and development of antibiotic related complications in patients who received pa to those who did not (non-pa). we identified pa patients and non-pa patients. discontinuation of pa did not result in an increase in frequency of ssi ( % of pa patients vs. . % of non-pa patients, p= . ). growth of resistant bacteria was not significantly reduced in the non-pa period in comparison to the pa period ( % vs. %, p= ). the cost of antibiotics for pa patients was $ , . , whereas the cost of antibiotics for the non-pa patients was $ . on a per patient basis, the cost associated with antibiotics and resistant infections was significantly greater for patients who received pa than for those who did not (median of $ . with iqr $ . -$ . vs. median of $ with iqr $ -$ ; p< . ). after discontinuing pa for patients who had instrumented spinal procedures, we did not observe an increase in the frequency of ssi. we did, however, note that there was a non-significant decrease in the frequency of growth of resistant organisms. these findings suggest that patients in this population do not need pa, and complications can be reduced if pa are withheld. the development of flow-diverting stents has allowed for new treatment options for giant vertebrobasilar aneurysms. however, the expertise required to perform these procedures safely and concerns about complications continue to limit their use. we sought to identify common complications of this treatment that can be anticipated by neurointensivists, to optimize management in the postoperative period. we retrospectively reviewed our hospital database of treated aneurysms to identify those with giant vertebrobasilar aneurysms. medical and neurological complications were recorded. six patients ( male, female) underwent treatment of giant vertebrobasilar aneurysms with pipeline embolization devices. five received adjunctive coiling. frequently reported pre-procedure symptoms were dysphagia (n= ), diplopia (n= ), dysarthria (n= ), facial weakness (n= ), hemiparesis (n= ), gaze palsy (n= ), and nystagmus (n= ). five patients ambulated normally. due to concerns about necessary procedures after stenting when on antiplatelet therapy, three patients received prophylactic ventriculoperitoneal shunts, two underwent gastrostomy, and two underwent tracheostomy. angiography confirmed successful aneurysm embolization in all patients. postoperatively, all patients developed new or worsened symptoms attributed to brainstem edema, including hemiparesis (n= ), facial weakness (n= ), dysphagia (n= ), diplopia (n= ), nystagmus (n= ), gaze palsy (n= ), and dysarthria (n= ). neurological symptoms were treated with steroids, with most symptoms subsiding by discharge. five patients had medical complications, including pneumonia (n= ), respiratory failure (n= ), gastrointestinal bleeding (n= ), arrhythmia (n= ), urinary tract infection (n= ), and myocardial infarction (n= ). two patients were re-intubated, three underwent gastrostomy, and one underwent tracheostomy. functional status at -months was available for five patients. three achieved modified rankin scale scores between - , one regressed to a , and one died. the treatment of giant vertebrobasilar aneurysms presents significant challenges. practitioners should anticipate temporary postoperative neurological worsening and various medical complications. prophylactic shunt placement, gastrostomy, and/or tracheostomy should be considered in patients anticipated to likely need these procedures after treatment. ventriculostomy-related infection (vri) remains a major complication of external ventricular drain (evd) placement. historically, prophylactic antimicrobials are utilized to decrease the incidence of vri after evd placement. recent guidelines for the insertion and management of evds recommend a single preoperative dose prior to evd insertion and urges against the use of duration antibiotic prophylaxis. prior to the publication of this guideline, we hypothesized that significant variations existed among institutions with respect to antibiotic prophylaxis practices in this setting. the purpose of this practice survey was to determine trends in antimicrobial prophylactic strategies utilized by various healthcare institutions for evd placement prior to publication of the neurocritical care society (ncs) evidence-based guidelines for the insertion and management of evds. a seven-question practice survey on antimicrobial prophylaxis for evd placement was distributed to active pharmacist members of the ncs by email and open for response from / / to / / . the following information was collected: antimicrobial prophylaxis regimen utilized, pharmacologic class, utilization of impregnated catheters, and institution guidance. survey results were analyzed for trends in antimicrobial prophylaxis in the setting of evd placement. respondents ( / , % response rate) from institutions completed a seven-question evd management survey. most institutions initiate a single dose of antibiotics prior to evd insertion ( / , %). periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by respondents ( / , %). of respondents who do not continue antimicrobial prophylaxis for the duration of evd placement, % ( / ) utilize antimicrobial-impregnated catheters to reduce incidence of vri. the importance of antimicrobial prophylaxis to prevent infectious complications associated with evd placement is widely accepted. prophylactic strategies vary between institutions. periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by survey respondents. antimicrobial-impregnated catheters are commonly utilized in institutions using periprocedural antimicrobial prophylaxis. the postoperative course seen in critically ill neurosurgical patients is known to vary depending on the timing of the surgical procedure. this study seeks to compare the clinical characteristics, complications, and outcomes between elective or urgent surgery patients admitted to the intensive care unit (icu). retrospective review of a two-year neurosurgical patients' cohort. the pre and postoperative conditions and outcomes were compared between elective (group a) and emergency (group b) surgery patients. a total of patients were evaluated, in group a and in group b. the most common diagnosis was intracranial tumor. the mean american society of anesthesiology (asa) score was significantly higher in group b than in group a ( . vs. . , p< . ). mean sequential organ failure assessment (sofa) score on admission was higher in group b ( . vs. . , p< . ). these patients were more likely to require mechanical ventilation (or . , p< . ) and vasopressors (or . , p< . ) . group b had a higher probability of rebleeding (or . , p< . ), intracranial hypertension (or . , p< . ), hydrocephalus (or . , p< . ), and reintervention (or . , p= . ). post-operative nausea and vomiting were less likely in group b ( . % vs. . % and vs. . %, respectively). mean hospital and icu los were shorter in group a than in group b ( . vs. . and . vs. . , p< . respectively). mortality rate during icu stay was higher in group b ( . % vs. . %; or . , p< . ). the preoperative glasgow coma scale (gcs) in patients who died, was below in only a minority of them ( . % in group b; % in group a). in this cohort of neurosurgical patients, emergency, compared to elective operations, were associated with higher post-operative complications and mortality rates. emergency surgery was associated with a higher severity of illness measured by the sofa and asa scores. intraprocedure rupture (ipr) is a rare but potentially serious complication of endovascular coiling of intracranial aneurysms. potential complications include hemorrhage, ischemic stroke, vasospasm and hydrocephalus which can lead to increased morbidity and mortality. the clinical course for these patients is not well studied and characterized. we performed a retrospective review of prospectively collected data for all unruptured aneurysms treated with endovascular coil embolization between july and march at a large universitybased hospital. out of cases of all unruptured aneurysms coil embolizations, ( . %) patients had ipr. we reviewed baseline data, procedure notes, clinical course, and outcomes at discharge and at , and months. among the ten patients, the location of the aneurysms included: basilar apex, internal carotid artery anterior communicating artery, posterior cerebral artery, and posterior communicating artery aneurysm. patients were monitored in the icu for variable lengths of time and daily transcranial doppler ultrasound detected no significant sonographic vasospasm. the large majority of the patients ( / ) were discharged to home at their baseline functional status assessed by modified rankin scale. one patient was discharged to inpatient rehabilitation for cognitive deficits from ipr of a basilar apex aneurysm. they were subsequently discharged home with supervision. there was a single mortality in a patient receiving retreatment of a proximal ica aneurysm with prior stenting and coil embolization who developed massive subarachnoid hemorrhage with diffuse intraventricular hemorrhage with external ventricular drain placement. the incidence of ipr is very low and potentially serious complications occur rarely in these patients. the location and factors associated with ipr are highly variable and without clear associations. outcomes of such complications are overall favorable. a short observation period in the hospital is likely warranted with a benign clinical course the most likely outcome. the standard treatment of cerebral venous-sinus thrombosis (cvst) is anticoagulation. however some patients clinically deteriorate secondary to mass-effect from infarct or intracerebral-hemorrhage (ich). the role of decompressive-craniectomy (dc) in this patient population is unknown. we elucidate the baseline characteristics of patients treated with dc, and report their outcomes. a retrospective chart review of our institutional database identified patients with cvst who were treated with dc. demographic and clinical data were collected. imaging variables collected from ct-head or mri-brain immediately before dc were intracerebral-hemorrhage volume (ich-v), combined volume of mass-effect from infarct/ich and peri-lesional edema (me-v), midline-shift at level of pinealgland (mds-p), midline-shift at cranial-most portion of corpus-callosum (mds-cc), and herniation-type. favorable outcome was defined as glasgow-outcomes scale of - upon last-known follow-up. a total of patients (females= ) treated with dc were identified with mean-age . (+/- . ), mean glasgow-coma scale (gcs) before surgery (+/- . ), mean-ich-v . ml (+/- . ), mean-me-v . ml (+/- . ), mean-mds-p . mm (+/- . ), and mean-mds-cc . mm (+/- . ). transverse-sinus was most commonly involved (n= ). / patients had any herniation, most commonly cingulate (n= ). meanchange in gcs from admission to before-surgery was - . (+/- . ). ten patients were anticoagulated before surgery. on last-known follow-up, / patients had a favorable outcome. four had died. on chisquare analysis, superior-sagittal sinus thrombosis was associated with unfavorable outcomes (p= . ), and mortality (p= . ). on univariate binary-logistic regression, there was a non-significant trend towards unfavorable outcomes (p= . ) and mortality (p= . ) with every-point decrease in mean-gcs before surgery. the predictive-value of other factors towards outcomes is unknown given limited sample-size. decompressive-craniectomy might improve outcomes even in patients with cvst who have developed coma, cerebral herniation, have failed treatment with anticoagulation, and have large-volume masslesions causing midline-shifts of > mm. a prospective multi-institutional observational-cohort would poster presentations better delineate outcomes in comparison to matched-patients who are not treated with decompressivecraniectomy. meningiomas are often benign and mostly asymptomatic, and the treatment approaches may include open surgical resection, radiosurgery, and/or watchful waiting. reported morbidity and mortality rates for elderly patients undergoing meningioma resection vary widely. we sought to investigate mortality rates for elderly patients undergoing craniotomy for meningioma resection using the nationwide inpatient sample (nis). the nis datasets from to were used to identify patient admissions for meningioma resection based on the icd- -cm code . . age categories were defined as years of age. primary outcomes were in-hospital mortality, poor outcomes (defined as death or discharge to a facility other than home), cost and length of hospitalization. a total of , patients were identified who underwent meningioma resection during - of which . % were elderly (> years). each of the primary outcomes was heavily influenced by the advancing age. in-hospital mortality was higher in the elderly as compared to the younger patients ( . % vs % p< . ), as was the rate of a poor outcome ( . % vs . %, p< . ). elderly patients also had a higher cost ($ vs $ , p= . ) and increased length of hospitalization ( . vs . days, p< . ). in our study, age > was strongly associated with adverse outcomes after meningioma resection. this increased risk should be taken into account when considering surgical intervention in this subgroup. based on this study, closer perioperative monitoring may be warranted in the elderly patient subgroup. treatment with anticoagulation improves outcomes in cerebral venous-sinus thrombosis (cvst). however patients who develop extensive infarcts and/or intracerebral-hemorrhage with mass-effect resulting in comatose-state are at risk of poor outcomes, and may benefit from decompressive craniectomy (dc). we evaluated the role of dc in the management of malignant cvst and its impact on outcomes. literature-search was conducted on pubmed and google-scholar using terms "craniectomy", and "cerebral venous-sinus thrombosis". we included studies that described any number of patients with cvst who underwent dc after clinical deterioration and reported their outcomes. a similar search strategy identified patients from our institute. outcomes were reported as modified-rankin scale (mrs) or glasgow-outcomes scale (gos) and were classified as favorable (mrs - ; gos - ), or unfavorable (mrs - ; gos - ). a total of patients (females= ; males= ; unknown= ) who underwent dc for malignant-cvst were identified from studies (n= ) and our institute (n= ). age and gcs (before-surgery) were only available from patients, with mean-age . (+/- . ) and mean-gcs . (+/- . ). patients ( . %) had favorable-outcomes, while patients ( . %) died. in the multi-variate binarylogistic regression-model, every point-drop in gcs decreased the odds of favorable-outcomes by . times (p< . ; %ci= . - . ), and survival by . -times (p= . ; %ci= . - . ). thrombosis in internal-jugular vein (ijv) (or= . ; %ci= . - . ; p= . ) and deep-cerebral veins (dcv) (or= . ; %ci= . - . ; p= . ) predicted unfavorable-outcomes. ijv-thrombosis (or= . ; %ci= . - . ; p= . ) and dcv-thrombosis (or= . ; %ci= . - . ; p= . ) also predicted mortality. interestingly, cortical-vein thrombosis was associated with lower odds of unfavorable outcomes (or= . ; %ci= . - . ; p= . ). data regarding anticoagulation and long-term follow-up were not uniformly available. for patients with malignant-cvst, craniectomy could potentially improve outcomes. factors such as gcs before-surgery and cvst location can help predict outcome following dc and aid the decision-making process. a multi-institutional observational cohort should be designed to prospectively evaluate predictors for, timing of, and outcomes after craniectomy in cvst. the external ventricular drain (evd) is commonly used in the neurocritical care unit to help monitor intracranial pressure (icp) with the added advantage of therapeutically treating elevated icp by diverting cerebrospinal fluid (csf). placement of an evd can be complicated by hemorrhage surrounding the catheter insertion tract, which in some cases may prove to be fatal. this retrospective study was designed to look at the rate of tract hemorrhages after evd placement that were performed at our institution as well as associated outcomes. we conducted a retrospective review of all patients who underwent evd placement during a year period using our institutional database. postinsertion computerized tomography (ct) scans of the head were analyzed independently by physicians to identifying tract hemorrhages. data on primary diagnosis, age, sex, length of icu stay and mortality were collected and analyzed. a total of patients were identified as having had an evd placed during their hospital course. patients were excluded as there were no images of evds present in their records. patients were analyzed, of which % were male. mean age was . years. % of patients had a diagnosis of subarachnoid hemorrhage, % with intraparenchymal hemorrhage and % with ischemic stroke. mortality was % among all evd patients. the rate of tract hemorrhages among all patients with evd images was %. asymptomatic tract hemorrhages occurred in patients ( . %) with patient ( . %) dying due to the tract hemorrhage itself. among patients with tract hemorrhages mortality was . %. the rate of tract hemorrhages was noted to be % with the majority being asymptomatic. there was no difference in mortality among patients with evds who developed tract hemorrhages compared to patients with no tract hemorrhages. verapamil is a phenylalkylamine calcium channel blocker that blocks the calcium ion influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells resulting in vascular relaxation and vasodilatation. symptomatic hypotension and/or extreme bradycardia/asystole are often seen with intravenous verapamil administration requiring pharmacologic treatment. in neuroendovascular field verapamil is mainly being used as a vasodilator agent. current lack of pharmacokinetic/pharmacodynamics data of intra-arterial verapamil often makes very challenging to neurointerventionalists during endovascular procedures. the purpose of this study is to observe acute hemodynamic effects of intra-arterial verapamil administration as well as the safety of higher dose of the medication during endovascular treatment. ten patients who underwent endovascular treatment for acute ischemic stroke were evaluated pre and post procedure with vital signs. the dosage of intra-arterial verapamil was documented and tabulated along with the pre and post heart rate and systolic blood pressure. the dose of intra-arterial verapamil varied from to mg in each internal carotid or vertebral artery, total dose per patient per procedure varied from . to . the average dose of intra-arterial verapamil administered was . ± . mg or . ± . mcg/kg that were infused over to minutes. at the baseline before administration of intra-arterial verapamil, the mean systolic blood pressure (sbp) was . ± . mm hg and the mean heart rate (hr) was . ± . bpm. after administration of intraarterial verapamil, sbp decreased by mean of . ± . mm hg but we observed no symptomatic hypotension requiring any pharmacologic treatment. hr changed only by mean of . ± . bpm post intra-arterial verapamil. we observed no acute significant changes in hemodynamic parameters with administration of verapamil in carotid or vertebral arteries. this may represent its safe use during neuro-endovascular therapy. growing evidence suggests inflammation is critical in epileptogenesis. endogenous brain apolipoprotein e protein (apoe) modulates neuroinflammatory responses to injury through downregulation of glial activation and secondary neuronal injury. we created a amino acid peptide (cn- ) mimicking the binding face of apoe. cn- downregulates the inflammatory response in vitro and in vivo and improved histologic and clinical outcomes across several injury models in mice. we hypothesized that downregulation of inflammation by administration of cn- will reduce the development of epilepsy after pilocarpine induced status epilepticus in mice. c bl/ mice were intraperitoneally injected with pilocarpine to induce status epilepticus. following induction of status, animals were randomized to receive two doses of cn- or vehicle at minutes and hours. status was terminated by injection of benzodiazepine at minutes. epidural eeg leads were surgically placed at weeks and continuous video-eeg (cveeg) monitoring was performed for several days in a row at - weeks post status to determine spontaneous seizure development and frequency. at - weeks following induction of status epilepticus, administration of . or . mg/kg cn- reduced the development of epilepsy by approximately % compared to vehicle treated animals. further, cn- treated animals that did develop seizures had significantly fewer seizures than vehicle mice. similar results were seen with daily doses of mg/kg starting at minutes. importantly, cn- is not an anticonvulsant as cveeg monitoring during status induction clearly demonstrated that seizures were not stopped or reduced by injection of cn- . these results are consistent with the hypothesis that inflammation plays an important role in the development of epilepsy after injury and demonstrates treatments that target inflammation, like cn- , can prevent and/or reduce the development of epilepsy. this represents the first therapy to prevent the development of epilepsy that has entered into clinical trials. to determine the speed of brain entrance of the antiepileptic drugs (aeds) brivaracetam (brv) and levetiracetam (lev) after single intravenous dosing in humans. brv and lev both bind to synaptic vesicle protein a (sv a), but brv has more rapid brain entry than lev in mice and monkeys [ ] . sv a can be quantified in the living human brain using pet imaging with [ c]ucb-j[ ]. pet scans (n= ) were performed with [ c]ucb-j administered by a bolus-infusion protocol in healthy volunteers (n= ). therapeutic dosages of brv ( mg, n= ; mg, n= ; or mg, n= ) or lev ( mg, n= ) were administered as -minute intravenous infusions minutes after the start of the first pet scan. tracer displacement half-times were determined by subtracting the radioligand clearance halftime from the radioligand displacement half-times estimated by exponential fitting of the post-aed drop in distribution volumes (vt). data were also analyzed using an advanced mathematical model that described the relationship between brain [ c]ucb-j pet data and time-varying aed plasma curves to directly estimate brain entrance (k ) of both aeds and [ c]ucb-j, free fraction of [ c]ucb-j in the brain, and vt values. the radioligand clearance half-time was minutes. tracer displacement half-times were . and . minutes for brv mg, and ± minutes for lev mg. lower brv doses had longer half-times, but values were misleading as they assumed % sv a occupancy. the advanced compartment model described well -dose scans. using the advanced model, the brv uptake rate (~ ul/min/cm ) was found to be at least -fold higher than that of lev (~ ul/min/cm ). the results demonstrate that brv enters the human brain faster than lev. the potential therapeutic benefit of this has yet to be determined. while intravenous anesthetic therapy (ivat) represents the gold-standard for treatment of refractory status epilepticus (rse), the optimal depth and duration of therapy is not known. the goal of this retrospective observational study was to describe the relationship between the depth of burst suppression and the ability to successfully wean ivat during rse treatment. fifty patients were identified with rse who underwent continuous electroencephalography. using persyst, the suppression ratio (sr) was calculated up to hours prior to weaning ivat. the type and duration of ivat was recorded, as well as complications. we compared these variables between successful and unsuccessful weans. the mean sr for all patients was . ± . %, with a mean treatment duration of . ± . hours. there was no difference in treatment duration between successful and unsuccessful weans(p= . ), but sr was significantly lower in successful weans ( . ± . % vs . ± . %, p= . ). the receiver operating curve (roc) for the sensitivity and specificity of the mean sr to predict a successful weaning attempt did not identify a threshold to predict weaning success. the use of pentobarbital was associated with a significantly higher sr when compared to midazolam ( . ± . % vs . ± . %, p < . ). patients failed ivat weaning a mean . ± . hours after initiating the ivat wean, which occurred after a mean decrease in the midazolam infusion rate of ± %. depth of sr was not associated with infection risk (p= . ), but was associated with the need for tracheostomy ( . ± . % versus . ± . %, p= . ). vasopressors were required in . % of patients while on ivat. unsuccessful weaning of ivat was associated with a higher depth of sr, which is likely a marker of disease severity. depth of sedation was not associated with increased risk of infection, but was associated with the need for tracheostomy. vasopressor requirements are common. the primary objective of this study was to determine the sensitivity and specificity of real-time neuro icu nurse interpretation of quantitative eeg (qeeg) trends in the identification of recurrent nonconvulsive electrographic seizures in adult patients admitted to the neuro icu. thirteen adult patients admitted to the neuro icu that had nonconvulsive seizures on continuous eeg (ceeg) monitoring were included in the study. neuro icu nurses consented for their participation and underwent a brief, standardized qeeg training session. a -hour qeeg panel (rhythmicity spectrogram, left/right and amplitude-integrated eeg, left/right) printout containing the marked sentinel seizure(s) was displayed next to the bedside ceeg/qeeg monitor. at one-hour intervals, the nurses logged the number of seizures seen in the past hour based on their qeeg interpretation for the duration of their shift. their answers were compared with the gold standard of neurophysiologist interpretation of seizure occurrence on raw eeg. a total of hours of qeeg data was reviewed for patients. average length of data collection was . hours. for the neuro icu nurses' ability to detect the presence of seizures on real-time qeeg the sensitivity was . % ( % ci, . - . %) and specificity was . % ( % ci, . - . %). the positive predictive value for seizure detection was . % ( % ci, . - . %) and the negative predictive value was . % ( % ci, . - . %). the false-positive rate was . /hr. a simplified panel of qeeg trends can be used by neuro icu nurses to screen for recurrent electrographic seizures in critically ill patients with a reasonable sensitivity, an excellent specificity and a very low false-positive rate. this may facilitate earlier identification of recurrent electrographic seizures by notifying the neurophysiologist who is not present in the icu and not able to perform real-time ceeg interpretation. nonconvulsive status epilepticus (ncse) is an indicator of poor outcomes in neurocritical care settings. however, because of unfamiliarity with continuous electroencephalography monitoring (ceeg), the diagnosis and treatment of ncse remains challenging, and its clinical impact and prognostic factors have not been sufficiently reported in japan. we performed ceeg for adult patients in our neurocritical care unit with coma or unexplained altered mental status from april to september . we reviewed all ceeg records according to the american clinical neurophysiology society's terminology ( version), and diagnosed patients with ncse when the ceeg revealed spatiotemporally evolving or fluctuating periodic or rhythmic discharges and after considering clinical information based on the modified salzburg consensus criteria. patients with ncse were aggressively treated with benzodiazepines, fosphenytoin, and levetiracetam. they were divided into a generalized convulsive status epilepticus (gcse) group and a non-gcse group. we compared mortality and outcomes between the two groups after months using fischer's exact test. outcomes were defined as poor when the glasgow outcome scale score was worse at the -month follow-up than at admission. we excluded cases undergoing supportive care or lacking of follow-up. of cases in the study, cases were diagnosed with ncse, including cases with accompanying gcse and cases without. mortality rates at the -month follow-up were significantly higher in the non-gcse group than the gcse group ( % vs. %, respectively; p = . ). the rate of poor outcomes was significantly higher in the non-gcse group than in the gcse group ( % vs. %, respectively; p = . ). this study suggests that the absence of gcse is associated with increased mortality and poor outcomes among ncse patients. limitations of this study include its retrospective design and small number of ncse patients. further studies are necessary to identify additional prognostic factors. super-refractory status epilepticus (srse) is a life-threatening condition in which status epilepticus recurs or continues for over hours despite first-, second-, and anesthetic third-line agent (tla) medications. no treatments are currently approved for srse. a randomized, double-blind, multi-center, placebo-controlled phase trial evaluated brexanolone (usan; formerly sage- injection), a synaptic and extrasynaptic gabaa receptor positive allosteric modulator as adjunctive therapy for srse (nct ; "status trial"). enrolled subjects underwent a qualifying tla wean after at least hours of seizure-or burstsuppression. srse subjects failing the qualifying wean were randomized : to a blinded infusion of brexanolone or placebo as adjunctive therapy following resumption of one or more tla infusions. subjects were administered the blinded infusion for days, during which attempts were made to wean off tla infusions. clinical standardization guidelines (csgs) facilitated standardization across sites by outlining eeg patterns for which tla weaning should be continued, paused, or discontinued. an on-call clinical standardization team provided real-time support. safety was assessed via adverse events, laboratory testing, vital signs, and ecg parameters. the primary endpoint was defined as successfully super-refractory status epilepticus (srse) is a life-threatening neurological condition characterized by status epilepticus persisting over hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. currently, there is no consensus around treatment protocols for srse. this study aims to describe srse treatment patterns and related outcomes in a us population. we retrospectively identified srse cases in cerner healthfacts®, a large, de-identified, us electronic health record database, using records from - . cases were classified as srse using a modified version of a previously published algorithm using icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . , and . ) , ventilator support, pharmacotherapies. descriptive and univariate statistics were used to evaluate anesthetic treatment, anti-epileptic medications, and the association between glasgow coma score (gcs) and mortality. using our algorithm, srse cases ( patients) were classified. multiple tlas were received in % of cases, and in %, > concurrent tlas were received. the first post-admission tlas were propofol, lorazepam and midazolam, respectively, in %, % and % of cases. median anesthetic duration was . days. mortality was higher in - ( . vs. . days; p< . ). srse patients identified in our analysis underwent variable treatment patterns, reflecting lack of co days of tla treatment. nonconvulsive seizures (ncs) and nonconvulsive status epilepticus (ncse) occur in approximately % of neurologically critically ill patients. the most effective antiepileptic drug (aed) regimen to treat ncs and ncse is unknown. this study was designed to determine the efficacy of add-on clobazam, a unique , -benzodiazepine with favorable pharmacokinetic properties, in the treatment of ncs and ncse. a retrospective chart review was performed on adult patients who were admitted to the neurological intensive care unit between january , and june , , were diagnosed with ncs or ncse by continuous eeg monitoring and received clobazam as add-on therapy. the primary efficacy endpoint was defined as clobazam being the last aed added before ncs/ncse cessation, regardless of latency between dosing and ncs/ncse cessation. of the patients included in this study, ( %) had ncs vs. ( %) with ncse. the most common etiologies were autoimmune (n= ) and cns tumor (n= ), with patients ( %) having pre-existing epilepsy. clobazam was the last aed added before cessation of ncs/ncse in of ( %) subjects. clobazam was chosen as the rd to th line agent. clobazam was started at a median of days from the onset ncs/ncse (range - days). the median total daily dose of clobazam was mg (range - mg). this study suggests that clobazam may be effective at various time points in the treatment of ncs/nsce and may prevent the need for addition of intravenous anesthetic drugs to control seizures. however, a prospective study is warranted to determine efficacy and optimal dosing. continuous electroencephalography monitoring(ceegm) with international - system is essential for detect nonconvulsive status epilepticus (ncse). in japan, both ceegm systems and human resources are lacking, and few facilities are able to conduct such advanced monitoring. the ceegm headset, described in this report, is a novel and easy-to-use technology. we attempted to validate the novel ceegm headset by comparing it with a conventional, international - ceegm system (conventional ceegm). we completed this study at a single center, eight-bed neurocritical care unit, between january and june . the new, ceegm headset features eight electrodes (f, c, t, o), and is capable of simultaneously transmitting eeg data by bluetooth. patients with disturbed consciousness, of unknown etiology, underwent ceegm headset followed by conventional ceegm. we verified the concordance rate of the two systems for detecting eeg morphologies (e.g. periodic discharges, rhythmic delta activity, spikes and waves), and diagnosing ncse. eeg morphologies were appreciated according to "american clinical neurophysiology society's standardized critical care eeg terminology: version" and diagnosis of ncse were done according to modified salzburg consensus criteria. among this period, we enrolled thirty patients. three patients were excluded because of not satisfying protocol. final analyses included verified data from patients. the mean age was years old (range: - ), % were male, mean acute physiology and chronic health evaluation (apache) ii score was (range: - ), and mean full outline of unresponsiveness (four) score was (range: - ). we appreciated concordant eeg morphologies, and ncse, in % ( / ), and % ( / ) of patients, respectively. this easy novel ceegm headset may be useful in settings with limited resources or access to conventional ceegm technology. further study is needed to validate the actual diagnostic ability of this novel headset. the traditional approach to interpreting eeg requires physicians with formal training to visually assess the waveforms. this approach is less practical in critical settings when a trained eeg specialist is not readily available to diagnose subclinical seizures, such as non-convulsive status epilepticus, in patients with altered mental status. we have recently invented an algorithm for sonifying eeg, and in the current study, we explored whether individuals without eeg training can detect ongoing seizures by simply listening to one channel of sonified eeg. we sonified eeg samples ( -second long) that represented various conditions commonly seen in the icu ( seizures; lpd, gpd, or burst suppression, and normal or slowing). medical students and nurses were asked to indicate each audio sample as "seizure" or "non-seizure". we then compared their performance with that of eeg experts [epilepsy attendings with > years of experience (n= ) and epilepsy fellows (n= )] and some of the medical students (n= ) who also diagnosed the same eegs on visual display. non-experts listening to single-channel sonified eegs detected seizures with remarkable sensitivity (students: ± %; nurses: ± %) compared to experts or non-experts reviewing the same eegs on visual display (attendings: %; fellows: ± %; students: ± %). if the eegs contained seizures or seizure-like activity, non-experts listening to sonified eegs rated them as seizures with high specificity (students: ± %; nurses: ± %) compared to experts or non-experts viewing the eegs visually (attendings: ± %; fellows: ± %; students: ± %). our study confirms that individuals without eeg training can detect ongoing seizures or seizure-like rhythmic periodic activity by merely listening to short duration of sonified eeg. while sonification of eeg cannot replace the traditional approaches to eeg interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures. super-refractory status epilepticus (srse) is a life-threatening form of status epilepticus (se) that continues despite, or recurs after, hours of therapeutic interventions, including continuous intravenous anesthetic third-line agents (tlas). no therapies are approved for srse, leading to substantial variation in both management and determination of treatment response. for the phase trial of brexanolone as adjunctive therapy for srse involving up to international sites, we developed and implemented clinical standardization guidelines (csgs) for real-time support of tla administration, weaning, and outcome assessment under eeg neuromonitoring. a clinical standardization team (cst), including investigators and se experts, developed consensus csgs defining acceptable eeg patterns for continuation, termination, or pausing the weaning of tlas. csg implementation was facilitated by training and cst call centers staffed internationally by physicians with critical care eeg expertise. in cases of disagreement, the local site retained final decision-making authority. a "traffic light" system defined: )"green" tolerated eeg patterns (improving background, seizures within hours, discharges > hz, or discharges - . hz with evolution and no improvement over hours), and )"amber" eeg patterns not meeting the above, for which tla weaning should be paused while optimizing anti-epileptic medications and monitoring for transitions to green/red eeg patterns. the initial cst consultations yielded % csg compliance; % of eegs underwent cst review. few cst consultations lasted > minutes ( %); most lasted < minutes ( %). this phase trial demonstrates the feasibility of applying neuromonitoring csgs for tla weaning in srse patients, to ensure better consistency of clinical care and reliability of the primary outcome measure in clinical trials. csgs were well accepted by investigators and may serve as a framework for future clinical trials or clinical therapies in srse. severe brain trauma is a leading cause of death and disability worldwide. post-traumatic epilepsy (pte) is a chronic complication that occurs in up to % of cases (frey, ; najafi et al., ) . drugs and other interventions to prevent epileptogenesis would likely be most effective early after traumatic brain injury (tbi), but cannot be given indiscriminately. there is a critical need for tools that quantify those at high risk for pte. abnormal neural activity, in the form of ictal-interictal continuum abnormalities(iicas) are increased acute brain injuries, and appear to differentiate patients at risk for secondary brain injury (e.g. kim et al., ) . we hypothesized that iicas acutely following tbi may be a marker of posttraumatic epilepsy risk. we evaluated continuous eeg data from moderate to severe tbi patients who did and did not develop pte, (any seizure - months post-tbi; n= ). seizures < month post-tbi were classified as symptomatic, not pte. conventional - scalp electrode placement was used and eegs were reviewed by standard visual analysis, by the mgh neurophysiology service. daily eeg reports were scored for the presence of iicas and seizures. demographic data including gender, age, tbi severity and type of brain injury were recorded. univariate and multivariate regression analyses were performed to determine which iica and demographic features correlated with pte. gcs (p= . ) and tbi severity (p= . ) were significantly associated with pte, as expected. seizures (p= . ), epileptiform discharges (p= . ), generalized periodic discharges ( . ) and lateralized rhythmic delta activity (p= . ) independently predicted risk for post-traumatic epilepsy. epileptiform discharges, in particular, were more prevalent acutely post-tbi in pte patients. increased iica prevalence is significantly associated with pte and may be a predictive marker for identifying patients who may benefit from anti-epileptogenesis trials. rapidly obtaining eeg signals in the ed and icu for at-risk patients can enhance diagnosis accuracy and speed, while cutting down time until treatment. ceribell inc has developed a portable eeg data recorder and electrode headset with rapid setup (~ min) technology without any eeg technician required to overcome the inaccessibility of eeg in urgent situations when seizures are suspected. the purpose of this study is to evaluate the signal quality and performance of the ceribell system compared to a reputable clinical eeg system. we collected eeg samples in the laboratory and at stanford university medical center. laboratory collections on healthy volunteers included simultaneous collection of eeg using ceribell and nihon kohden systems, and a split-signal that recorded eeg to both data recorders from the same electrodes. in the icu, eeg was recorded with the ceribell system on patients and subsequently with the clinical eeg system. data was filtered and spectral densities, mean frequency (mf), spectral entropy (se), and % spectral edge frequency (sef ) were computed. in the split-signal test, the waveforms consistently appeared similar by visual inspection. the analysis of ceribell data revealed (mf = . hz, se= . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the simultaneous test, the ceribell system produced (mf = . hz, se = . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the clinical setting, the ceribell system showed spectral density distributions comparable with the commercial system. our results indicate that the signal quality of the ceribell system is similar to a commercially available eeg used widely in the clinical setting, while requiring less setup time and allowing more portability. status epilepticus (se) is a life-threatening condition characterized by prolonged seizures without regaining consciousness between seizure events. when se continues or recurs hours or more after treatment with third line anesthetic agents, it is considered super-refractory se (srse). there are few population-based studies on the descriptive epidemiology of srse at a national level. the objective was to estimate the incidence of srse in canada in - . we analyzed standardized national administrative record-level data covering all provinces across canada as provided by the canadian institute for health information. srse episodes were classified from two databases for acute care admissions (discharge abstract database) and emergency visits (national ambulatory care reporting system) over fiscal years ( / to / ). cases were identified as srse using a modification of a previously published algorithm using icd- -ca diagnostic codes for epilepsy (g ), status epilepticus (g ), or convulsions (r ) plus an intensive care unit stay of days or more with mechanical invasive ventilation. using our algorithm, from - , the mean annual number of cases classified as srse was , ( . / , persons per year). the annual incidence was higher in males ( . / , per year) than females ( . / , per year). the highest rates were in the age group - years: . and . per , per year for females and males, respectively. the mean age of srse patients was years (sd= years), with % males. the most common comorbidities for srse included metabolic disturbances ( %), sepsis ( %), toxic withdrawal state ( %), cardiovascular disease ( %), and head trauma ( %). in-hospital mortality for srse was %. this is the first study reporting estimates of srse incidence in canada. these results suggest that srse is associated with a substantial disease burden. interventions that improve patient outcomes and reduce mortality are required. new-onset refractory status epilepticus (norse) is a condition characterized by prolonged pharmacoresistant seizures in a previously healthy individual with no identifiable etiology during initial evaluation. typical magnetic resonance imaging (mri) findings include bilateral limbic and neocortical t -weighted hyperintense lesions. fluorodeoxyglucose (fdg)-positron emission tomography (pet) findings have not been previously reported. this study sought to describe fdg-pet and mri characteristics in patients with norse. methods patients were retrospectively identified amongst a database of autoimmune-mediated encephalitis from - , meeting diagnostic criteria for norse and having undergone mri and pet over the course of their illness. imaging findings were confirmed with a board-certified neuroradiologist. nine patients were autoantibody positive: three n-methyl-d-aspartic acid (nmda) receptor, two glutamic acid decarboxylase (gad), three voltage-gated potassium channel (vgkc)-complex with two having leucine-rich glioma-inactivated protein igg positivity, and one gamma-aminobutyric acid (gaba) b receptor. all patients had identifiable abnormalities on fdg-pet. hypometabolism was most common, with of patients having diffuse, bilateral, or unilateral frontal, parietal, or occipital cortical hypometabolism. nine patients also had bilateral ( ) or unilateral ( ) mesial temporal hypermetabolism. two patients had multifocal hypermetabolism with bilateral or unilateral frontal abnormalities in addition to mesial temporal findings. of the nine patients with fdg-pet hypermetabolism, concurrent mri scans failed to show corresponding t -weighted hyperintense lesions in the mesial temporal and medial frontal regions in two patients. fdg-pet findings in norse include bilateral or unilateral mesial temporal or mesial frontal hypermetabolism with diffuse, bilateral, or focal cortical hypometabolism. hypermetabolism may reflect regions predominantly involved in acute epileptogenesis. fdg-pet may improve sensitivity when compared to mri alone. while seizures are uncommon but reported in primary intraventricular hemorrhage (ivh), little evidence is available on the prevalence of hyperexcitable patterns on long term eeg monitoring. we sought to determine the prevalence of hyperexcitable patterns and seizures in patients with primary ivh who were extracted from a cohort consisting of patients with spontaneous intracerebral hemorrhage (sich) who underwent continuous electroencephalogram (ceeg) monitoring between january and december at yale-new haven hospital. indications for ceeg monitoring included fluctuation of or depressed mental status, abnormal movements and a limited clinical exam. we recorded demographics, radiologic hydrocephalus, duration of eeg recording and eeg findings. hyperexcitable patterns comprised generalized, bilateral independent or lateralized periodic discharges (pds), lateralized rhythmic delta activity (rda), brief potentially ictal rhythmic discharges (b(i)rds), and spike-and-wave discharges (sw). of adults with sich who had ceeg performed, patients had primary ivh. hydrocephalus was present in patients ( %). patients were monitored for a mean duration of . (± . ) hours. patients had hyperexcitable patterns and/or electrographic seizures ( %): electrographic seizures and co-existent hyperexcitable patterns were captured in of patients ( %) and hyperexcitable patterns without seizures in of patients ( %). hyperexcitable patterns included periodic discharges (pds) ( ) (generalized, lateralized and bilateral independent, with and without rhythmicity), rhythmic delta activity (rda) ( ) (both lateralized and generalized, with and without sharps), brief potentially ictal rhythmic discharges(b(i)rds) ( ) and spike-and-wave discharges (sw) ( ). there was no significant difference between patients with and without hydrocephalus and hyperexcitability or electrographic seizures (p= . ). both electrographic seizures and/or patterns of hyperexcitability on eeg are common in our selected cohort of primary ivh patients. this underscores the importance of continuous eeg monitoring in this patient population, since the detection of non-convulsive seizures may offer an opportunity for therapeutic intervention. patients with aneurysmal sah (asah) frequently have ictal-interictal continuum (iic) eeg patterns. while seizure burden can worsen outcomes, less is known about iic burden. we investigated the impact of iic burden and anti-epileptic drug (aed) treatment on asah outcomes. we included patients with asah undergoing continuous eeg (ceeg) from - . patients with nonaneurysmal sah or %, - %, - %, - %, < %. age gender, admission gcs, apache ii score, fisher and hunt and hess (hh) scores, aed dosing and discharge gos were ascertained by chart review. presence of iic patterns in asah independently predicts worse neurologic outcome, although maximum burden does not. although nearly half of these patients receive aed treatment, our data suggest that aed treatment may not influence outcome. prospective studies may further delineate the clinical risks and benefits of aed treatment. refractory status epilepticus (rse) is defined by failure to control epileptic activity after the administration of st and nd line antiepileptic agents. mortality associated with rse has been estimated to be around - % at hospital discharge. we conducted this study to analyze trends in the frequency and management of rse. we conducted a cross-consortium (uhc) database from to . this is a database from academic medical centers and their affiliated hospitals in the united states and consists of a sample of , , patients. data including age, sex, antiepileptics (aed) and length of stay was collected. total mean age was . years and females were . %. there was an increasing trend of using lorazepam as the first line aed ( . % in to . % in ) and a decreasing trend was noted of using midazolam as the first line aed ( . % in aed ( . % in to . % in . leviteracetam was the most common second line aed used throughout all years which was followed by propofol followed by phenytoin/fosphenytoin. mean length of hospital stay was . days. between to , the proportion of hospitalized patients in the united states diagnosed with rse has increased. lorazepam and leviteracetam have been the most common aeds used. mean length of hospital stay has not changed. status epilepticus is associated with high risk of multi-organ dysfunction. ketamine for the treatment of super refractory status epilepticus (srse) has the benefit of a different mechanism and lack of cardiac depression when compared with other anesthetic agents. this study evaluated the improvement in sequential organ failure assessment (sofa) score in patients treated with ketamine for srse. this is a retrospective study of patients with srse from to . the timing and dosage of anesthetic agents used in their treatment were abstracted. sofa scores at admission and for the first days after initiation of ketamine were calculated. the presence of shock prior to initiation of ketamine included septic shock and cardiogenic shock. outcomes including mortality, organ failure, and hospital associated infections (hais) were also recorded. a total of patients were treated with ketamine after failure of seizure control using other anesthetic agents. seventeen ( . %) had an improvement of their sofa score while ( . %) did not. the median sofa score on admission was (iqr - ) for those who had an improvement and (iqr - ) for those who did not (p= . ). cardiac arrest was the etiology of srse for ( . %) patients who improved vs. ( . %) patients who did not (p= . ). patients required to vasopressors for hemodynamic support, with less needed for those who had an improvement (p= . ). there was a higher rate of hais in patient who did not have an improvement of their sofa score (p= . ). there is a subset of patients treated with ketamine for srse who have an improvement in their sofa score, require less vasopressor support, and have a lower rate of hais. further studies are needed to better understand which patient population may most benefit from the use of ketamine for treatment of srse. the ceribell eeg system (ces) is a novel channel eeg device with instant sonification and visual display capability that can be set up quickly without an eeg technician. we hypothesized that by using ces, we can decrease time to eeg acquisition and improve diagnosis and treatment decisions in suspected nonconvulsive seizures (ncs). adult icu patients (gcs < ) who had continuous eeg (ceeg) as part of clinical care were enrolled. once ceeg was ordered, consent was obtained and ces was placed by the treating physician (n= ) who listened to the left/right hemisphere signals for seconds each. suspicion for seizure ( =low, =high) and decision to treat (yes/no/not sure) were rated pre-and post-sonification. three blinded epileptologists compared accuracy of sonification with visual ces eeg. outcomes were difference in time to eeg acquisition, change in suspicion for seizure and decision to treat, and ease of use ( =challenging; =easy). patients (mean age +/- , median gcs of (iqr - . ) were enrolled from : am to : pm. start of eeg acquisition was significantly faster for ces ( minutes (iqr - ) vs minutes (iqr - ) p< . ), median difference minutes (iqr - ). one patient had ncs during sonification and this was accurately identified and treated. low suspicion for seizure ( ) was more likely postsonification ( % vs %, p= . ). treatment decision changed in % after sonification, and this was in the correct direction % of the time. inappropriate decision to treat decreased from % to % (p= . ). negative predictive value was % ( % ci - %). ces was consistently rated easy to use. the ceribell eeg system is easy to use, speeds eeg acquisition, accurately identifies ncs, and enables appropriate treatment decisions. it has the potential to greatly enhance timely diagnosis and treatment of ncs in critically ill patients. the aim of the study was to understand the efficacy of ketamine in refractory status epilepticus and identify the underlying factors affecting the effectiveness of ketamine. moreover, we also studied the rate of complications in patients who underwent continuous midazolam ketamine dual therapy for treatment of refractory status epilepticus. this is retrospective cohort study evaluating the efficacy of ketamine in patient with refractory status epilepticus in total of patients admitted to university of maryland medical center in either neuro intensive care unit /micu during the last five years between ( - ). we established a standardized algorithm for managing refractory status epilepticus. electrographic and clinical control of seizures was classified into four groups: likely response, possible response, permanent response and no response reviewed by a team of epileptologist and neuro intensivist. the effective doses of ketamine to abort rse were studied. complications intensive care unit stay while on therapy were reviewed. of the patients, were male, were female. % of the patients had cardiac arrest as an etiology of seizures. median loading dose was . mg/kg, median maintenance dosage was mg/kg/hr. % of the patients had no response to ketamine. % were responsive to ketamine of which, patients had likely response to ketamine, patients had possible response. . % of the patients had permanent response to ketamine. % patients had hospital acquired infections, % patient had metabolic acidosis, % had ards. this is one of the largest single center study illustrating the efficacy of ketamine in aborting rse. further study should address the difference in incidence of complications in patients with usage of ketamine versus groups alternative therapies. this study also demonstrates the etiology of seizures and its influence on efficacy of ketamine in aborting rse. acute cardiopulmonary complications are frequently observed in convulsive status epilepticus but mechanism is poorly understood. complications include tachy-arrhythmias, myocardial ischemia, takotsubo cardiomyopathy and neurogenic pulmonary edema. herein, we mapped evolution of cardiac dysautonomia as function of sequential electrographic stages of se in four subjects admitted to icu. we hypothesize pathological co-activation of both arms of autonomic system contributes to cardiac complications. heart rate variability (hrv) is considered a proxy for ans tone on heart. we analyzed hrv in time and frequency domain, complexity measure (lempel ziv-lz) during se and mapped changes as function of stages of se as determined by scalp eeg. conventional scalp eeg recording and lead i-ekg (sampled at hz) were analyzed using kubios hrv software . . cardiac vagal index (cvi) and cardiac sympathetic index (csi) were calculated using geometric lorenz-plot method. parasympathetic activity is expressed in rmssd, pnn, cvi, and hf power four adults (range - ; m= ) were admitted to icu following convulsive se. ictal hrv changes initially reflected high sympathetic system activation (high csi) and reduced vagal tone (low hf, rmssd) as reported previously with convulsive seizure. earlier stages of se (stage i and ii) were marked by dual activation of the ans with sympathetic predominance (lower cvi/csi ratio). later stages of se (stage iv and v), demonstrated progressive increase in parasympathetic activity (hf power, rmssd, cvi, cvi/csi ratio). hf power and rmssd at stage v se was three times higher than during discrete seizure. lz complexity measure downtrended with the loss of fluctuations in late stages of se. in one subject se terminated with asystole this case series highlights dynamic changes in sympatho-vagal imbalances with progressive se. dual activation of sympatho-parasympathetic system and loss of complexity measures are associated with increased cardiac complications. therapies directed towards stabilization of cardiac dysautonomia might minimize complications super-refractory status epilepticus (srse) is a life-threatening neurological condition that is characterized by status epilepticus that persists for hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. srse is associated with limited treatment options, and high morbidity and mortality. this study aims to describe and quantify inpatient srse treatment and its associated outcomes in the us. srse cases were classified retrospectively using a modified version of a previously published algorithm applied to a large, de-identified, us electronic health record database (cerner health facts®) covering > hospitals ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . cases were classified utilizing icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . and . ) , ventilator support or with los> days or missing age were excluded. univariate statistics were used to describe mortality, hospital los, icu los, and discharge disposition. our algorithm classified cases as srse ( patients). most cases ( %) were to large ( + beds) and/or teaching hospitals ( %). mean hospital los was . days, and icu los was . days. both los and icu los were significa average mortality rate was . %. mortality rates increased with number of tlas used ( - tla= . %; -rged home ( % with tracheostomy), while % (n= ) were discharged to another facility. treatment of srse requires acute, intensive management in the hospital setting. los and mortality rates were high and increased with increasing use of tlas. while good outcomes remain possible even after srse, additional interventions are needed that enable seizure control, liberation from anesthetic and ventilator management, and improved mortality. refractory status epilepticus (se) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. initially used in childhood epilepsies, ketogenic diet (kd) has also accumulated supporting evidence in the treatment of pediatric se. recently, the implementation of kd in adults with refractory and super-refractory se has been shown to be feasible and effective. we describe our recent experience with a new onset refractory status epilepticus (norse) patient and the unexpected challenge of achieving and maintaining a ketotic target. practical advice, a comprehensive review of offenders jeopardizing ketosis commonly used in the neurocritical care unit and alternatives is provided. a previously healthy -year-old woman was admitted with cryptogenic norse following a febrile illness with a course complicated by prolonged super-refractory se. a comprehensive work-up was notable only for mild cerebral spinal fluid (csf) pleocytosis, elevated non-specific inflammatory serum markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (mri). repeat csf testing was normal and serial mris demonstrated resolution of edema and diffusion restriction with gradually progressive hippocampal and diffuse atrophy. she required an aggressive approach including high anesthetic infusion rates, anti-seizure drug trials (in various combinations), empiric partial bilateral oophorectomy, and immunosuppression. enteral ketogenic formula was started on hospital day , however, sustained beta-hydroxybutyrate levels > mmol/l were only achieved days later following a careful comprehensive adjustment of the care plan. notably, a significant response to kd was only achieved with beta-hydroxybutyrate levels > . mmol/l. there are hidden carbohydrates in commonly administered medications for se, antibiotics, and even electrolyte repletion formulations and solutions used for oral care -all challenging the use of kd in this setting. tailoring comprehensive care and being aware of possible complications of kd are important for the successful implementation and maintenance of ketosis. early seizures are estimated to occur in - % of patients with moderate to severe traumatic brain injury (tbi) (herman , vespa ). continuous eeg (ceeg) is essential for detection of nonconvulsive seizures (claassen ) the university of california davis protocol for tbi includes ceeg on a case by case basis, which we reviewed. a retrospective review of patients admitted to icu for tbi from / / - / / was performed for demographics, icu length of stay (los), and ceeg. patients with ceeg were assessed for demographics, tbi severity, gcs, ceeg indication and findings. patients were identified. twenty-one were monitored on eeg. median age was , % were female. indications for ceeg included seizure prior to admission (n= ), altered mental status (ams) (n= ), ams with paroxysmal events (n= ). seizures were recorded in patients. median duration of ceeg was . , . , and . hours among the groups. those with seizures prior to hospitalization were connected to ceeg earliest (median . hours) but had the longest median icu los ( . hours), followed by ams ( . and . hours) and ams with paroxysmal events ( . and . hours). median gcs was , , and respectively. median los for patients without seizures or interictal epileptiform activity (iea) was . hours, . for those with iea only, and . for those with seizures. median gcs was . , , and among the eeg groupings. our data suggests seizures prior to hospitalization, ceeg recorded seizures, and iea predict longer icu los. associated lower gcs likely indicates more severe injuries. tbi patients with ams may have delay to seizure detection and treatment. our rate of seizure detection is lower than expected. a more consistent protocol for ceeg will likely improve seizure detection. prospective studies are needed to determine if ceeg can predict and influence outcomes. status epilepticus is a serious neurologic emergency. although many studies have been published on incident status epilepticus, there are few data on the risk of recurrent status epilepticus. we performed a retrospective cohort study using administrative claims data to identify all patients hospitalized with status epilepticus in california, new york, and florida between - . our primary outcome was a recurrent hospitalization for status epilepticus. survival statistics were used to calculate the cumulative rate of recurrence at days, year, and years. in subgroup analyses, we compared rates of recurrence according to age, gender, race, and etiology (stroke, traumatic brain injury, acute and chronic central nervous system (cns) infections, brain tumors, dementia, autoimmune cns disease, or unspecified etiology). we identified , patients with status epilepticus. during a mean follow-up of . (± . ) years, , ( . %; % ci, . - . %) developed recurrent status epilepticus. the cumulative rate of recurrence was . % ( % ci, . - . %) at days, . % ( % ci, . - . %) at year, and . % ( % ci, . - . %) at years. the -year cumulative rate of recurrence was . % ( % ci, . - . %) in women versus . % ( % ci, . - . %) in men, . % ( % ci, . - . % ( % ci, . - . %) in patients < , and . % ( % ci, . - . %) in white patients versus . % ( % ci, . %- . %) in non-white patients. the -year cumulative rate of recurrence was highest for status epilepticus associated with autoimmune cns disease ( . %; % ci, . - . %) and chronic cns infection ( . %; % ci, . - . %). approximately in patients with status epilepticus experienced a recurrent episode within years. recurrence was most often seen in younger patients, non-white patients, and patients with underlying autoimmune cns disease or chronic cns infection. super-refractory status epilepticus (srse) is a rare, life-threatening form of status epilepticus (se) refractory to multiple therapies including anesthetic third-line agents (tlas). enrollment in a srse clinical trial is challenging because patients may present urgently before srse is confirmed or may dynamically improve before randomization. pivotal clinical trials in srse require patient selection criteria accurately identifying srse at randomization. in this phase trial of brexanolone as adjunctive therapy for confirmed srse, the enrollment scheme enabled operationally confirming srse prior to randomization during a qualifying wean (qw) under real-time eeg neuromonitoring. informed consent was obtained for all subjects ) admitted in se having failed first-and second-line therapies; ) transferred on tlas in seizure-or burst-suppression; or ) transferred without seizure-or burst-suppression or not receiving tlas. subjects were required to achieve seizure-or burst-suppression for hours through continuous administration of one or more tlas, followed by a post-enrollment qw of tlas. enrolled subjects failing the qw were randomized to concomitant brexanolone or placebo following reinstitution of one or more tlas. subjects not randomized after a successful qw underwent a -week follow-up. the qw protocol and criteria for qw failure were developed and implemented utilizing eeg neuromonitoring to confirm srse after enrollment using the definition of shorvon and colleagues. a qw was performed on over evaluable subjects across international sites to enable enrollment of patients with confirmed srse. subjects with a successful qws who were not randomized provided insight into outcomes associated with se and avoided the randomization of patients who did not meet srse criteria following enrollment. the use of neuromonitoring-guided diagnosis during a structured qw helped confirm srse, facilitating the enrollment of appropriate patients into this phase trial in a rare, critically ill, and dynamic srse patient population. autoantibodies to the kda isoform of gulutamic acid decarboxylase (gad ab), commonly found in t dm patients, have been associated with drug resistant epilepsy. ketosis prone diabetes is a heterogenous syndrome encompassing various forms of beta cell dysfunction culminating in diabetic ketoacidosis. rates of epilepsy in patients with ketosis prone diabetes are not known. we compared the prevalence of epilepsy in patients with ketosis prone diabetes in a multi-ethnic population with the prevalence of epilepsy in the type diabetes population as well as the general population in a metropolitan medical center. our study design is prospective review of retrospectively collected sera of patients admitted for diabetic ketoacidosis (defined as ph < . , bicarb < , with ketonemia or ketonuria) for the presence of gad ab. all these sera were assessed separately for autoantibody presence or absence at dr hampe's lab in washington, seattle. we also reviewed patients medical records for neurological diagnoses. this done in a blinded fashion by two separate reviewers. out of our patients with ketosis prone diabetes, . % also had epilepsy. this is higher than the published rate in type diabetics ( . %) and the general population in the surrounding area (< . %). antibody testing revealed % of patients with ketosis prone diabetes were gad ab positive with a rate of epilepsy of %. a two-tailed t test between the gad ab + group and gad ab -group showed no statistically significant difference in prevalence of epilepsy in these two groups. while prevalence of epilepsy is higher in the ketosis prone diabetes population than the general population of houston, the difference is not related to titers of gad ab, and must be due to some other unknown factor in these patients management of refractory status epilepticus commonly involves the induction of seizure-or burstsuppression using anesthetic agents. however, the duration and endpoints of these therapies are not well defined. specifically, weaning anesthetic agents is complicated by the emergence of eeg patterns on the ictal-interictal continuum (iic), which have uncertain significance, given that iic patterns may worsen cerebral metabolism and oxygenation, have a dissociation between scalp and depth eeg recordings, and indicate a late stage of status epilepticus itself. determining the significance of iic patterns in the unique context of anesthetic weaning is important to prevent the potential for unnecessarily prolonging anesthetic coma. we identified a series of patients who underwent over hours of burst-suppression therapy, multiple weaning attempts, and continued weaning despite the initial emergence of iic patterns. patients who experienced anoxic brain injury were excluded from the series. we report cases of patients who underwent successful weaning despite initial emergence of iic patterns. eeg patterns following anesthetic weaning (including lateralized periodic discharges approaching hz frequency and lateralized rhythmic delta activity) as well as terminal eeg patterns are described in detail. in these patients, continuing weaning of anesthetic agents despite the emergence of iic patterns did not result in relapse to status epilepticus. while the metabolic impact of these patterns on brain activity is uncertain, weaning strategies that treat iic as a surrogate of recurrent status epilepticus risk further prolonging anesthetic management and its known toxicity. we speculate that iic patterns are transitional and may have a context-specific association with status epilepticus relapse, with less risk conferred when these patterns are observed during the weaning of anesthetic agents after prolonged burst-suppression therapy. other electrographic features aside from this clinical context may discriminate the risk of status epilepticus relapse, such as eeg background activity. brivaracetam (brv) is approved as adjunctive therapy for focal (partialyears) with epilepsy. brv is available as oral tablets, oral solution, and an intravenous (iv) formulation. the formulations are interchangeable. this abstract reports the safety and tolerability of iv brv. during clinical development, participants received iv brv. we report pooled safety findings from participants receiving brv - mg doses. the therapeutic range of brv is - mg twice daily. in n , healthy volunteers received iv brv as a -minute infusion or mg/min bolus ( , , , or mg single doses; n= in all groups). in ep (nct ), healthy volunteers received iv brv mg as a single -minute bolus injection or oral tablets. in n (nct ), patients received days of brv oral tablets mg twice daily or placebo, and then . days of iv brv mg twice daily either as a -minute bolus or -minute infusion for nine doses in total. treatment-emergent adverse event (teae) data were pooled. data reported are for iv brv - mg (n= ). most frequent teaes were somnolence . %, dizziness . %, fatigue . %, headache . %, dysgeusia . %, euphoric mood . %, feeling drunk . %, and infusion-site pain . %. infusion-site pain was specific to administration route. most teaes were mild or moderate and occurred mostly in healthy volunteers. iv brv was well tolerated, with an ae profile consistent with oral administration except for routespecific injection-site aes, dysgeusia, euphoric mood and feeling drunk. the interpretation of these data was complicated by the difficulty of pooling disparate studies involving healthy volunteers and epilepsy patients with heterogeneous medical histories and concomitant antiepileptic drug use. further clinical trials or real-world experience are needed to understand potential clinical impact. ucb pharma funded refractory status epilepticus (rse) is a challenging condition that requires multiple antiepileptic drugs (aed) to treat. during rse, the brain is under excessive excitation, which results in an increase in glutamate receptors such as alpha-amino- -hydroxy- -methyl- -isoxazolepropionic acid (ampa) and nmethyl-daspartate (nmda).. perampanel (per), a novel, noncompetitive ampa-receptor antagonist, may have a role in the treatment of rse and there are positive results in different animal models with rse. we identified adults patients over a month period who were treated with per for different forms of rse. one was excluded as the etiology of rse was anoxic brain injury and care was transitioned to comfort only within hours of initiating per. three patients had a definite response to per, which we defined as resolution of ictal patterns on electroencephalogram (eeg) within hours of per without adding a new aed. one had a possible response with significant improvement in eeg findings; however, there was some eeg improvement predating the initiation of per. in observed several treatment factors that may have increased response to per. those who responded had it used earlier in the treatment cascade (sixth or seventh vs. ninth or tenthaed ), higher initial dose ( mg vs mg), and were escalated to maximum dosage within hours. they were also more likely be receiving continuous ketamine and midazolam, suggesting a possible synergy with per. there were no documented adverse effects in any patient prior to discharge. one patient did experience a decline in phenytoin levels, which could be related to per as there are reports of enzyme-inducing properties. we observed efficacy of per in several patients with focal and generalized rse without a significant adverse effect profile. further studies are needed to clarify the dosing, timing and appropriate indications in rse treatment. topiramate is a potent broad-spectrum anti-epileptic drug (aed) with several mechanisms of action including blockage of the inotropic glutamatergic ampa receptor, voltage-gated sodium channels, antagonism of non-nmda glutamate receptors and enhancement of gaba mediated chloride conductance. we hypothesize that topiramate is an effective adjunctive therapy in rse and srse due to multiple mechanisms of action. we performed a retrospective analysis of patients admitted to the intensive care unit with status epilepticus (se) at a tertiary referral center from - . we reviewed demographics, age, seizure type, etiology, prior aed/topiramate exposure, time to response to treatment, eeg reports and neuroimaging results. rse was defined as failure of benzodiazepine and another conventional second line aed to stop se. srse was defined as se that continues or recurs hours after being treated with an anesthetic agent. ( %) were male, ( %) had a history of seizures; mean age of patients with se was . years. of treated patients, ( %) had focal non-convulsive se (ncse), ( %) had myoclonic se, had myoclonic, followed by generalized ncse, ( %) had generalized ncse, and ( %) had focal and generalized nonconvulsive se, prior to administration of topiramate. ( %) patients were treated with aeds, ( %) patients with aeds prior to topiramate. electrographic seizures improved in ( %) patients after receiving topiramate. resolution of electrographic seizures occurred within hours in ( %) patients, hours in ( %) patients, hours in ( %) patients and hours in ( %) patients. our findings suggest that topiramate could be an effective adjunctive treatment in rse and srse. however, prospective studies, including larger number of patients are needed to confirm these findings. patients with refractory status epilepticus (se) require multiple antiepileptic drugs (aeds) to abort seizures, and often barbiturates. there is a paucity of data on how to wean aeds safely once seizures are controlled while minimizing medication side-effects or withdrawal symptoms. a retrospective review of patients admitted to mayo clinic in rochester, minnesota for se between and was performed. patient demographics, se type (focal versus generalized, convulsive, and refractoriness), seizure etiology, aeds in admission and at outpatient follow-up, aed side effects from use and withdrawal, and functional outcomes in terms of modified rankin scale were recorded. of ( . %) patients had refractory se, ( . %) patients had refractory non-convulsive status epilepticus (ncse), ( . %) patients had convulsive se, ( . %) patients had ncse, and ( . %) patients had epilepsia partialis continua. of the patients with outpatient follow-up (ranging to weeks following hospital discharge with . % patients following-up within one month), patients were on an aed regardless of etiology. patients were on a median of aed in both refractory and nonrefractory se at follow-up. ( . %) patients had withdrawal seizures after aeds were weaned ( had a prior stroke, traumatic brain injury, idiopathic, multifactorial). none of the patients completely weaned off a barbiturate had seizure recurrence at follow-up. -month mortality in refractory se was / ( . %) and / ( . %) in non-refractory cases. favorable functional outcome at follow-up was achieved in / ( . %) patients with refractory se versus / ( . %) in non-refractory se. we found a low rate of late seizure recurrence after weaning aeds in refractory and non-refractory se, particularly in the case of barbiturates. spreading depolarizations (sd) are strongly associated with secondary brain injury after aneurysmal subarachnoid hemorrhage (sah). however, studies to understand whether sds play a causal role in secondary injury are hindered by existing sd induction methods which are invasive, cumbersome, and cause primary tissue injury. we developed a method to study the role of sds after experimental sah using commercially available transgenic optogenetic mice which express channelrhodopsin (chr ) in cortical neurons. we used in vivo laser speckle and doppler flowmetry, intrinsic signal imaging, and local field potential (lfp) and extracellular potassium shifts to detect sds. we optogenetically induced sds with light through intact and unaltered skull in multiple regions without causing primary brain injury. we found regional differences in thresholds for optogenetically-induced sds (from lowest to highest threshold): ( ) whisker barrel, ( ) motor, ( ) sensory, and ( ) visual cortex. lower thresholds were associated with higher chr tissue expression. changes in lfp and increased extracellular potassium concentrations at the site of stimulation preceded precipitation of an sd. finally, we induced and detected sds in the setting of sah over several days through chronically implanted glass coverslips non-invasive optogenetic light stimulation can reliably induce sds in the setting of sah. longitudinal optogenetic induction of sds in chr transgenic mice is a potentially useful tool to study the role of sds in the pathogenesis of secondary brain injury after sah. aneurysmal subarachnoid hemorrhage is a devastating neurologic injury with significantly prolonged hospital courses and high morbidity and mortality. when aneurysms are detected, they often require securement either via surgical clipping or endovascular techniques. a subset of intracranial aneurysms, given location, poor surgical approach, and wide neck are amenable to flow diversion which promotes thrombosis through redirecting of blood flow within an aneurysm leading to slow obliteration. approximately % of treated aneurysms with flow diversion do not obliterate after months, but currently there is no validated way to predict treatment failure. computational models of blood flow of flow diverted aneurysms predict a significant difference in the hemodynamic energy loss across aneurysms between cases that resolve and those that do not. energy loss could be estimated clinically during angiography, however, this hypothesis needs to be validated experimentally because computer models often over estimate hemodynamic parameters, poorly predict flow through stents, and may not have the resolution to fully describe intra-aneurysmal blood flow. in this pilot study, four cases of giant fusiform intracranial aneurysms will be selected --two with resolution following flow diversion treatment, and two without resolution. models of each vessel geometry will be fabricated using additive manufacturing techniques. under fluoroscopy, within the model vessel, flow diverting stents will be placed within the aneurysm in the same configuration that was achieved clinically. model blood, containing tracer particles will be pumped through model aneurysms and using particle image velocimetry, energy loss will be calculating within model vessels following treatment. energy loss between aneurysms successfully and unsuccessfully treated with flow diversion will be compared experimentally. hemodynamic energy loss may be a clinically measurable value which could predict treatment failure after flow diversion. additive manufacturing techniques can be used to test patient specific hemodynamics to improve understanding of flow-diversion treatment success or failure. the national institute of neurological disorders and stroke (ninds) and the national library of medicine (nlm) initiated development of unruptured cerebral aneurysms and subarachnoid hemorrhage (sah)specific common data elements (cdes) in as part of a joint project to develop data standards for funded neuroscience clinical research. through the development of these data standards, the ninds and nlm sah joint cde initiative strives to improve sah data collection by increasing efficiency, improving data quality, reducing study start-up time, facilitating data sharing/meta-analyses and helping educate new clinical investigators. the sah cde working group (wg) consisted of international members with varied fields of sahrelated expertise and was divided into domains such as subject characteristics and assessments and exams. the wg developed a set of sah-specific cde recommendations by selecting among, refining and adding to existing field-tested data elements, especially established stroke cdes. wg cde recommendations were drafted into the nih cde repository. following an internal review of recommendations, the sah cdes were vetted during a public review on the ninds website for weeks and later posted on nlm and ninds websites. version . of the sah cdes was available on the ninds cde website in april . these new sah cdes and recommendations include those developed for unruptured intracranial aneurysms and long-term therapies. the website provides uniform names and structures for each data element, as well as guidance documents and template case report forms using the cdes. the ninds encourages the use of cdes by the clinical research community in order to standardize the collection of research data across studies. the ninds cdes are a continually evolving resource, requiring updates as research advancements indicate. these newly developed sah cdes will serve to be a valuable starting point for researchers and facilitate streamlining and sharing data. subarachnoid hemorrhage (sah) represents % of stroke admissions in the us. aneurysmal hemorrhage represents the most dangerous etiology, however - % of sah have negative digital subtraction angiography (dsa). there is variation in practice with regards to repeat diagnostic studies and timing of such studies. it is not uncommon to repeat dsa in - days of the initial assessments. this study aims to describe the costs associated with prolonged icu stay and repeat diagnostic studies this patient cohort. retrospective review of all patients admitted for spontaneous sah between january and april at our single institution. patients with at least one negative initial angiogram for suspected spontaneous sah were included. patients were categorized into diffuse patterns of sah and nondiffuse. cost estimates were based on standard costs as provided by our financial department and cdc estimates for costs of hospital acquired infections. one hundred fifty-four patients were identified with initial negative dsa. second angiograms were performed in % of patients, and potentially positive causal findings in / ( . %). icu los for angiogram negative diffuse sah and non-diffuse were . and . days respectively. other indications for icu stay included vasospasm ( . %), evd placement ( . %), and intubation ( %). the excess cost estimates per patient for angiogram negative diffuse and non-diffuse sah were $ , and $ , respectively. hospital acquired complications were an additional total $ , for the cohort. this is the first study to our knowledge attempting a cost analysis of the diagnosis and management of patients with angiogram negative sah. we had a high frequency of patients requiring icu admission for other indications, which should continue to dictate the level of care. however, there may be a cohort of lower risk patients in which de-escalation would not harm, and be of benefit in the reduction of morbidity and cost. purpose: to evaluate the feasibility and potential role of bedside optical coherence tomography (oct) as a diagnostic protocol in terson's syndrome (ts) in patients with acute subarachnoid hemorrhage (asah). background: % of sah patients become permanently legally blind. the average cost of lifetime support and unpaid taxes for each blind person is approximately $ , . ts presents as ocular bleeding commonly associated with asah. it can be diagnosed by fundoscopy, yet retinal haemorrhages, detachments and macular holes may be undetected. early ts identification is critical since untreated it may lead to legal blindness, limit rehabilitation and impair quality of life. pilot study: sah patients were screened for ts with dilated fundoscopy and then with oct. mood assessments (phq- , hds), quality of life measures (nih-promis) and subjective visual function scales (vfq- ) were performed. there was a . % (n= ) incidence of ts. dilated retinal fundoscopy significantly failed to detect ts (n= , . % missed cases). ivh was significantly more in ts ( . % vs. %). no participants experienced any complications from oct examinations. neither decreased quality of life visual scores nor a depressed mood correlated with objective oct pathological findings at weeks follow-up after discharge. there were no significant mood differences between ts cases and controls. oct is the gold-standard in retinal disease diagnosis. this pilot study showcases its bedside feasibility in asah. in our series, oct was a safe procedure that enhanced ts detection by decreasing false negative/ inconclusive fundoscopic examinations. it allows early diagnosis of macular holes and severe retinal detachments, which require acute surgical therapy to prevent legal blindness. besides, oct aids ruling out potential false positive visual deficits in individuals with a depressed mood at follow up. a comprehensive study is underway to understand the impact oct might exert on blindness prevention and quality of life. fever is common in patients with aneurysmal subarachnoid hemorrhage (asah), and blood cultures are commonly sent to diagnose etiology. several studies have shown a low incidence of positive blood cultures, but no studies have assessed blood cultures in patients with asah. we performed a retrospective analysis of patients admitted with asah between january to december . blood cultures were adjudicated as true positive (tp) or false positive (fp) based on speciation, time to positivity, number of cultures positive, and repeat culture results. tp patients were compared to all other patients. age, gender, hunt hess, modified fisher, aneurysm treatment, incidence of delayed cerebral ischemia (dci), length of stay (los), and neurological outcomes were analyzed. patients with asah were included. blood cultures were sent on ( %). sixteen were positive. eleven were adjudicated tp and fp. thus, . % ( / ) of patients had true bacteremia, and blood culture yield for true infection was . % ( / ). fp rate was . % ( / ). eight tps were gram negative ( %), and all contaminants were staphylococcus non-aureus. median post-bleed day for tp results was . only patients were tp within the first week of admission ( . %). tp patients had higher admission wfns (p=. ) and ivh score (p=. ), but age, gender, aneurysm treatment, and fisher score did not differ. tp patients had longer icu and hospital los and higher incidence of dci ( % vs %, p=. ). mortality did not differ in the two groups either. the yield of blood cultures in asah patients is low. even with a contamination rate under %, % of positive blood cultures are fp. future studies should evaluate factors to identify patients at higher risk of bacteremia to reduce costs and improve care. intra-arterial verapamil therapy reduces cerebral vasospasm after aneurysmal subarachnoid hemorrhage (sah). there is little literature that quantitatively describes its safety, required dosing, or efficacy. as a result, therapeutic outcomes need to be subjectively analyzed by experienced radiologists during the intervention and clinically correlated by cerebral perfusion pressure, intracranial pressures and transcranial dopplers. we present a novel imaging analysis to quantify cerebral perfusion in realtime and apply this technology to patients undergoing therapy for vasospasm. we developed software to evaluate changes in contrast flow dynamics for digital subtraction angiography (dsa) scans performed pre-and post-intra-arterial therapy for vasospasm. performing signal intensity curve deconvolution on a voxel by voxel basis provides quantitative d perfusion parameters including: time to peak, time to drain, area under the curve, root mean transit time, arrival time, tissue concentration, arterial input functions and cerebral blood flow at each voxel. after aligning perfusion studies, our software then displays and automatically creates regions of interests for changes in perfusion to visualize the effects of interventions. our software quantitatively measures perfusion from dsas and can normalize two dsas accounting for differences in volume and speed of contrast administration. two applications of this technology are demonstrated. the first subtracts perfusion from pre-and post intra-arterial interventions quantifying exact changes in perfusion at each voxel. the second compares two dsa studies of the same patient at different dates to contour the territories susceptible to delayed cerebral ischemia. we compare this analysis to mri imaging when applicable demonstrating ischemic changes aligning to the susceptible territories outlined by our analysis. dsa based perfusion is an effective study to quantify the need for and the precise effects of endovascular interventions. quantitative thresholds and analysis based on dsa perfusion may assist with real-time assessment of treatment efficacy for patients undergoing intra-arterial verapamil therapy. we aim to characterize the clinical predictors of ventriculoperitoneal shunt (vps) placement in aneurysmal subarachnoid hemorrhage (asah) patients. there has been no clear consensus as to effective measures of predicting vps placement in these patients. we reviewed the clinical data of patients with aneurysmal subarachnoid hemorrhage (asah) who were treated at our institution between - . we eliminated patients who died or had withdrawal of care during admission. we recorded patient demographics and clinical predictors including admission/discharge glasgow coma scale (gcs), hunt hess score, aneurysm size/location, modified fischer score, modified rankin scale (mrs), intracranial pressure (icp) values during evd clamp trial, and incidence of vasospasm requiring intra-arterial therapy. there were patients included in this study and % of patients required vps (n= / ). vps patients had significantly worse mrs functional scores at discharge ( . vs . ; p= . ), but this began to balance at year ( . vs . ; p= . ). aneurysms were significantly larger in vps patients ( . cm vs . cm; ci: . to . ; p= . ). a greater percentage of vps patients had posterior fossa aneurysms, but this was not found to be statistically significant ( % vs %; p= . ). vps patients had significantly lower gcs scores at admission ( . vs . ; p= . ), and discharge ( . vs . ; p= . ). there was no difference in modified fischer score (p= . ) or hunt hess (p= . ), but both variables were higher in the vps cohort. there was no difference in the frequency of vasospasm in the vps cohort (p= . ), or icp values (p= . ). patients presenting with large aneurysms and poor gcs scores had a significantly higher likelihood of requiring vps during admission. these patients had significantly poorer mrs scores at discharge but not at year. subarachnoid hemorrhage (sah) affects a young population and results in death or disability in the majority of those who experience it. this epidemiology is very different from other forms of stroke. consequently, patients with sah and their families may have different priorities for recovery. involving patient perspectives is encouraged in research and is often accomplished using patient-reported outcome measures (proms). however, whether proms reflect patient and family priorities is unclear given that (a) proms are often developed without their input; and (b) generic proms may not apply to specific conditions. we aimed to systematically review the sah literature that has: a) involved patient, family or caregivers in evaluating existing outcome measures, b) developed novel outcome measures by incorporating their perspectives (including co-development), or c) described outcomes important to patients, families, or caregivers. we searched embase and ovid medline from inception to december , . study eligibility and data extraction was performed independently and in duplicate. for each eligible citation, we abstracted the following: study population, design, type of patient involvement, and outcome measure(s), as applicable. we planned a qualitative summary of all included studies. our search yielded unique citations. only four articles have met our eligibility criteria. in each, patients (n= ) self-report impairments resulting from sah and their impact on their lives (aim c). none involve the evaluation of prom applicability. additionally, we found articles that, although they did not meet our a priori eligibility criteria, discuss collecting proms (n= ), using proms to predict health outcomes (n= ), and comparing prom applicability without patient perspectives (n= ) in sah populations. based on our findings, there is alack of patient, family, or caregiver involvement in selecting or identifying outcomes after sah with direct relevance to them. sah research may be overlooking outcomes that are important to patients. early brain injury (ebi) after aneurysmal subarachnoid hemorrhage (asah) is defined as brain injury occurring within hours of aneurysmal rupture. although ebi is the most significant predictor of outcomes after asah, its underlying pathophysiology is not well understood. we hypothesize that ebi after asah is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes associations between cytokines. methods asah patients were enrolled into a prospective observational study and were assessed for markers of ebi: global cerebral edema (gce), subarachnoid hemorrhage early brain edema score (sebes), and huntassays to determine levels of pro-and anti-inflammatory cytokines. pairwise correlation coefficients between cytokines were represented as networks. cytokines levels and differences in correlation networks were compared between ebi groups. of the patients enrolled in t associated with high grade sebes. correlation network analysis suggests higher systematic inflammation conclusions ebi after sah is associated with increased levels of specific cytokines. peripheral levels of il , il and ession levels of individual cytokines may offer deeper insight into the underlying mechanisms related to ebi. few recent studies have evaluated health resource utilization and patient outcomes in aneurysmal subarachnoid hemorrhage (asah) in the united states. empirical evidence implicates asah as one of the highest cost diseases treated in the hospital. we identified asah patients to determine hospital charge, length of stay (los) and patient disposition associated with care in u.s. hospitals using claims data from the national inpatient sample (nis). patients within the international classification of disease, th revision (icd- ) diagnosis code were identified; a secondary analysis of the nis ( ) was conducted utilizing icd- clinical modification codes excluding patients with traumatic and non-aneurysmal sah. population size, patient outcome, average charge and average los were calculated using subgroups including: aneurysmal clipping or endovascular coiling (n= , ), aneurysmal clipping or coiling with external ventricular drain (evd) (n= , ), use of evd only (n= , ), other surgical procedures (n= ) and medically managed (n= , ). analyses were survey-weighted and adjusted for patient and hospital characteristics. in , asah resulted in an average per patient hospital charge of $ , , an average los of days, an average mortality of % and total, annual hospital charges of $ . billion. the highest average charge per patient ($ , ) and hospital los ( days) were attributed to clipped or coiled patients with evd, and highest mortality ( %) found in medically managed patients. these data support the conclusion that asah is a high cost illness managed in u.s. hospitals, and help raise awareness to the potential economic benefits resulting from developing safer, more effective therapies. additional analyses with updated datasets including lifetime burden of asah (e.g. physician fees, long term medical and care costs, hospital re-admission impact, quality of life, productivity loss, caregiver burden) should be explored to understand the full economic burden of asah and the potential cost effectiveness of new therapies. external ventricular drain (evd) placement is a mainstay of treatment for patients with aneurysmal subarachnoid hemorrhage with hydrocephalus or elevated intracranial pressures, but the optimal strategy for evd management is still unclear. the goal of this study was to compare the impact of evd clamping at three different levels on the duration of drain placement and the intensive care unit (icu) length of stay. we performed a retrospective analysis of patients admitted with aneurysmal subarachnoid hemorrhage to the neurological icu from december to january and included all patients who had an evd placed. patients who died were excluded from the study. patients were divided into three groups: patients whose evd was clamped at mmhg, patients whose evd was clamped at mmhg, and patients whose evd was clamped at mmhg. duration of drain placement in days and icu length of stay in days was compared among the groups using an analysis of variance (anova). outcomes were adjusted for presenting hunt-hess score, modified fisher grade, gender, and age. there were patients who had their evd clamped at mmhg, who had their evd clamped at mmhg, and who had their evd clamped at mmhg. there was no difference in duration of evd placement among the three groups (adjusted p-value . , unadjusted p-value . ) nor in icu length of stay (adjusted p-value . , unadjusted p-value . ). evd clamping at three different levels did not affect drain duration nor length of stay in icu. this study was limited by the small number of patients enrolled. further studies are need to clarify optimal strategies for evd management in the icu. headache is a presenting complaint in majority of patients with asah and is known to persist long after initial icu care. various medications have been used for control of headache with major emphasis on opiate use. history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder. we looked at prevalence of opiate use at discharge and its associated factors. chart review of all patients admitted in a tertiary care center between jan and march was carried out. along with baseline demographic data, information about use of pain scores, csf diversion, use of opiates, average morphine equivalent doses, use of opiates at discharge and destination at discharge was collected. analysis was carried out using microsoft excel. the study was approved by hospital irb. patients were admitted with asah in above period ( % female, average age: yrs). ( % home, % snf) survived to discharge. among survivors, % required csf diversion for hydrocephalus. all people complained of pain on presentation and were prescribed opiates during hospital stay. average oral morphine equivalent doses used was mg per day. ( %) patients were prescribed opiates on discharge. alternative regimens included ( patients: tricyclic antidepressant (tca), opiate + tca, acetaminophen, dexamethasone, tca and opiates). most common prescribed form of opiate was oxycodone. there was no significant association between opiate use/morphine dosing and age, gender, final disposition and csf diversion, opiate prescription at discharge is common in patients with asah. no clinical characteristic seem to predict analgesic need at discharge. little data exists about better alternatives leading to variety of treatment approaches. further controlled trials are needed to decrease opiate use and prevent adverse effects delayed cerebral ischemia (dci) in sah has been associated with vasospasm-dependent and vasospasmindependent phenomena. for more than years isolated hemostasis disorders have been reported in these patients. the objective of this systematic review is to describe the natural history of hemostasis in sah. we systematically reviewed the medline, embase, cochrane and lilacs databases using controlled language and the prisma statement and included studies on spontaneous sah analyzing any hemostasis parameter. we screened titles, of which observational were included. evidence was evaluated following the strobe statement. no meta-analysis was attempted because of the methodological nature and heterogeneity of the studies. hemostasis is profoundly altered during the first hours after bleeding, with several alterations noted including a hypercoagulable state concomitant with increased fibrinolysis activation and reduced clot stability. direct and indirect coagulation markers show a trend towards normalization of hemostasis in the first to days. platelet count decreases with a nadir to days after bleeding and a recovery in the following weeks. a later nadir is associated with dci. platelet aggregability is consistently decreased in the first few days, regaining its normal function around the second week after bleeding. in addition, the persistence of these alterations or the presence of a second peak in pro-coagulatory activity is associated consistently with dci and worse functional outcomes. the hyperacute phase of sah is characterized by a profound activation in hemostasis with reduced clot stability, probably due to an increase in the fibrinolytic pathways. on the second day post-bleeding, a slow trend towards normalization takes place, except in patients evolving towards dci. further research on the pharmacologic manipulation of hemostasis in sah might be warranted to decrease dci and improve outcomes in this population. hypertonic saline(hts) is a treatment for sah-related cerebral edema, administered to improve cerebral perfusion and reduce brain injury. hts a supra-physiological chloride concentration that can contribute to acute kidney injury which can lead to a poor outcome. in a previously published single-center cohort of , l sah patients, . % developed acute kidney injury (aki). hyperchloremia, but not hypernatremia, was correlated with an increased risk to develop aki (o.r. . ). aki was correlated with increased mortality. a secondary analysis of the aforementioned sah patient cohort ( ) ( ) ( ) ( ) ( ) ( ) , was analyzed. trends of acute kidney injury were evaluated in relation to the burden of exposure to intravenous chloride, as well as serum levels of sodium and chloride. the proportion of patients developing aki with a maximal serum chloride concentration of (p , will be randomized into one of two treatment groups: standard hypertonic saline solution (nacl . %) versus a solution of nacl/na-acetate. we hypothesize that by reducing the iv chloride burden(baseline compared to post randomization exposure), the delta serum chloride level will decrease, and will subsequently reduce aki occurrence (acetate trial, clinicaltrials.gov nct ). aki is common in sah patient population, and associated with worse outcomes. serum chloride concentrations are a significant risk factor for the development of aki. a prospective randomized clinical trial now underway examining the relationship between the hypertonic solution composition and serum chloride concentration, and to the development of acute kidney injury in aneurysmal sah. spontaneous spinal subarachnoid hemorrhage (ssah) is a rare but serious condition that can lead to a variety of medical complications. literature to this point primarily includes isolated case reports, and none have looked at hyponatremia as a complication. patients were identified from the electronic medical record database at the mayo clinic in rochester, minnesota. the advanced cohort explorer tool was used, searching from january to december . inclusion criteria were spinal subarachnoid blood products due to hemorrhage into the spinal subarachnoid space not due to ( ) redistribution of blood from intracranial subarachnoid hemorrhage, ( ) trauma, ( ) medical procedures, or ) predominant hematomyelia who experienced symptoms and received treatment at our facility. eight patients (median age years, range - ) were identified as meeting the study criteria. five of these eight patients experienced hyponatremia during hospitalization with a median value of meq/l. all of these patients were treated with free water restriction and one patient briefly received . % sodium chloride solution; in all cases the hyponatremia improved after free water restriction. in all cases the hyponatremia improved with fluid restriction, and there was no documentation of increased urine output, suggesting that it was likely due to siadh. cord compression and hyponatremia were present together in two patients, and in these cases treatment of the hyponatremia was particularly useful to avoid worsening edema. to our knowledge this is the first compilation of cases of spontaneous ssah highlighting hyponatremia as a complication. there is significant morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (sah) and only about % of patients survive and resume their previous lifestyle after - months. many randomized clinical trials (rcts) have been conducted yet no treatment definitively improves outcome from sah. outcome is strongly related to baseline factors, yet imbalances are common in early trials. we developed a technique to identify promising treatments at early phase using a pooled control arm model (ppredicts: kent, shah, mandava neurology ) that compares early studies at their own baselines. we applied this method to sah to develop a multi-dimensional model (ppredicts-sah). models for functional outcome and mortality (dependent variables) were developed based on baseline variables (eg: wfns grade - % and age) using methodology developed for ischemic stroke (mandava, kent, stroke ). the outcome model is a -dimensional surface bounded on either side by +/- . prediction interval surfaces. these prediction interval surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome. treatment arms from rcts and single arm trials, of various treatments of sah were compared against the pooled controlled arm. the best model fit was for good outcome (modified rankin score - equivalents) based on % patients with wfns - and age (r = . ; p< . ). seven trials of known negative drug tirilazad were superimposed on the model and fall within the +/- . prediction interval surfaces confirming futility. three trials were neutral and within the prediction interval surfaces while case series using implanted prolonged release nicardipine and a low dose heparin study were above the +p= . surface showing promise. models were also developed for mortality (r = . , p=. ). outcome models based on percentage of high grade wfns and age were successfully developed. this approach may be useful to prioritize treatments worthy of further study. oral nimodipine is recommended to improve outcome in treatment of aneurysmal subarachnoid hemorrhage (asah). fda approved nimodipine liquid oral solution (nos) in to reduce complications associated with administering nimodipine capsules (nc) to patients with impaired swallow. experience with nos at our center has been complicated by increased liquid bowel movements (lbm) prompting unnecessary testing for infectious diarrhea and exposure to invasive fecal management devices. study approved by local qualtiy improvement review committee. data was collected prospectively in consecutive patients diagnosed with asah during intensive care unit (icu) course. formulations of nimodipine available were generic nc (heritage pharmaceutical) and nos (arbor pharmaceuticals). we examined total icu days exposed to nos, icu days with lbm, infectious diarrhea investigations, and fecal management device use. all statistical tests were performed using minitab. patients were studied from / / to / / ; patients exposed to nos for icu days, icu days with lbm, infectious diarrhea investigations, and required fecal management devices. patients exposed to nc for icu days, icu days with lbm (all cases were also received nos), no infectious diarrhea investigations, and no fecal management device requirements. odds ratio for lbm with exposure to nos was . ( % ci . to . , p < . ). the high incidence of lbm with nos resulted in more infectious diarrhea testing and fecal management device use. uncontrolled diarrhea may increase risk for dehydration and delayed cerebral ischemia, although this is not explored in the current study. nos can mitigate risks associated with needle aspiration of nc, however these issues coupled with higher cost may limit benefit of its use. possible solutions may include compounding nc into a liquid formulation by pharmacists or pharmacy technicians. possible safety and cost benefits require further investigation. headache (ha) management after subarachnoid hemorrhage (sah) is challenging and lacks standardization. we hypothesized that inadequate inpatient ha pain management leads to the development of chronic ha (cha) after sah. prospective, observational study of non-traumatic hunt and hess (hh) grades i-iii sah patients admitted from / to / . after informed consent we recorded demographics, clinical and radiographic features, analgesic and steroid doses, hospital course and inpatient pain scores using numeric rating scale (nrs, - ) before (nrs-pre) and after each analgesic administration over post-bleed days - . a phone survey administered - months after admission evaluated cha burden. inpatient ha control effectiveness was evaluated by percent pain resolution from initial pain score, using nrs-pre. the percentage of administrations yielding full pain resolution was compared between those with and without cha. chi-square and t-tests were used for statistical analyses. patients, % female, mean age . ± . years with hh grade i ( / ), ii ( / ), and iii ( / ) sah were enrolled with lost to follow-up. at follow-up, . % patients ( / ) reported daily ha, . % ( / ) occasional ha, and % ( / ) no ha. full pain resolution after analgesic administration was associated with less cha ( [ . %] vs. [ . %], p= . ). mean daily inpatient opioid dose (morphine equivalents) for patients with and without cha was . mg and . mg, respectively (p= . ). mean nrs-pre were . vs . for patients with vs without cha, respectively (p= . ). inpatient analgesia for sah-related ha is inadequate and may be associated with the development of chronic ha. patients with cha had higher mean inpatient pain score and fewer analgesic administrations resulting in complete pain resolution. inpatient opioid dose per day was higher in cha group, although not statistically significant. additional research is needed to characterize the relationship between inpatient headache management and chronic headache after sah. subarachnoid hemorrhage (sah) remains a significant cause of neurological morbidity and mortality with few interventions to prevent delayed cerebral ischemia. hypocapnia has been associated with worse outcomes in brain injury. sah patients may be particularly susceptible to hypocapnia induced vasoconstriction. this study aims to describe the incidence of iatrogenic and spontaneous hyperventilation in sah patients. a descriptive analysis was performed on a retrospective cohort of adult sah patients admitted to beth israel deaconess medical center icus between and with gcs < who were treated with mechanical ventilation and an extraventricular drain, and had at least one abg. patients on chronic ventilator support were excluded. the lowest paco per icu day was analyzed. patients were included with days with at least one documented paco . mean gcs on admission was . (sd . ). . % of patients survived to hospital discharge. . % of patients were exposed to severe hypocapnia (paco mmhg, those with severe hypocapnia had similar pao and pao /fio ratios, but mildly increased leukocytosis ( . vs . ). . % of paco s < mmhg occurred during spontaneous ventilation or over-breathing. prior studies have shown that hypocapnia causes decreased brain tissue perfusion and is associated with worse outcomes in sah patients. these recent data demonstrate that severe hypocapnia is common in patients with sah severe enough to warrant intubation, and is associated with both iatrogenic and spontaneous hyperventilation. hypocapnia is not primarily compensatory or hypoxia driven, as suggested by mean ph and pao . confirmation of this association and potential future interventions require further study. although delirium is associated with higher rates of hospital complications among critical care patients, limited data exist on risk factors for delirium in aneurysmal subarachnoid hemorrhage (sah). a previous study identified older age, high hunt hess grade, intraventricular hemorrhage (ivh), and hydrocephalus as risk factors for delirium. we sought to identify risk factors for delirium during admission after sah. retrospective review was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study. baseline data and clinical complications during each admission, including delirium, were recorded. statistical analysis was performed using univariate and multivariate logistical regression. sah patients from july to january were reviewed. while age was not singly associated with delirium during icu admission, higher hunt hess grade, ivh, hydrocephalus, hospital-acquired infection, elevated troponin, and intubation were significantly associated with delirium on univariate analyses. upon stepwise multivariate logistic regression, ivh (or . , p= . ) and intubation (or . , p= . ) remained significantly associated with delirium. ivh and intubation predicts delirium during icu admission for sah. further analyses are needed to determine if the relationship between ivh and delirium is primarily explained by risk of hydrocephalus, risk of fever, medication exposure, or through independent mechanisms. stroke triage scales are very important in order to expedite acute evaluation, assure quick door to neuroimaging time and decrease door to needle time in patients with ischemic stroke eligible to intravenous thrombolysis. subarachnoid hemorrhage (sah) is associated with a high mortality in the acute phase due to a particular risk of early and devastating re-bleeding. therefore patients with sah also need urgent assessment. the performance of classic triage stroke scales in the identification of patients with sah was not previously evaluated. the objective of our work was to evaluate the performance of the los angeles prehospital stroke screen (lapss) in identifying patients with sah admitted to a tertiary hospital. we evaluated consecutive patients admitted to a tertiary hospital with sah from january to may . at hospital admission, lapss was applied by trained nurse personnel to all noncomatose patients with complaints suggestive of neurological disease. a total of with sah patients were evaluated (mean age . +/- . ), . % females). lapss was applied to patients. lapss was positive in only patients ( . %). patients with a positive lapss had higher nihss stroke score at admission ( , [ , ] versus , p< . ), lower glasgow coma scores ( [ , ] versus , p< . ) and a significant shorter door to neuroimaging time (p< . ). in patients with sah and mild symptoms, lapss was not a sensitive screening tool in our series. hospital and pre hospital services using lapss for triage of patients with stroke should be aware of this limitation and include in triage flowcharts specific questions evaluating sah specific symptoms. spontaneous subarachnoid hemorrhage (sah) is a neurological emergency, which despite current advances in management strategies and advent of institutional protocols, remains with significant rates of mortality due to poorly understood causes. our objectives were to characterize in-hospital mortality by evaluating the primary cause of death and externally validate the hair score, a clinical score that prognosticates mortality. in this retrospective cohort study, we reviewed all sah patients admitted to our neuro-icu between april , and march , . univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality, our primary outcome. to validate the hair score, the model's predictors were hunt and hess score at treatment decision, age, intraventricular hemorrhage, and re-bleeding within hours. discrimination was assessed by visualizing the receiver-operating curve and calculating the area under the curve (auc). among sah patients with a median age of years (interquartile range, - ), . % females, inhospital mortality was . % (n= ). of those, ( . %) had a neurological cause for death or withdrawal of care and ( . %) had a cardiac death. median time from sah to death was days. the main causes of death were the primary effects of the initial hemorrhage, re-bleeding and refractory edema. factors significantly associated with in-hospital mortality in the multivariate analysis were age, hunt and hess score, and intra-cerebral hemorrhage. maximum lumen size was also a significant risk factor among aneurysmal sah patients. the hair score had a satisfactory discriminative ability, with an auc of . . our in-hospital mortality is lower than previous reports, attesting to the continuing improvement of our protocolized subarachnoid hemorrhage care. the major causes are the same as previous reports. the hair score showed good discrimination and could be a useful tool for predicting mortality. so far, scientific and therapeutic efforts mainly focused on the prevention of rebleeding and ischemic complications(dci) in patients with subarachnoid hemorrhage(sah). however, data regarding the impact of parenchymatous hemorrhage(ph) on longterm outcome in these patients is limited. all consecutive patients with atraumatic sah admitted to our hospital over a -year-period( - ) were retrospectively analyzed. extent of sah as well as presence, localization and volume of ph were evaluated. functional and health outcome were assessed after months using the modified rankin scale (unfavorable: - ) and the eq- d. propensity-score(ps)-matching was performed to minimize potential bias due to confounding variables between sah-patients with and without ph. of overall patients with atraumatic sah, ( . %) patients had ph on initial imaging. ph-patients had a worse clinical condition on admission (wfns: ph ( - ) vs. Øph ( - );p< . ) and a greater extent of sah (modified fisher: ph ( - ) vs. Øph ( - );p= . ). median ph-volume was . ( . - . )ml with largest volumes in patients with ruptured )ml). after successful ps-matching (parameters: age, wfns, modified fisher and graeb score) patients with ph had worse functional and health outcome after months compared to those without ph (mrs - : ph / ( . %) vs. Øph / ( . %);p= . ; eq- d: ph ( - ) vs. Øph ( - ); p< . ). in multivariate analysis presence of ph was the strongest independent predictor of unfavorable outcome after months followed by the occurrence of dci (risk-ratio( %ci): ph . ( . - . ); p< . ). parenchymatous hemorrhage is frequent and associated with functional and subjective impairments in patients with atraumatic sah. aneurysmal subarachnoid hemorrhage (asah) is associated with early and delayed brain injury. insulin growth factor (igf ) is a potent cellular growth-promoting factor with demonstrated independent neuroprotective actions in stroke and neurologic disease but has not been well characterized after asah. this study sought to examine the relationship between plasma igf levels and outcomes after asah. this cohort of asah patients was . years (sd . ) and female ( %) with a mean hh ( %), wfns ( %) and fisher ( %). initial and peak plasma igf concentrations were measured in plasma samples from a banked biorepository using a commercial sandwich solid-phase elisa kit. delayed neurological deterioration (dnd) and delayed cerebral ischemia (dci) were determined using radiologic and clinical information. igf levels were log transformed due to non-normality. anova, t-tests, pearson correlations and logistic regression analyses were completed using spss and sas. older age was significantly associated with lower initial and peak plasma igf levels (r=. , p<. ; r=. , p<. ). men had higher initial and peak plasma igf levels than women (p<. ; p=. ), and premenopausal women had higher initial and peak plasma igf levels than post-menopausal women (p=. ; p=. ). lower peak plasma igf levels were associated with increased clinical severity by wfns (p=. ) and fisher grade (p=. ) as well as the development of dnd (p=. ; p=. ). lower peak igf levels were associated with the presence of dci (p=. ). controlling for age and fisher grade, log peak plasma igf levels remained significantly associated with the presence of dnd (p=. ; or . ; ci: . -. ) and dci (p=. ; or . ; ci: . - . ). igf levels have not been well characterized after asah. these results suggest lower plasma igf are associated with clinical severity and outcomes after asah and provide impetus for future work to further examine these relationships. induced hypertension (ih) is the mainstay of medical management for delayed cerebral ischemia (dci) after subarachnoid hemorrhage. however, using vasopressors to raise systemic blood pressure well above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (pres) has been increasingly recognized. however, the frequency and risk factors for ih-induced pres have never been systemically evaluated we identified patients treated with ih from sah patients admitted over a three-year period. pres was diagnosed based on clinical suspicion (i.e. unexplained deterioration), confirmed by imaging. we conducted retrospective extraction of data on ih therapy, including baseline and highest target mean arterial pressure (map) and vasopressor dose/duration. we compared those with pres to ihtreated controls and also described the clinical features and sequelae of all pres cases. five sah patients were diagnosed with pres, with median time from initiation of vasopressors to diagnosis of . days (range - days). baseline map did not differ between pres and ih controls, but highest target map was greater ( vs. mm hg, p= . ). magnitude of ih was similarly greater ( vs. mm hg above baseline, p= . ). all cases presented with lethargy, three had new focal deficits, and one had a seizure. one died from cardiac complications but the other four patients had complete resolution with ih discontinuation, without infarction or residual disability. pres was diagnosed in % of patients undergoing ih therapy and was most likely when map was raised well above baseline to levels exceeding the traditional limits of autoregulation ( - mm hg). high clinical suspicion for this reversible disorder appears warranted when aggressive ih targets are maintained for several days or in the presence of unexplained neurological deterioration. other interventions may be preferable for refractory dci when moderate degrees of ih have been attempted. patients with aneurysmal subarachnoid hemorrhage (asah) may receive significant exposure to potentially harmful ionizing radiation exposure (phire) from diagnostic tests and therapeutic procedures during their initial hospitalization. we hypothesized that risk factors to detect excessive phire are present at the time of admission. following irb approval, all patients admitted to our institution with documented asah over a -year period were retrospectively evaluated for inclusion and exclusion criteria. patients were excluded if they died prior to discharge. all study data, including sah-specific and patient-specific risk factors, were obtained from the electronic medical record. the total effective dose of ionizing radiation (tedir) per patient was calculated from previously published radiation exposure data. phire was considered to have occurred if tedir was greater than msv, the annual phire limit for radiation workers. logistic regression models were then fit to the dataset to evaluate clinical variables that significantly the risk of phire in these patients. data were collected from patients ( . % of all asah patients evaluated). the mean tedir in these patients was . msv. forty-two ( . %) of patients met criteria for phire. in multivariate logistic regression modeling, male gender (or= . , ci= . - . ), posterior circulation aneurysms (or= . , ci= . - . ) and ventriculostomy (or= . , ci= . - . ) were significantly associated with an increased risk of phire. in this study, approximately % of asah patients received phire. male gender, posterior circulation aneurysms and ventriculostomy were significantly associated with increased risk of phire. these factors may serve as important predictors of patients who require additional or complex care necessitating repeated diagnostic or therapeutic procedures during their hospitalization. alternative diagnostic or therapeutic modalities should be considered for patients with these risk factors to limit the risk of phire. future research should also evaluate the effect of phire on neurologic outcomes in these patients. it remains unclear whether patients with unruptured intracranial aneurysms (ica) should be treated. vessel wall enhancement (vwe) in high-resolution magnetic resonance vessel wall imaging constitutes a promising marker of aneurysm instability in this population. to find risk factors for aneurysm instability, we sought to identify predictors of vwe in patients with unruptured icas. we conducted a retrospective analysis of prospectively collected data on patients with unruptured ica evaluated by a single provider. all patients were evaluated using a previously validated algorithm to ascertain vwe using high-resolution magnetic resonance vessel wall imaging. two different raters, blinded to the study data, categorized all observed aneurysms as vwe-positive or vwe-negative. kappa statistics were used to evaluate the reproducibility of this approach. univariable and multivariate logistic regression modelling was utilized to identify factors associated with vwe after adjusting for potential confounders. patients with unruptured ica were included in the analysis (mean age [sd ] , female sex [ %]). of these, ( %) were vwe-positive and ( %) were vwe-negative. inter-rater reliability for vwe ascertainment was excellent (kappa . , %ci . , . ). out of ( %) patients presenting with cranial nerve palsy were vwe-positive. in univariable analysis, age (p= . ), headache on presentation (p= . ), and size (p< . , per additional millimeter) were associated with vwe-positive status. in multivariable analysis, headache on presentation (p= . ) and size (p= . ) remained independently associated with vwe. cranial nerve palsy is an established clinical marker of aneurysm instability; consequently, our results confirm the role of vwe as a marker of aneurysm instability. headache on presentation and aneurysm size are independently associated with vwe; these risk factors for aneurysm instability could be used to select patients with unruptured icas that may benefit from vessel wall imaging. prognostication in subarachnoid hemorrhage (sah) patients presenting in coma is crucial for surgical decision making. indications for aggressive aneurysmal treatment are unlikely for those not demonstrating signs of neurological improvement chronologically or after ventricular drainage. early neurological evaluation is, however, challenging in critically ill sah patients requiring anesthesia and intubation for airway protection. in this single-center retrospective study, we applied continuous amplitude-integrated eeg (aeeg) monitoring using a subhairline montage for wfns grade v patients who did not undergo emergency aneurysm treatment. monitoring was initiated soon after admission to the icu. patterns of aeeg findings were classified according to rundgren, et al. as follows: flat (f); suppression-burst (sb); electrographic status epilepticus (ese); and continuous (c). based on the aeeg findings, indications for aneurysm treatment were reevaluated. outcome was assessed at six months using the glasgow outcome scale. twenty-three patients, men and women, aged . ± . years (mean ± sd), were eligible since december . all patients underwent prophylactic intravenous sedation. the population represented % of all grade v patients including those resuscitated after cardiac (n= ) or respiratory (n= ) arrest. the glasgow coma scale scores were (n= ), (n= ), and (n= ), respectively. aneurysms were located in the posterior fossa in patients ( %). aeeg monitoring was initiated . ± . hours median . , . - . hours after arrival. all patients showing early f (n= ) or sb patterns (n= ) died. one patient demonstrated ese remained in a persistent vegetative state. five out of patients with a c pattern underwent aneurysm treatment; clippings and coil embolization. moderate disability was attained in and severe disability in . two patients undergoing conservative therapy died. continuous aeeg provided useful prognostic information for identifying salvageable sah patients undergoing sedation in the early phase. delayed cerebral ischemia (dci) may result in focal neurological deficits and cerebral infarction after subarachnoid hemorrhage. while global cerebral blood flow (cbf) may be variably reduced, dci is more likely related to regional impairments in cbf below critical perfusion thresholds. we applied volumetric methods to assess the proportion of brain exhibiting hypoperfusion (pbh) in those with clinical dci and in the symptomatic hemisphere of those with focal deficits. methods patients with aneurysmal sah underwent o-pet and ct imaging during period of risk for dci (median days after sah, iqr - ). we measured pbh as proportion of voxels with cbf < ml/ g/min, after excluding regions of infarction/hematoma on ct. we compared pbh in patients with vs. without dci at time of pet and, in those with focal deficits, we compared hypoperfusion between affected and unaffected hemispheres. pbh was greater in the ( %) with dci compared to those without dci ( %, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) p= . ) despite higher mean arterial pressure (map) and most being on active hemodynamic therapies. global cbf was also lower in those with dci ( . vs. . ml/ g/min, p= . ) but did not differ between those remaining symptomatic and those whose deficits had resolved. while mean hemispheric cbf was not lower in the affected hemispheres of with lateralizing deficits ( . vs. . ml/ g/min, p= . ), there was greater pbh in the symptomatic hemisphere ( % vs. %, p= . ). sah patients with dci have a greater proportion of brain with hypoperfusion despite active hemodynamic therapy and higher map. there was also larger proportion of the symptomatic hemisphere with hypoperfusion despite no asymmetry of hemispheric cbf. such measurements of hypoperfusion may better reflect the regional pathophysiology of dci than global averaged measures of cbf. further studies should determine whether burden of hypoperfusion correlates with tissue and patient outcomes. patients who survive aneurysmal subarachnoid hemorrhage (asah) are often burdened with lasting cognitive impairment due to a combination of sequelae including neuro-cardiac injury. the impact of neurocardiac injury after asah is poorly understood. this study sought to examine if neurocardiac injury detected by global longitudinal strain (gls) is associated with poor performance in neuropsychological np memory impairment after asah. we studied asah patients at months and at months (sahmii study r nr ) after hemorrhage. speckle tracking gls from apical views were assessed days - from bleed from transthoracic echocardiograms. neuropsychological (np) outcomes covering domains were completed at and months after hemorrhage by trained personnel. memory tests included controlled oral word association (cowa), wechsler memory scale (wms) and rey auditory (r-aud) and complex figure (reyc). anova and kruskal-wallis, pearson and spearman correlations and logistic regression were completed using spss and sas. there were ( %) patients with abnormal gls (defined as >- %) and ( %) in the and months groups respectively. gls groups had similar age, gender and fisher grade. abnormal gls was associated with higher hh at (p=. ) and (p=. ) months. abnormal gls was significantly associated with decreased performance in r-aud memory domains at months (p=. ) and months (p=. ) after asah and even when controlling for age and hh at months (p=. ). gls<- was associated with poor memory performance months after asah in cowa (p=. ) and the wms (p=. ) even after adjusting for age and hh, cowa (p=. ) and wms (. ). neuro-cardiac injury detected by gls was associated with decreased performance in memory domains of np function at and months after asah. while these relationships require further examination, neurocardiac injury may contribute to long term np impairment after asah. delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. we hypothesize that ketamine infusion (k), as compared to traditional sedatives (control), will safely improve the hemodynamic profile in high grade ventilated asah patients retrospective review of asah patients admitted / to / requiring mechanical delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. ventilation > hrs, and without dnr within hrs from admission. we assessed demographics, hemodynamics, pressor, dci at weeks, ventilator and icu los, and mortality. fisher exact, wilcoxon, and paired t-test applied. comparing k (n= ) vs control (n= ), median (q , q ) results for: age ( , ) vs ( , ); hunt and hess ( , ) vs. ( , ); mpm- day estimated mortality . % vs. . %; and gcs ( , ) vs ( , ) . ketamine initiated on day ( , ); icu los ( , ) vs. ( , ); and vent los ( , ) vs. ( , ) . mean (sd +/-) for hours before and after ketamine: map ( ) vs ( ), p . , except where noted. ketamine infusion, as a second line sedative, had no effect on mortality or icp, and improved map. however, there was a nonsignificant increase in dci as well as vent los, without a greater rate of tracheostomy. prospective studies are needed to study the effect on dci and long term outcomes. seizures are a well-known complication of aneurysmal subarachnoid hemorrhage(asah) and occur most commonly in the immediate post-hemorrhagic period. most commonly used antiepileptic drugs (aeds) for seizure prophylaxis in asah include phenytoin and levetiracetam. there is no reliable data available on the safety and efficacy of restricting aed prophylaxis only till the aneurysm is secured. we retrospectively chart reviewed patients admitted to our neurosciences intensive-care-unit with asah during the last two years. seizure incidence was studied in patients treated with phenytoin versus levetiracetam and in patients treated for to days versus those where aed was discontinued immediately after aneurysm was secured. in patients aed prophylaxis was discontinued immediately after the aneurysm was secured, and in patients it was continued for to days. of th phenytoin was used in patients and levetiracetam was used in patients. in patients receiving aed prophylaxis for to days, phenytoin was used in cases and levetiracetam was used in cases. none of these patients had seizures reported during hospitalization or at three month follow-up. stopping the aed prophylaxis immediately after aneurysm coiling is not associated with increased risk of seizures. seizures at presentation in patients with asah are not associated with development of epilepsy at months. both phenytoin and levetiracetam are well tolerated in patients with asah when limited to the immediate post-hemorrhagic period. the main preceding factor of delayed cerebral ischemia (dci) in asah is cerebral vasospasm (cvs). anticipating dci can have major impact on patient outcomes. studies have attempted to predict dci in patients with asah by using various imaging modalities that measure cvs, ranging from transcranial doppler ultrasonography, ctp, and mr perfusion. few compare these imaging modalities to the accepted gold standard of dsa. we propose that mri using asl imaging can be used as a sensitive and specific measure of cvs and can be used as a marker to identify patients with asah who are at risk for developing dci. to support our hypothesis, we compare asl results in patients with documented cvs on dsa who developed dci. patients in the academic years to with the diagnosis of asah were admitted to our nicu. the inclusion criteria for the patient population was the presence of asah confirmed by dsa, diagnosis of dci by a neurointensivist, mri with asl, and a repeated dsa during the hospitalization after dci was suspected. all patients underwent mra with asl on day in an attempt to capture the peak time of cvs. nine patients were included in this study. all cases with perfusion defects on asl sequences had confirmed cvs on dsa except for one. the outlier in our cohort developed dci with asymmetry on asl that was not demonstrated on dsa. to our knowledge, no studies have compared the specificity of asl with dsa in detecting cvs. this study highlights the utility of asl in detecting cvs in patients with asah. our limited data suggests asl can be utilized for detection of dci and cvs with greater confidence than the conventional modalities. we also suggest that asl approaches the utility of dsa in the detection of cvs. blood glucose dysregulation following aneurysmal subarachnoid hemorrhage is associated with serious complications and poor clinical outcome. an influence of hyperglycemia on the occurrence of delayed cerebral ischemia (dci) is assumed, nevertheless the exact mechanism remains unclear. the goal of the present study aims to investigate the influence of systemic blood glucose level on cerebral perfusion measured by dynamic perfusion computed tomography (pct) and outcome. daily serial blood glucose levels and pct data sets of patients treated at our neurointensive care unit after asah were retrospectively analyzed. serial pcts were performed between six hours and days after aneurysm repair. mean average of mean transit times (mtts) was calculated for each perfusion scan. the maximum mean transit time (maxmtt) and outcome assessed with glasgow outcome scale were correlated with defined blood glucose ranges as followed .) > mg/dl (hyperglycemia) .) - mg/dl (elevated glucose level) .) - mg/dl (strict glucose control) and < mg/dl (low glucose level). hyperglycemia (> mg/dl) was associated with prolonged maxmtt (p< . , rs = . ) and was linked to an increased risk of infarction (p < . ) whereas strict glucose control ( - mg/dl) correlated significantly negative with maxmtt (p < . , rs = -. ). strict glucose control was also associated with a lower occurrence of cerebral infarction and good outcome (p < . , rs = . ). in contrast, elevated blood glucose levels ( - mg/dl) and hyperglycemia showed a negative correlation with good outcome (p < . , rs = -. , rs = -. ). the present analysis supports for the first time the assumption that dysregulation of blood glucose balance influences cerebral perfusion and thus may contribute to the occurrence of dci and poor outcome. therefore careful monitoring and prompt treatment of blood glucose levels after asah should be highly valued to avoid cerebral perfusion deficits correlated with poor outcome. the aim of this study was to determine the correlation between transcranial doppler (tcd) velocities and angiographic vasospasm after subarachnoid hemorrhage (sah). methods patients with sah were evaluated with spencer technologies tcd power m mode from - days, following the sah. both the temporal windows were insonnated to determine flow velocities in the middle (mca) and anterior cerebral arteries (aca) and the suboccipital widow was used to determine flow velocities in the vertebral (va) and basilar arteries (ba). the middle cerebral artery/ipsilateral extracranial internal carotid artery velocity ratio (lindegaard ratio) was also correlated with vasospasm ct angiography and conventional cerebral angiography was used to confirm tcd findings suggestive of vasospasm. the sensitivity, specificity, likelihood ratios for positive and negative tcd results, positive there was males and females and with mean age . +- . years. % were aneurysmal sah. delayed ischemic neurological deficits (dind) developed in / patients ( . %). interobserver ue of cm/s were useful (likelihood ratio for negative result = . , likelihood ratio for positive result = . ). lindegaard ratios correlated well with vasospasm. tcd diagnosis of vasospasm was more often present in the mca, followed by aca and basilar arteries. tcd is a good non invasive method to detect vasospasm and predict the occurrence of dind. very high angiographic vasospasm. tcd is also useful to follow up patients with angiographically proved vasospasm. aneurysmal subarachnoid hemorrhage (asah) is a significant cause of morbidity and mortality. the mortality rate approaches %. nearly half of the survivors remain unable to care for themselves . dci occurs in % of these patients . when present, it doubles the risk of poor outcome. -several methods have been used to treat cerebral vasospasm and dci, which is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (sah). milrinone safe and, potentially, effective treatment of dci as reported in low level of evidence literature . however, the efficacy not compared in a randomized way to placebo. we will examine the effectiveness and safety of intra-venous injection of milrinone for the treatment of dci following aneurysmal sub-arachnoid haemorrhage. our intension is to study the outcome of using milrinone as an addition to current therapies such as hypertensive therapy are not effective enough, yet can not be replaced as it is standard of care. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. the study is a pilot trial of a randomized placebo-controlled double blind trial testing the potential beneficial effect of milrinone, a phosphodiesterase inhibitor, on clinical neurological outcome in patients with dci after aneurysmal subarachnoid hemorrhage. the study drug will be given along with the standard therapy when dci occurs. the administration of milrinone increases cerebral blood flow most likely as a result of cerebral vasodilation. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. milirinone promising treatment for delayed cerebral ischemia following aneurysmal sub-arachnoid haemorrhage .particulary by using standardized protocol as a finding suggestive of good prognosis fever in the neurocritical care population is very common and is strongly associated with increased mortality and poor outcome. fever is aggressively treated in the icu due to its deleterious effects. yet despite best efforts with standard antipyretic agents and even with aggressive cooling measures with endovascular cooling catheters some patients may still have refractory fevers. celecoxib, a cyclooxygenase- (cox- ) inhibitor, has been used as an adjunctive antipyretic agent. this is a retrospective analysis to evaluate the effectiveness of celecoxib in lowering temperatures in patients with refractory fevers. this is a retrospective chart review of patients admitted to a neurointensive care unit at a single institution with fevers (> . c) that do not respond to convention treatment with acetaminophen, endovascular cooling catheters and ibuprofen. patients with severe traumatic brain injury, subarachnoid hemorrhages and intracerebral hemorrhages were included. patient temperature recordings were obtained in the period of hours before and hours after administration to the first dose of celecoxib. the mean temperature of the before and after periods were compared and temperature difference was calculated. patient records were included. the average of the mean temperatures in the before periods and after periods were . c (+/-sem . ) and . c (+/-sem . respectively. there was a significant difference on mann-whitney-wilcoxon rank sum test (p< . ). one average there was a drop of . (+/-sem . ) degree celsius of the mean temperature after the start of treatment. in neurocritically ill patients with fevers that are refractory to conventional treatments adding celecoxib, a cox- inhibitor seems to be effective at lowering the core body temperature. further study is warranted to evaluate for adverse effects such as risk of cardiovascular events. achieving and maintaining normothermia (nt) after subarachnoid hemorrhage (sah) or intracerebral hemorrhage (ich) often requires temperature modulating devices (tmd). shivering is a common adverse effect of tmd's that can lead to further costs and complications. we evaluated a new esophageal tmd, the ensoetm (attune medical: chicago, il), to compare nt performance, shiver burden, and cost of shivering interventions with existing tmd's. patients with sah or ich and refractory fever were treated with the ensoetm. patient demographics, temperature data, shiver severity, and amount and costs of medication used for shiver management were prospectively collected. control patients who received other tmds were matched for age, gender, and body surface area (bsa) to ensoetm recipients and similar retrospective data was collected. all patients were mechanically-ventilated. fever burden was calculated as areas of curves of time spent above . or c. demographics, temperature data, and costs of ensoetm recipients were compared to recipients of other tmd's. eight ensoetm recipients and controls between october and november were analyzed. there were no differences between the two groups in demographics or patient characteristics. no difference was found in temperature at initiation (p = . ) and fever burden above °c (p = . ). ensoetm recipients showed a non-significant trend in taking longer to achieve nt than other tmd's (p = . ). ensoetm recipients required fewer shiver interventions than controls (p = . ). ensoetm recipients incurred fewer costs than controls per day (p = . ). the ensoetm achieved and maintained nt in sah and ich patients and was associated with less shivering and lower pharmaceutical costs than other tmd's. further studies in larger populations are needed to determine the ensoetm's efficacy in comparison to other tmd's. targeted temperature management is an important aspect of care in neurologically impaired patients. however, achieving optimum temperature for a specific patient can be challenging; a patient's size, body composition, metabolism, and hypothalamic function contribute to his or her response to a given temperature management modality. the purpose of this study is to evaluate patient response to esophageal temperature management when continuously applied for at least h. deidentified core temperature data for patients (a total of measurements) were obtained from three hospital sites where esophageal temperature management was used for at least h (range - h). indications for active temperature management included: cardiac arrest ( ), refractory fever ( ), subarachnoid hemorrhage ( ), intracranial hemorrhage ( ), and traumatic brain injury ( ). goal temperatures ranged from - °c and initial patient temperatures ranged from - °c. deviation from goal was calculated by subtracting target temperature from actual temperature for each measurement which allowed the calculation of the mean and standard deviation for each time point across all temperature management protocols. across time points, representing an average treatment time of . h, . % of mean deviations from goal were within ± °c and . % were within ± . °c. in interpreting these results, several limitations must be considered. this dataset reflects a wide range of temperature management protocols and clinical scenarios. for example, a larger than average deviation in measurements recorded in the - h period was related to rewarming in cardiac arrest patients who rewarmed slowly. also, the later time points were dominated by sah, ich, and refractory fever patients who often experience more pronounced fever spikes. this analysis indicates that esophageal temperature management is a feasible option for patients who require active temperature management for or more hours. the role of therapeutic temperature management (ttm) in neurocritical care is uncertain. one question that has been inadequately addressed is the diversity of practice across multiple neurocritical care units (nccu) throughout the world. a barrier to understanding this practice variance is a data collection method that would provide adequate understanding of how ttm is implemented in various nccus. the purpose of this pilot study is to test the efficacy of a data collection method that would provide unitlevel data on ttm practice. the design of this study was prospective, observational, and cross-sectional study using quality assurance methodology. the study received institutional review board approval. to reduce the risk of loss of confidentiality and promote privacy, individual patients were not consented. data on temperature management was collected each day for consecutive days. completed data was available for days. mean daily census of patients included the following mean number of patients with sah ( ), ich ( ), ischemic stroke ( ) and other ( ). of those, ttm was provided to at least one patient during of days ( . %). the most common ttm method (tylenol) was used on patient days; surface cooling was used on patient days. ttm was initiated for fever management ( patient days) and normothermia ( patient days). the most common associated complication was hypocalcemia ( ) and hypokalemia ( ). the data collection form was easily and quickly filled completed on a daily basis, but provides limited data. although the form captured a significant number of events surrounding the use of ttm, the primary limitation noted is the inability to link specific events (e.g., hypokalemia) to specific patients or diagnoses. this pilot study demonstrates the efficacy of data capture and provides insight towards refining a prospective observational study to describe ttm practice. brainstem tumors are exceedingly dangerous due to its proximity to the structures responsible for basic human survival in the neurocritical care setting. these lesions may cause autonomic dysregulation. we report on a rare case of a female with a past surgical history of ventriculoperitoneal shunt with a brainstem mass of müllerian type epithelial tissue. methods year old caucasian female presented to our hospital status-post fall after episodes of lightheadedness, as well as, episodes of decreased respirations in her sleep. mri showed a medullary contrast enhancing mass with calcifications measuring . x . x . cm and a small calcified lesion in the right lateral ventricle. suboccipital craniectomy for biopsy and decompression was performed. intraoperatively, the heart rate and blood pressure dropped transiently due to the mass being firmly adhered with calcification to the medulla. the neuropathologist diagnosed the tissue as mullerian type epithelium with estrogen receptors. post-operatively, our patient encountered several instances of cardiac pauses on monitoring that required the need for cardiology to place a permanent pacemaker. the above is a rare case of a calcified heterogeneously contrast enhancing brainstem mass that underwent neurosurgical biopsy. histopathology results indicated müllerian type epithelial tissue which is tissue that gives rise to female reproductive organs. the origin of a brainstem lesion from an embryologically gynecological site could be speculated to have traveled retrograde via the ventriculoperitoneal shunt catheter. patient required postoperative cardiac management and intervention with a pacemaker for encroachment or mechanical conflict of the mass onto the rostral ventrolateral medulla. oncology recommended pet ct scan and further consideration for tamoxifen chemotherapeutic regimen. this case is a reaffirmation of the importance of brain tumor location and tissue diagnosis for the purpose of adjuvant treatment of neurosurgical lesions in the neurocritical care setting. tranexamic acid (txa) has been used off label in cardiovascular and orthopedic surgery, as well as in trauma resuscitation. the use of txa has increased since the publication of crash- ( ) and matters ( ), demonstrating its efficacy in trauma patients to reduce bleeding. there remains concern about the thrombotic risk as well the reduction in the seizure threshold after txa administration. case description: we present a case of a -year-old female admitted to the surgical icu after a motor vehicle accident with multiple traumatic pelvic and extremity fractures and soft tissue injury. she subsequently developed extensive arterial and venous thromboses with bilateral acute ischemic strokes with superimposed posterior reversible encephalopathy syndrome after txa administration. a second case involved a -year-old female who had a fall from standing and given txa in the field by ems. shewas admitted to the neurocritical care unit with status epilepticus and suffered a complicated course with cardiogenic shock due to stress induced cardiomyopathy. discussion: the risk-benefit balance of txa administration is generally considered acceptable in severe bleeding. the cases presented here suggest the neurological risks of txa administration may be poorly understood and demonstrate the need for better patient selection and heightened awareness for early identification and management of complications given the possible severity of neurologic sequelae. conclusion: txa is an anti-plasmin drug that is increasingly used in the areas of trauma and postoperative bleeding. we aim to educate clinicians in the potential neurological complications that can arise with its use. cryptococcus neoformans is normally an opportunistic infection known to cause meningoencephalitis and can present with stroke like symptoms. in imaging, cns vasculitis can be identified, which can lead to cerebral infarcts. when involved, these cerebral vessels are small sized leading to lacunar infarcts. we present a case that involved a large vessel territory leading to patient mortality. initial treatment with glucocorticoids, though beneficial in other meningoencephalitidies, may actually be harmful in fungal cns infections. case: a year old male with a presents with weeks slurred speech and worsening headache. an enhancing lesion on brain mri in left temporal lobe was concerning for vasculitis. patient was treated with glucocorticoids, with a negative rheumatologic workup and discharged home. patient subsequently presented days later with worsening symptoms, with ct imaging showing completed infarcts. blood cultures were positive for cryptococcus neoformans; patient died due to diffuse right mca territory edema and brain herniation syndrome. discussion: it is important to consider cns infection even in immunocompetent patients who present with any of the following: fever, nuchal rigidity, mental status change, and headache. cns vasculitis in association with infection is caused by basilar meningeal exudates. these cause traversing vessels to become inflamed, leading to distal inflammation and subsequent thrombus and infarction. we present a right mca territory infarct , presumed to be based on the aforementioned vasculitic process. when acute infarcts are associated with opportunistic cns infections, they are usually not associated with large vessel infarction. we also examine the adjunctive use of glucocorticoid therapy for treatment of fungal cns infections. this is an infrequent case of cryptococcus neoformans causing a cns infection in an hiv-seronegative patient not on chronic immunosuppressive medications. this case presents a unique complication of cryptococcal infections, a cns vasculitis leading to infarction in a large vessel territory. we describe the baseline characteristics, continuous intravenous midazolam doses, seizure control, hospital course and outcomes in patients who received high dose continuous midazolam infusion for refractory status epilepticus in this retrospective case series study, we evaluated adult patients with refractory status epilepticus treated with high continuous intravenous midazolam doses in an academic neurocritical care unit between august and june . four patients were identified. the maximum midazolam dose for each patient was: withdrawal seizures (occurring within hours of discontinuation of continuous iv midazolam) occurred in patient b. "ultimate continuous iv midazolam failure" (patient requiring change to a different continuous intravenous antiepileptic drug despite maximum optimized dose) was not observed in any of the four patients. hospital complications occurred in patient a and b due to infections. hypotension related to continuous infusion midazolam occurred in patient a. three out of four patients discharged alive to a skilled nursing facility; after a goals of care discussion with the family, the fourth patient had withdrawal of care due to the severity of his brain injury. in this case series, we report the use of high dose continuous iv midazolam for treatment of refractory status epilepticus. there were no midazolam-related deaths. neurologic complications in infective endocarditis (ie) occur up to % and are independent predictors of mortality. infectious intracranial aneurysms known as "mycotic aneurysm" (ma) are rare constituting - %. hemorrhaging rate is %. mortality is % with rupture. ruptured ma poses significant management conundrum due to lack of available solid prospective data guiding the order (cardiac vs neurosurgical) or timing (early vs delayed) of surgery. a y/o male iv drug abuser presented with acute hypoxemic respiratory failure secondary to pneumonia and suspected meningitis. gsc intubated on iv antibiotic. hemodynamic instability prompted tee showing large aortic valve vegetation. blood cultures positive mssa fulfilled criteria for ie. tests showed kidneys infarctions. ct brain showed r mca territory infarct with sah.cta head revealed small ma along the distal r mca m branch confirmed with cerebral angiogram. acute heart failure and arrhythmia led discussion on cardiothoracic surgery for valve replacement. due to ruptured ma, decision to secure it was made prior to cardiac surgery. after failed endovascular intervention, patient underwent surgical clipping. post operative mri brain showed new infarcts suggesting recurrent embolization. due to risk of intracranial bleeding, cardiac surgery was postponed for at least weeks initially then to weeks. patient underwent avr after completed weeks of antimicrobial therapy with st jude mechanical valve and discharged on anticoagulation with a modified rankin scale of . this case reflects on how urgent surgical intervention should take place.safety period between neurological event and cardiac surgery is largely debated because of lack of controlled studies. there has been no consensus on how to approach those cases as paucity of robust evidence. given their rarity the best management modality remains unclear. this case stress the importance of multimodal therapy in achieving good outcome although the timing of surgery remains a matter of debate. we present a patient with vertebral cerebral artery embolism (cae) following blunt trauma. case presentation: a year-old male was admitted with a right vertebral artery dissection and occlusion with intraluminal air, widespread pneumocephalus, bilateral pneumothoraces, a pulmonary laceration, and multiple fractures including ribs, c transverse foramen (with normal alignment), and femur following a motor vehicle collision. his pupils were initially nonreactive, and he experienced one hour of witnessed generalized seizure activity on arrival despite aggressive treatment. management: midazolam infusion, levetiracetam, and fosphenytoin were initiated for seizure control. targeted temperature management to celsius was initiated on arrival out of concern for hypoxic brain injury. computed tomography at hours demonstrated resolution of vertebral and intracerebral air, diffuse edema, and diffuse loss of gray-white matter differentiation, thus a hypertonic saline infusion was initiated. the following day, an mri demonstrated diffusion restriction in the areas adjacent to the air, including c - and diffusely throughout bilateral cerebral hemispheres. prognosis was thought to be poor. however, the following day, the patient awoke. by day four he followed commands. he was discharged to skilled nursing on day . at three months he had only minimal residual right hip weakness. discussion: there are only three case reports of cae following blunt trauma, and only one involving the vertebral artery. air migrates to the arterial circulation due to a positive gradient from low central venous pressure or high airway pressure. pulmonary venous air then embolizes to cerebral vasculature. as little as ml of arterial air emboli can be fatal with the major cause of death being circulatory obstruction and arrest from air trapped in the right ventricular outflow tract. conclusion: this patient developed pneumocephalus and cae due to a pulmonary laceration. as the cerebral air reabsorbed, his seizures resolved and his exam improved. petrous ica aneurysms are extremely rare - and difficult to treat surgically, due to the inherent challenges of microsurgical access to the carotid canal of the petrous bone - . endovascular approaches may also prove challenging, typically as the consequence of therapeutically-unamenable morphology, but occasionally due to size considerations as well. a -year-old male presented with headache and vertigo for the past weeks. the patient was hivpositive with medication noncompliance and denied any history of trauma or head injury. head ct identified a . x . cm heterogeneous soft tissue density lesion in the right petrous bone. ct angiography revealed a . x . x . cm lobulated giant aneurysm of the right petrous ica. mri/mra was performed to rule out thrombosis and showed giant partially thrombosed right petrous ica aneurysm. the decision was made to treat using flow diversion. the patient underwent catheter angiography, confirming a giant x . cm right internal carotid artery petrous segment aneurysm. we proceeded with flow diversion pipeline endovascular device, placement of two pipeline endovascular devices (flex x and x ) successfully. final angiographic runs showed significant stasis within the aneurysm and demonstrated the flow-diverter construct was well placed both proximal and distal to the aneurysm neck with no sign of endovascular leak. the patient was discharged home well. we suggest that flow diversion is an ideal treatment for petrous ica aneurysms, specifically un-ruptured lesions of complex morphology. other options for treating petrous ica aneurysms challenging, not possible, less effective, and/or carry substantial risks. second, several of the disadvantages of pedocclusion of side vessel branches and preclusion of future coil embolization, do not apply to the petrous segment of the ica. lastly, use of ped in petrous ica aneurysms has proven effective in the vast majority of reports. the spot sign is a focus of enhancement within the hematoma on ct angiogram (cta) with unique characteristics. it has a spot-like appearance within the margin of a parenchymal hematoma without connection to an outside vessel. it should measure greater than . mm in diameter in at least one dimension. its contrast density (hounsfield units, hu) is at least double that of the background hematoma. finally, there should be no hyperdensity at the corresponding location on non-contrast ct. it is a strong predictor of hematoma expansion and poor prognosis in intra-parenchymal hemorrhage. the pathogenesis of spot sign remains unclear. some studies showed an association with faster rates of contrast leakage which indicates continued bleeding. a spot sign has not been reported with isolated intraventricular hemorrhage (ivh) before. a case report of a -year-old man with a past medical history of hypertension who got admitted to the er with acute encephalopathy and right-sided weakness. head ct-scan (hct) revealed isolated ivh. cta was notable for a spot sign. it measures . mm in diameter and hu in density (surrounding hematoma measures hu). it lies within the hematoma without connections to any adjacent vessel. a follow-up hct after four hours showed expansion of the ivh. although seems uncommon, looking for a spot sign in isolated ivh can also anticipate expansion of the hemorrhage. a further study is needed to validate this observation and calculate the prevalence of the spot sign in isolated ivh. west nile neuroinvasive disease may present with nonspecific physical exam and imaging findings. to our knowledge, this is the first report of wnnd involving the temporal lobe in adults with neuroimaging suggestive of limbic encephalitis. our patient presented in winter and developed autonomic instability and sensory deficits, which are all rare findings in wnnd. -year-old texan with dm presented with acute confusion and seizure in november. patient complained of headache, fever, diarrhea and lower extremity weakness after a fishing trip. patient was febrile with mosquito bites on his arms. neurological exam was significant for comatose state, absent brainstem and deep tendon reflexes, and flaccid paraparesis. he developed autonomic instability with labile blood pressures. lp revealed wbc/mm (monocyte predominance), rbc/mm , glucose mg/dl, elevated protein of mg/dl, and a positive west nile virus (wnv) igm antibody; gram stain, hcv pcr, and the paraneoplastic and autoimmune panels were negative. eeg showed severe diffuse brain slowing. mri brain had t flair and dwi changes in right hippocampus and posterior limb of internal capsule. emg described severe subacute sensorimotor axonal polyneuropathy without prolonged distal latencies and normal conduction velocities. he received days of ivig without improvement and was terminally extubated. our patient presented with both clinical entities of west nile: wn fever and wnnd (present in less than % of cases). our patient had axonal polyneuropathy with paralysis which is due to inflammatory changes in the white matter tracts affecting spinal sensory pathways. sympathetic ganglia involvement caused the autonomic instability, another very rare manifestation of wnnd. november presentation was due to warmer texas winter. recognize that west nile fever and west nile neuroinvasive disease may present together in winter. recognize that west nile neuroinvasive disease can present with rare temporal lobe neuroimaging, sensory involvement, and autonomic instability. intracerebral hemorrhage (ich) is a common pathology seen in the neurocritical care setting that can be associated with significant morbidity and mortality. the use of sympathomimetic agents containing phenylpropanolamine (ppa) have been associated with ich in the past which lead to the drugs' removal by the fda as an over the counter medication in . we report a case in which ppa was the etiology for a spontaneous ich in a patient who was taking an appetite suppressant. case report and review of the literature we report a case of a year old female with no prior medical history, who presented with sudden onset left sided hemiparesis and hemianesthesia found to be due to a right striatocapsular intraparenchymal hematoma. systolic blood pressures at presentation and throughout the hospital course were normal. extensive work up including multiple ct scans of the head, mri brain, ct angiography, mr angiography and digital subtraction angiography were performed with no evidence of any vessel abnormality. etiology of the ich was attributed to the use of ppa. in young patients with no known comorbidities, ppa use should be considered a primary etiology of ich when no intracranial vessel abnormality can be detected. seizures have been known to cause sudden death, but reports in the literature of only cardiopulmonary failure in cases of sudden unexpected death in epilepsy (sudep). we present the case of a patient who presented post-seizure and developed sudden progressive and fatal cerebral edema within hours after a second seizure. a year old female with a history of down syndrome and epilepsy presented to the emergency department after a prolonged convulsive seizure. she received doses of mg lorazepam and levatiracetam . mg/kg with cessation of seizure activity and return to baseline neurologic status within hours of the initial event. head ct showed lack of sulci throughout the cerebral hemispheres and basilar cistern effacement despite being at her baseline neurologic status. hours after presentation the patient had another seizure, vomited, was intubated and an additional mg/kg of levatiracetam given. hours after presentation, the patient was admitted to the neuroicu with absent brainstem reflexes and repeat head ct with worsened cerebral edema and tonsillar herniation. formal brain death testing was performed approximately hours after the patient's initial presentation. seizures are known to cause a hypermetabolic state in the brain. uncontrolled neuronal firing leads to hyperemia, failure of na+/k+ atp pump, increased levels of neuronal chloride, and inability for cells to maintain homeostasis. in this case, the patient's initial head ct showed cerebral edema, likely from prolonged seizure activity. once the second convulsive seizure occurred, a period of pre-intubation hypoxemia coupled with post-intubation hypotension allowed for progression of cerebral edema in an already compromised brain; similar to what is seen in post-cardiac arrest and traumatic brain injury. this case illustrates the importance of controlling for factors that can contribute to secondary brain injury in seizure patients. posterior reversible encephalopathy syndrome (pres) is a clinico-radiographic syndrome characterized by seizure, headache, encephalopathy and neuroimaging findings of symmetric white matter edema in the posterior cerebral hemispheres. cerebellar and brainstem involvement occurs rarely. here, we report a patient who presented with severe pres complicated by diffuse cerebellar edema and obstructive hydrocephalus requiring decompression with ventriculostomy placement. this is a case report from a tertiary medical center. a -year-old woman with a history of migraine presented to the emergency room with -day history of fever, right upper quadrant abdominal pain, nausea and vomiting. on day two of hospitalization, the patient developed worsening headache, dizziness and lethargy and her blood pressure was elevated to / mmhg. ct of the brain showed cerebellar edema and bilateral occipital lobes with effacement of the fourth ventricles and associated hydrocephalus involving the lateral and third ventricle. mri obtained post-operatively revealed t -weighted/flair diffuse hyperintensities in the parietal, occipital lobes and cerebellum. there was no mass lesion or restricted diffusion in diffusion weighted images (dwi) suggestive of acute infarction. cerebellar edema with compression of the fourth ventricles with hydrocephalus was slightly improved status post interval ventricular drain placement. ventriculostomy was weaned off over the course of seven days. follow up mri showed improvement of the hydrocephalus with decreased in t -weighted hyperintensities in posterior parietal and occipital lobes as well as within the cerebellum. severe cerebellar edema with obstructive hydrocephalus is an exceedingly rare complication of pres; however, prompt recognition and surgical decompression in addition to usual medical management is critical to achieve a favorable outcome. while obstructive hydrocephalus may be successfully treated with medical management and blood pressure reduction, this case emphasizes that clinical evidence of brain herniation should prompt immediate consideration for emergent ventriculostomy placement or surgical decompression to redirect cerebrospinal fluid and reduce intracranial pressure. one of the biggest uses of qeeg is the alpha delta ratio (adr). adr drops of % from baseline are associated with vasospasm (vsp/dind). we describe a case in which subtle qeeg adr change occurred in a poor grade sah patient over a number of days, making it challenging to detect an acute adr drop. this is a case report and literature review. this study also compared hemispheric adr values against the mca values by tcd, dsa, cta and clinical exam. a year old female with hunt hess iii, wfns iv, came in comatose with a ruptured ica aneurysm. over six days, she developed refractory vsp/dind. the patient's adr was gradually declining but their increased icp required propofol sedation, which itself lowers adr. re-analysis over multiple days had to be performed, and that re-analysis showed a gradual adr decline preceding the vsp/dind. when looking at our cases, we found a sensitivity and specificity of ( , %) when using the adr nadir compared to cta/dsa. recent publications have shown the adr method has less than ideal sensitivity and specificity of ( , %). qeeg adr is a useful multimodal monitoring parameter in neuroicu patients with relatively good baseline adr. however, its ability to detect vsp and dind in poor grade sah patients who have adr values that are already low (< . ) is challenging, particularly given the confounders in this population, such as eeg artifact which artificially raise adr values, and sedation (e.g., propofol) which suppress adr values. based on this information, we would suggest neuroicu centers carefully use continuous eeg monitoring for other indications such as nonconvulsive seizures, unless they have sophisticated bedside protocols about sedation vacation (baseline daily adr that is not) and eeg department resources (technicians who can fix eeg electrode artifacts). hypoxic-ischemic brain injury is a severe consequence of global cerebral hypoperfusion following cardiac arrest. brain ct findings may include diffuse sulcal effacement, loss of cisternal spaces, poor differentiation of grey/white matter, and decreased densities in the basal ganglia and watershed territories. the connection between aggressive resuscitation, as seen with in-hospital cardiac arrest, and cerebral edema is unclear. here we present the case of a hemodynamically unstable patient who developed transient reversible cerebral edema believed secondary to aggressive resuscitative efforts and pressor therapies. a year old female with a past medical history significant for diabetes and hypertension presented to the emergency department with headache and non-bilious vomiting. workup revealed isolated ventricular hemorrhage secondary to a ruptured left posterior inferior cerebellar artery (pica) aneurysm and cerebellar arteriovenous malformation, which underwent subsequent embolization. during her early hospital course she remained intubated due to pulmonary factors, but awake and alert with a non-focal neurologic examination. her course was subsequently complicated by a severe metabolic acidosis requiring several doses of bicarbonate boluses and continuous infusion, cvvhd, intravenous crystalloids, hydrocortisone and multiple pressors to maintain stability. over a hour period she received liters of volume while maintaining a mean arterial pressure above mm hg and o saturations above %, without requiring cpr. subsequent progressive encephalopathy developed, with a ct brain revealing diffuse sulcal effacement prompting hyperosmolar therapy. gradually her encephalopathy began to improve, with repeat imaging showing improvement of cerebral edema and return of grey/white matter differentiation. this case highlights a potential etiology of reversible cerebral edema that may confound early prognostication in patients with hemodynamic instability such as multi-organ failure and in-hospital cardiac arrest. further investigations are warranted. langerhans cell histiocytosis (lch) is a rare disease with an incidence of . - . cases per , children under years of age. frequency in adults is unknown. the hypothalamic-pituitary manifestations of lch (commonly diabetes insipidus) and hypernatremia are well known complications. here we present a case where a patient presented with poor mental status and the etiology remained unknown initially despite extensive testing. electronic medical record was reviewed regarding hospital course, sodium trends, and radiology images. this patient is a year old female with history of langerhans' cell histiocytosis with biopsy-confirmed suprasellar metastases (complicated by pan-hypopituitarism) who was transferred to our institution for hypernatremia and hydrocephalus. she had undergone two cycles of chemotherapy, most recently one week prior to presentation, and five rounds of radiation completed three months earlier. her presentation to the community hospital from a nursing facility was with unresponsiveness and she was intubated on arrival. her sodium was at that time; and had been three days prior. sodium was corrected from to over the course of four days with a drop from to within the first ten hours. her mental status improved to the point where she was awake and following commands; however still remained intubated. when she presented to our institution her sodium was and subsequently became unresponsive with a poor neurological exam limited to cranial nerve function only. she was evaluated with eeg monitoring and mri brain; however both were unrevealing for a cause. she had an external ventricular drain placed for concern for hydrocephalus that did not change her exam. one week later repeat mri brain revealed extrapontine myelinolysis. this case highlights the complications associated with intracranial lch and the need for repeat imaging in patients with rapid sodium correction to identify effects of osmotic demyelination. cangrelor is a rapid-acting, intravenous p y platelet receptor inhibitor with a plasma half-life of - minutes and full platelet recovery achieved within one hour after discontinuation. because it is rapidly reversible, cangrelor is commonly used to bridge patients with recent coronary stents to cabg surgery. oral p y inhibitors, such as clopidogrel, have a delayed onset and offset with platelet recovery occurring over - days, making their use challenging perioperatively or in the setting of an acute bleed. safety and efficacy data of cangrelor in noncoronary stents are lacking. we present two patients in whom cangrelor was used to maintain internal carotid artery (ica) stent patency acutely. both patients presented with an ischemic stroke secondary to acute occlusions of the left ica and left middle cerebral artery (mca) and were taken emergently to the neurointerventional suite for carotid artery stenting (cas) and mechanical embolectomy of the mca clot. heparin and eptifibatide were administered intraoperatively. post-procedure dynact demonstrated intracranial hemorrhage complications. dual antiplatelet therapy (dapt) with clopidogrel and aspirin, typically initiated following cas, was deferred given the difficulty of reversing their antiplatelet effect in hemorrhage expansion. instead, cangrelor was initiated to maintain carotid stent patency at . mcg/kg/min in one patient and . mcg/kg/min in the other patient and infused for . and hours, respectively. platelet reactivity was trended with the verifynow® assay and used to adjust cangrelor dosing. serial imaging was obtained to monitor hemorrhage expansion. one patient was transitioned to oral dapt and discharged while the other patient deteriorated neurologically from malignant cerebral edema and expired. cangrelor may be useful following cas complicated by intracranial hemorrhage when the need to maintain stent patency must be balanced with the risk of hemorrhage expansion. further research is warranted to determine its safety and efficacy in noncoronary stents. cerebral amyloid angiopathy (caa) although has been described in the literature, the different categories of this entity and its recognition and subsequent treatment are still elusive. it is important for neuro intensivists to recognize its variable presentation . we describe a single case report and perform a systemic review. caa depending on pathology can be categorized as inflammatory-caa where perivasculitis is seen on biopsy. this causes a non-destructive perivascular inflammatory infiltration and amyloid deposition pattern. on the other hand, amyloid beta related angitis (abra) results in a vasculitis and there is predominantly granulomatous angio-destructive inflammatory mediated disease affecting leptomeningeal and cortical vessels characterized by meningeal lymphocytosis and abundant amyloid-beta deposition within the vessel walls. caa on the other hand results in no inflammation of vessels but rather just deposition of amyloid deposition in the walls of vessels. we report a case of a year old man with an extensive cardiac history, who presented with syncope. initial computed tomography (ct) of head was negative. during admission, he acutely started having trouble answering questions including his name, and was unable to communicate his needs. repeat ct head showed hypodensity in left frontal region which was attributed to a stroke. he than developed complex partial seizures requiring intubation and seizure management. lumbar puncture showed mild pleocytosis. mri brain showed edematous changes of the left subcortical and deep white matter frontal lobe region which on repeat imaging subsequently worsened. biopsy was eventually performed which confirmed inflammatory cerebral amyloid angiopathy. he was treated with steroids and immunosuppression with gradual improvement. month follow up in clinic with continued improvement to independence. recognize the various subtypes of caa in their pathology, presentation and potential treatment. in acute emergency situations, intraosseous vascular access represents an alternative route of vascular access when peripheral vein insertion is difficult. we present the first documented case of intraosseous alteplase (tpa) administration in a patient with acute ischemic stroke symptoms. methods year old male with past medical history of hypertension, end stage renal disease, and diabetes mellitus presented to the hospital with sudden onset expressive aphasia and right sided numbness minutes prior to ed arrival. nihss was and code stroke was activated. patient blood pressure was / . ct head did not show any acute intracranial hemorrhage. it was decided to proceed with thrombolytic therapy. one peripheral venous access was obtained through which nicardipine drip was started to lower the blood pressure however second peripheral venous access was attempted multiple times but was unable to be obtained. tpa is more effective the faster it is administrated, and there was no known contraindications to administering tpa via intraosseous access (io). we report the first known case of successful and safe administration of fibrinolytic therapy through the intraosseous route in a patient with acute ischemic stroke symptoms. intraosseous access has been considered to be more invasive than intravenous (iv) and carries theoretical risk of bleeding however we were able to demonstrate tpa administration through io without any local or systemic complications. the bioavailability of alteplase through io access has not been studied however it is considered to be close to iv infusion in case of morphine and vasopressors. no studies negate or support the use of intraosseous access in stroke patients. contraindications are few and complications are uncommon. the findings of our case report suggest that intraosseous cannulation may be safely used for fibrinolysis in acute ischemic stroke patients with difficult peripheral venous access in in-hospital or out-of-hospital setting. tufts medical center, boston, massachusetts, usa we report a case of a pregnant patient with bilateral ovarian teratomas who presented with treatment refractory nmda receptor encephalitis despite removal of bilateral teratomas, successfully treated with rituximab. case report and discussion of treatment and outcome. year old weeks pregnant female with known ovarian cysts who presented with one week of confusion and subsequent status epilepticus. she was started on empiric treatment with ivig while undergoing workup. nmda receptor antibody was confirmed. left oophorectomy and right ovarian cystectomy were performed, both of which confirmed ovarian teratoma. she was given high dose steroids. her worsening condition prompted consideration of additional agents. plasma exchange and rituximab were initiated and then she was continued on rituximab alone. she improved dramatically over six weeks and delivered at full term via spontaneous vaginal delivery. at one year follow up, the child was healthy and meeting appropriate milestones. we report the use of rituximab for safe and successful treatment of nmda receptor encephalitis in a gravid female. neovascular glaucoma (nvg) is a known complication of carotid endarterectomy in patients with carotid stenosis. there are no previous reports of acute nvg refractory to medical treatment following carotid artery stenting (cas). we report a patient who needed surgical treatment for acute exacerbation of nvg following cas. a -year-old man with hypertension, diabetes, and hypercholesterolemia presented with recurrent transient weakness in his right hand. fifteen days before presentation, he had experienced acute loss of vision on the left side because of central retinal artery occlusion. magnetic resonance imaging of the brain was unremarkable. conventional angiography showed an occlusion of the left proximal internal carotid artery. ophthalmological evaluation before cas showed neovascularization of the iris and a normal intraocular pressure (iop) of mm hg in the left eye. cas was uneventful, but the following morning, the patient developed pain in the left eyeball with an iop of mm hg. anterior chamber paracentesis followed by intraocular injection of bevacizumab, panretinal photocoagulation, and medical treatment failed to reduce the iop below - mm hg. eighteen days following cas, an ahmed glaucoma valve was implanted in the left eye to treat the refractory nvg. iop decreased to mmhg and his ocular pain resolved completely post implantation. although nvg is a rare complication of cas, it should be suspected in patients who develop acute ocular pain following cas. nvg may respond to anterior chamber paracentesis, panretinal photocoagulation, and bevacizumab, but surgical treatment, such as implantation of an ahmed glaucoma valve, should be considered in cases with refractory nvg. background: cerebral amyloid angiopathy is a common cause of spontaneous lobar intracerebral hemorrhage. convexal subarachnoid hemorrhage can be a manifestation of cerebral amyloid angiopathy. whether focal amyloid burden predicts future hemorrhage is unclear. case: an -year-old man presented with transient left arm weakness and paresthesias in the setting of previous cognitive decline. mri showed a convexal subarachnoid hemorrhage of the right central sulcus, as well as susceptibility weighted imaging findings consistent with superficial siderosis. lumbar puncture revealed normal cell count with a mildly elevated protein. he had spontaneous resolution of his symptoms after several hours. one year later he presented with sudden onset confusion and imaging again showed a convexal subarachnoid hemorrhage over the posterior right frontal lobe. susceptibility weighted mri revealed hemosiderin over the right posterior frontal and anterior parietal lobes. an amyloid-pet, obtained one year prior to his first spell as a research participant, demonstrated asymmetric amyloid deposition in the right temporo-parietal region. years after his initial episode he presented again with confusion, headache, and decreased level of alertness. a ct scan demonstrated a right-sided temporo-parietal intracerebral hemorrhage in the area of asymmetric amyloid deposition on pet. his family opted for comfort measures only, and he was discharged to hospice. autopsy revealed severe amyloid angiopathy, as well as alzheimer disease, braak stage vi. discussion: this case illustrates the clinical course of a patient with amyloid angiopathy, including recurrent convexal subarachnoid hemorrhages, and superficial siderosis. of importance, the amyloid pet scan predicted the location of his intracerebral hemorrhage years later. the case of a -year-old man, presenting with a past medical history of migraine headaches, dipola, vertigo, with symptoms later progressing to lethargy and confusion for days. brain mri revealed a peripherally enhancing mass within the left thalamus with central restricted diffusion, which is consistent with a cerebral abscess. case report of congenital heart disease when discovered in adulthood is an interesting entity, especially when it is the source of brain abscesses. detailed history taking, physical examination and appropriate imaging can usually reveal the anomaly. the diagnosis of brain abscess should promote the clinician to consider right to left shunts as a possible predisposing condition for brain abscess management of acute cerebral embolism in patients with implanted ventricular assist devices (vads) is particularly challenging, since chronic anticoagulation often precludes the use of intravenous tissue plasminogen activator (iv-tpa). we describe a vad patient who suffered cerebral embolization, and was successfully treated with thrombectomy, emphasizing the nuances particular to this clinical scenario in the context of limited historical experience. a year-old man with heart failure (ejection fraction %) and heartware ii vad implantation about months prior, was found at the scene of a car accident with expressive aphasia, right homonymous hemianopia, extinction and right hemiplegia, with a national institutes of health stroke scale (nihss) score of . upon arrival, his ct was unremarkable, but cta revealed occlusion of the left middle cerebral artery (m segment). since his inr was . , he underwent emergent thrombectomy with the solitaire device, resulting in complete revascularization (tici = ) minutes from onset, with rapid deficit resolution (nihss = ). the procedural and clinical success was accompanied by lack of evidence of infarction in subsequent ct studies, and a modified rankin score of upon discharge. the removed thrombus displayed early organization, suggesting unexpected firmness, and underscoring the potential importance of mechanical removal rather than chemical lysis in vad patients. our case has attributes that set it apart from those previously reported: ) the use of a hybrid (i.e. retrieval plus aspiration) endovascular retrieval technique, ) the lack of concurrent use of thrombolytic drugs, and ) the rapid, sustained and optimal clinical improvement. the utilization of vads continues to grow, yet the literature regarding endovascular techniques for managing these types of patients remain scarce. however, the increasing availability of centers capable of delivering this type of treatment, suggests that thrombectomy should be strongly considered in vad patients with acute cerebral embolism. extreme cerebral oxygen changes has not been reported via monitoring of partial brain tissue oxygen levels. here we present an asah patient with brain tissue oxygen (pbto ) monitoring, who developed cerebral hypoxia due to cerebral vasospasm, then went on to develop cerebral hyperoxia with associated cerebral infarction. methods yo female with hh fg sah with initial gcs of t underwent coiling of a ruptured basilar tip aneurysm. a pbto monitor was inserted to guide therapy. this patient had multiple episodes of low pbto ( mmhg). this corresponded to infarction on follow up head ct and mri with preservation of local arterial vessels on mra, consistent with diagnosis of dci. in the present case, high pbto is more likely resulted from a combined effect of ) increased cbf from co-administration of ketamine at the time of milrinone infusion; ) decreased cerebral metabolic demands in already infarcted left frontal lobe, resulting in reduced oxygen uptake; ) accelerated reperfusion and thus hyperemia with milrinone. restoration of flow with milrinone may have been too late to reverse the prolonged period of vasospasm induced ischemia, resulting in perfusion of infarcted tissue, or luxury perfusion. clinicians utilizing pbto monitoring for dci management should be cautious of high pbto values, as it may herald cerebral infarction. further studies are needed to better elucidate the mechanism of reperfusion injury and potential treatments. patients with acute brain injury, especially those with intracranial hemorrhages are at a higher risk for hemorrhage while on therapeutic anticoagulation. unfractionated heparin (ufh) is frequently used as it is easily reversible and has a short half-life. activated partial thromboplastin time (aptt) is traditionally used to monitor its effect. several disadvantages with aptt monitoring include inability to reach therapeutic goal, over-or under-dosing and its associated complications. anti-xa level is reported to have better correlation with actual degree of anticoagulation using ufh. retrospective chart review of patients with acute brain injury who required initiation of early therapeutic anticoagulation and monitored with anti-xa level. case - year-old-man with intracerebral hemorrhage (ich) developed lower extremity deep vein thrombosis (dvt) and required therapeutic anticoagulation. patient became therapeutic within six hours of titrating infusion based of anti-xa levels and remained therapeutic. asymptomatic rectal bleeding associated with fecal management system was noted. case - year-old-man with cerebral venous sinus thrombosis presented required therapeutic anticoagulation. ufh infusion was initially monitored using aptt levels which had widely varied lab results, thus monitoring was switched to anti-xa levels which provided a more consistent therapeutic range. however, patient developed thrombocytopenia in the setting of inflammatory bowel disease. therefore, ufh infusion was changed to argatroban infusion. case - year-old-man with lower medullary acute ischemic stroke due vertebral artery dissection required therapeutic anticoagulation to prevent recurrence. patient became therapeutic within hours of titrating based of anti-xa levels. to monitor therapeutic anticoagulation, anti-xa level appears to achieve target anticoagulation level faster and without serial variation as compared to aptt. however, anti-xa level estimation is costlier as compared to aptt and not widely available. by restricting it to special populations like those with acute brain injury might justify its use and underscore cost-effectiveness. neurological admissions presenting to the icu benefit from a dedicated neurocritical care team but many community hospitals lack this subspecialty expertise. with an aging population and a neurointensivist shortage, more patients are transferred to designated neurocritical care units which increases healthcare spending and resource utilization. recognizing this obstacle, we describe the management of a patient in status epilepticus via our novel "eneuro-icu" consult program in which a 'sub-hub' of the northwell health tele-icu was set up at the only hospital out of in our health system that is staffed / by neurointensivists. a -year-old man with history of a left frontal meningioma presented with multiple seizures to a hospital within our healthcare system. he received mg of lorazepam and levetiracitam in the emergency department and was admitted to the icu for further monitoring. there he was witnessed to have recurrence of clinical activity concerning for ongoing seizure. levetiracitam was increased and phenytoin was added. neither immediate neurological consult nor continuous eeg was available, thus an "eneuro-icu" consult was obtained. in this model, the bedside provider contacts the tele-icu that facilitates a conference call with the neurointensivist. av technology was used to provide consultations and follow ups. the neurointensivist determined the patient was rapidly returning to baseline and recommended a head ct, lab studies and continuation of the anti-epileptic drugs. the eicu team monitored the patient overnight. by leveraging the infrastructure in place for management of critically ill patients remotely, an additional level of subspecialty care was offered in a timely manner and allowed the patient to remain at their local facility. based on the success of the initial program we are currently in the process of extending the virtual consult service to various community hospitals' eds/icus to improve outcomes for patients who would benefit from neurocritical care services. hypoglycemic encephalopathy is a potentially life-threatening manifestation of hypoglycemia, it is usually caused by metabolic change, hypoglycemic agents, and malignancy. here, we report a patient with hypoglycemic encephalopathy caused by sleeve gastrectomy a -year-old woman was admitted due to unconsciousness of acute onset. she showed normal corneal and vestibulo-ocular reflex but sluggish pupil light reflex and decerebrated posture by painful stimulation. she has taken severe medications for weight control including orthosiphon powder and hydrochlorothiazide after bariatric surgery. laboratory studies showed significantly low blood glucose level ( mg/dl) with normal liver enzyme and creatinine. there was no evidence of adrenal insufficiency. electroencephalography showed no epileptiform discharge. initial and follow-up brain magnetic resonance imaging revealed diffuse high signal intensity on white matter expanded to cortex, corpus callosum and posterior limb of the left internal capsule, suggesting hypoglycemic encephalopathy. in abdomen-pelvic ct, there is no mass lesion like carcinomas or insulinoma. the clinical diagnosis of hypoglycemic encephalopathy followed by sleeve gastrectomy was made by given history of bariatric surgery and the lack of evidence of hypoglycemic agent overdose, adrenal insufficiency, endogenous hyperinsulinism or malignancy. there are several hypotheses that sleeve gastrectomy can encourage hypertrophy of beta cells, hypersecretion of glucagon-like peptide, glucagon abnormality and increased insulin sensitivity, that may induce hypoglycemia. we suggest that clinicians should consider sleeve gastrectomy itself as a possible cause of profound hypoglycemia pulmonary embolism (pe) is a fatal complication in neurological conditions with plegic extremities. clinical presentations and supportive testing can be variable. we present a case of pe which presented with st segment elevations weeks after spontaneous intracerebral hemorrhage (sich). case report and review of the literature we present a case of a year old female with a history of a recent sich with resultant left hemiplegia who presented with a syncopal episode and chest pain. on physical examination, she was noted to be tachypneic and tachycardic with an unchanged neurological exam. pulmonary embolism can present with a variety of ekg abnormalities including st elevations after sich and the treating physician should be aware of these idiosyncrasies. anticoagulation should be cautiously initiated in such cases. infectious intracranial aneurysms (iia) are rare neurovascular lesions associated with infective endocarditis. we present a case of a large iia which developed within hours of a negative ct angiogram and ruptured despite weeks of appropriate antibiotic treatment. a year-old woman presented with fevers and malaise. her initial workup revealed an aortic valve mass and blood cultures grew out streptococcus. three days after intravenous penicillin therapy was initiated for bacterial endocarditis, she developed a new headache and right hemianopsia. a head ct demonstrated a left occipital lobe stroke with hemorrhagic transformation. further workup with ct angiography revealed a mm outpouching along of the distal branch of the left pca, consistent with an infectious intracranial aneurysm. on repeat imaging, this aneurysm demonstrated growth despite medical treatment, and required coil embolization/occlusion. aortic valve replacement was planned after weeks of antibiotic therapy because of continued severe aortic insufficiency and persistent valve vegetation. on the day of surgery, she developed acute word-finding difficulty followed by a rapid neurologic deterioration resulting in coma. a head ct demonstrated a new left frontal intraparenchymal and subarachnoid hemorrhage associated with the rupture of an mm x mm irregularly shaped aneurysm in the region of the left mca bifurcation, which had been absent on a prior surveillance ct angiography just hours prior. she underwent emergent coil embolization, extraventricular drain placement, and decompressive hemicraniectomy. despite these measures, her exam did not improve. she was transitioned to comfort measures and life-sustaining therapies were withdrawn. the development of iia can occur despite appropriate medical treatment. these aneurysms may rapidly expand and rupture within hours, as shown by our case. even with prior exonerating imaging, clinicians should have a high suspicion for iia development in all infective endocarditis patients. the corneomandibular reflex, also known as wartenburg reflex or von solder phenomenon, is a rare pathological reflex signifying severe supranuclear trigeminal injury. it presents as contralateral jaw deviation to corneal stimulation. etiologies include upper brainstem lesions, large hemispheric lesions with brainstem compression, as well as advanced amyotrophic lateral sclerosis and multiple sclerosis when corticobulbar pathways are affected. this clinical finding is useful in differentiating structural and metabolic causes of coma, as this examination finding would not be present in metabolic phenomena. a middle aged man presents with a hypertensive right thalamic hemorrhage and a four score of e m b r . the patient's cornea was stimulated with a cotton swab. the cornea was tested bilaterally to determine any lateralizing features. recording on video was performed with patient's family written consent as patient was comatose. upon stimulation of the patient's cornea a contralateral jaw jerk was appreciated. this was replicated contralaterally. this case describes a common patient with a rare physical examination finding. there is utility in recognizing this finding as it will aid in determination of the underlying cause of a comatose state. the corneomandibular reflex present at presentation rules out a metabolic cause. a structural cause was validated by imaging studies (shown). the reflex arc was researched and has been independently artistically rendered (shown), which demonstrates the pathway beginning with the afferent limb of the corneal stimulus (v ) which travels to the main trigeminal sensory nucleus via the trigeminal ganglion. severe supranuclear trigeminal lesions will inhibit inhibitory interneurons within the mesencephalic nucleus, leading to activation of the motor nucleus of the trigeminal nerve. this causes activation of the ipsilateral external pterygoid muscle which produces a contralateral jaw jerk. overall this patient fared poorly and expired several days after admission. pneumocephalus is when air enters and is contained inside the intracranial compartment. when intracranial pressure increases causing neurological decline, patients can experience nausea, vomiting, seizures, dizziness, and altered mental status. here we present three cases of postoperative pneumocephalus which resolved quickly with humidified oxygen delivery via high-flow nasal cannula. we follow the cases with a review of the mechanisms and pathophysiology of pneumocephalus and its treatment, as well as future directions in management. case series of patients with post-operative pneumocephalus who were treated with high-flow nasal cannula. case describes a -year-old woman who underwent hemicraniotomy for removal of meningiomas, with focal postoperative neurological signs and mm of midline shift on head ct due to pneumocephalus. case describes a -year-old woman who underwent right anterior temporal lobectomy for seizures, who developed postoperative focal prefrontal lobe signs and mount fuji sign on head ct. case describes a -year-old man with bilateral subdural hematomas, status post bilateral burr hole evacuation. he was excessively somnalent postoperatively with bilateral pneumocephalus. with high-flow nasal cannula, they all returned to clinical, and near radiographic baseline within , , and hours, respectively. recognizing the limitations of a small case series, we believe these cases support use of high-flow nasal cannula when treating patients with symptomatic pneumocephalus. thsee patients showed more rapid clinical and radiographic improvement after implementation of hfnc oxygen therapy than previously described using other methods. high-flow nasal cannula may help washout nitrogen from the lungs, allowing a downward gradient from the nitrogen in the intracranial air bubble out the lungs. in addition, high-flow nasal cannula is more comfortable for the patient, allowing for more consistent treatment. randomized studies are needed to confirm our findings. the neurotoxin produced by clostridium botulinum is the most lethal toxin known by weight. early recognition and treatment of botulism are crucial for full recovery. we present a case of progressive paralysis secondary to botulism toxemia following a gunshot wound (gsw). a -year-old man suffered a gsw to the right lower extremity. he was treated in the emergency department where the wound was irrigated and closed. some bullet fragments could not be retrieved due to close proximity to popliteal vessels and surrounding nerves. he returned ten days later with diplopia and nausea. he denied consumption of canned foods or illicit substances and had no preceding upper respiratory or gastrointestinal illnesses. on examination, he exhibited ptosis and symmetric bilateral motor weakness with diminished deep tendon reflexes. the gsw showed no signs of infection. progressive respiratory insufficiency resulted in intubation and mechanical ventilation. a lumbar puncture revealed normal opening pressures and cerebrospinal fluid analysis was unremarkable. titers for acetylcholine receptor and anti-muscle specific kinase antibodies were negative, as was a tensilon test. blood toxicology analysis showed no evidence of illicit substances or heavy metal poisoning. a high suspicion for wound botulism led to consultation with the regional poison center and cdc. blood and anaerobic wound samples were obtained for toxin bioassay and culture. empiric intravenous penicillin g therapy was started. equine heptavalent antitoxin (h-bat) was obtained and administered on hospital day . serum toxin bioassay tested positive for botulinum neurotoxin type a. the patient required a gastrostomy tube due to persistent dysphagia. after one month of hospitalization, he was discharged home and continues outpatient physical therapy. wound botulism from traumatic injury is exceedingly rare with only one to two cases reported annually. our case is the first reported incidence of wound botulism from a single gunshot wound. hyperammonemic cerebral edema (hce) with brain herniation carries a dismal prognosis historically despite aggressive treatment. however, we report a case where a patient with severe hce and herniation returned to her neurological baseline after aggressive medical management. a -year-old woman became acutely comatose with a blown left pupil and required intubation several days after admission for encephalopathy. head ct demonstrated diffuse cerebral edema with central and bilateral uncal herniation. profound hyperammonemia ( ug/dl) was implicated, though hepatic function was normal. her intracranial hypertension was ultimately controlled using hyperventilation, sedation, and osmotherapy, resulting normalization of her brainstem reflexes and improvement in her coma and imaging. continuous veno-venous hemodialysis (cvvhd) normalized her ammonia and encephalopathy that was initially refractory. multiple porto-hepatic shunts were identified on hepatic ct angiogram as the cause of her hyperammonemia, and were embolized. she was eventually weaned off cvvhd and extubated, without residual neurological deficits. our case demonstrates that, with contemporary management, clinical and radiographic reversal of hce and herniation is possible and prognosis is not uniformly poor. therefore, neurological prognostication in these patients should only be performed after assessing the clinical trajectory following cerebral resuscitation and ammonia reduction. furthermore, our case provides an example of how cvvhd can be used to reduce refractory hyperammonemia quickly until the cause of the hyperammonemia can be ascertained and addressed. finally, this is the first case reported of hce secondary to primary portosystemic shunt in absence of hepatic disorder; vascular imaging of the liver should be considered in the work-up of patients with hyperammonemia. a good neurological prognosis is possible for patients with hce and cerebral herniation with aggressive management that includes reduction of icp and ammonia. ccvhd is a useful adjunct to treat refractory hyperammonemia. a porto-systemic shunt should be considered as an etiology for hyperammonemia. cerebral venous sinus thrombosis (cvst) often presents with intracerebral hemorrhage and seizures. extensive involvement of the cerebral sinuses can lead to comatose state due to cerebral edema and associated intracranial hypertension. if not reversed with early therapeutic anticoagulation, then mechanical thrombectomy and decompressive hemicraniectomy (dhc) may be necessary as life-saving measures. however, etiological diagnosis of associated hypercoagulable state is needed for successful long-term treatment. case report of a patient presenting with cvst requiring anticoagulation, dhc and total colectomy (to treat underlying ulcerative colitis) as treatment with full anticoagulation was associated with lifethreatening hematochezia. twenty-five year old man with one week history of diarrhea presented with left sided weakness. imaging studies confirmed extensive cvst with minimal venous drainage through bilateral cavernous sinuses as well as right hemiparesis secondary to left post cingulate intracranial hemorrhage. patient subsequently developed loss of vision and became encephalopathic, despite initiation of anticoagulation with heparin. hence, mechanical thrombectomy was attempted but was unsuccessful. he also developed consumptive thrombocytopenia for which his anticoagulation was switched to argatroban. progressive neurologic deterioration necessitated dhc. his neurological examination progressively improved upon re-initiation of anticoagulation resulting in restoration of vision and resolution of left hemiparesis. later in the disease course, he developed symptomatic hematochezia associated with his primary disease, ulcerative colitis and required total colectomy. subsequently he was transitioned to oral anticoagulation and transferred to inpatient rehabilitation facility due to deconditioning from prolonged hospitalization. cvst can be life-threatening unless early treatment is initiated. appropriate and timely treatment including etiological diagnosis can lead to favorable patient outcomes. adverse effects of intrathecal non-ionic contrast during myelography are rare but can include seizures and encephalopathy. to our knowledge, cerebral edema has only been reported in the literature in two previous cases. we report a case of malignant cerebral edema following intrathecal administration of non-ionic contrast who developed seizure like activity with radiographic evidence on a head computerized tomography (ct) scan of acute diffuse cerebral edema. an year-old male underwent an elective spinal ct myelogram using mm of isovue m non-ionic contrast to evaluate chronic lumbar pain related to spinal stenosis. no complications were reported intra-procedurally and the patient was discharged home. the patient began to complain of progressive worsening headaches. the following morning he started complaining of nausea/vomiting, lost consciousness with posturing vs seizure like activity. a head ct revealed extensive brain edema and swelling with crowding of the brainstem and herniation ( fig. ). this patient was intubated and given an iv mannitol, . % hypertonic saline followed by an infusion of % hypertonic saline infusion. serial cts revealed complete resolution of his cerebral edema hours after admission ( fig. and ) . the patient's mental status improved, was extubated, and then was discharged home days after admission. while significant adverse effects of non-ionic contrast following spinal myelography are rare, the potential life threatening severity of these incidents warrants further patient education following this routine outpatient procedure. we recommend close neurological monitoring after intrathecal administration of contrast media. patients should be provided with detailed instructions about the potential side effects of non-ionic contrast and how to seek medical attention if symptoms of cerebral edema are noted post procedurally. a large acute traumatic subdural hematoma with brain compression and midline shift is typically considered a neurological emergency necessitation surgery. spontaneous resolution of a large subdural hematoma is considered a rare phenomenon with a few case reported in the literature. to our knowledge, we present the first case of spontaneous resolution of a traumatic acute subdural hematoma with brain compression and midline shift on dual antiplatelet therapy. a year-old patient initially presented after being found down and unresponsive in his home. the patient was on aspirin and clopidigrel. he was found to have altered mental status, wasn't following commands, and had a glascow come scale score of < . the patient's initial head ct revealed a large left acute subdural hematoma (sdh) measuring . cm in diameter. neurosurgery was consulted upon arrival for possible emergent evacuation. the patient's repeat head ct showed a decreased sdh to . cm in diameter. given the rapidly resolving sdh, surgery was postponed. another repeat head ct the following day revealed a decrease in size of the sdh to mm in diameter. several theories have been proposed for the rapid resolution of an acute sdh including csf leaking into the sdh through a tear in the arachnoid membrane with rapid reabsorption, redistribution of the hematoma in the subdural space, and acute fluctuations in icp driving the spontaneous resolution of the sdh. close neurological and repeat imaging may be helpful in managing these patients. as seen in our patient and others, a low density band in the subdural hematoma may indicate csf and be a predictor for spontaneous resolution of an acute sdh. the features of this atypical case offer points of discussion regarding the surgical or non-surgical approach of these patients. early post-hypoxic myoclonus -or myoclonic status epilepticus -develops within hours of the initial anoxic injury and is associated with poor outcomes per current aan practice guidelines. late posthypoxic myoclonus -or lance-adams syndrome -develops > hours after the anoxic injury, consciousness is regained, and is associated with relatively good outcomes. the patient is a yo man with a history of alcohol and cannabis use disorder, bipolar disorder, pnes who presented after attempted hanging for up to minutes. intial rhythm was pea; he had rounds of cpr, received mg epinephrine, and was intubated prior to rosc. myoclonic jerks were noted within hours post arrest. hypothermia protocol was initiated as gcs was t. ct head showed subtle loss of grey-white differentiation. eeg initially showed that his generalized myoclonic jerks correlated with cortical activity. he was started on versed gtt, keppra, vpa with improvement in the frequency of jerks. on post-arrest day , mri brain showed mild cerebellar edema. mri c-spine was negative for significant myelopathy, arguing against myoclonus as a spinal reflex. mentation gradually improved; on post-arrest day he opened his eyes to command. eeg evolved to show gpeds and sirpids and oxc and tpm were added. on post-arrest day a paralytic challenge resolved electrographic spikes, suggesting subcortical origin of myoclonus. he continued to improve cognitively, but despite clonazepam, vpa, home oxc he continues to have severe intention myoclonus. despite the presumed poor prognosis, the patient's family pursued aggressive measures and his mentation gradually improved. early post-hypoxic myoclonus carries a poor prognosis, however, in this case, the patient survived with a good cognitive outcome likely owing to his age and relatively few comorbidities. further studies are needed to differentiate early-onset lance-adams from myoclonic status since prognosis differs greatly. posterior reversible encephalopathy syndrome (pres) can occur from multiple etiologies and often presents with rapid-onset headache, altered consciousness, seizures and/or visual disturbances. vasogenic edema involving predominantly cerebral white matter is a key finding on imaging studies. although seizures are a frequent presenting symptom of pres, refractory status epilepticus (rse) requiring multiple antiepileptic medications is very rare. a case report of a patient presenting with pres and clinical course complicated with rse necessitating use of intravenous anesthesia, ketamine, and newly-available brivaracetam. -year-old woman with history of congestive heart failure, chronic iron deficiency anemia and uncontrolled hypertension was admitted for severe encephalopathy and convulsive status epilepticus (cse) for longer than minutes necessitating propofol and midazolam infusions. her admission systolic blood pressures were in the s, and mri brain revealed bilateral parieto-occipital t /flair hyperintensities consistent with pres. despite adequate control of hypertension following admission, patient remained encephalopathic and continuous electroencephalography (eeg) demonstrated nonconvulsive status epilepticus (ncse). the patient's ncse continued despite use of maintenance antiepileptics (fosphenytoin, lacosamide, levetiracetam) and high-dose infusions of midazolam and propofol. ketamine infusion was started to maximize nmda receptor blocking properties, and burstsuppression pattern on eeg was easily achieved with bolus infusions followed by continuous infusion. addition of brivaracetam was used to replace levetiracetam and allowed patient to remain seizure-free when iv anesthetics were weaned off. patient required prolonged hospitalization with gastrostomy tube placement and tracheostomy, which was later decannulated prior to patient's discharge to home with family. high index of suspicion is necessary to identify patients in ncse with prolonged encephalopathy that have pres. early use of ketamine along with a benzodiazepine may result in rapid achievement of burstsuppression to treat se. brivaracetam may be a useful agent to treat rse. diagnosis of diabetes insipidus(di) includes polyuria, hypernatremia and low urine specific gravity. we present two patients, receiving hyperosmolar therapy for intracranial hypertension (iht), in whom using low urine specific gravity to diagnose di lead to delayed treatment. this is a retrospective case series. criteria used to diagnose di at our institution include polyuria, sodium < mosm/kg and urine to plasma osmolality ratio < . case : -year-old male with subdural hematoma, iht on hyperosmolar therapy, developed polyuria. sodium rose from to meq/l. urine specific gravity was . excluding di. eventually, sodium rose to meq/l. specific gravity remained . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . , consistent with di. vasopressin was initiated, however the patient had already developed lactic acidosis and renal failure due to hypovolemia. case : -year-old female with intracerebral hemorrhage and iht on hyperosmolar therapy, developed polyuria. sodium rose to meq/l, specific gravity remained > . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . consistent with di. vasopressin was initiated. hyperosmolar therapy increases urine osmoles and raises urine specific gravity. this interferes with diagnosis of di which requires low urine specific gravity. while specific gravity measures the weight of particles, osmolality measures particles independent of their weight and thus accurately measures urine tonicity in the presence of heavy particles like mannitol. moreover, urine/plasma osmolality ratio is able to demonstrate relative hyposmolarity of urine when compared to serum assisting with diagnosis of di even when urine specific gravity is elevated. we conclude that urine specific gravity does not reliably detect di in patients receiving hyperosmolar therapy. urine osmolality and urine/plasma osmolality ratio may detect di earlier and prevent dehydration and kidney injury. these findings should be validated prospectively. endovascular intervention in the treatment of cvt(cerebral venous thrombosis) is an alternative strategy when cases deteriorate despite best medical management or develop refractory intracranialhypertension. we present a patient with cvt due to heparin-induced thrombocytopenia(hit), with intraparenchymal hemorrhage(iph) and refractory intracranial-hypertension, who was managed with systemic anticoagulation, continuous intra-sinus infusion of rtpa and mechanical thrombectomy(mt) resulting in excellent outcome. case report: a -year-old woman with left parafalcine meningioma s/p cyberknife was started on subcutaneous heparin for radiation necrosis days prior to admission. she presented to the hospital with new onset headaches and nausea. ct head showed increased edema with mid-line shift around the meningioma, for which steroids were started. within days her headaches worsened and repeat imaging demonstrated right temporal iph. emergent hematoma evacuation was performed. mri brain showed right cerebellar infarct and mra head showed extensive cavernous sinus thromboses, from right internal jugular vein and into sigmoid and transverse venous sinuses. she tested positive for hit and was switched to argatroban drip. patient however continued to deteriorate due to refractory intracranial-hypertension. intra-cavernous rtpa injection and mt was done but the thrombosis was noted to recur on repeat angiogram hrs later. an intra-sinus catheter was left in place for continuous infusion of rtpa at mg/hr. for hrs was done while argatroban drip was continued. the patient's intracranial pressure returned to normal. repeat venogram showed resolution of cvt. patient tolerated the therapies well, without any further hemorrhagic complications. modified rankin score at month follow-up was . this case features successful aggressive endovascular interventions including in-situ rtpa infusion, mt and concomitant systemic anticoagulation for cvt due to hit, complicated by intracranial hemorrhage and refractory intracranial hypertension. the paucity of high quality evidence related to safety, efficacy and modality of endovascular treatment lead to making therapeutic decision on individual basis. acute brain injury may be followed by encephalopathy marked by electroencephalographic features along the ictal-interictal continuum (iic). the use of perfusion imaging to co-localize radiographic features of known malignant eeg patterns may add an important context to guide treatment escalation or de-escalation. this is only the second report in which widely available ct or mr perfusion techniques were favored for this application over more cumbersome metabolic imaging such as pet. retrospective analysis was performed on records for patients admitted to a neurosciences icu, exhibiting encephalopathy, with eeg features on the iic, who underwent perfusion imaging. studies included ct perfusion, mr perfusion, arterial spin labeling, or spect. these studies were obtained for unrelated purposes. escalation or de-escalation of anti-convulsant and sedative medication, hospital course, and patient outcomes were extracted. perfusion imaging data was juxtaposed with eeg patterns along the iic, and patient outcomes are described in narrative form. seven cases were identified. four cases occurred in the context of intraparenchymal hemorrhage, of which one was secondary to meningioma resection. two cases occurred after treatment for subdural hematoma, and one case was related to ischemic stroke. anti-convulsant and sedative management was escalated or de-escalated relative to the presence or absence of radiographic co-localization of hyperperfusion in all but one case. emerging data indicates that some iic eeg patterns may merit aggressive treatment. metabolic signatures of secondary brain injury as measured by cerebro-oximetry or microdialysis have associated these patterns with unfavorable outcomes. we report case studies in which information gleaned from basic perfusion imaging may suffice to distinguish between benign iic patterns and those that should be regarded as near-ictal. the cases hint at novel ways to conceptualize treatment of encephalopathy following acute brain injury and suggest a dimensional shift in thinking towards electroperfusive status epilepticus. sudep has classically been a diagnosis of exclusion. recent studies have shown, however, that similar genes -and even genes within the same family -are associated with sudep and brugada. this suggests that perhaps the cardiac irritability of brugada syndrome exists on a spectrum with epileptic sudden death. a yo man with a history of presumed seizure disorder presented as a transfer from another hospital after being found to have anoxic brain injury following cardiac arrest. he had been shopping with his wife when he was thought to have one of his typical seizures. he was non-responsive for about minutes. on arrival ems found him pulseless. cpr was started en route and continued for minutes in the ed where he was defibrillated three times before achieving rosc. he completed the therapeutic hypothermia protocol. cardiac catheterization was clean. eeg showed diffuse slowing with no epileptiform discharges. imaging showed diffuse anoxic brain injury. after nearly two weeks without clinical improvement he was made comfort care. . of note, previous seizure workup failed to identify epileptiform activity. he was given an aed prescription which he never filled. further chart review showed that he had previously presented to the ed after a "seizure" episode which lasted minutes. his neuroexam was non-focal. ct head was negative. review of his ekg at that time showed type brugada syndrome pattern with an elevated jpoint and t-wave inversions in v and v . his sudden cardiac arrest is most likely a result of symptomatic brugada symptomatic brugada is important to identify early since deaths such as the one discussed above may be prevented by an implanted defibrillator. this case highlights the need for heightened awareness and more effective testing for brugada in the setting of seizure or pseudoseizure. patients with cerebral air embolism (cae) often exhibit more severe symptoms than those typically associated with the number of air emboli and size of infarcts on brain images. however, this discrepancy between symptoms and imaging findings has not been sufficiently explained. we report a case of cae in which disruption of the blood-brain barrier (bbb) and perfusion defects were identified via brain magnetic resonance imaging (mri). a -year old man with a lung mass was admitted to our hospital. percutaneous needle aspiration of the mass was performed in the left lower lobe of the lung. the patient developed sudden confusion and irritability after the procedure. during neurological examination, he could follow only simple commands and exhibited symptoms of left-sided weakness and neglect (medical research council grade ). noncontrast computed tomography (ct) of the brain revealed a few small air emboli in the right frontal subcortical area. multimodal mri of the brain was performed minutes after the onset of symptoms. t -weighted gradient-echo imaging revealed only a few small air emboli in the right frontal area, and diffusion-weighted imaging findings were unremarkable. in contrast, time-to-peak imaging revealed widely distributed perfusion defects in the right hemisphere, while contrast-enhanced t -weighted imaging revealed prominent leptomeningeal enhancement, suggestive of bbb disruption in the right hemisphere. magnetic resonance angiography revealed no steno-occlusive lesions. the patient was treated with % oxygen via a high-flow nasal cannula. his weakness subsided the next day, although his confusion persisted for days. follow-up mri performed five days after the onset of symptoms revealed resolution of the abnormal findings. our findings suggest that disruption of bbb and perfusion defects may develop in patients with cae. extensive impairments of the bbb and perfusion may explain the mismatch between severe neurological symptoms and small air emboli/infarcts. co-existence of cerebral salt wasting and diabetes insipidus is an extremely rare entity that has only been described in adult case series and a paediatric series. due to the complex nature of diagnosing this entity, mistreatment may ensue and lead to high morbidity and mortality rates. we report a case of a patient who was admitted to the neurosurgical intensive care unit after sustaining a subarachnoid haemorrhage secondary to a ruptured anterior communicating artery aneurysm. a -year old lady presented with sudden onset of severe headache and nausea. gcs was (e v m ) with no focal neurological deficits. she underwent endovascular coiling and embolisation of the aneurysm under general anaesthesia and had a left external ventricular drain inserted. in the immediate postoperative period, she was found to be polyuric, with the initial workup suggestive of diabetes insipidus. desmopressin was administered with initial good effect. however, her polyuria recurred and persisted despite desmopressin. the repeat workup revealed the presence of concomitant cerebral saltwasting. she was then treated with fludrocortisone and sodium chloride supplementation. careful monitoring of her serum sodium levels and overall fluid balance allowed close titration of the desmopressin, fludrocortisone and sodium chloride supplementation. she was eventually weaned off treatment and discharged well with normal sodium levels and with no neurological deficits. this case highlights the difficulty encountered in managing concomitant cerebral salt wasting and diabetes insipidus in critically ill neurosurgical patients and the need to for a high index of clinical suspicion, early intervention and close monitoring. levetiracetam is a commonly used antiepileptic drug (aed) used to treat epilepsy. this agent was approved by the fda in , is available in oral and intravenous formulations, and offers advantageous pharmacokinetics, minimal drug interactions, and a favorable side effect profile. the purpose of this case report is to describe a case of severe, asymptomatic rhabdomyolysis exacerbated by levetiracetam administration. the medical record was reviewed and data was collected to describe a case with a pertinent review of the literature. a -year-old african-american male with a history of hypertension presented to the emergency department following a tonic-clonic seizure. baseline labs were drawn and revealed a ck level of , iu/l, negative urine myoglobin and normal renal function. levetiracetam therapy was initiated and no further seizures were noted. the patient's ck continued to trend up throughout his stay despite aggressive fluid resuscitation with a positive myoglobin on hospital day . the ck reached a peak of , iu/l on hospital day . after a literature review and evaluation of his medication list, six casereports were identified linking elevated ck and rhabdomyolysis to levetiracetam administration. at that time levetiracetam was discontinued and the ck rapidly declined to , iu/l on hospital day . the patient never had muscle pain or kidney injury and was discharged on hospital day . this case-report describes rhabdomyolysis associated with levetiracetam administration with a naranjo probability scale score of indicating a probable adverse drug reaction. the adverse effects of generalized pain and neck pain are described in the package insert with an incidence of - %; however, it is not reported that ck levels were monitored. due to the frequent use of this aed and given the rare yet serious adverse effect of rhabdomyolysis, ck levels should be monitored upon initiation. acute toxic leukoencephalopathy (atl) is a potentially reversible disturbance to white matter caused by exposure to toxins. we report the first case of a patient with atl in the setting of a fentanyl overdose and reviewed the literature. a year-old man with a history of opiate abuse was found unconscious, last seen well nine hours prior. he was known to have purchased mg of fentanyl that day. he was intubated and briefly required blood pressure support. he was initially hypoglycemic and suffered fulminant liver damage, acute kidney injury, rhabdomyolysis, and stunned myocardium. comprehensive toxicology screen was positive for cannabis and fentanyl. mri of the brain showed pronounced bilateral restricted diffusion in the high frontoparietal subcortical white matter with radiographic stability five days later. he remained intubated and neurologic exam poor with fluctuating brainstem reflexes and posturing despite improvement in end-organ function. atl has been reported in a -month-old girl and an -year-old man with exposure to transdermal fentanyl, both of whom had favorable outcomes ( , ). one case has been reported following oral oxycodone ingestion ( ). of cases of atl secondary to inhaled heroin, % were fatal ( ). preferential white matter injury has been seen in cases of hypoxic ischemic encephalopathy (hie) ( , ). it was initially thought to be secondary to wallerian degeneration following grey matter damage, but post-mortem pathology has shown direct insult to axons ( ). atl has been reported in one case of hypoglycemic coma ( ) and one case of uremia ( ). it has never been reported in isolated hepatic encephalopathy, secondary to seizure, or with cannabis use alone. based on our review of the literature, the most likely causes of this patient's atl are fentanyl or hie. fentanyl should remain on the differential as a previously unreported cause of atl. autonomic dysregulation is a common complication of acute spinal cord injury (sci). subsequent hypotension may worsen central nervous system injury as well as neurologic and mortality outcomes. to help mitigate this occurrence, consensus guidelines recommend maintaining patients' mean arterial pressure (map) > mmhg within the first seven days based on evidence from limited clinical trials. limited data exists describing the use of midodrine, an alpha- agonist and the previously only available enteral vasopressor, for blood pressure (bp) augmentation in this setting. the use of midodrine is limited by cardiovascular side effects such as bradycardia. droxidopa, a novel enteral precursor of norepinephrine that works independently of the central nervous system, may serve a role in sustaining map in acute sci. we describe a novel case of droxidopa use in a -year old male who sustained a spinal cord contusion secondary to severe stenosis at the fourth cervical vertebrae following a ten-foot fall. droxidopa was used to facilitate vasopressor wean in the setting of neurogenic shock as a complication of acute spinal cord injury. to sustain adequate cns perfusion (map goal > - mmhg) and facilitate patient transfer to a lower level of care, droxidopa mg three times daily was initiated after five days of continuous infusion of intravenous norepinephrine. daily assessments of hemodynamic parameters were performed, including blood pressure, heart rate, map, and an electrocardiogram. successful wean of norepinephrine was achieved within hours of droxidopa initiation, with an average map sustained above mmhg. the patient was transferred to a lower level of care within hours of droxidopa initiation. no cardiovascular side effects were observed. droxidopa was well tolerated and facilitated transition from norepinephrine infusion to an enteral option. droxidopa may be a viable option in stable neurocritical care patients who require vasopressors to sustain adequate cns perfusion. traumatic brain injury is acute and sometimes rapidly aggravated during or after surgical treatment. imaging study is most important and computed tomography (ct) is the golden standard in tbi. however the patient should be transfer to ct room or relatively high cost mobile ct scanner may be used. ultrasound is not expensive and also does not produce radiation exposure. we studied the effectiveness and advantages of intra-operative ultrasound examination in traumatic brain injury patients intra-operative ultrasound was used after decompression of injured brain from june to april . the ultrasound device was the affiniti (philips ultrasound inc, usa) and . mhz transducer was used. the transducer was covered by thin transparent sterilized vinyl with ultrasonic gel with aseptic manner. to protect brain injury by the ultrasonic probe, a saline soaked gauze was applied on the cerebral cortex. the axial images were captured and then stored in pacs system promptly. ultrasound images were compared to postoperative ct scan. there were male and female patients were examined by ultrasound during there surgery. ipsilateral hemisphere, especially cortical layer was slightly distorted to identification. brain stem area was visible in most cases. contralateral hemisphere was seen in unilateral craniotomy and craniectomy cases. in bilateral craniectomy cases, both hemispheres were observed well. parenchymal hemorrhage was also identified and confirmed for removal using ultrasound. in severe brain swelling cases, arachnoid space was seen increased echogenicity. ultrasound image was compared to postoperative ct scan. intra-operative ultrasound is effective in real time inspection of brain during surgery and may helpful detect opposite or parenchymal hemorrhage before closure and leaving operation room. to describe a rare case of a varicella zoster virus (vzv) meningitis with progressive multiple cranial nerve deficits in the absence of cutaneous zoster rash. a young woman with idiopathic thrombocytopenic pupura on steroids presents with horizontal diplopia in the setting of seven days of intractable headache. she had no meningeal signs, fever, leukocytosis or cutaneous rash. within three days into hospitalization, she developed bilateral cn vi, cn iii, right cn v and right cn vii palsies in a progressive fashion. csf analysis revealed cell count of , /mm , a protein of mg/dl and glucose mg/dl. cytology, tuberculosis, bacterial and fungal cultures, ace and hiv testing were negative. vzv-dna was detected in csf in high titers vzv quant: . million. contrasted brain mri revealed mild diffuse leptomeningeal enhancement in the basilar region. she recovered almost all cranial nerve function within days of treatment with acyclovir and high dose steroids. a diagnosis of polyneuritis cranialis with zoster sine herpete (zsh) was made given pcr positive vzv-dna in csf. vzv reactivation with a wide array of neurological deficits can present without rash making diagnosis challenging. zsh should be in the differential for acute cranial nerve deficits as prompt treatment with acyclovir can lead to rapid recovery. stress-induced cardiomyopathy or neurogenic stunned myocardium is a well-documented cardiac complication following aneurysmal subarachnoid hemorrhage (sah). onset is usually immediate, within hours after aneurysm rupture, and is characterized by left ventricular dysfunction with pulmonary edema and elevation in cardiac biomarkers. this can often be mistaken for an acute myocardial infarction or ischemia. the pathogenesis appears to be the result of elevated catecholamine levels following injury leading to myocardial contraction band necrosis and cardiac dysfunction. this syndrome occurs more commonly in patients with severe or "high-grade" sah. we review a case of delayed cardiac dysfunction coinciding with the onset of vasospasm. a -year-old female presented with a h&h , mf sah. she appeared to have lost consciousness prior to arrival and was reporting worst headache of life. she had an evd placed upon arrival with opening pressure at . she underwent endovascular coiling of a ruptured aneurysm of her anterior communicating artery aneurysm. initial echocardiogram demonstrated normal wall motion with ef of %, and minimal troponin i elevation at . ng/ml. on post-bleed day the patient became more somnolent and developed chest pain with an ecg demonstrating st-elevation in all anterolateral leads concerning for acs. she was taken for cardiac catheterization where she had non-obstructive vessels with no vasospasm seen. her ef was reported at - % with apical ballooning present. her repeat echocardiogram also demonstrated a new apical akinesis with ef %, and troponin peaked to ng/ml. her tcds at the time were suggestive of vasospasm with bilateral lr > , but no focal deficit present. it appears that regardless of timeline, stress-induced cardiomyopathy or neurogenic stunned myocardium occurs after sympathetic or catecholamine surge and may occur after the onset of vasospasm in patients with aneurysmal sah. the rapid neurological assessment of critically ill patients with neurologic disease is paramount when determining a course of action. neuromuscular blockade is often used during critical care transport and in the emergency department. unfortunately, this can delay examination and assessment leading to unnecessary testing and procedures. historically, neuromuscular blockade reversal was accomplished using a combination of neostigmine and glycopyrrolate. however, this can lead to incomplete reversal and unwanted side effects from these medications. sugammadex is a cyclodextran injectable compound that has been fda approved in the united states since for rapid reversal of rocuronium induced neuromuscular blockade. sugammadex works by forming a complex with rocuronium and rendering it unable to bind to nicotinic cholinergic receptors at the neuromuscular junction. sugammadex can reverse neuromuscular blockade without the unwanted side effects of cholinesterase inhibitors. this is a case report of the successful use of sugammadex to reverse the effects of neuromuscular blockade in an intracerebral hemorrhage patient. a year old male with a history of atrial fibrillation and a supratherapeutic inr presented via aeromedical ambulance with a ml left frontal intracerebral hermorrhage causing a mm midline shift. he received a mg bolus of rocuronium prior to arrival and had a gcs of upon presenting to the neurosciences icu. a train-of-four revealed / twitches. he was given mg/kg of sugammadex with a return of / twitches within seconds. a more accurate neurological examination was then obtained demonstrating that his brainstem reflexes were intact, he could open his eyes spontaneously and reacted purposefully to painful stimulation. this allowed a non-operative course to be taken. sugammadex can reliably and quickly reverse neuromuscular blockade allowing for the immediate assessment of the neurocritical care patient. it is a useful tool with minimal side effects. piperacillin-tazobactam is commonly deployed as empiric antibiotic therapy. piperacillin-induced hematologic laboratory test abnormalities were rare in pre-marketing studies, and whether these alterations are of clinical significance has been studied little. aberrations in platelet function have not been implicated. in the present case, we discuss a patient presenting with hypertensive intracerebral hemorrhage (ich) who sustained two additional hemorrhages in distinct locations after routine removal of intracranial monitors and an external ventricular drain (evd). these significant bleeding events occurred exclusively during piperacillin-tazobactam therapy and were correlated with new abnormalities in the patient's platelet function assay (pfa) results. a -year old vietnamese male with hypertension presented for treatment of a left basal ganglia ich. epinephrine/collagen and adenosine diphosphate/collagen pfas at the time of evd and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. hospital course was complicated by aspiration pneumonia requiring empiric piperacillin-tazobactam administration. after removal of the quad-lumen bolt and evd on separate days, both follow-up ct scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. repeat pfas were abnormally prolonged, representing a distinct change from baseline. a trend toward normalization of pfas was observed after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter. the present case is unique in that the significant bleeding that occurred was attributable to objectively confirmed platelet dysfunction rather than thrombocytopenia. other possible innate causes of bleeding were less likely as the patient demonstrated normal platelet count, von willebrand multimers, platelet morphology, and clotting factors. this is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed. the life-saving potential of extracorporeal membrane oxygenation (ecmo) has been well recognized since the s. modern advancements of research and technology have allowed ecmo to be accepted as a dependable intervention for patients with severe pulmonary or cardiac failure. however, with increased use, associated complications that detract from the benefit of ecmo are surfacing as well. this case report describes a case of diffuse intracerebral hemorrhage (ich) after prolonged ecmo resulting in cerebral edema, mass effect, and eventual brain herniation. the patient is a previously healthy year old female who presented with fever, chills, and myalgia. when evaluated at urgent care, she was noted to be hypoxic and was sent to an outside hospital where her monospot test was positive. upon arrival, the patient was placed on venovenous ecmo (vv-ecmo) due to severe hypoxia. she was also in acute renal failure requiring continuous renal replacement therapy (crrt). she had an episode of hypotension with bradycardia. subsequently, her pupils were noted to be fixed and dilated. a stat ct head then showed diffuse bilateral hemorrhages at the graywhite junction as well as diffuse edema. labs showed thrombocytopenia likely due to disseminated intravascular coagulation (dic). her exam was consistent with brain death. it has been estimated that up to % of patients who were placed on ecmo as a last resort for respiratory failure have neurological complications including ich. there is no stereotypical pattern of bleeding but diffuse hemorrhage has been seen, which is consistent with the pattern seen in our patient. notably, those with ich have significantly higher rates of mortality. thrombocytopenia, dic, and platelet dysfunction that develop as a result of ecmo are thought to play a role in the development of ich. to present a case report of syndrome of the trepheined (sot) and paradoxical herniation without craniectomy. sot is reported when a constellation of positional neurological symptoms arise following large craniectomy, resolving in a delayed fashion following cranioplasty. paradoxical herniation may occur in extreme cases.the pathophysiology is incompletely understood however proposed mechanisms include compression of underlying brain by the flaccid skin flap due to the gradient between atmospheric and intracranial pressure exacerbated by upright pressure, changes in cerebral blood flow, and csf fluid. a middle aged woman with a history of mood changes eight months preceding admission presents with worsening left hemiplegia over one week. mri revealed a x mm right frontal cystic mass. hyperosmolar therapy and steroids were initiated for midline shift and brainstem compression. her immediate post operative course after tumour excision was uncomplicated. on post-operative day two, she developed uncontrolled hypertension, worsening anisocoria, and decerebrate posturing requiring urgent intubation. head ct revealed uncal and subfalcine herniation despite a large resection cavity. an external ventricular drain was placed and removed due to lack of drainage. within hours of trendelenburg positioning, she improved both clinically and radiographically. she did not undergo an intraoperative csf reduction and no preadmission history (back pain, orthostatic headache, trauma) to support an occult csf leak. she had a recurrence of symptoms on post-operative day eight which also resolved upon lying flat for hours. she was ultimately discharged to acute rehab and tumor pathology returned as glioblastoma (who grade ). this novel case of sot in the absence of craniectomy demonstrates the complex and poorly understood consequences of slow growing massive tumors, csf dynamics and exertional force on static cns structures. this case also illustrates the benefits of a collaborative, multidisciplinary approach to patient care in the neuroicu. to present a lesser known leukoencephalopathy that occurs when patients overdose on inhaled heroin vapor 'chasing the dragon" is a method of inhaled heroin vapor that is different from smoking or snorting heroin. heroin powder is placed on aluminum foil, which is heated by placing a flame underneath. the white powder turns into a reddish-brown gelatinous substance that releases a thick, white smoke, which resembles a dragon's tail. the fumes are "chased" or inhaled through a straw or small tube. currently the us is facing a growing epidemic of heroin use making this leukoencephalopathy more pronounced. a -year-old female with history of drug abuse presented to the emergency department with altered mental status. the boyfriend informed staff that she likely smoked heroin. on arrival, she was drowsy but easily arousable. her brainstem reflexes were intact but she was grossly dysmetric. urine drug screen was positive for opiates only. initial ct of the brain demonstrated extensive loss of gray-white differentiation within the cerebellar hemispheres and bilateral lucency in the globus pallidus and developing hydrocephalus. patient was placed in the neurointensive care unit to monitor and was managed medically with hypertonic therapy to combat her cerebral edema. an mri was done which demonstrated a distinctive pattern of symmetrical white matter t hyperintensities in the cerebellum, hippocampus and internal capsule bilaterally characteristically known as "chasing the dragon" sign. the patient gradually improved with supportive treatment, but continued to have mild ataxia upon discharge. we present a case of leukoencephalopathy that was generally rare to see, but now that heroin use is now at a year high within the us, this phenomenon may become more prominent. heroin inhalation leukoencephalopathy should be suspected in all patients with a history of chasing the dragon when they present with neurological abnormalities. the use of intra-venous (iv) thrombolysis for the treatment of acute ischemic stroke is now the standard of care. this is typically followed by endovascular thrombectomy if patient is eligible does not improve . we present a rare acute ischemic posterior circulation stroke that had progression of the stroke despite receiving both intra-venous thrombolysis and endovascular thrombectomy. case report: a years old african-american gentleman with past history of obesity, sleep apnea and prostatic hyperplasia, presented with acute onset left hemiparesis, with limb ataxia, who then progressed to altered sensorium in the emergency room needing endotracheal intubation. his initial nihss was . he was given iv thrombolysis, with subsequent vascular imaging that showed a top of the basilar clot, that was removed via endovascular intervention. a sister and one of the aunts reported a history of 'clots' when asked about family history. despite initial improvement, the patient deteriorated clinically after about hours from symptom onset, and was found to have extension of stroke into the brainstem, with simultaneous acute loss of brainstem reflexes . the patient was started on palliative withdrawal of care by the family about days from the initial onset of symptoms. his thrombophilia work-up revealed later that he was homozygous for methylenetetrahydrofolate reductase (mthfr) gene mutation, c >t. this case with a poor outcome due to extension of the ischemic stroke despite receiving the standard of care therapy, highlights the need for considering the use of anticoagulation within hours postthrombolysis and thrombectomy in cases with underlying thrombophilia. the current guidelines do not support this aggressive approach. there is a dire need for randomized controlled trial about such cases to provide evidence based care to avoid a repetition of a similar poor outcome. barbiturate therapy has shown benefit in reducing intracranial pressure (icp) in patients who are refractory to other treatment modalities. however, severe adverse drug effects can accompany barbiturate use when used at the high doses required for icp management, such as hypotension, hepatic/renal dysfunction, and infection, among other deleterious consequences. dyskalemia has been reported infrequently in the literature with most of the cases involving patients on thiopental. there remains little guidance for management of this adverse effect. we present a case of severe dyskalemia induced by high-dose pentobarbital therapy and experience with management of this rare but life threatening effect. the patient was a -year-old male with traumatic brain injury and subdural hematomas complicated by refractory icp elevations. after hyperosmolar therapy, sedation, and csf drainage failed to control icp, and he was deemed to not be a candidate for surgical decompression, high-dose pentobarbital was started. after initiation of pentobarbital, his initial potassium of . mmol/l decreased to a nadir of . mmol/l over the next hours despite aggressive repletion with a total of meq of oral and intravenous potassium chloride. upon down-titration and discontinuation of pentobarbital, the serum potassium rapidly rebounded to . mmol/l with st-segment elevations on ekg. pentobarbital was restarted in an attempt to stabilize escalating icps and elevated serum potassium. subsequently a slow taper was utilized to mitigate dyskalemia during barbiturate discontinuation. dyskalemia associated with high-dose barbiturate therapy presents a significant dilemma to practitioners as both severe hypo-and hyperkalemia can be life threatening. published literature provides little guidance on how to safely manage patients who experience this adverse effect. patients receiving barbiturate therapy should have frequent potassium monitoring especially in the initiation and discontinuation phases. potassium repletion should be approached with caution, especially preceding discontinuation of barbiturate therapy. diffuse astrocytoma (formerly known as 'gliomatosis cerebri') may present with seizures or symptomatic raised intra-cranial pressure. this is typically followed by a few months of relatively stable phase (with treatment) and then possible subsequent development of glioblastoma multiforme. we present a rare case of a previously healthy caucasian lady who had new onset seizures, that showed glioblastoma multiforme already present on a background of diffuse astrocytoma. case report: a years old caucasian lady with no significant past medical history was admitted with new onset focal seizures with secondary generalization, needing intubation and propofol for airway protection. brain imaging showed left frontal ring-enhancing mass, with a smaller satellite lesion in the left insular cortex, on a background of diffuse infiltrative lesion involving left fronto-temporal lobe and a smaller area of right parafalcine frontal lobe. biopsy of the left frontal mass revealed it to be glioblastoma multiforme. this is a rare situation when a previously healthy patient presents with new onset seizures and already has glioblastoma multiforme on a background of diffuse astrocytoma (or 'gliomatosis cerebri'). her post operative imaging revealed disease progression with increase in the size of the left insular cortical lesion. she was discharged home with plan for radiotherapy and chemotherapy. diffuse astrocytoma with glioblastoma multiforme within can remain asymptomatic till late in the disease course. diffuse astrocytoma (or 'gliomatosis cerebri') is a rare disease and even more rare is to have this remain asymptomatic till the development of glioblastoma multiforme within. this particular case highlights the need for vigilance about such a possibility, as this aggressive brain tumor carries a grave prognosis, especially when it develops on background of a diffuse astrocytoma. subdural hygromas (sdg) are cerebral spinal fluid collections in the subdural space that may occur following trauma. decompressive craniotomy may increase the risk for acute sdg or other forms of external hydrocephalus along the surgical plane. while these are traditionally benign and resolve spontaneously, they may in rare cases cause clinical deterioration. we report three cases. cases and were alcoholic men aged and , respectively, who suffered severe traumatic brain injury (tbi) following falls while intoxicated. they had early clinical deterioration prompting emergent hemicraniectomy for left-sided sdh with midline shift (mls). case clinically worsened on postoperative day (pod) with posturing, decreased pupillary responses, and new-onset seizures. new bilateral, extensive subdural hygromas were noted, enlarging over serial ct scans up to -cm with progressive mass effect. uncal herniation and downward brainstem displacement occurred by pod despite external ventricular drainage. case deteriorated on pod with fluctuating exam and newonset seizures. imaging revealed new subgaleal fluid collection measuring . -cm and a contralateral sdg. on pod , hemicraniectomy was performed for new mls from enlarging fluid and hemorrhage in extradural component. both died shortly after withdrawal-of-care. case was a year-old man with dural arteriovenous fistula who presented with spontaneous left-sided sdh and underwent left hemicraniectomy. on pod , he had new-onset seizures and new bilateral sdg measuring . -cm on the left and . -cm on the right without mass effect. two days later; the right sdg grew to . -cm causing significant mass effect. he recovered after burr-hole evacuation and temporary subdural drain placement. sdg following sdh evacuation can have a malignant course, causing clinical deterioration without prompt recognition and csf diversion. all patients had large volume sdh and two were alcoholic; larger prospective cohorts are required to identify risk factors. seizures may be an early clinical sign. moyamoya disease is an intracranial vasculopathy that results in stenosis of bilateral internal carotid arteries with subsequent development of extensive collateralization. the diagnostic criteria for moyamoya disease are well established and generally accepted, yet reaching the diagnosis can be challenging in some cases. herein, we present an unusual case of progressive cerebral vasospasm triggered by pituitary apoplexy that led to a delay in the underlying diagnosis of moyamoya disease. case report. a -year-old female with hyperlipidemia presented to the emergency department with a bifrontal headache, right-sided weakness, and dysarthria. ct angiogram showed extensive multifocal narrowing of the bilateral supraclinoid icas, proximal aca/mcas, and posterior circulation. mri brain revealed a left insular stroke as well as a sellar mass with a central hemorrhagic component. mr perfusion demonstrated decreased perfusion in the right hemisphere. lumbar puncture and extensive vasculitic workup was unremarkable. endocrine studies were notable for elevated prolactin with low fsh and lh levels. despite protracted blood pressure augmentation strategies, the patient continued to experience progressive infarcts in the left mca/aca territory. repeat ct angiogram showed progression of vasculopathy, and transcranial doppler studies demonstrated worsening vasospasm of the right mca and left pca arteries. the patient received corticosteroids given concern for apoplexy, and was maintained on aspirin and verapamil. given the aggressive nature of her vasculopathy, the patient underwent conventional angiography two weeks later, which revealed bilateral suzuki grade iii moyamoya. following this diagnosis, she received bilateral sta-mca bypass surgeries. it is important to revisit the differential diagnosis of cerebral vasospasm when the clinical course does not conform to expectations. this case highlights moyamoya as the causative agent in progressive vasculopathy likely masqueraded by pituitary apoplexy and concomitant vasospasm. moyamoya is an important diagnosis to consider in patients with a fulminant vasculopathy refractory to traditional treatment of vasospasm. visualization of intracranial structures by ultrasound in adults is limited by the presence of skull, though ultrasound imaging can occur through temporal windows. point of care ultrasound allows assessment of midline shift, brainstem, and ventricles. doppler allows visualization of cerebral perfusion patterns. patients with a hemicraniectomy have better temporal windows available since a portion of their skull has been removed. in such patients, ultrasound can provide a non-invasive method to serially assess midline shift, intracranial hematomas, and focal ischemia at the bedside. we present images of a cranial ultrasound that shows remarkable anatomical details that correlate well with computed tomography (ct) head. a year-old male presented with right-sided weakness and confusion and was found to have a left parietal intraparenchymal hemorrhage with cerebral edema and left-to-right midline shift on ct head. increase in cerebral edema and expansion of the hematoma caused clinical neurological decline necessitating a left-sided hemicraniectomy with clot evacuation. a cranial ultrasound was performed two days after surgery to assess for progression of cerebral edema and intracranial hemorrhage. a transtemporal approach in axial plane was used to visualize intracranial structures through the craniectomy window. physiological structures like the falx cerebri, lateral ventricles, midbrain, mammillary bodies, choroid plexus, splenium of corpus callosum, thalami, and circle of willis were visualized with incredible anatomical detail. pathology such as intracranial hemorrhage, focal ischemic areas, vasogenic edema as well as encephalomalacia were identified with close correlation to the noncontrast head ct. the patient is currently recovering in the neurocritical care unit with supportive care. cranial ultrasound has potential applications in point of care assessment of intracranial pathology in neurocritical care patients. this application has promising use in directing therapy in patients who are otherwise unstable for transport or are unable to undergo neuroimaging secondary to positioning needed for management of cerebral edema. cerebral mucormycosis is a rare infection caused by fungi found in soil and decaying vegetation. the rhino-orbital-cerebral type is classically associated with aids, diabetes, malignancy and immunosuppression. we observed a series of young immunocompetent patients who presented with a fulminant form of isolated cerebral mucor associated with severe meningoencephalitis, parenchymal necrosis and symptomatic cerebral edema. six patients with histopathological diagnosis of cns mucormycosis admitted to the university of cincinnati neurocritical care unit between and are presented. patient ages ranged from - (median ). none had diabetes or hiv. drug use (intravenous and intranasal) was confirmed in patients. they presented with altered mental status ( ) and focal neurologic deficits ( ). four patients presented with fever and leukocytosis. mri revealed lesions in the basal ganglia ( ) or cerebellum ( ) which were characterized by t hyperintensities with patchy restriction and susceptibility signal. contrast enhancement was present in patients. mass effect ( ) and midline shift ( ) were prominent. mechanical ventilation was required in four patients. all but one patient received amphotericin b. three died from intractable intracranial pressure (icp). one patient eventually gained functional independence, one still requires high level of care, and one was lost to follow-up. csf analysis was negative for mucor in all cases. fulminant cerebral mucormycosis should be considered in every young patient presenting with rapid onset meningo-encephalitis and necrotized cerebral lesions, especially if located in the basal ganglia. history of ivdu should raise further suspicion. these patients should be monitored in intensive care settings as they can rapidly develop malignant cerebral edema and increased icp. antifungal therapy should be initiated upon presentation as it has been shown to improve morbidity and mortality. the incidence of acute ischemic stroke in the immediate post-partum period ranges between - % and is considered a serious cause of morbidity and mortality. pregnant or postpartum women are less likely to receive iv tissue plasminogen activator (tpa) primarily because of pregnancy, ongoing peripartum bleeding and/or recent delivery. the fda classifies tpa as a category c drug and current recommendations consider pregnancy a relative contraindication for receiving tpa. we present two cases of peripartum ischemic strokes with varying ischemic stroke time windows requiring aggressive revascularization therapy (endovascular and pharmacologic). a y g p presented to an outside hospital days post-partum with new onset of facial droop and left upper extremity weakness (nihss ). imaging showed right m cutoff and occlusion of several m branches. the patient was not a candidate for tpa given ongoing vaginal bleeding. the decision was made to proceed with mechanical thrombectomy when her exam worsened to nihss . the thrombectomy was successful with tici c reperfusion. she was discharged home days later with a nihss of zero. a y g p presented days post-partum with new onset of left facial droop and slurred speech (nihss ). imaging showed right m cutoff with reconstitution, but with significant associated penumbra. acute worsening of exam post tpa triggered a push for mechanical thrombectomy achieving a tici recanalization. post procedure the patient's only symptom was decreased sensation in left fingertips. at -day follow up the patient had returned to her baseline with a nihss of zero. endovascular and pharmacologic revascularization therapy should be considered on an individual basis in the peripartum population. current literature is limited to case reports /case series. larger multicenter trials are warranted and anticipated in the near future. while the optimal duration of burst suppression for status epilepticus (se) has not been established, burst suppression poses significant morbidity that may be dependent on the amount of time spent in burst suppression. herein, we report a case of se that resolved after ultra-short burst suppression. case report. a year-old female was admitted to the neuro-intensive care unit after experiencing several brief tonic-clonic seizures characterized by right-sided shaking and left-sided head turn. despite lorazepam and levetiracetam administration, the patient did not return to baseline and was transferred to our unit. on presentation, her workup revealed a leukocytosis and a glucose level > mg/dl. lumbar puncture showed a mild pleocytosis for which broad spectrum antibiotics were initiated. on initial examination, she was unresponsive and was not following commands. electroencephalogram (eeg) demonstrated frequent sharp and slow discharges in the right posterior quadrant with generalization (~ seizures/hour) with minimal improvement following levetiracetam and phenytoin administration. given the refractory nature of seizures, the patient was intubated and treated with general anesthetics. using propofol, burst suppression was achieved (consisting of - s bursts with intermixed suppressions) and was continued for < hours. following weaning, the patient had no further evidence of seizures, and eeg showed lateralized periodic discharges in the right occipital lobe. mri did not demonstrate an occipital focus, but did reveal cortical diffusion restriction in the bilateral posterior hemispheres. the patient was extubated the following morning, and was transferred to the neurology floor two days later. this case provides evidence that in certain situations, relatively brief periods of burst suppression in se can serve as a "reset switch", allowing for resolution of seizures while minimizing toxicities associated with prolonged burst suppression. further studies to determine which patients may benefit from ultrashort burst suppression are warranted. there are two systems of facial control, voluntary and emotional; these are independent up to the level of the facial nucleus. we described a case of a patient who presented with isolated emotional facial palsy after intracerebral hemorrhage (ich). retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital. a year-old woman with history of migraines who presented to the emergency room after a colleague noticed she was not moving the left lower side of her face when she smiled. head ct showed a large right frontal ich involving the medial frontal lobes and anterior thalami. on review of an old mri done, an underlying developmental venous anomaly with an associated cavernoma was seen. her exam was notable for a flattened emotional affect, no facial palsy when asked to activate on command, but a facial droop that occurred in the context of her smiling to jokes and other humor. her nccu course was complicated with significant brain edema requiring osmotherapy up to weeks out from the initial insult with self-limited episodes of brain herniation characterized by extensor posturing, dilated pupils, hypertension, hyperventilation and tachycardia. these were initially dismissed as sympathetic storming vs seizures as she will come out of those to her baseline (awake with mild left sided weakness) many times without therapy. she eventually required a hemicraniectomy two weeks after presentation. conclusions solated emotional facial palsy can be the presenting sign after ich when the hemorrhage involves the contralateral thalamus, of the striato-capsular region or the medial frontal lobes. in this case, transient icp elevations were leading to dilated pupils, tachycardia and hypertension -highlighting that heart rate changes can be variable with elevated icps and that in young patients, brain herniation episodes can be self-resolved with hyperventilation. yo female with no pmh developed fever, headache, and neck pain. she presented to outside hospital day after ct head was negative, patient was discharged. symptoms did not improve and she went to her pcp on day and was instructed to go to the ed. she presented to osh and underwent a lp that was indicative of viral meningitis with wbc cells/mm and protein mg/dl. patient admitted and treated with acyclovir. on day , she developed generalized body aches. on day , she was trying to stand with assistance and she became rigid. parents report a total of seizures and was intubated for airway protection. she underwent another lp on day with an opening pressure of cm h o. csf was sent for paraneoplastic panel. csf analyses and blood cultures were negative. evd placed for icp pressures of - cm h o. history obtained from mother and father who reported the patient had been hiking weeks prior. results mri brain showed meningeal enhancement scattered throughout the supratentorial and infratentorial brain and most compatible with inflammatory sequela of meningitis. patient continued on keppra, high dose steroids, antibiotic, antiviral, antifungal therapy until cultures resulted. additional treatments included ivig therapy followed by plasmapheresis, and finally rituximab. continued workup with brain biopsy showed demyelinating process and possible necrotizing encephalitis. mri four weeks after initial presentation showed white matter demyelination and deep gray nuclei lesions consistent with adem. four score of on admission improved to (e , m , b , r ) weeks after patient presented from osh. diagnosis of adem vs ms variant made based on the above data. case provides information for the clinician diagnosing and treating adem. potential for further studies with treatments described above and their effect on meaningful neurological outcomes. dengue is a flaviviruses transmitted via mosquitos and prevalent in south east asia. neurological complications are rare but can involve encephalitis, myelitis, neuromuscular dysfunction and neuroophthalmological problems. we describe an interesting case of dengue encephalomyelitis. retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital a year-old ship filipino captain with no significant past medical history but an extensive exposure to heavy metals, travel throughout the pacific, who presented with progressively worsening fevers, encephalopathy, urinary retention and tremors. he was transporting iron ore and other metals in a cargo ship from russia through south-east asia through to bermuda. while passing through the pacific, he began to experience malaise, myalgia, and fever. he was treated with amoxicillin but became worse, developing urinary retention, periods of confusion, and word finding difficulties. he was initially hospitalized in bermuda and then transferred to our hospital for further workup. given his rapid deterioration, he was initially in the nccu. his exam was notable for mild expressive aphasia, paratonias, right-sided weakness with hyper-reflexia, and a low amplitude tremor. his csf was notable for lymphocytic pleocytosis, elevated protein, low glucose. mri brain showed flair hyper-intensities in the frontal lobes, and diffusion restrictions in the bilateral basal ganglia and thalami. mri spine showed extensive flair hyper-intensity lesions. an extensive workup evaluated for heavy metal toxicities, autoimmune disorders and infectious workup. csf analysis came back positive for dengue igg and igm, leading to a diagnosis of acute dengue fever and encephalomyelitis. with supportive care in the nccu, he improved considerably over - weeks and was discharged home to the philippines. dengue encephalomyelitis is a rare infection but should be considered in patients living in endemic areas. treatment includes supportive care with fluid resuscitation, neurological monitoring and monitoring for hemorrhage. posterior reversible encephalopathy syndrome (pres) is known to cause altered mental status and leukoencephalopathy in the setting hypertensive emergency. we present a novel case of severely asymmetric pres due to a concurrent right transverse sinus dural arteriovenous fistula (davf). a year-old woman with hypertension, non-compliant on medication, had fatigue and weeks of intermittent left sided weakness when she presented to an outside hospital for evaluation. initially upon arrival her glascow coma scale (gcs) was . her mental status deteriorated over hours, eventually requiring intubation. her peak blood pressure was / . outside ct demonstrated scattered intracerebral hemorrhage (ich) and she was transferred for higher level of care. on admission her gcs was . review of her outside ct was remarkable for extreme right-sided white matter hypodensity, moderate left white matter hypodensity, and small scattered ich. workup including infectious, inflammatory, and neoplastic processes were excluded through serum, csf studies, and mri. conventional angiogram demonstrated a right transverse sinus davf with reflux into cortical veins, which was subsequently embolized. her white matter t -weighted hyperintensities improved on follow-up mri, and her gcs was at the time of discharge. our case highlights the possibility of asymmetric pres due to abnormal venous congestion due to the right-sided davf. venous hypertension likely caused the patient's intermittent left sided symptoms in the weeks prior to admission. few cases of unilateral or asymmetric pres have been reported following induced hypertension for treatment of subarachnoid hemorrhage or in the setting of vascular malformation. to our knowledge, this is the only case of severely asymmetric pres and preceding stroke like symptoms due to a davf. the most common pathology associated with an intraluminal carotid thrombus is underlying atherosclerosis. in rare cases it may be associated to thrombocytosis. currently there are no clear recommendations for the treatment of ischemic stroke associated with thrombocytosis. our case describes the use of plateletpheresis for the acute management of thrombocytosis complicated by an internal carotid artery thrombus resulting in a right mca stroke. a -year-old female with past medical history of menorrhagia who presented complaining of left face, arm and leg weakness with associated shortness of breath. upon arrival her nihss was and the initial head ct was unremarkable. laboratory results revealed a hemoglobin . mg/dl, hematocrit mg/dl, and platelet count of x /ml. she was not a candidate for thrombolytic therapy due to the time window. soon after admission she had acute worsening of symptoms with an nihss of . a cta of the head and neck showed acute ischemic infarction involving the right mca territory with non-occlusive intraluminal thrombus within the right carotid bulb. asa mg and heparin infusion were initiated promptly. after a thorough work-up for thrombocytosis, reactive thrombocytosis secondary to iron deficiency anemia was diagnosed. plateletpheresis as well as oral ferrous sulfate were started. after one plateletpheresis cycle the platelet count stabilized at x /ml. complete thrombus resolution was confirmed on follow-up cta on day of admission without need for surgical revascularization. the role for plateletpheresis is not well established in secondary thrombocytosis. in cases with extreme thrombocytosis immediate surgical thrombectomy may be contraindicated due to high risk of rethrombosis. urgent cytoreduction with correction of the putative mechanism for thromboyctosis should be undertaken for optimal management. plateletpheresis is safe and efficient in reducing the platelet count to decrease the risk of clot progression or further clot formations which could worsen patient outcome. hyperpyrexia is an elevated core body temperature secondary to an elevated hypothalamic set temperature. hyperthermia is an elevated core body temperature beyond the normal hypothalamic set temperature. intracranial hypotension can present with a wide variety of symptoms ranging from orthostatic headache up to coma. it has never been reported to present with fever, namely hyperpyrexia. a case report of a year old female patient with a history of depression, diabetes mellitus, hypertension, and angiogram negative subarachnoid hemorrhage status post ventriculo-peritoneal (vp) shunt placement six years ago who was complaining of worsening headaches and slurred speech for the past three months but acutely decompensated one morning. she suddenly became confused and agitated but became obtunded. initially, she was given haldol. she was found to be febrile (rectal temperature of . f). she was given dantrolene and bromocriptine for suspected malignant neuroleptic syndrome with no effect. creatine phospho-kinase was not elevated. she underwent infectious work up which later came negative. cooling measures like external cooling, peripheral iv cooling, tylenol and nsaids were also not helpful. fever responded to central intravascular cooling but encephalopathy did not. several expert attempts of lp and shunt tapping failed to obtain csf. brain imaging showed bilateral chronic symmetrical hygromas, diffuse pachy-meningeal thickening and enhancement, slit-like ventricles and slumping of the midbrain with closure of the mammillary pontine distance. following shunt setting adjustment, the encephalopathy markedly improved and the fever did not recur after stopping the cooling measures and antimicrobials. intracranial hypotension might present with hyperpyrexia, likely secondary to hypothalamic dysfunction. in our case, hyperpyrexia was reversible as the intracranial hypotension was emergently treated. nevertheless, spontaneous intracranial hypotension might be difficult to diagnose especially if it presented with non-classical symptoms like fever. complex emotions about critical illness can affect families in the icu. rightfully, we put focus on how they are impacted, but we also need to pay attention to how it can affect providers and our decision making. a poignant case from my training was a -year-old girl struggling with lupus. she had now developed lupus cerebritis and had massive intracranial hemorrhages. despite aggressive efforts to manage cerebral edema, she repeatedly herniated brain matter out of old craniotomy scars with incredible force. it was the most horrifying thing i've ever seen. other organs were also failing, with four consulting services working to salvage them unsuccessfully, prompting numerous procedures. this went on for a month. the therapies that we can offer have limits from a physiological standpoint which we must recognize and respect. we struggle with reconciling the interventions we feel compelled to implement versus what is realistic. i remembered the most valuable advice that i once received: "only do something to someone if it does the complexity of the neuro icu is amplified by the nature of intracranial catastrophes and poor recovery (in contrast to pure medical illness). providers cling to what is technically indicated while families cling to hope, but neither is enough and concurrently too much. we lose our autonomy to grieving families telling us to "do everything" losing sight of the bigger picture. we lose our autonomy to one another by pushing onwards, which can unintentionally push each other into the territory of doing more harm than good. something for them". all services began to share this view, thus slowly dialysis, steroids and immunosuppression stopped. eventually, her heart stopped. my experiences have reiterated a simple paradigm: to do no harm. through this, i can empower myself to take control of each situation by first taking control of myself. we report a case of an hiv positive patient who presented with cryptococcus gattii meningitis who then developed acute respiratory distress syndrome (ards) secondary to pneumocystis jirovecii pneumonia (pjp) that required ecmo support. ards in immunocompromised hiv positive patients is associated with extremely high mortality. ecmo can improve oxygenation in patients without increasing alveolar pressure and therefore avoid mechanical lung damage with ventilation. we present a patient with newly diagnosed aids with cryptococcus gattii meningitis and course complicated by pjp that progressed to severe acute respiratory distress syndrome (ards) for which veno-venous ecmo was initiated. patient is a year old male who presented to the emergency department with new onset seizures. lumbar puncture in the ed overflowed the manometer and demonstrated wbc , rbc , protein , glucose , positive yeast gram stain positive for yeast with pcr and ag positive. his cultures later grew out cryptoccoccus gattii. he was admitted to the nsicu and we placed a lumbar drain and an intraparenchymal ipc monitor that demonstrated elevated icps to the - mmh but improved with drainage. the day of admission he acutely desaturated and required emergent endotracheal intubation. chest x-ray demonstrated bilateral infiltrates. bal was positive for pj. five days following presentation and respiratory failure he was started on veno-venous ecmo. two days following initiation of pjp treatment with bactrim his chest x-rays and lung compliance began to improve. he remained on ecmo for a total of days before decannulation. he underwent induction chemotherapy for four weeks for meningitis. this case report demonstrates the use of ecmo in a complicated and critically ill patient with aids, pjp, and cryptoccous gattii meningitis. to our knowledge, few cases of ards secondary to pjp are reported and none are reported with concurrent cryptococcus gattii infection. sympathetic storming occurs during the acute care of patients following severe brain injury. cannabinoid cb receptors (cb r) mediate the effects of delta( )-tetrahydrocannabinol (thc), the psychoactive component in marijuana. expression of cb r is widespread in the central nervous system and includes the hypothalamus, which is thought to mediate the hypothermic inducing effects of cannabinoids. dronabinol is a synthetic analogue of thc we present a novel therapeutic use of cannabinoids in a case of super-refractory sympathetic storming following coccidioidal meningitis and extensive bilateral subcortical stroke a -year-old previously healthy man was transferred from an outside hospital for treatment of meningitis, vasculitis, and hydrocephalus requiring placement of a ventriculostomy. workup subsequently revealed coccidioidal meningitis. during hospitalization the patient had severe vasospasm, elevated intracranial pressure, diabetes insipidus, cerebral salt wasting, and severe sympathetic storming. intermittent storming episodes with high fever persisted for over weeks despite treatment with bromocriptine, dantrolene, tylenol, ibuprofen, phenobarbital, and sinemet. due to its mechanism of action, a trial of dronabinol mg divided twice daily was tried. the storming episodes ceased and within hours the average temperature decreased by about . degree centigrade. temperature over the next several days was better controlled with a substantial reduction in use of anti-pyretics, surface cooling measures, and other storming medications our case highlights a novel therapeutic use of cannabinoids in super-refractory sympathetic storming related to brain injury. dronabinol may be an alternative pharmacotherapy with unique mechanism of action in difficult to control sympathetic storming patients with poor grade subarachnoid hemorrhage(sah) commonly present with significant mental status changes that preclude reliance on neurologic exam for screening for neurologic deterioration. jugular venous oximetry monitoring has been suggested for use in guidance of hyperventilation therapy, barbiturate coma, and vasospasm monitoring. no studies are found in literature validating its use in sah. milrinone has been using for the treatment of vasospasm in sah in an established protocol in the montreal neurological hospital. this study was performed using multiple methods of monitoring, but not jugular bulb oximetry. we report one case with high grade subarachnoid hemorrhage complicated by vasospasm treated with milrinone using jugular bulb monitoring for dose titration. methods years old female presented with thunderclap headache and subsequently became comatose. noncontrast head computer tomography showed posterior fossa subarachnoid blood. she was intubated, external ventricular drain (evd) was placed and she was admitted to neurosurgical intensive care unit (nsicu). angiogram showed left posterior inferior cerebellar artery aneurysm and was successfully coiled. her hospital course was complicated by refractory symptomatic vasospasm. angiogram showed basilar artery vasospasm treated with intra-arterial verapamil. post procedure patient was not able to tolerate norepinephrine due to tachycardia and could not maintain hypertension on phenylephrine. milrinone was then started. jugular bulb catheter was place because the area at risk was not amenable to invasive multimodality monitoring. oximetry was monitored and her milrinone rate was titrated to goal of venous oximetry in the range of - %. on day , angiogram showed no more evidence of vasospasm. her exam was back to her prior poor baseline. subsequently, she was discharged to long term care facility. our case demonstrates the benefit of using jugular venous oximetry monitoring guidance for milrinone dose titration. further, it may be an effective tool is research studying treatments of cerebral vasospasm repetitive transcranial magnetic stimulation (rtms) is increasingly used in treatment of various conditions including depression, chronic pain, and movement disorders. the use of rtms for chronic management of medically refractory epilepsy has grown substantially in the last years. however, little literature exists on use of rtms for acute status epilepticus. the exact antiepileptic mechanism of rtms remains unclear, but may be secondary to inhibition of cortical excitability. we report promising response to rtms in a case of super-refractory focal status epilepticus. the study is a case report. a daily dose of pulses of hz rtms was applied to the left occipital lobe. treatment course was divided into periods of - consecutive days each for a total of days of treatment over days. a -year-old woman with recent hemiarthroplasty complicated by wound infection presented with acute unresponsiveness and right gaze deviation, evolving into fluctuating encephalopathy, word finding difficulty, and right hemineglect. eeg revealed persistent left posterior quadrant lateralized periodic discharges (lpds), at times evolving into electrographic seizures, and positron emission tomography demonstrated a co-localized hypermetabolic focus. mri revealed subtle bilateral occipital t hyperintensity without diffusion restriction, which later resolved; cerebrospinal fluid was noninflammatory. seizures continued despite treatment with multiple aeds, burst suppression, and empiric trial of high dose corticosteroids. the patient demonstrated abrupt electrographic and clinical improvement after rtms initiation. previously unseen brief periods of lpd resolution were observed within minutes after first tms session with further improvement in eeg background correlating with improvement in encephalopathy and clinical findings over subsequent days. given excellent safety profile, rtms may be useful transitional therapy in management of some cases of status epilepticus. durability of efficacy, patient selection, and optimal treatment schedules remain important unresolved questions. further study is required. central pontine myelinolysis (cpm) occurs due to rapid osmotic shifts causing demyelination in white matter, typically due to rapid correction of hyponatremia mostly in setting of alcoholism, malnutrition, and/or liver/renal dysfunction. sequelae may include cranial neuropathies, quadriparesis, seizures, and encephalopathy. no specific treatment exists; literature reports indicate favorable outcomes in only - % of patients. our patient is a year old male with hypertension, tobacco and alcohol abuse, admitted with severe aortic stenosis, complicated by alcohol withdrawal, pneumonia, and acute kidney injury. he was treated with benzodiazepines, broad spectrum antibiotics, and fluid resuscitation. on hospital day (hd) , he had to be intubated for airway protection due to acute confusion and quadriparesis. his blood work was notable for wide fluctuations in serum sodium, from on admission to on hd to on hd . otherwise, laboratory evaluation was remarkable only for mildly elevated ast and serum creatinine. mri brain days after symptom onset (hd ) showed dwi and flair hyperintensities around central pons bilaterally crossing midline. eeg showed severe generalized slowing. diagnosis of cpm was made and intravenous immunoglobulin (ivig) ( . g/kg/day for days) was initiated within days of symptom onset, on hd . after initiation of ivig, patient showed rapid improvement, first noted in the bilateral upper extremities. by hd i.e., days after initiation of ivig, he was able to be successfully extubated; and he had regained - / strength in all extremities. neuropsychology testing at month demonstrated intact cognition. we describe a case of rapid clinical improvement in cpm following treatment with ivig. in addition to ours, about similar cases have been reported, in which beneficial outcomes were demonstrated following prompt initiation of ivig. one proposed theory would be through reduction of myelinotoxic antibodies, thus promoting remyelination. few cases have reported central neuronal hyperventilation (cnh) secondary to infiltrative malignancy or autoimmune disease. the lesion is usually located at the pontine tegmentum and interrupts the fibers between the respiratory centers in the pons and those in the medulla. we report a case of a year old female with multiple comorbidities who was admitted to the neurocritical-care unit after intra-operative rupture of a mm distal basilar aneurysm while being electively coiled. an external ventricular drain (evd) was placed due to early signs of ventriculomegaly. the postoperative exam showed progressive encephalopathy, left > right hemiplegia progressive tachypnea (rate and depth) despite being on assisted mode ventilation leading to severe hypocapnia ( . mmhg) and compensatory renal acidosis (bicarbonate = . mmol/l) to maintain normal ph. attempt to sedate the patient led to severe metabolic acidosis. intraventricular nicardipine was started and the patient ventilator settings were changed to bi-level pressure control. transcranial doppler (tcd) showed markedly improved vasospasms. the patient respiratory rate and, to a lesser extent, the tidal volumes improved after several days. sedation was weaned off successfully. evd was successfully weaned off and removed. tcd and ct angiogram showed severed basilar artery vasospasm while mri done later showed bilateral tegmental midbrain ischemia. one case has reported acute central neuronal hyperventilation following left thalamic bleed while another reported chronic neuronal hyperventilation that was attributed to old bilateral lacunar thalamic strokes by exclusion. our case is the first to report central neuronal hyperventilation following aneurysmal subacrachnoid hemorrhage that got complicated by bilateral tegmental midbrain strokes. while respiratory centers are known to exist in the medulla and the pons, more recent articles have described networks that regulate breathing extending to the midbrain peri-acquiductal grey and possibly the thalami. our unique case supports this hypothesis. serotonergic and atypical antipsychotic drugs are often used in the critically ill in the treatment of posttraumatic depression and anxiety disorders. hyperactive delirium may mask serotonin syndrome, which carries high morbidity and mortality if left untreated. we describe a case of serotonin syndrome in a critically ill patient in the setting of surgical and neurocritical intensive care unit. a -year-old male with remote trauma presented with left upper abdominal pain. a ct-scan of abdomen showed left diaphragmatic hernia. he underwent left thoracotomy and repair of diaphragmatic hernia. his postoperative course was complicated by sepsis, ileus, and aspiration pneumonitis. he was started on sertraline and quetiapine for stress-induced anxiety disorder, depression and agitation. despite increasing doses of sertraline, patient became agitated, tremulous, and confused. physical examination included fever, tachycardia, hypertension, diaphoresis, dilated pupils, hyperactivity, and clonus. initially considered to be due to hyperactive delirium, these manifestations did not improve with haloperidol. neurocritical care was consulted. due to presence of hyperactivity, fever and clonus, serotonin syndrome was strongly suspected. sertraline and quetiapine was discontinued and cyproheptadine added. within -hours his symptoms improved and cyproheptadine was tapered over days. serotonin syndrome, a potentially life-threatening syndrome, is manifested by triad of mental status changes, neuromuscular and autonomic hyperactivity. a multitude of drug combinations can result in serotonin syndrome. serotonin syndrome is a diagnosis of exclusion, based on history and neurological examination in a patient taking serotonergic drug. ht- a receptors are most commonly incriminated along with high levels of norepinephrine.the keys to management include discontinuation of all serotonergic agents, supportive care, and cyproheptadine. cyproheptadine, a potent ht- a antagonist, is effective in ameliorating symptoms. a high suspicion for diagnosis is important for reducing morbidity and mortality associated with this neurologic syndrome in the critically ill. ruptured cerebral mycotic aneurysm as consequence of infective endocarditis (ie): a management qeeg adr in poor grade sah: is it really useful? recognize the various subtypes of cerebral amyloid angiopathy bilal butt baylor college of medicine -hour development of a giant infectious intracranial aneurysm: a case report catherine albin intra-operative ultrasound in traumatic brain injury patients namkyu you syndrome of the trepheined (sot) and paradoxical herniation without craniectomy elysia james spectrum health neurosciences -icu division stephen a. trevick , andrew naidech , leah tatebe patients were included. median age was years. % were female, % smokers, % hypertensive and % diabetic. % had a history of cad or mi and % had hyperlipidemia. in the multivariable analysis, the odds ratio for unfavorable outcome, defined as mrs score of - , was . ( %c.i: . - . ) and . ( %ci: . - . ) for the intermediate-grade(iii) and high-grade(iv and v) hh groups respectively, when compared to the low-grade(i and ii) hh group. age, hypertension and diabetes were found to be negatively associated with mrs, while hyperlipidemia was positively associated. gender, race, smoking and history of cad/mi were not significantly related to mrs. a positive trend for better mrs outcome was observed across years (p= . ). this trend was not related to hh grade on admission, (p= . for interaction between hh grade and year). hh scale on admission is associated with the mrs outcome upon discharge for patients with nontraumatic sah. models predicting the probability of a good mrs outcome could be created based on the hh grade on admission, age, hypertension, diabetes and hyperlipidemia status. the data suggest a trend toward improvement in medical and surgical care for this patient population across years. ciro poor-grade subarachnoid hemorrhage (sah) is associated with high mortality rates. although death rates have decreased in the last three decades, the exact mechanisms of demise are still to be determined in this patient population. a retrospective study of consecutive poor-grade sah patients (world federation of neurosurgical societies grades iv and v) aggressively treated in two academic high-volume centers, one in the netherlands (amc) and one in canada (smh). the primary outcome was in-hospital mortality. the main reasons of death were evaluated. a total of poor-grade sah patients were admitted between and , to amc and to smh. ( %) patients died, and ( %) of those patients died before having the culprit aneurysm treated. the median interval between hospital admission and death was three days (iqr - ).withdrawal of life support was the main reason of death in both centers (total of deaths - %), cardiopulmonary causes, aneurysm rebleeding, refractory intracranial hypertension, and other extracranial causes), represented less than %. extensive review of patients chart for all the data collection including literature search for similar cases if reported before. although rare, there are multiple case reports and series of nkh and clinical findings of hemichorea-hemiballism (hc-hb). there are few case reports of nkh with unilateral signal changes in the caudate and putamen. our patient presented with acute right basal ganglia ich. despite the typical imaging findings of nkh, work-up and management of ich took precedence over control of bg. mri findings were different in our patient given presence of positive gre and dwi/adc in areas other than t hyperintensity, which is known to be associated with nkh. we hypothesize an association between ischemia and hemosiderin deposition with hyperglycemia. the selective vulnerability of unilateral involvement of basal ganglia and caudate is unclear and needs more research. identification of neuroimaging findings in nkh in absence of focal neurological deficits (hc-hb) is important, especially for a first responder. early recognition can prevent icu admission, provide efficient patient care and allocation of resources. although most metabolic diseases affect basal ganglia bilaterally; nkh is associated with specific unilateral neuroimaging findings even in absence of movement disorders or focal neurological deficits. a year old male with a history of seizure disorder due to mesial temporal lobe sclerosis, presented with altered mental status after a lamotrigine overdose. he had consumed . gm of the drug. he was awake and alert at presentation. urine toxicology was negative. initial creatine kinase (ck) was iu/l and peaked at iu/l; his creatinine was . mg/dl. lamotrigine level went from mcg/ml to . mcg/ml after hours. four days after admission it was mcg/ml. a head ct at admission was negative. despite initial alertness, he developed profound encephalopathy with agitation and rigidity, requiring heavy sedation, induced paralysis, and intubation. this in turn lead to hemodynamic instability, which along with persistently elevated lamotrigine levels, prompted initiation of continuous veno-venous hemodia-filtration (cvvhdf) on hospital day . the lamotrigine level declined to . mcg/ml within hours, the encephalopathy and rigidity resolved, and he was extubated. to our knowledge, this is the first reported case of lamotrigine toxicity managed with cvvhdf. overdoses up to g have been reported and can even result in death. while cleared hepatically, the half-life of lamotrigine is approximately twice as long when patients have chronic renal failure. in a small series of patients with renal failure, approximately % of lamotrigine was reported to be removed by hemodialysis. we applied this principal to our patient. our experience suggests that augmenting drug clearance with dialysis may help reduce the time on mechanical ventilation, need for higher doses of sedatives, and improve time to discharge. cvvhdf should be considered a supplemental treatment option for lamotrigine toxicity. traumatic brain injury (tbi) complicated by percutaneous coronary intervention (pci) remains a significant clinical dilemma. dual anti-platelet therapy (dapt) is standard after pci, but may contribute to progression of tbi. novel antiplatelet drugs with ultra-short half-lives, such as the p y -adenosine receptor antagonist, cangrelor, may provide added clinical flexibility in avoiding tbi-associated hematoma progression, particularly in the absence of reversibility options. case report. we report a year-old female who presented to the ed after a syncopal episode with a fall down a flight of stairs. an ekg was obtained demonstrating inferior wall stemi. signs of head trauma included facial and scalp contusions, and bloody otorrhea. initial gcs was . a non-contrast head ct demonstrated tsah and contusions of bilateral frontal lobes and left temporal lobe, and a non-displaced fracture of the left temporal bone. neurosurgery, interventional cardiology and critical care were consulted. the patient developed signs of cardiogenic shock related to stemi and was taken emergently to cath lab. successful revascularization of proximal rca occlusion was achieved. heparin was given per protocol, and aspirin and cangrelor administered post-pci. cath lab was complicated by tonic-clonic seizures requiring intubation. repeat head ct demonstrated blossoming of bifrontal contusions, trace subdural hematoma development and increased tsah conspicuity. dapt infusion was continued, and subsequent imaging was stable, allowing transition to asa and clopidogrel. she survived with only minor disability. newer generation p y inhibitors can be administered intravenously with reliable platelet inhibition similar to older p y receptor inhibitors. with rapid reversibility upon discontinuation, their utilization should be considered any time pci complicates tbi. cerebral air embolism (cae) is a rare but potentially fatal entity with high morbidity and mortality, commonly seen secondary to iatrogenic causes like neurosurgical procedures, vascular surgeries, etc. as also deep sea diving. cae after esophagogastroduodenoscopy (egd) is extremely uncommon. we present a rare case of cae post egd resulting in diffuse cortical infarction. an year old man underwent an elective (egd) for esophageal stricture with biopsy and balloon dilatation. patient did not wake up after procedure. on initial exam, patient was comatose, glasgow coma scale t with decerebrate posturing. computed tomography (ct) revealed multiple foci of cerebral air embolism. ct angiogram of the brain was negative. diffusion weighted imaging and apparent diffusion coefficient imaging sequences in magnetic resonance imaging (mri) showed diffuse, global bi-hemispheric cortical infarction. ct chest showed pneumomediastinum. only cases of cae from egd have been reported in literature prior to this case. received hyperbaric oxygen therapy(hbo). patients had a documented patent foramen ovale (pfo) or some form of arteriovenous (av) shunt. presence of av shunts/ pfo, therapeutic endoscopic procedures providing vascular communication as well as providing pressure gradient are all factors facilitating air embolism associated with egd. hbo therapy has been shown to improve outcomes in cae patients, initiating therapy > hours after insult and early and significant ischemic changes seen on ct/ mri prior to starting therapy were strong predictors of poor outcomes. our patient did not have a documented echocardiogram with a shunt study prior to the egd. cae after egd causing global cerebral bi-hemispheric ischemia as seen in our case is extremely rare. hbo has been shown to improve outcomes. time to treatment > hours and early ct/ mri changes suggest poor outcomes. studies do not recommend benefit of screening for pfo or av shunts prior to every egd. key: cord- -oecpqf j authors: nan title: aspho abstracts date: - - journal: pediatr blood cancer doi: . /pbc. sha: doc_id: cord_uid: oecpqf j nan myelodysplastic syndrome (mds) and frequently arise in the context of inherited bone marrow failure (bmf) syndromes, such as shwachman diamond syndrome (sds). monosomy /del( q) is associated with high grade mds and propensity to progress to acute myelogenous leukemia, a major cause of morbidity and mortality for patients with inherited bmf. development of non-transplant strategies to treat bone marrow failure without simultaneously stimulating outgrowth of malignant clones remains a major challenge. objectives: the aim of this study is to investigate the molecular consequences of del( q) in the context of bmf with the goal of developing more effective treatments. design/method: to study the biological and molecular consequences of monosomy/del( q) in bmf, induced pluripotent stem cells were generated from sds patients (sds-ipsc) . a deletion of the mds-associated region of the long arm of chromosome was then introduced using a previously published modified cre-lox approach. results: the sds ipsc phenocopied bone marrow failure with slow proliferation and impaired hematopoietic differentiation. we next explored whether deletion of q conferred a relative fitness advantage within the context of bone marrow failure. proliferation of the sds-del( q) ipscs was reduced below that of both the isogenic sds ipscs and normal controls without an increase in cell death. sds-del( q) demonstrated reduced hematopoietic differentiation compared with isogenic sds cells. these data demonstrate that deletion of q fails to confer a relative growth advantage relative to isogenic sds ipscs and results in further impairment of hematopoiesis. to gain insight into the mechanisms of del q-associated clonal evolution in sds, we performed rna sequencing (rnaseq) of sds+/-del( q) ipsc. expression of tgf pathways and their downstream targets were reduced in sds-del( q) ipscs compared to isogenic sds ipsc. single cell rnaseq analysis of primary sds bone marrow cells confirmed that the tgf pathway is hyperactivated in sds. western blot analysis showed increased phospho-smad levels in sds ipscs compared to sds-del( q) and normal controls, while total levels of smad were unchanged. pharmacological targeting of tfg with small molecule inhibitors resulted in selective improvement of sds hematopoietic colony formation and myeloid differentiation without stimulating outgrowth of the isogenic sds-del( q) cells or normal controls. these results demonstrate that del( q) reverses the tgf pathway hyperactivation of sds. furthermore, inhibition of tgf selectively rescues hematopoiesis in sds but not in isogenic del q cells, suggesting a potential strategy to treat bone marrow failure without stimulating del q clonal outgrowth. background: standard therapy of medulloblastoma consists of treatment with alkylating agents and radiation after surgical resection. although a statistically significant increase in survival is reported with this regimen, / rd recur and become resistant this class of agents ultimately leading to mortality. large numbers of somatic mutations were observed in recurrent medulloblastoma (rm) after alkylating agent and radiation treatment. high mutation rates in tumors can have twofold effect; ) a large number of non-synonymous mutations that have no role as drivers can still cause functional tumor antigens increasing the neoantigen burden and immunogenicity. moreover, ) such tumors can gain mutations in canonical or non-canonical dna repair pathways leading to a gain in the number of mutations as seen in case of glioblastoma, this can lead to even higher accelerated mutational rate. evidences suggest that high mutational load can cause higher neoantigen burden thereby making the tumor more susceptible to immune checkpoint inhibition. we propose that post therapy recurrent medulloblastoma gain mutational signature and immunophenotype of malignancies demonstrating clinical response to immune checkpoint therapy. objectives: ) rm has molecular signatures identical to tumors with high immunogenicity and clinical response to immune check point inhibition. ) rm has the immune inflammatory phenotype; harboring high percentage of tumor infiltrating lymphocytes (tils), macrophages and monocytes. design/method: to test our hypothesis, we downloaded the raw bam files of previously published data from international cancer genome consortium (icgc) . this set of about matched primaries and recurrent medulloblastoma cases forms our discovery cohort. we have called somatic variants using the gatk pipeline by the broad institute. to validate our key findings, we have procured human medulloblastoma specimens and are conducting whole exome sequencing. the primary assays utilized to assess immunogenicity are immunohistochemical (ihc) staining of formalin fixed and embedded recurrent medulloblastoma tissue to identify tils, tumor associated macrophages and other markers. mg/m had dlts of dyspnea (grade )/hypoxia (grade ) but no dlts were observed in any other cohort. adverse events were generally mild to moderate, consistent with the safety profile observed in adults. across the desc cohorts, plasma concentrations were dose-proportional and steady state concentrations were lower on day vs. day . mean systemic exposure in the mg/m cohort was ∼ -fold greater compared with the adult rp d of mg bid. a pk:pd relationship between tazemetostat exposure and h k me levels in peripheral blood monocytes and granulocytes was observed in the desc phase. consistent and significant post-dose reductions in h k me occurred at doses ≥ mg/m . further analysis of twelve patients treated at the rp d confirmed that h k me inhibition was maximally inhibited. doses - mg/m showed confirmed objective responses (cr/pr) per recist/rano in patients with es (n = ), chordoma (n = ), and atrt (n = ). background: previous studies established that the platelet/ fibrin(ogen) axis promotes metastatic potential by impeding the clearance of newly formed micrometastases by natural killer (nk) cells. however, multiple important questions remain, including the potential of fibrin(ogen) to promote metastasis through interactions with cells other than platelets (e.g., inflammatory cells), and the fundamental question of whether fibrin polymerization is required for metastasis. objectives: determine the role of fibrin polymerization and fibrin(ogen) engagement of integrins iib and m in metastasis. design/method: we performed experimental and spontaneous metastasis assays in immunocompetent mice carrying specific fibrinogen structure/function alterations. results: expression of a mutant fibrinogen lacking the binding motif for the leukocyte integrin m (fib - a) significantly decreased metastatic potential relative to wildtype fibrinogen, suggesting a role for fibrin(ogen)inflammatory cell interactions mediated by m in metastasis. to directly determine the importance of thrombinmediated fibrin polymerization in metastasis, we analyzed metastatic potential in fibaek mice, which carry a form of fibrinogen essentially "locked" in the soluble state due to a mutation in the a chain thrombin cleavage site. metastatic potential in fibaek mice was diminished relative to control mice, speaking to the importance of thrombin-mediated fibrin polymerization in the metastatic process. however, the fibaek mice retained significant metastatic potential relative to complete fibrinogen deficiency, indicating that fibrinogen monomer retains significant prometastatic properties. in order to better define the role of fibrin(ogen)-platelet interactions in metastasis, we compared metastatic potential in control and fib Δ mice, carrying a form of fibrinogen lacking the chain binding motif for the platelet integrin iib . surprisingly, this mutation had no impact on metastatic potential. together, these studies suggest fibrinogen plays a multifaceted role in metastasis. fibrin(ogen)-leukocyte interactions mediated by m appear to have a role in metastasis. previous studies showed that macrophages promote the metastatic potential of circulating tumor cells, which may represent at least one important m expressing cell type whose prometastatic behavior is influenced by fibrin(ogen) interactions. these studies show that thrombin-mediated fibrin polymerization promotes metastasis, but soluble fibrinogen retains some significant prometastatic capacity. surprisingly, loss of the fibrinogen chain iib binding motif had no impact on metastasis. given the established importance of platelets in metastasis, these findings suggest that fibrin (ogen) is capable of platelet stabilization through mechanism(s) independent of this iib binding motif. platelets may bind polymerized fibrin at other sites, and/or fibrin interactions with other matrix proteins capable of binding iib are sufficient to support platelet functions required for metastasis. the role of platelets in hemostasis and thrombosis is well defined, but it is becoming increasingly evident that platelets also assist in host defense and inflammation. platelets participate in the innate immune system through direct antimicrobial activity and interactions with effector cells (chapman , garlanda , kapur ). in the adaptive immune system, platelets recruit and costimulate t-cells, and promote b-cell differentiation and antibody class switching (kapur , morrell ). the question remains: which mechanisms influence platelet immune function and are they developmentally regulated? preliminary studies in the palis lab have revealed significant dif-ferences in embryonic versus adult platelet gene expression, including regulators of immune and inflammatory responses such as beta -microglobulin (b m) and major histocompatibility complex class i (mhc ). mhc is expressed on all cell surfaces except red blood cells and its molecular chaperone b m is a marker of inflammation highly expressed in platelet alpha granules (zufferey ). preliminary data from the morrell lab reveals a mass release of b m during platelet activation, which drives monocyte differentiation to an inflammatory phenotype through tgfb receptor signaling. we therefore sought to determine whether developmental changes in platelet b m expression mediate differences in platelet-mediated monocyte activation. with trilineage hematopoiesis with a predominance of early myeloid precursors, with full maturation. microarray, elane and sbds sequencing and deletion/duplication analyses were negative. immunologic evaluation was significant for agammaglobulinemia and an absence of memory (cd +cd +) b cells. a gene primary immunodeficiency panel revealed two variants of unknown significance-c. g>a and c. g>t in dnmt b; one previously reported in association with icf . parental testing demonstrated parental heterozygosity. centromeric instability was confirmed in mitogen stimulated lymphocytes showing characteristic, multibranched chromosomes containing at least arms of chromosome and joined near the centromere. decondensation of the qh and qh regions and triradial configuration of chromosome was noted, and a diagnosis of icf syndrome was made. the patient was started on monthly intravenous immunoglobulin (ivig). prophylaxis for pneumocystis jiroveci pneumonia and respiratory syncytial virus was initiated. a / matched sibling hsct is being planned. demonstrated the diagnosis of high grade osteosarcoma. the patient was started on multi-agent chemotherapy with planned a whole femur prosthesis at time of local control. cases of osteosarcoma have been described in the literature in patients with nf (median age; years, range - years) with slightly male predominance ( cases). the femur was the most common site of involvement ( cases). four patients died of metastatic disease despite surgery and multi-agent chemotherapy. conclusion: nf represents a major risk factor for development of malignancy and uncommonly osteosarcoma in adolescents and adults. we report a rare case of an extensive involvement of osteosarcoma of the left femur in a child with known diagnosis nf . this presentation should alert the pediatric oncologists to monitor for bone tumors in patients with nf by physical exam and detailed medical history. hasbro children's hospital, providence, rhode island, united states background: dysautonomia is a paraneoplastic syndrome most commonly described in adult malignancies. despite current therapies aimed at symptoms management, it is often debilitating. we present a case of a -year-old girl who initially presented with autonomic dysfunction and was subsequently found to have hodgkin lymphoma. objectives: describe hodgkin lymphoma presenting with dysautonomia and discuss symptom management with rituximab design/method: case report a year-old-girl presented with severe symptoms of orthostatic hypotension necessitating prone positioning to prevent syncopal episodes. additionally, she reported anhidrosis, xerostomia, urinary retention, and constipation. she had unmanageable peripheral neuropathic pain despite multiple analgesia medications. initially, it was suspected that her symptoms were caused by an atypical presentation of guillain-barre syndrome. she was treated with intravenous immunoglobulin g, without response. due to a suspicion of a paraneoplastic syndrome a positron emission test/cat scan (pet/ct) was performed and revealed widespread fdg-avid nodal and splenic disease. pathology from a thoracoscopic biopsy of a mediastinal lymph node demonstrated classical hodgkin lymphoma. she was classified as stage ivb. a paraneoplastic panel obtained during the first cycle of chemotherapy revealed elevated anti-amphiphysin antibodies and glutamic acid decarboxylase (gad) antibodies. therapy was initiated with abe-pc (doxorubicin, bleomycin, etoposide, prednisone, cyclophosphamide) ; vincristine was held given her significant neuropathy. due to persistence of autonomic symptoms following her first cycle and presence of antiamphiphysin and gad antibodies, rituximab was incorporated into her treatment. following two cycles abe-pc, she had a rapid early response by fdg-pet/ct. she completed an additional three cycles of abd-pc. end of therapy imaging demonstrated complete response with a single persistent mildly fdg-pet avid lymph node (deauville ) and her antibodies were negative. she continues treatment of maintenance rituximab with significant improvement, but not resolution, of her orthostatic hypotension. at this time, the patient can ambulate with assistance. constipation and urinary retention have fully resolved and, her peripheral neuropathy, xerostomia, anhidrosis have improved. conclusion: this is rare case of a pediatric hodgkin lymphoma patient developing dysautonomia associated with antiamphiphysin and glutamic acid decarboxylase antibodies and subsequently managed with chemotherapy and rituximab. clinicians should be suspicious of a paraneoplastic syndrome when a neurologic disorder fails to improve with standard treatment. results: labs obtained at an outside hospital one month prior to presentation showed absolute neutrophil count (anc) and hemoglobin . g/dl. she presented to our institution with days of fever, hepatomegaly cm below costal margin, a white plaque on her tongue, and circumferential perianal ulceration. labs were significant for anc and hemoglobin . g/dl. anti-granulocyte antibody testing was positive. bone marrow biopsy showed arrest of neutrophil maturation. after initiation of filgrastim ( . mcg/kg/day), her anc increased to > and repeat bone marrow biopsy demonstrated left shifted myelopoiesis. biopsy of her oral lesion demonstrated invasive actinomyces prompting a prolonged course of antibiotics. biopsies of her oral and anal lesions were reported as myeloid sarcoma without mll rearrangement. chemotherapy was not initiated due to complete resolution of both lesions within weeks of initiating filgrastim and appropriate antibiotic coverage. she has not developed any further lesions concerning for malignancy. testing for common genes associated with severe congenital neutropenia and autoimmune lymphoproliferative syndrome was negative. her immunoglobulin levels and the measurement of age-appropriate vaccine responses were normal. after her lymphocyte subpopulation analysis indicated a selective deficiency in cd positive t-lymphocytes (absolute cd cell count ), the severe combined immunodeficiency panel from genedx showed compound heterozygous mutations in results: a male infant was born with a large thigh mass. the child was clinically well aside from restricted movement of affected leg. mri showed mass expanding into pelvis without other lesions. an interventional-radiology guided core biopsy of the mass was reported as high-grade spindle cell sarcoma without etv rearrangement. surgery was deferred because of concern that it would result in excessive morbidity. the mass was treated with vincristine and dactinomycin per infantile fibrosarcoma protocols. after months of therapy, no significant change in size of the mass was noted on physical exam or imaging. repeat biopsy was obtained to confirm diagnosis and allow for expanded tumor testing. this biopsy showed triphasic distribution of adipose, fibrous and mesenchymal tissue consistent with fhi with rare sarcomatous foci. additional chemotherapy was deferred and the child was followed clinically. his tumor has remained approximately the same size and still unresectable. next generation sequencing of tumor utilizing panel based technology revealed braf-erc fusion consistent with braf activating mutation. this mutation was confirmed by fluorescent in situ hybridization (fish) probe for braf. braf and mek inhibitors have been pursued as treatments to decrease size of tumor and allow for resection. conclusion: braf mutations have been characterized in a variety of malignancies. inhibition of braf and downstream signaling components has produced promising results in a variety of patients. this is the first case report of a braf mutation in a fhi. although management of fhi is typically surgical, this does suggest a potential therapeutic target and may allow for improved surgical outcomes especially in cases where up-front surgery would result in unacceptable morbidity. genetic sequencing of fhi and other rare tumors is an important tool and has the potential to identify mutations amenable to targeted therapies. background: icf is a rare autosomal recessive disorder characterized by hypo-or agammaglobulinemia and often opportunistic infections suggesting t-cell dysfunction. it is further categorized into subtypes - based on mutations in dna methylation. mutations in the helicase-lymphoid specific (hells) gene, which is required for t-cell proliferation and participates in de novo dna methylation, are characteristic of icf type (icf ). of approximately reported cases of icf, less than percent are characterized as icf . while malignancy has been reported in icf (angiosarcoma, acute lymphoblastic leukemia), and icf (hodgkin lymphoma), here we describe the diagnosis and management of an icf patient with neuroblastoma and neutropenia, which has not been previously described. objectives: describe a novel phenotype and mutation of icf and its management to further expand our understanding of this disease. results: a month ex- week premature male with bronchopulmonary disease and failure to thrive presented with acute respiratory failure in the setting of recent viral bronchiolitis with associated chronic diarrhea. he was subsequently diagnosed with multiple infections including pjp pneumonia, norovirus, parainfluenza, rhinovirus, and pseudemonal cellulitis. he presented with profound neutropenia and agammaglobulinemia with presence of b and t cells on lymphocyte phenotyping. ct revealed a paraspinal mass that was mibg-avid on further study, strongly suggesting neuroblastoma. bone marrow was normocellular and negative for malignancy, however revealed marked granulocytic hypoplasia and maturation arrest concerning for severe congenital or, less likely, immune-mediated neutropenia. metastatic workup was negative. whole exome sequencing revealed a homozygous variant of unknown significance (c. t>c) in the hells gene, portending a working diagnosis of icf syndrome. immunoglobulin supplementation, pentamidine prophylaxis, and g-csf were initiated. he was able discontinue g-csf after months of treatment. his neuroblastoma, initially categorized as l , met criteria for observation. however, followup mri revealed interval growth nearing the spinal canal. he underwent tumor resection, confirming mycn non-amplified, favorable histology neuroblastoma. after infectious prophylaxis and immunologic support were initiated, he incurred two other hospitalizations, the first for g-tube cellulitis and the second for parainfluenza respiratory illness. he now has stable neutrophil counts off g-csf and remains in remission from neuroblastoma. current plan is to proceed with bone marrow transplantation for immunodeficiency. conclusion: icf has not previously been described with neutropenia or neuroblastoma. this report not only describes a novel mutation and phenotype of icf and the management thereof, but also reveals the potential curative role of bone marrow transplantation in such disease. staten island university hospital -northwell health, staten island, new york, united states background: desmoid tumors are rare tumors that arise from highly differentiated fibroblasts. they occur in isolation or as part of the disease spectrum of familial adenomatous polyposis (fap) . fap mutations between codons - typically correlate with increased extraintestinal disease such as desmoid tumors and upper gastrointestinal polyps. we describe a patient with a large intra-abdominal desmoid tumor who is heterozygous for a c. c>t (p.arg cys) apc gene mutation. we are not aware of any other patients reported with this germline apc mutation presenting with a desmoid tumor. objectives: to discuss a novel apc mutation and the presentation of a rare case. design/method: review of clinical presentation, genetic analysis and management of a rare tumor. a -year-old female with no significant medical history presented with abdominal asymmetry and intermittent pain. she reported urinary urgency, shortness of breath, early satiety, decreased appetite and a -pound weight loss over the course of months. ct scan of the abdomen demonstrated a × cm abdominal tumor abutting the local organs but no presence of bowel obstruction. a biopsy revealed a spindle cell neoplasm favoring fibromatosis. there was no known family history of fap, colon cancer, or desmoid tumors. apc gene mutation analysis demonstrated a c. c>t (p.arg cys) heterozygous gene variant. due to size and location of the tumor, it was initially deemed unresectable. the patient was started on a course of monthly liposomal doxorubicin. she tolerated the initial cycles well and interval ct after cycles of chemotherapy revealed a % decrease in tumor volume. variability exists in phenotypic presentation with regards to the location of the afp mutation locus. while fap mutations associated with desmoid tumors typically have changes in the - codon region, our patient presented with a heterozygous mutation resulting in a missense mutation at codon . due to the change in polarity and size, the mutation is not considered to be of conservative nature. we are only aware of one other report of this mutation, which occurred in an individual with a personal and family history of colon cancer. we are not aware of any patients with desmoid tumors who also have this germline apc gene mutation. our case report highlights an apc gene mutation that is not well-described; we are not aware of any other cases of this mutation reported in patients with desmoid tumors. future evaluation and tracking of this mutation may lead to the determination of further clinical significance. background: over time, advanced care planning for location of death has been associated with increased deaths at home rather than in the hospital. in some cases, however, complex management and symptom control can prevent families from achieving their goal of keeping their child out of the hospital and at home at the end of life. ascites is a sequelae of many conditions including malignancy that might lead to significant morbidity. increasingly, interventional procedures are being utilized. peritoneovenous "denver" shunts are placed internally with one end in the peritoneal space and the other buried within a major vessel such as the svc. a one-way valve and pump buried under the skin allows the patient to pump fluid from the peritoneal to the vascular space. the shunt is used frequently in adults, but has not seen much use in pediatric oncology patients. objectives: to describe a case of a terminally ill patient with refractory wilms tumor with ivc involvement who received symptomatic relief with denver shunt placement. results: an -year-old female was diagnosed with relapsed, refractory, metastatic wilms tumor with pulmonary and hepatic involvement, with tumor extension to the hepatic veins and ivc. multiple chemotherapeutic regimens and palliative radiation to the ivc were administered, but her disease continued to progress, leading to pressure on the portal vein and portal hypertension. the resulting ascites was causing the patient significant pain and was difficult to manage. the patient's code status was changed to dnr/dni after discussion with her mother, who identified a desire to have the child die at home as comfortably as possible. a peritoneovenous shunt was placed in order to control the patient's pain and avoid frequent medical procedures and therapies. despite initial anxiety, the patient was able to utilize the pump and achieve significant improvement in her ascites and pain. she was able to spend the remaining six weeks of her life at home. ascites is a common phenomenon of end stage disease. peritoneovenous shunts are a treatment modality that may be considered to allow for pain control at the end of life for pediatric oncology patients with ascites. the procedure is relatively low risk, allows for self-control of the pump to maintain comfort, and is easy enough to use by the patient or family. background: extraneural metastases (enm) from pediatric glioblastoma multiforme (gbm) are rare, with an estimated frequency of . %. etiologic factors include multiple neurosurgical procedures and sarcomatous dedifferentiation. their occurrence can seriously affect the patient's quality of life and survival. while enms have been well documented in adults, pediatric cases have not been previously summarized. a year old male with a cerebral gbm developed extension of disease outside of the neuraxis approximately months post initial presentation and at the time of disease progression. metastases included exracranial temporal lesions, cervical and mediastinal lymph nodes and s of s bilateral lung nodules. a large pleural-based soft tissue metastatic focus was identified on imaging when the patient presented with respiratory distress secondary to a right tension pneumothorax, which was recognized and managed promptly. we summarize the main reported cases in literature to better define risk factors for and evaluate the proposed mechanisms underlying these systemic metastases. design/method: we performed a literature review on the pubmed database using the terms gbm and enm. patients under years of age who met the weiss criteria for the diagnosis of enm from primary cns tumors were included. results: our patient fulfilled two of the three weiss criteria with confirmed gbm at the primary site with all enm in the temporal soft tissue and cervical lymph nodes displaying histopathologic features similar to the primary cns tumor. the intrathoracic adenopathy and lung nodules detected upon chest imaging during workup for respiratory distress were assumed to represent additional metastatic foci. our literature review identified pediatric patients with enm from gbm with a median age of years (range . - years) and a slight female predominance ( % females vs. % males). the most common sites of metastases reported were pleura/lungs, bones, lymph nodes and liver. in of patients, metastases were associated with csf shunting. conclusion: pediatric oncologists should have an increased index of suspicion when caring for patients with gbm, particularly those who have undergone shunting procedures and present with systemic symptoms including bony pain, respiratory changes, transaminitis or cytopenias which should prompt timely investigation for enm. although enm of cns tumors carry very poor prognosis, their diagnosis has potential therapeutic importance because treatment of metastatic lesions may alleviate symptoms and improve the quality of life. additional studies may be warranted to evaluate the incidence of enm that can provide valuable insight into the pathogenesis and biology of high-grade gliomas. nicklaus children's hospital, miami, florida, united states background: sinusoidal obstruction syndrome (sos) has been reported in patients undergoing intensive chemotherapy and as a complication post-hematopoietic stem cell transplan-tation. sos may be complicated by portal hypertension, hepatorenal disease or multi-organ failure. however, despite treatment, there may be further potential complications that can be anticipated in patients with history sos. we report two patients with history of sos presented with post-procedural bleeding after gastric tube placement. we believe that their presentations may be associated to their previous diagnosis of sos. design/method: pubmed search was done with search for terminology including "sinusoidal obstruction syndrome" "defibrotide", and "bleeding". papers relevant to our cases were selected for literature review. results: case : a year-old female with history of desmosplastic medulloblastoma status-post resection and intensive chemotherapy was diagnosed with sos one month after her second part of planned tandem transplant. she was managed with paracentesis and defibrotide. due to malnourishment, patient had a gastric tube placement months after she completed therapy and had an episode of upper gastrointestinal bleeding postoperatively from the g tube site. case : similarly, a year-old male diagnosed with anaplastic medulloblastoma status post resection and adjuvant multiagent chemotherapy. his treatment course was complicated with sos after the second cycle of induction chemotherapy which responded to -day course of defibrotide. likewise, the patient had a major bleeding event from the g-tube site approximately two months after sos diagnosis. defibrotide was discontinued in both cases before g-tube placement. both patients had no previous history of bleeding disorders or relevant family history. in addition, comprehensive laboratory evaluations were within normal limits before both procedures. in sos, there is blockage of fluid out of the liver that leads to congestion, ascites, ischemia of the liver, and post-sinusoidal portal hypertension. two related causes of sos should be considered as an explanation for g-tube bleeding. similar patients should have close monitoring postoperatively or if possible surgical intervention should be delayed until the sos process has been evolved. nicklaus children's hospital, miami, florida, united states background: the development of treatment related acute myeloid leukemia (t-aml) and myelodysplastic syndromes (t-mds) is a potential complication after cytotoxic chemotherapy or radiation therapy. the incidence of development of t-aml/t-mds varies from - % depending on the treatment regimen used. cutaneous myeloid sarcoma (ms) is a common presentation of extramedullary leukemia and usually occurs in the setting of aml. we report a rare case of cutaneous ms in an adolescent female after successful treatment for ovarian yolk sac tumor (yst) stage i with bep (bleomycin, etoposide and cisplatin) therapy. the ms was managed only with biopsy and close observation. design/method: a pubmed search was conducted for queries including t-aml/t-mds, cytotoxic agents, cutaneous myeloid sarcoma, regression. relevant papers were selected for literature review. a year-old female was diagnosed with a left ovarian yolk sac tumor, for which she underwent left salpingooophorectomy and successfully completed cycles of bep over months. during routine follow-up months after initiation of treatment for ovarian yst, she was noted to have a small, non-tender, indurated nodule on the left side of her upper back approximately cm in diameter. punch biopsy of the skin nodule was performed and pathology was positive for cutaneous myeloid sarcoma. at the time of next follow-up less than one month later, the skin lesion had resolved. two subsequent bone marrow aspirates were performed one month apart and were negative for leukemic involvement or mds. examinations and work-up including whole body pet with ct scan were negative for evidence of disease. although cutaneous ms can be regarded as the herald of systemic myeloid disease rather than a localized process, our patient was monitored periodically with physical exam and laboratory evaluations. she remains free of disease more than four years after the presentation of cutaneous ms without any further treatment. spontaneous regression ms has been previously reported. the authors would like to stress that a conservative approach with close observation could be an option in cutaneous ms even with history of chemotherapy exposure. nesreen ali, iman sidhom, sonia soliman, sherine salem national cancer institute, cairouniversity, egypt children cancer hospital egypt, egypt background: acute leukemia is the commonest malignancy in childhood. the coincidental occurrence of leukemia with hemophilia is extremely rare. hemophilia is a congenital rare x linked bleeding disorder. the main complication of the two diseases is bleeding diathesis which may be lifethreatening due to many factors, deficiency of coagulation factors in hemophilic patients, thrombocytopenia from disease and chemotherapy in leukemic patients, certain cytotoxic drugs such as asparaginase which may result in coagulation disorders and infection which may lead to disseminated intravascular coagulation. objectives: reporting such a case is imperative to set up treatment guidelines for prevention of bleeding and to optimize the therapeutic approach for these patients. design/method: seventeen years old boy, presented to children cancer hospital egypt in june with pallor and multiple ecchymoses.he was diagnosed with precursor b acute lymphoblastic leukemia, cerebrospinal fluid (csf) was free, the chromosomal analysis revealed hypodiploidy , xy. he had moderate type of hemophilia a since birth, factor viii level was . % at time of diagnosis, coagulation profile revealed prolonged partial thromboplastin time (normal - ), factor viii was low %, prothrombin concentration and prothrombin time were normal % and seconds, virology screening for hepatitis b core igg/igm, hbs ag, hiv and hc igg /igm were negative.the patient started induction total xv sjcrh protocol, factor viii unit/kg was given at presentation before doing bone marrow aspiration(bma), csf and as a prophylactic before intramuscular asparaginase injection, intrathecal and bma. it was given immediately within hours before the procedures and platelets transfusion was given regularly to maintain platelets count about , . the minimal residual disease by flow cytometry was . % and . % at d and d induction. results: our patient received his induction and reintensification chemotherapy without any major bleeding event which reveals the success of our guidelines for the prevention of bleeding. he developed very early relapse at w maintenance by the same clone. he received salvage chemotherapy but didn't achieve remission and died out of disease and resistant clone. the development of leukemia on top of hemophilia is a major problem. bleeding complication during chemotherapy can be prevented by regular prophylactic factor viii and platelets concentrate transfusion with good supportive care. life threating bleeding complication may be correlated with the severity of hemophilia. we need to collect data about the biology of leukemic cells, complications, and cause of death to optimize care for these patients. background: mucoepidermoid carcinoma (mec) is a rare malignancy that arises from exocrine glands in the upper aerodigestive tract and tracheobronchial tree. conventionally, mec diagnosis is based on histology, with prognosis based on the extent of resection and detection of metastases. mec is characterized by a translocation of chromosomes q and p resulting in a fusion between the mect and maml genes, that occurs in - % of cases. this fusion transcript has been recognized to have a favorable impact on disease features and prognosis of mec. however, recent studies indicate that high grade mec can have mect -maml fusion positivity and multiple other genomic imbalances that have not been studied in much detail. owing to the rarity of mec tumors, more definitive data related to the clinical and prognostic significance of these molecular markers are limited. objectives: . identify the presence or absence of mect -maml fusion in the tissue of our patient. . analyze the incidence of the fusion in mec cases in children and young adults retrieved from the iowa cancer registry. . determine if fusion status correlates with clinical, pathological and outcome data in our cohort. design/method: we describe the case of a year-old caucasian male who presented with recurrent pneumonia, persistent cough and radiographic evidence of right lobar collapse. bronchoscopy revealed an endobronchial lesion and the patient underwent right upper lobe sleeve resection. pathology report was consistent with low grade muco-epidermoid carcinoma. we retrieved archived formalin-fixed paraffinembedded (ffpe) specimens of pediatric and young adult mec cases (ages - ) reported in iowa from - using the iowa cancer registry. testing for the mect -maml fusion in the index case and ffpe specimens will be done using a custom-designed laboratory validated next generation sequencing (ngs) assay with the ability to detect novel fusion partners. clinical, pathological and outcome data (age, sex, tumor site, tumor size, nodal metastases, clinical stage, histologic grade, treatment and follow up) will be analyzed to correlate with fusion status. the mect -maml fusion tested positive in our index patient. we will obtain irb approval to test for the fusion in the archived ffpe specimens and correlate clinical, pathological and outcome data. conclusion: mect -maml fusion is a frequent event in mec that has prognostic and potential therapeutic applications in adults. the results of this study may enlighten the clinical management of mec in children and young adults. children 's mercy hospital, kansas city, missouri, united states background: mutations in the samd gene are associated with a rare syndrome comprising of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (mirage syndrome). diagnosis is made through exome sequencing. in the largest reported case series, of eleven patients diagnosed with mirage syndrome, two developed loss of chromosome . given the potent growth restricting activity of samd mutants, the loss of chromosome is considered the first documentation of adaptation by aneuploidy mechanisms in humans and led to myelodysplastic syndrome (mds), with deaths occurring from related complications at and years of age. objectives: to report a case of mirage syndrome with congenital thrombocytopenia progressing to bone marrow failure, managed uniquely with bone marrow transplantation. results: male born at weeks gestation with prenatal diagnosis of iugr, two vessel cord, oligohydramnios was found to have ambiguous genitalia, adrenal insufficiency, partial panhypopituitarism and congenital thrombocytopenia with bone marrow showing absence of megakaryocytic precursors. severe thrombocytopenia was present from birth. bone marrow evaluation demonstrated a hypocellular marrow with markedly reduced megakaryocytic and myeloid precursors and no evidence of myelodysplasia. he required gastric tube placement for failure to thrive, had a laryngeal cleft repaired and developed focal segmental glomerulosclerosis. mpl gene testing for congenital amegakaryocytic thrombocytopenia was negative. testing for fanconi anemia, shwachman-diamond syndrome and dyskeratosis congenita was also negative. approximately % of cells had loss of heterozygosity on chromosome q. exome sequencing showed that he is heterozygous for a de novo gain of function variant, c. g>a (p.arg gln), identified in the samd gene, confirmed by sanger sequencing and consistent with a diagnosis of mirage syndrome. at years of age, he developed pancytopenia requiring frequent transfusions with platelets and packed red blood cells. he underwent a successful bone marrow transplant at years of age without significant complications, and remains transfusion independent without cytopenias greater than months from bone marrow transplantation. conclusion: it is imperative to pursue work up for persistent congenital thrombocytopenia in a stepwise multidisciplinary manner. to the best of our knowledge, this is the first case of mirage syndrome associated bone marrow failure treated with bone marrow transplant. due to the individual rarity of mirage syndrome and pediatric myelodysplastic syndrome, it is important to maintain an index of suspicion given their association and explore bone marrow transplant as a therapeutic option. results: the patient demonstrated disease regression, initially, and continued without disease progression for months. the regimen has been well tolerated with only minimal side effects of dry skin (ctcae grade ) and a transient episode of brief erythrodysesthesia (ctacae grade ) that resolved spontaneously. the combination of sorafenib and capecitabine was effective and well tolerated in this adolescent patient with fl-hcc. our observations, although in a single patient, lend support for further testing of this novel oral chemotherapy regimen in patients with fl-hcc, a disease for which there is no effective standard chemotherapy approach. background: epstein-barr virus (ebv) is a ubiquitous virus associated with a broad range of malignancies due to its oncogenic potential. history of organ or bone marrow transplantation, immunosuppressive therapy, and primary or acquired immunodeficiency syndromes increases the risk of ebvassociated tumors. epstein-barr virus associated smooth muscle tumors (ebv-smt) are unique and rare neoplasms typically discovered in immunocompromised patients. most information related to pathogenesis and therapeutic options is limited to case reports and case series of adult patients. there are several gene expression pathways that ebv utilizes, the most notable of which is the mammalian target of rapamycin (mtor) pathway. the mtor pathway performs a key role through integrating various cell growth signals and factors to regulate protein synthesis and metabolism related to smooth muscle proliferation. sirolimus is an immune modulating therapy that targets the mtor pathway to block activation of lymphocytes. objectives: several case reports have demonstrated shortterm clinical remission of ebv-smt in adult patients with the use of sirolimus. we report the first case of long-term background: bilateral neuroblastoma is characterized as neuroblastoma arising in both adrenal glands, a rare presentation with little data on its genetic make-up. a two-monthold patient was diagnosed with bilateral neuroblastoma in our clinic. her risk assignment was based on biopsy of the left adrenal lesion, which showed mycn amplification, an unfavorable genetic marker. treatment regimen was intensified accordingly and after courses of chemotherapy tumors were excised. patient went on to receive a stem cell transplant and immunotherapy. with no knowledge of genetic similarity between the two tumors it is unclear whether biopsy of the right lesion would have yielded similar results or whether bilateral biopsies are needed for risk assessment of bilateral neuroblastoma. objectives: utilize whole exome sequencing (wes) to characterize the genomic signature of bilateral adrenal neuroblastomas excised following chemotherapy treatment. design/method: paraffin-embedded samples from left (l) and right (r) tumors underwent wes at the broad institute. we analyzed resulting data including somatic variant calls, indel mutations, and copy number variants (cnvs) using ingenuity software to evaluate and compare differences between the two tumor samples. preliminary analysis of the data shows important descriptive information on the two tumor samples. out of somatic mutations in the r tumor cells and mutations in the l tumor cells, only two common somatic mutations were present. out of cnv calls in the r tumor and in the l tumor, cnvs were common between the two tumors, or % of each tumor's cnv calls. there was a fold higher frequency in gains versus losses. the median size of the common cnvs was , (range to , , bp). cancerrelated genes with increased copy numbers included transcription factors, receptors for signal transduction pathways, and histone methylation proteins. conclusion: preliminary analysis of the wes results of the two adrenal tumors show some genomic divergence. because the tumor tissue was exposed to chemotherapy prior to excision it is difficult to determine whether genomic divergence is a result of independently originated tumors or subsequent adaptation to chemotherapy of a clonal cell population. the high number of common cnvs in the two tumors points to a common cell of origin, however the low number of common somatic mutations does not fit that picture. a future study to help elucidate the question will be wes of the original biopsy tissue to provide information on tumor mutations prior to the effects of chemotherapy. baylor college of medicine, houston, texas, united states background: although there has been significant improvement in the overall survival rates of children with cancer many children will still die from their illness or complications secondary to treatment. research surrounding the deaths of children who succumb to their disease is warranted to ensure we are providing the best care possible for these patients. objectives: this case series aims to explore pediatric cancer deaths by focusing on perhaps the most extreme cases of high intensity end of life care. we explore those patients whom we know are dying or our very likely to die as evidence by their do not resuscitate (dnr) orders. in all of these cases despite the patients very grim prognosis, their great likelihood of death and limitations placed of resuscitation methods all patients continued end of life care in the pediatric intensive care unit (picu). the primary medical records of all children with a cancer diagnosis who died between february , and january , in the picu with a dnr order seven days or earlier prior to death. each medical history included disease-directed treatment history and response with particular attention to the events surrounding the terminal admission. results: eight patients met criteria for this study representing . % of all cancer patients who died during this time period and . % of those who died in the icu. the average time between dnr and death is . days ( days - days). the average length of terminal admission was . days ( day - days). the average time between diagnosis and dnr is . months ( months - months). the average time between diagnosis and death is . months ( months - months). conclusion: these cases highlight the journey that patients, families and providers endure leading up to death. medical care is complex, there are very few absolutes that are encountered when caring for patients and decisions around limiting or withdrawing medical care are made in a context of the prior journey. . these cases help to understand the complexity of death and how two seemingly opposite ideals can be congruent in the event of an anticipated death. most of these cases show the need for improved anticipatory guidance surrounding death and greater consideration for de-escalation of care when death is expected. the hospital for sick children, toronto, ontario, canada background: rhabdomyosarcoma (rms) is the most common soft tissue sarcoma in children, with embryonal (erms) and alveolar (arms) representing the most common subtypes. arms tumors are associated with inferior outcome when compared to erms, and they are characterized in about % of the cases by a t ( ; ) or t( ; ) chromosomal translocation with creation of a pax -foxo or pax -foxo fusion gene, respectively. it is increasingly clear that the pax-foxo fusion status is an important poor prognostic factor, thus the histological classification tends to be replaced by the fusion status, particularly in terms of risk stratifica-tion in contrast to arms, there are no recurrent chromosome alterations in erms; however, there are multiple numerical chromosome changes that are frequent in these tumours: gain of chromosome , , and have been found in to % of emrs karyotypes. moreover, erms tumors show frequently allelic loss, the .p . chromosomal region being the most frequently involved. recently, novel gene fusions have been described also in erms tumours. these fusions involved mainly the ncoa and or the vggl genes. the rearrangement partners are variable, and include, i.e. pax ( q ), srf ( q ) and tead ( p ). objectives: to present a patient who died as a consequence of brain metastases while on therapy in the setting of an foxo negative rms and the identification of a new translocation t( ; )(q ;q ). design/method: case report and retrospective review of the literature. we report a case of pelvic embryonal rhabdomyosarcoma in a -month old boy. he was treated as per cog arst intermediate risk group, but unfortunately was found to have a large cerebellar tumour during the course of his chemotherapy treatment and he subsequently passed away. a novel translocation between chromosomes and was observed in of metaphase cells by g-band analysis in the autopsy sample of the brain lesion. breakpoints of the translocation were estimated to be at q and q . there were no additional clonal chromosome abnormalities in the tumour cells. conclusion: erms tumors with fusion genes involved have been exclusively described in patients less than months of age; they seem to be associated with spindle cell histology and, a favorable outcome. in our patient, a novel ( ; ) translocation was found and clinically, the patient had a dismal outcome. further studies are indicated to inquire whether this finding is of significance in term of prognosis for these patients. children 's national medical center, washington, district of columbia, united states background: iatrogenic immunodeficiency-associated lymphoproliferative disorders (lpds) are a group of lymphoid s of s proliferations or lymphomas that are well known to be associated with an immunosuppressed state. these disorders most commonly occur following hematopoietic or solid organ transplantation (called post-transplant lymphoproliferative disorders or ptld), but cases have also been described during the treatment of autoimmune and rheumatologic disorders by immunosuppressive and immunomodulatory medications. these disorders are strongly associated with infection by the epstein-barr virus (ebv) as a result of impaired immune function in the immunosuppressed state. while this phenomenon has been well documented in autoimmune conditions, cases affecting pediatric patients while on antileukemia chemotherapy are lacking. background: atypical teratoid/rhabdoid tumor (at/rt) of the central nervous system (cns) in children younger than years old has a prevalence of % to % and accounts for . % of all pediatric cns tumors. only - % of patients have leptomeningeal dissemination. rhabdomyosarcoma is the most common soft tissue tumor in childhood, but represent only - % of all pediatric cancers. rarely, it can metastasize or even directly extend into the cns, but typically, cases of cns involvement arise either from parameningeal areas or other primary sites. primary spinal or meningeal rhabdomyosarcoma is extremely rare. objectives: our objective is to describe two unique cns malignancies presenting as rare, primary leptomeningeal disease. design/method: case a -month-old female presented with vomiting, fatigue and listlessness, despite a normal head ct and brain mri. csf showed hypoglycorrhachia and mild pleocytosis. ceftriaxone was started, but she developed nuchal rigidity and cranial nerve vii palsy. repeat brain mri showed evolving leptomeningeal enhancement concerning for meningitis. she gradually developed worsening opisthotonus and ultimately a brain biopsy of the temporal lobe was consistent with at/rt. case a -year-old male presented with new generalized tonic-clonic seizure activity and intermittent headaches with photophobia, phonophobia, and vomiting. brain mri was significant for enhancement of interpenducular and suprasellar cisterns extending to the optic nerves and chiasm most consistent with meningitis. neurosurgery ultimately placed a lumbar drain for hydrocephalus, and a tissue biopsy demonstrated primary meningeal rhabdomyosacroma. results: in case , our patient's temporal lobe biopsy demonstrated grade iv malignant tumor cells consistent with atypical teratoid/rhabdoid tumor. fish demonstrated a homozygous deletion of smarcb ( q . ). she was started on chemotherapy per the dana farber at/rt protocol but ultimately was discharged home on hospice. in case , our patient's lumbar arachnoid biopsy demonstrated cellular tumor consistent with group iiia embryonal rhabdomyosarcoma. immunostaining was positive for cd , desmin, myogenin, and myo-d with neural markers ema and gfap highlighting the meninges but without a neural component to the tumor. he completed craniospinal radiation to gy total with lumbar boost to . gy total. he is currently receiving chemotherapy per arst protocol. conclusion: these two cases are particularly instructive because of their similar initial presentations and neuroimaging, but with very different and unique diagnoses. university of iowa, iowa city, iowa, united states background: ebf -pdgfrb fusion causes ph-like b-cell acute lymphoblastic leukemia (b-all), which has a philadelphia positive phenotype without the bcr-abl translocation. this is one of several mutations associated with ph-like b-all and leads to downstream overexpression of tyrosine kinase. ebf -pdgfrb fusion accounts for about % of children with ph-like b-all. patients with ph-like b-all previously had poorer outcomes with conventional chemotherapy. the addition of tyrosine kinase inhibitors (tki), like imatinib, has improved the outcome for many patients predicted to have tki sensitive mutations. objectives: to review clinical characteristics and outcomes of two cases of ph-like b-all at the university of iowa stead family children's hospital and to compare these outcomes to similar cases reported in the literature. design/method: a retrospective chart review was performed for two cases of ph-like b-all diagnosed and treated at the university of iowa stead family children's hospital. results: both patients were males diagnosed at years of age with high wbc count ( , and , ) and positive for ebf -pdgfrb gene fusion. patient (pt ) was cns b at presentation while patient (pt ) was cns negative; neither had testicular involvement. both started treatment according to cog protocol aall . peripheral blasts cleared by induction day for pt and induction day for pt . at end of induction, pt had m bone marrow and pt had m bone marrow but mrd %. dasatinib was started induction day for pt and induction day for pt . pt was still not in remission at end of consolidation; bone marrow cell culture for tki resistance showed best response to dasatinib. pt proceeded to anti-cd car t-cell therapy followed by tbi-based matched unrelated donor bone marrow transplant. pt had negative mrd at the end of consolidation and continues chemotherapy according to aall , dasatinib arm. both patients are currently clinically well. our patients had the same tyrosine kinase gene fusion and similar initial clinical courses. while both patients had persistent disease at end of induction, pt had almost % blasts while pt had significant reduction of disease burden before starting tki. pt showed good response with the addition of dasatinib while pt did not. these findings suggest that response to conventional chemotherapy may potentiate the effect of tki and may predict overall outcome. there are likely additional factors which must be taken into account when determining response to tki for patients with ph-like b-all which have not yet been identified. background: medulloblastoma is the most common malignant brain tumor of childhood. classically, medulloblastoma presents as a well-defined mass lesion in the cerebellum, with a high rate of metastatic dissemination. primary leptomeningeal medulloblastoma (plmb) is an exceedingly rare type of medulloblastoma presentation with a dismal prognosis in which patients present with isolated leptomeningeal disease without an associated mass. to our knowledge, only three pediatric and three adult cases of plmb (ages - years) have been reported, all of which died within months of diagnosis. this is the first case of plmb to report a molecular classification. objectives: to report the case of a pediatric patient with plmb in which histopathologic and molecular characterization was performed and to describe the patient's treatment and clinical course. design/method: retrospective review of the patient's electronic medical record and review of the literature. a -year-old boy presented with headache, vomiting, diplopia, and fatigue. physical examination revealed upward gaze palsy, left-sided extremity and facial weakness, and ataxia. magnetic resonance imaging (mri) of the brain revealed diffuse cerebellar leptomeningeal enhancement and edema without an identifiable mass and moderate hydrocephalus. mri of the spine and cerebral spinal fluid analysis were normal. a diagnosis of cerebellitis was rendered, and the patient underwent placement of a ventriculoperitoneal shunt. an extensive infectious, neurologic, rheumatologic, and oncologic workup did not identify an etiology. empiric antibiotics, high-dose steroids, and intravenous immunoglobulin therapy yielded minimal improvement. two months later, repeat mri of the brain performed for declining mental status demonstrated progressive thickening of cerebellar leptomeningeal disease. a suboccipital craniectomy with decompression and cerebellar biopsy were performed. pathologic examination revealed a diagnosis of plmb, classic histology, non-wnt/non-shh, without gain/amplification of myc/mycn, and p wild type pattern. craniospinal radiation to cgy with a cgy boost to the posterior fossa was delivered with concurrent carboplatin/vincristine over six weeks. two months following chemoradiation, mri of s of s the brain demonstrates significantly reduced pathological leptomeningeal enhancement of the cerebellum, and the patient is awaiting initiation of systemic chemotherapy while recovering from a surgical wound infection. conclusion: plmb is extremely rare but should be considered in patients with cerebellitis and diffuse leptomeningeal involvement who are refractory to medical management or in whom an etiology has not been identified. cerebellar biopsy is recommended early to enable timely treatment and improved outcomes. molecular classification should be performed in cases of plmb to further characterize this disease, inform treatment decisions, and improve clinical outcomes. background: primary intracerebral osteosarcoma is extremely rare and limited to case reports. ptpn gain of function is associated with noonan syndrome, which has increased risk of multiple cancer types including brain tumors, but osteosarcoma has never been described. ptpn mutations have been reported in many cancers as both oncogenes and tumor suppressors, however no ptpn mutations have been described in osteosarcoma. pdgfr-a is a growth factor receptor whose activation is implicated in several malignancies. pdgfr-a and ptpn concurrent mutations are described in glioblastoma. there is no known link between holoprosencephaly, noonan syndrome, and osteosarcoma. we report a case of multifocal intracerebral osteosarcoma in a child with lobar holoprosencephaly and chronic subdural hemorrhage and discuss the genetic changes found in the tumor. design/method: a seven-year-old caucasian female, with a known diagnosis of lobar holoprosencephaly, chronic subdural hemorrhage and well controlled seizure disorder presented with status epilepticus shortly after completing antibiotic therapy for infection of subdural hematoma. mri showed diffuse dural thickening with mass lesions in the frontal lobe, temporal lobe, and the parasagittal region, the largest of which was contiguous with the subdural space but none of the lesions were associated with bone on mri or by direct neurosurgical visualization. tissue obtained for concern for recurrent infec-tion resulted in a diagnosis of high grade osteosarcoma. dna analysis was performed to help guide treatment choice. results: standard metastatic work-up was negative for skeletal primary tumor or metastatic lesions outside of the brain. she was treated with high dose methotrexate for two cycles per modified aost . despite maximal supportive care, she quickly developed rapid tumor growth as well as intratumoral hemorrhage with resultant herniation and death from respiratory failure just three months after diagnosis. tumor gene sequencing discovered three mutations with described roles in cancer: pdgfra d >vr, kdm a loss of exons - , and ptpn a v. conclusion: to our knowledge, primary multifocal extraosseus intracerebral osteosarcoma has not been previously described. despite known cns penetration of high dose methotrexate, this tumor proved resistant and aggressive. holoprosencephaly is associated with a multitude of known genetic drivers, but none are found in this case. furthermore, the genetic changes in this tumor are not typical for osteosarcoma. pdgfr-a over-expression is described in osteosarcoma, but is not clearly correlated with worse overall survival. further research is required to determine the role of ptpn in osteosarcoma. background: anaplastic lymphoma kinase (alk) encodes a receptor tyrosine kinase whose activation induces pathways associated with cell proliferation, angiogenesis, and cell survival. alk rearrangements are rare in neuroblastoma, while alk mutations and gene amplification occur more frequently. alk mutations have been found to be associated with increased alk protein expression that is associated with a worse prognosis. alk is commonly mutated in neuroblastoma at three hotspots (f , r , and f ). the eml -alk rearrangement has mostly been associated with lung adenocarcinomas, with only a few cases of non-lung cancers found. it has never been reported in neuroblastoma. multimodal therapy and to report the successful management of treatment related iron overload. results: a -year old male presented with abdominal swelling and ct showed a right kidney mass and bilateral lung nodules. he underwent right radical nephrectomy with lymph node sampling. pathology was reviewed centrally and revealed wilms tumor with diffuse anaplasia with rhabdomyosarcoma arising within the stromal component and of nodes positive. he received adjuvant intensive chemotherapy and radiation to the hemiabdomen and whole lungs. the -week chemotherapy regimen was vincristine, doxorubicin, cyclophosphamide (per cog arst ) alternating with carboplatin and etoposide (per cog aren revised uh- ). treatment was complicated by multiple episodes of fever and neutropenia and anorexia requiring g-tube placement. post-therapy, he had persistent neutropenia and thrombocytopenia without related complications. every months for evaluations he underwent a bone marrow which revealed normocellular marrow with maturing trilineage hematopoiesis. evaluation for a bone marrow failure syndrome was unrevealing. starting at months into therapy and all posttherapy imaging showed splenomegaly. he received units of packed red blood cells through the duration of therapy. he was diagnosed with iron overload based on serum ferritin and imaging, including t *mri. he received therapeutic phlebotomy for years with normalization of serum iron studies, t * of the heart, and liver iron concentration. he is more than years from completing therapy with no evidence of recurrent disease. asymptomatic cytopenias persist and he has no evidence of iron overload. conclusion: though a rare development, clonal sarcomatous transformation can occur in wilms tumor. our patient's tumor was successfully treated with intensive multimodal therapy targeting the diffusely anaplastic wilms and the rhabdomyosarcomatous component. treatment-related iron overload in a pediatric patient with a solid tumor was successfully treated with phlebotomy. consideration should be given to screen patients with solid tumors who receive multiple packed red cell transfusions for iron overload at the completion of cancer therapy. primary children's hospital, university of utah, salt lake city, utah, united states background: malignant solid tumors are less frequently encountered in infants. primitive myxoid mesenchymal tumors of infancy (pmmti) are a myofibroblastic malignancy and cases are rarely reported in the literature. cure is achieved in the majority of cases with surgical resection, however treatment for unresectable cases remains an enigma. recently published literature postulates that the newly discovered bcor duplication found in pmmti is tumorigenic via an epigenetic pathway. this molecular signature resembles that of clear cell sarcoma of the kidney (ccsk) and the growing number of bcor mutated sarcomas. a similar chemotherapeutic backbone and local control used for ccsk, has been proposed for the unresectable subset of pmmti. utilizing this approach a month-old with relapsed disease has remained disease free for months. however, given the rarity of this disease and the lack of published literature, there is no known standard of care treatment for unresectable and/or recurrent ppmti. we report a case of unresectable recurrent pmmti, a rare infant tumor, with less than cases reported. design/method: medical record, radiological studies, pathology and literature was reviewed. results: our patient is a now month-old female who presented with constipation and lower extremity weakness in the first weeks of life. an mri demonstrated a large lumbar epidural mass with spinal cord impingement. given prolonged (> days) neurological symptoms and location, emergent chemotherapy was initiated. biopsy showed a bcor positive, primitive myxoid mesenchymal tumor of infancy (pmmti). she was treated with ifosfamide, carboplatin and etoposide, and demonstrated clinical and radiographic response. we gave two additional cycles of cyclophosphamide, carboplatin and etoposide until surgical resection was feasible followed by two post-surgical cycles of chemotherapy. unfortunately, four month post-therapy mri demonstrated two new lesions; an unresectable paraspinal soft tissue mass and a left iliopsoas groove mass. given bcor association and reported successful therapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide, we elected to incorporate vinca-alkaloid and anthracycline into her regimen. she is being treated with vdc/ie with plan for radiation consolidation. conclusion: pmmti is a locally aggressive tumor, for which surgical resection is curative. for those not amendable to resection, best care practices are still being determined. we report a case of pmmti initially responsive to chemotherapy, but not curative. this is the second case to conclusively demonstrate chemo-responsiveness. bcor mutation seems to be a common feature of this cancer; its role in the pathogenesis and as a target is an area of investigation. medical college of wisconsin, milwaukee, wisconsin, united states background: atypical teratoid/rhabdoid tumors (atrt) are central nervous system (cns) tumors that most commonly occur in very young children. there is no widely accepted standard of care for atrt patients, and while survival rates are improving they are historically poor. patients with metastatic disease to the spine at diagnosis have a worse prognosis, and for patients > years old, the presence of metastatic disease often results in the use of craniospinal radiation. the importance of correctly identifying metastatic disease at diagnosis aids in decision making and can have both prognostic and therapeutic implications. mr imaging at diagnosis is used to identify metastatic disease; however, here we present a case of diffuse leptomeningeal enhancement that spontaneously resolved after resection of a primary supratentorial atrt. objectives: to describe the resolution of diffuse leptomeningeal enhancement after resection of a primary atrt tumor in a -month-old prior to any adjuvant therapy. results: a -month-old male presented with a month history of vomiting and weight loss, regression of gross motor developmental milestones, and left hemiparesis. a brain mri demonstrated a × . × . cm solid and cystic right atrial mass with diffusion restriction and post-contrast enhancement. smooth diffuse enhancement was noted along the surface of the brainstem and within the interpeduncular fossa. a spine mri demonstrated diffuse circumferential post-contrast enhancement along the surface of the entire spinal cord. the patient underwent a successful near total surgical resection of the primary mass. pathology confirmed the loss of ini- staining in tumor cells, consistent with a diagnosis of atrt. no immediate adjuvant radiation or chemotherapy was given. repeat imaging was completed days after resection. brain mr demonstrated expected post-operative changes within the surgical cavity without definitive residual mass or leptomeningeal enhancement. spine mr demonstrated complete resolution of the previously seen circumferential enhance-ment along the entire spinal cord. csf evaluation at that time was negative for tumor cells. after recovery from surgery, chemotherapy treatment was initiated. conclusion: leptomeningeal enhancement at the time of diagnosis of atrt has historically been considered clear evidence of metastatic disease. this case raises questions about the previously accepted etiology of these imaging changes and suggests that widespread leptomeningeal enhancement should be carefully interpreted in future patients with similar imaging findings. in this setting, clinicians should consider repeat imaging following primary surgical resection in order to provide appropriate prognostic information and inform therapeutic decisions. poster # primary ewings sarcoma of cervical cord mimicking cauda equina syndrome sucharita bhaumik, joshua chan nyu winthrop hospital, mineola, new york, united states background: ewing's sarcoma (es) is a malignant primary bone tumor usually involving long bones. primary es of spine is quite uncommon ( . %) and its location in the cervical spine is even more rare. cauda equina syndrome (ces) is symptoms due to damage to the bundle of nerves below the end of the spinal cord known as the cauda equina (low back pain, radiating shooting pain down the legs, paraplegia, and loss of bowel or bladder control). it often occurs with lesions of lumbosacral spine. treatment with high-dose steroids may provide pain relief and improved neurologic function (by reducing edema) while awaiting diagnostic studies objectives: to demonstrate an unusual clinical presentation and emergent management of cervical es presenting with ces like symptoms. : year old male presented with a left sided posterior neck mass. soon after, he developed weakness of left arm, urinary and stool retention and inability to walk or bear weight in both legs. on physical exam a left tempero-occipital × cm fixed, non-tender, non-fluctuant mass was noted as well as motor and sensory impairment of left upper extremity, bilateral spastic paraplegia and loss of sphincter control. mri cervical spine showed a left cervical tumor with moth eaten appearance involving the vertebral bodies of c -c , adjacent muscles, displacing vital structures of the neck and compressing the cervical spinal cord. the thoracic and lumbosacral spine had no disease involvement. due to rapidly worsening spinal cord compression he was emergently treated with high dose steroids. he gained back all function in his extremities and regained bowel and bladder control. this eliminated need for urgent neurosurgical intervention. results: biopsy of the neck mass showed small blue round cells consistent with es with ewsr gene rearrangement. staging work up revealed no additional metastatic involvement. he then initiated treatment for localized es with systemic chemotherapy and radiotherapy and has had excellent response to treatment so far. conclusion: this is the first known case of non metastatic primary cervical es mimicking ces where an acutely enlarging mass presented with rapidly progressive neurologic deficits due to compression of anterior spinothalamic tract. in these unusual presentations of ces without lumbodorsal involvement it is important to consider cervical lesions. early rapid steroid initiation should be considered while awaiting biopsy results to prevent worsening cord compression followed by es focused treatments. this increases the chance of a successful outcome. the initial improvement with steroids may confuse the tumor with being a lymphoma children 's mercy hospital, kansas city, missouri, united states background: von willebrand disease (vwd) is a relatively common bleeding disorder with a high degree of genotypic and phenotypic variation. bleeding is usually mucocutaneous but can be severe and include muscle and joint bleeds especially in type vwd patients. most common bleeding management consists of desmopressin, anti-fibrinolytics, and/or plasma-derived antihemophilic factor/von willebrand factor (ahf/vwf) complex. a recombinant vwf has become available in the last few years. anaphylaxis and inhibitor development in vwd are rare. objectives: to describe the rare clinical manifestation of anaphylaxis to factor concentrate in a patient with severe type vwd. results: a -year-old female with severe type vwd [baseline vwag %, activity < %, factor viii (fviii) %] originally presented with heavy menstrual bleeding (hmb) leading to anemia requiring blood transfusion. she underwent placement of a levonorgestrel-releasing intrauterine device (lngiud) and began norethindrone. her hmb continued despite the lngiud and an increase in norethindrone dosing. plasma derived ahf/vwf complex was administered, which she had previously received. following the infusion, the patient developed anaphylaxis with hives, wheezing, tachycardia, and itching requiring doses of diphenhydramine and dose of hydrocortisone with resolution of symptoms. subsequently, she received recombinant vwf without incident. however, due to her low fviii level, she also required treatment with a full length recombinant fviii product. she again developed hives and itching after this infusion. she has since received recombinant vwf with recombinant fviii/fc fusion protein without further allergic reaction. there was no evidence of an inhibitor with her most recent post-infusion vwf level was %, factor viii %. conclusion: anaphylaxis to plasma derived factor products has been documented far less frequently within the vwd population compared to those with hemophilia and is typically seen in those with large gene deletions, usually with type disease. therefore, similar type vwd patients with severe disease may benefit from gene sequencing. it is unclear in this patient's case to which aspect of her treatment she is allergic, as she reacted to plasma-derived ahf/vwf and full length recombinant fviii, but not recombinant vwf or recombinant fviii/fc fusion protein. we hypothesize that she may be allergic to an epitope in the fviii b domain, or that the presence of fc fusion may have had a protective effect. further investigation including genetic analysis is planned. nodules. biopsies were consistent with neuroendocrine carcinoma, large cell type (g ). next generation sequencing revealed a khdrbs -braf fusion. he received conventional cytotoxic chemotherapy regimens both with cisplatin/doxorubicin, capecitabine/temozolomide, and doxorubicin/etoposide, but achieved a minimal response followed by rapid disease progression, massive ascites, and renal failure secondary to bilateral ureteral obstruction. results: based on his prior genomic testing, therapy with single agent mek inhibitor (trametinib) was initiated. this produced a rapid, dramatic response with greatly reduced disease burden at all sites, resolution of ascites and return to completely normal activity within months. this response lasted for approximately months before the tumor again progressed. further therapy with an erk inhibitor was ineffective, and the patient expired from progressive disease. located on the chromosome q , the braf oncogene, as part of the ras/mapk pathway, is involved in cellular proliferation, differentiation, migration, and apoptosis. braf mutations are recognized in a wide range of adult malignancies: thyroid cancers, non-small cell lung cancer, cholangiocarcinoma, ovarian cancers, and multiple myeloma. braf mutations have also been described in adult neuroendocrine carcinoma of the colon. trametinib is a highly specific inhibitor of mek /mek , a downstream mediator in the braf pathway. it has demonstrated activity in a number of tumors including advanced melanoma and gliomas. trametinib was chosen for this patient based on his atypical braf fusion. we believe this is the first documented case of its successful use in neuroendocrine carcinoma in the pediatric population. conclusion: this case demonstrates the presence of braf fusion in a case of pediatric neuroendocrine carcinoma and significant response to single agent mek inhibition in this context. this cases raises the question as to whether the combination of a targeted inhibitor, in addition to either conventional chemotherapy or other braf inhibitors, might offer a better approach to therapy than current treatment options. albany medical center, albany, new york, united states background: warm autoimmune hemolytic anemia (waiha) is characterized by autoantibody, and occasional complement binding of protein antigens, on the surface of red blood cells at temperatures ≥ oc resulting in targeted destruction. we describe the case of a year old male with a history of evan's syndrome, poor immune response to vaccines and lymphoid hyperplasia, presenting with altered mental status and severe anemia, found to have a warm igg pan agglutinin with evidence of both intra and extravascular hemolysis. his course was complicated by respiratory failure requiring intubation, pulmonary emboli, enterococcus bacteremia and hypertension. he received multiple transfusions with only transient increases in hemoglobin. the aiha was refractory to multiple rounds of treatment with high dose steroids, ivig, rituximab, cyclophosphamide, bortezomib, plasma exchange and mycophenolate mofetil (mmf). objectives: given the refractory nature of our patient's aiha the decision was made to trial eculizumab, a monoclonal antibody targeting c complement, preventing its cleavage and activation, and shown to be effective in treatment of atypical hemolytic uremic syndrome and hemolysis due to an igm cold agglutinin. prior to eculizumab infusion, ch and sc b- assays were significantly elevated. design/method: the patient was given two doses of eculizimab days apart. results: his hemoglobin steadily rose independent of red cell transfusions with a corresponding decrease in reticulocyte count, ldh and ch levels. the patient has remained stable with a normal hemoglobin ( - g/dl) on maintenance steroids and mmf. although we cannot definitively conclude that eculizumab directly caused his recovery, the clinical course post-eculizumab suggests this may be an efficacious treatment for aiha. genetic testing showed monoallelic frameshift mutation of the nfkb gene and monoallelic missense mutation of the dock gene. given the role of nfkb in both immunodeficiency and autoimmunity, it is thought that the patient's phenotype is due to nfkb haploinsufficiency and he is currently considering hematopoietic stem cell transplant. st. joseph's regional medical center, paterson, new jersey, united states background: heterozygous -thalassemia typically manifests as thalassemia minor, characterized by mild microcytic hypochromic anemia with minimal clinical ramifications. coinheritance of -globin gene triplication has been reported to exacerbate the clinical and hematological phenotype ofthalassemia trait, due to increase in the alpha/non-alpha-chain imbalance. reported phenotypes range from asymptomatic thalassemia minor to moderate thalassemia intermedia, usually diagnosed in adulthood without transfusion dependence. this combination has been described in mediterranean, european and asian populations, but rarely reported in hispanics. objectives: to report two cases of unusually severethalassemia intermedia in hispanic patients with heterozygosity for triplicated -globin gene and a ( )-thalassemia allele. results: case : sixteen-month-old male of mexican descent presented with persistent microcytic anemia and jaundice. peripheral smear showed nucleated rbcs with basophilic stippling and target cells. hemoglobin electrophoresis revealed: hba- %, hbf- %, hba - . %. -globin gene testing revealed heterozygosity for ( ) mutation (ivsi-i, g→a). given the unusually severe anemia, -gene testing was performed which showed -globin gene(anti . ) triplication ( / ). at four years, he had splenomegaly and bilateral maxillary prominence. head ct showed irregular contour of the parieto-occipital region due to medullary expansion. due to significant persistent anemia ( - g/dl) and progressive bony deformities of the skull, patient began chronic transfusions at age eight after family declined splenectomy.case : fifteen-year-old female, of peruvian and honduran descent, presented for evaluation prior to cholecystectomy for gallstones and recurrent ruq pain. father had known thalassemia trait. her hb was . g/dl with hypochromia, microcytosis, and target cells. electrophoresis indicated -thalassemia trait (hba- %, hba - . %, hbf- . %), confirmed by gene testing (heterozygous for a ( ) mutation in codon c>t). given jaundice and gallstones, -globin gene analysis was ordered showing triplication ( / ). ruq pain resolved post-cholecystectomy, but she developed persistent painful splenomegaly. she began hydroxyurea to increase gamma-globin production and decrease excess alpha chains, but it was discontinued due to hematological toxicity. due to recurrent luq pain and progressive splenomegaly, she underwent laparoscopic splenectomy at age with resolution of symptoms and improved hemoglobin. conclusion: -globin gene testing should be considered in -thalassemia carriers with an atypical clinical presentation including hispanic patients. the wide variability in the phenotypic expression of (anti . ) mutation andthalassemia trait suggest interplay of other genetic factors which remain undefined. the clinically significant presentation amongst certain subjects, as in our two cases, makes it imperative to identify these factors to aid in phenotype prediction and genetic counseling. ashley bonheur, shivakumar subramaniyam, jogarao vedula, sucharita bhaumik nyu winthrop hospital, mineola, new york, united states background: wilms tumor (wt) is one of the most common solid malignant neoplasms in children. a diverse range of genes and mechanisms are implicated in wt pathogenesis. predisposing syndromes result from a disruption of wt gene, crucial for renal and gonadal embryogenesis. another gene is wt gene locus at p , an area of imprinting. the p tumor suppressor gene on chromosome p . is seen in patients with anaplastic histology. in addition to these genes, whole and partial chromosome gains of q, , q, , , & and losses of p, p, q, q, as well as loss of heterozygosity (loh) are commonly seen. some genetic markers appear to be predictive of outcome and are now incorporated into the assigning of risk-directed therapy. patients with loh at chromosome p and q are treated with more intensive chemotherapy, as they have been associated with increased risk of relapse and mortality. objectives: to describe a new complex translocation involving chromosome , , and in a case of pediatric wt. design/method: a four-year old female presented with abdominal pain and emesis. on exam, patient had a firm and large abdominal mass. radiologic studies revealed a complex lobulated right renal mass. right radical nephrectomy was performed. histopathologic studies showed wt with triphasic histologic features with blastema predominance, invasion of the lymphovascular and perinephric adipose tissues, perinephric lymph node involvement and no anaplasia. chest ct scan showed bilateral lung metastases. tumor cytogenetics showed an abnormal karyotype, a complex translocation of , , and . the rearrangement occurred due to translocation between chromosomal bands q and q , with an insertion of q - on the q region. pcr based genotyping using microsatellite markers additionally identified loh for chromosome p and q . the patient was treated for high risk stage iv wilms tumor with favorable histology and received intensive chemotherapy and radiation therapy to the flank and the lungs. she is now in remission months after, with no evidence of recurrence on surveillance scans. complex translocations associated with wt have not been rigorously studied. a question for further study is whether there is any relationship between recurrence potential with a complex translocation compared to common chromosomal abnormalities. further knowledge of the molecular pathology and genetic changes in wt will help the development of new targeted therapies, as well as new biomarkers to aid diagnosis, risk stratification, and monitoring of treatment and relapse. results: a week-old girl was referred for evaluation of an abnormal newborn screen. mother was a known carrier of hb khartoum trait while father was a known carrier of thalassemia trait. patient's hemoglobin quantification performed by capillary zone electrophoresis showed hbf %, hb variant %, and no detectable hba. the hb variant ran in the d zone, a pattern consistent with mother's hb. alkaline agarose gel electrophoresis banding pattern showed f/s. acid agarose gel electrophoresis pattern showed v/f. later testing revealed abnormal isopropanol stability with + precipitation at minutes. this electrophoresis pattern is consistent with the pattern previously reported of hb khartoum. clinically, the patient is a healthy, active child whom we have followed for two years. she has not had any significant anemia outside of her physiologic nadir. she has not had any hemolytic episodes, and her bilirubin levels have always been within the normal range conclusion: to the best of our knowledge, this is the only reported case of hb khartoum/ thalassemia. the proline to arginine substitution of hb khartoum introduces a charged group on the chain at the site of contact. the resulting unstable chains can dissociate into monomers and favor the formation of methemoglobin, leading to hemoglobin instability. we had wondered if this unstable hemoglobin might result in clinical hemolysis when challenged with oxidative stress, such as in periods of infection. however, in the two years we have followed this patient, she has never had a hemolytic episode. at two years of age, she has hbf . %, hb khartoum . %, and hba . %. whether hbf elevation is protective from oxidative stress remains to be determined as we continue to follow this child. university of puerto rico -medical science campus, san juan, puerto rico, united states background: gm gangliosidosis is a lysosomal disorder caused by -galactosidase deficiency due to mutations in the glb gene. it is a rare autosomal recessive neurodegenerative disorder with an incidence of about : , - : , live births worldwide. this neurological disorder has three clinical forms. gm type , or infantile form is characterized by psychomotor regression by the age of months, visceromegaly (hepatosplenomegaly), macular cherry red spot, facial and skeletal abnormalities, seizures, and profound intellectual disability. we present a -year-old female with gm type and acute lymphocytic leukemia (all). design/method: she was diagnosed with gm type at the st months of age and family history was remarkable for an older sister with gm type . diagnostic studies reveal homozygous exon of the glb gene for a sequence variant defined as c. c>t, predicted to an amino acid substitution p.aarg cs. results: patient presented to our hospital with petechiae in lower extremities, pallor and intermittent tracheal bleeding. physical examination shows a hemodynamically stable girl that is chronically ill dependent of mechanical ventilation, severe mental retardation and scatter petechiae at upper and lower extremities. laboratory workup revealed severe normocytic anemia (hgb: . g/dl) with immature peripheral cells and thrombocytopenia ( × /l). serum chemistry revealed increase ldh ( u/l), increase hepatic enzymes (ast: u/l), normal uric acid level. there was no evidence coagulopathy. chest x ray was unremarkable except for evidence of chronic pulmonary illness. abdominal sonogram hepatosplenomegaly. during hospitalization, bone marrow aspirate and biopsy was performed which was diagnostic of b cell acute lymphoblastic leukemia (all) with . % lymphoblast and orderly myeloid/erythroid maturation. flow cytometry: % b lymphoblast with aberrant phenotype c/w b-acute lymphoblastic leukemia. karyotype revealed hyperdiploid female of favorable prognosis. cytogenetic by fish: hyperdiploid all with extra copies of runx and igh (no bcr-abl translocation). family was oriented about the new diagnosis and the dismal prognosis in conjunction to her primary condition. parents agree on no chemotherapy treatment for all with only supportive treatment. to this date, there is no evidence in literature that has previously described association of gm and leukemia. life expectancy of patient's primary condition is null therefore, correlation with leukemia might not be a coincidental finding. this patient opens the possibility of malignancy as part of gm type thus, malignancy diagnosis should be considered as part of their medical lifetime course. university of south florida, tampa, florida, united states background: hematological manifestations related to hiv infection are not uncommon, with thrombocytopenia having an estimated prevalence of - %. the pathophysiology is likely multifactorial. studies suggest that the primary mechanism may be immunologic resulting in accelerated platelet destruction. additional theories suggest that infection of megakaryocytes may also play a role causing inadequate platelet production. treatment of hiv-related thrombocytopenia is challenging. first-line treatments include initiation and optimization of antiretroviral therapies, immunoglobulin (ivig), and glucocorticoids. however, this approach is not effective in all patients and second line treatment options are less well studied, particularly in the pediatric population. objectives: we aim to present and discuss the case of a year old patient with perinatally acquired hiv- infection and persistent thrombocytopenia who, after failing first line therapies, showed normalization of platelet count on the novel thrombopoietin receptor agonist, eltrombopag. design/method: a retrospective chart review of the case patient's medical record was conducted. additionally, a thorough literature review was performed on this topic including the pathophysiology of hiv related thrombocytopenia and its treatment modalities. the patient required monthly ivig infusions for about year, but did not show a sustained response, often with platelet count dropping to less than , in between infusions. after initiation of mg eltrombopag daily the patient showed a sustained increase in platelet count (range , - , ). during a brief week lapse in eltrombopag treatment his platelet count dropped to , . upon re-initiation of therapy his count increased to , . the patient has remained asymptomatic, off of ivig for over one year, with undetectable hiv viral load and greater than cd t cell counts. no side effects or grade laboratory abnormalities were reported. conclusion: treatment of hiv-related thrombocytopenia can be challenging. first line therapies, including ivig and glucocorticoids, are not effective in all patients. several other treatment modalities have been utilized, including anti-d immunoglobulin, dapsone, danazol, interferon alfa, vincristine, thrombopoetic growth factors including romiplostim and eltrombopag, or splenectomy, but these are less well studied. this represents the first reported case of a pediatric patient with hiv who showed a positive response to eltrombopag with a sustained improvement in platelet count and no adverse effects from treatment. eltrombopag may be a safe alternative to first line therapies in those patients with hiv and refractory thrombocytopenia, however additional studies are needed. university of illinois college of medicine at peoria, peoria, illinois, united states background: achromobacter xylosoxidans is a gram negative rod with peritrichous flagella which causes rare opportunistic infections most commonly encountered by immunocompromised patients. it is primarily associated with uncomplicated bacteremia, cather-associated infections, and pneumonia. most reports of bacteremia associated with a. xylosoxidans are nosocomial, associated with neoplasm, and occurring mainly in adults. most reported infections with a. xylosoxidans in children are associated with cystic fibrosis. there are very few reported cases of septic shock from a. xylosoxidans bacteremia and pneumonia in the pediatric oncology population. objectives: to describe a rare case of a. xylosoxidans septic shock in a pediatric patient with relapsed neuroblastoma results: a -year old boy with history of stage iv highrisk neuroblastoma underwent standard frontline therapy with chemotherapy, hematopoietic stem cell transplant, radiation therapy, and immunotherapy, followed by a dfmo trial for maintenance. his -month follow-up scans demonstrated relapse and he was subsequently treated with additional chemotherapy, surgical resection, and mibg therapy, crizotinib for an eml -alk fusion and finally ifosfamide, carboplatin and etoposide (ice). he developed neutropenic fevers and was started on cefepime, vancomycin and fluconazole. blood cultures were initially negative. on the th day of fever, his previously scheduled pet scan was performed during hospitalization and showed new pulmonary opacities. he did not have respiratory symptoms, but therapy was escalated to meropenem, vancomycin and amphotericin. emergent bronchoscopy was performed the same day, with all bacterial and fungal cultures remaining negative. overnight, he developed tachypnea and saturations in the upper s, requiring nasal cannula. ir-guided lung biopsy was performed the next day, a flexible bronchoscopy was done to remove blood clots in the airway, the patient was placed on a ventilator, femoral lines were placed, granulocytes ordered and pressors were started for deterioration to presumed septic shock. arterial and femoral lines were placed but patient continued to have hemodynamic instability on multiple pressors. the following day, blood and respiratory cultures returned positive for results: at days after the start of iti, the inhibitor was < . bu and continued undetectable months after initiation of iti therapy. in this patient, iti with high-dose plasma-derived factor viii and von willebrand factor (vwf) complex was well tolerated and effective. genetic analysis confirmed a large factor viii gene duplication of exons to . we believe our patient developed inhibitor so quickly ( exposure days) due to the possibility of this mutation causing a frameshift that introduces a premature termination codon. this might be functionally similar to a deletion in the factor viii gene which poses the highest risk for inhibitor development in patients with severe hemophilia a. this variant has only been identified previously in two unrelated patients diagnosed with severe hemophilia a. this duplication is not listed in dbsnp variant database, nor observed in the general population database. our case proves the effectiveness of this method for patients with severe hemophilia a and an inhibitor. it also shows that more research is needed to identify patients at risk for inhibitor development. background: mercaptopurine ( -mp) is a prodrug that is a core component of maintenance chemotherapy for patients with a diagnosis of acute lymphoblastic leukemia (all). suppression of the neutrophil count is used to demonstrate adequate dosing of -mp during this phase of therapy. bone marrow suppression is mediated by the active metabolite -thioguanine ( -tgn), whereas the metabolite -methylmercaptopurine nucleotides ( -mmpn) has been shown to cause hepatotoxicity. allopurinol has been used infrequently in all maintenance therapy in the setting of skewed metabolism when adequate myelosuppression is difficult to achieve due to excessive hepatic toxicity. when given in combination with allopurinol a reduced dose of -mp may result in both increased -tgn levels and decreased -mmpn levels. objectives: describe the characteristics and clinical course of patients treated with allopurinol and reduced dose -mp during maintenance chemotherapy for all. we performed a retrospective chart review of patients at aflac cancer and blood disorders center of children's healthcare of atlanta with new diagnoses of b or t-cell all who received allopurinol during maintenance chemotherapy. we identified eleven patients with b-cell or tcell all who received allopurinol adjunctive therapy during maintenance chemotherapy at a single institution between - . these patients received adjunctive allopurinol for - weeks (median weeks) with reduced -mp ( - % of full dose). all ten patients with genetic testing for thiopurine s-methyltransferase (tpmt) had wildtype genotype associated with normal enzyme levels. indications for allopurinol use were most commonly unfavorable -mp metabolite levels, transaminitis (n = ), pancreatitis (n = ) and hyperbilirubinemia (n = ). favorable metabolite shift was achieved in all patients. liver enzymes improved in of patients with transaminitis after initiation of allopurinol/reduced -mp. three patients who experienced pancreatitis during maintenance did not have recurrence after initiation of allopurinol ( of these patients previously reported). six patients developed pancytopenia while on allopurinol, and two of those patients developed pancytopenia severe enough to require allopurinol cessation. four patients developed isolated anemia (hgb < . g/dl) without thrombocytopenia or severe neutropenia. no patient has experienced a recurrence of leukemia. overall, treatment with allopurinol and reduced dose -mp was successful in producing a favorable -mp metabolite distribution and reducing toxicity. therapy was generally tolerated; however a major and notable side effect was pancytopenia, in two cases severe enough to stop allopurinol treatment. anemia may be more prominent with allopurinol usage. allopurinol effect is variable among individual patients despite normal tpmt genotypes. baylor college of medicine, houston, texas, united states background: congenital sideroblastic anemia, b-cell immunodeficiency, periodic fevers and developmental delay syndrome (sifd) is a rare inherited sideroblastic anemia syndrome, first described in with clinically similar cases. genetic variations of trnt were identified as causative. objectives: to present an unusual presentation of a patient with sifd complicated by diagnosis of concomitant alpha thalassemia trait. design/method: retrospective chart review. a five month old male infant was referred to our hematology center for evaluation of elevated hemoglobin barts identified on newborn screen. despite numerous attempts, blood work was unable to be collected. at seven months of age he had microcytic anemia (hemoglobin . g/dl, mean corpuscular volume fl) more severe than what would be expected with alpha thalassemia trait. no variant hemoglobin was identified with isoelectric focusing or high performance liquid chromatography. by nine months of age he developed growth failure, intermittent emesis with fevers, developmental delays (predominantly gross motor), hearing loss, a disproportionally large head and coarse, thinning hair. over the next ten months, he was seen by numerous specialists for seemingly unconnected problems including sensorineural hearing loss, elevated liver enzymes and growth hormone deficiency. alpha globin analysis revealed deletion of two alpha globin genes. at months of age, he was admitted with one week of fevers, jaundice, and emesis. peripheral blood smear showed microcytic hypochromic anemia with marked anisopoikilocytosis including target cells, elliptocytes, tear drops, spherocytes, poikilocytes, marked polychromasia, and coarse basophilic stippling. given the inconsistency of his laboratory findings with the diagnosis of alpha thalassemia trait and clinical syndromic findings, bone marrow biopsy was performed which revealed rare ringed sideroblasts. one month later whole exome sequencing revealed trnt splicing variant c. - c>g and novel missense variant c. a>t consistent with sifd. hemoglobin barts on newborn screen with moderate to severe microcytic anemia directed initial diagnostic work-up towards variant alpha thalassemia. as additional medical conditions developed the focus shifted to a unifying syndrome. compared to previously described cases, our patient was diagnosed at an older age, presented with anemia rather than episodes of febrile illnesses, and had rare sideroblasts on bone marrow examination. diagnosis in this case led to identification of the novel c. a>t variant in his sister who had similar, but milder, features. sifd is a rare disease with variable phenotypic severity making diagnosis challenging without high index of suspicion which is crucial for appropriate management. wiseman, blood, . chakraborty, blood, background: cholelithiasis is uncommon in childhood. cholelithiasis is known to occur more frequently in children with predispositions, including female sex, obesity, parenteral nutrition, previous abdominal surgery, use of oral contraceptives, family history of gallstones, chronic hemolytic anemias, hepatobiliary disease, or exposure to specific drugs. although there have been occasional case reports linking cholelithiasis to childhood leukemia or leukemia therapy, the prevalence and risk factors of cholelithiasis in patients with childhood leukemia remain unclear. objectives: to estimate the prevalence of cholelithiasis in patients diagnosed with childhood acute lymphoblastic leukemia (all), and to evaluate possible risk factors for the development of cholelithiasis in patients with childhood all. we performed a computer-assisted review of the electronic medical records of patients diagnosed for b or t-cell all at children's healthcare of atlanta in the period from to . patients with diagnoses of cholelithiasis, cholecystitis or who had a cholecystectomy were identified. possible risk factors of age, sex, bmi, history of abdominal surgery and parenteral nutrition use were abstracted. patients with underlying chronic hemolytic anemia or pre-existing gallbladder disease were excluded. results: seventeen cases of cholelithiasis and cases of cholecystitis without documented cholelithiasis were identified. among patients with cholelithiasis, were female. median age at diagnosis of cholelithiasis was . (range . - . ) years. seven patients had no symptoms referable to cholelithiasis at the time of diagnosis. the median age of leukemia diagnosis among these patients was . (range . - . ) years. the median interval from diagnosis of leukemia to gallbladder disease was . years. four patients had bmi over the th percentile for age. two patients had a prior history of intraabdominal surgery. no patient received oral contraceptive pills. six patients received parenteral nutrition for more than days. there was no documented family history of cholelithiasis. seven patients did not receive any cholelithiasis directed therapy. two patients were managed with medical management only, with endoscopic retrograde cholangiopancreatogram with stone extraction, and with cholecystectomy. our study estimates the prevalence of cholelithiasis in childhood lymphoblastic leukemia to be . %, higher than the reported prevalence in the general pediatric population of . - . %. although our cohort size is small, it appears that all therapy and supportive care modalities associated with all are likely to play a larger role in the development of cholelithiasis than known predisposing factors in the general population. further studies are warranted. background: an uncommon side effect of intravenous immunoglobulin (ivig) administration is clinically apparent, sometimes severe hemolysis. we describe a severe case of coombs-positive hemolytic anemia secondary to ivig administration. ivig is a blood derivative manufactured from pools of , to , individual plasma donations. ivig is not abo-type restricted, so anti-a, anti-b and anti-a,b isoagglutinins are detectable. objectives: to describe a rare but serious type of transfusion reaction leading to gross hemolysis after ivig administration. results: a -year-old male with a past medical history of obstructive sleep apnea and obesity was admitted to the pediatric intensive care unit for adenoviral pneumonia and subsequent respiratory failure requiring mechanical ventilation. he had a complex hospital course with many complications including acute respiratory distress syndrome (ards), septic-shock, and coombs-positive hemolytic anemia. the patient was treated with commercial ivig (baxter/baxalta) -mg/kg daily for five days. he had two isolated episodes of severe hemolysis in relation to ivig administration requiring multiple transfusions of packed red blood cells (prbc). examination of pre-transfusion peripheral blood smear showed spherocytosis with rouleaux formation and large clumped rbc aggregates. the patient's blood type was classified as blood group a, rh-negative and his initial prbc transfusions were of this type. subsequently, the patient's coombs test was found to be positive using polyspecific and anti-igg typing sera. the patient's antibody screen against reagent group o screening cells was negative ruling out autoimmune hemolytic anemia. however, type specific anti-a antibodies were detected in his plasma as well as the acid eludate prepared from the coombs-positive red blood cells. it was concluded that the patient's hemolysis was due to anti-a antibodies presumed to arise from ivig. the patient's rbc transfusions were changed to o-negative blood and the hemolytic process resolved. the patient ultimately died due to complications of ards. although hemolysis is a known side effect of ivig, it is rarely considered when deciding to administer ivig. in addition, it has rarely been described in the pediatric population. ivig is used in the treatment of a growing number of medical conditions. due to the critical nature of many of these patients, hemolysis secondary to ivig may not be considered and continued blood transfusions with the patient's specific blood type may be used. it is crucial to remember that severe hemolysis can occur from ivig, and the importance of transfusing with blood group o, rh-negative blood when applicable. university of maryland medical center, children's hospital, baltimore, maryland, united states background: coagulopathy is a well-described complication of acute promyelocytic leukemia (apml), and remains a leading cause in induction failure. with treatment, coagulopathy associated with apml has been shown to rapidly improve. multiple organ dysfunction syndrome (mods) in apml, including acute respiratory distress syndrome (ards), has been associated with infection, traumatic injury, malignant infiltration, and cytokine release syndrome. when mechanical ventilation is no longer sufficient, extracorporeal membrane oxygenation (ecmo) can be considered; however, coagulopathy, severe end-organ damage, and malignancy are all relative contraindications to initiation of treatment. we report the case of a -year-old female presenting in respiratory failure, disseminated intravascular coagulopathy (dic), with intracranial hemorrhage, and mods, diagnosed with apml, successfully treated with ecmo therapy. design/method: retrospective case analysis and literature review. our patient, a -year-old female was admitted in respiratory failure and altered mental status, following a fall shortly prior to presentation. initial laboratory values were notable for pancytopenia, dic, and acute renal failure. a non-contrast head ct showed left temporal lobe intraparenchymal hemorrhage. she was diagnosed with apml by peripheral smear, later confirmed by fish for t( : ), and was started immediately on high-risk induction chemotherapy as per cog protocol aaml , including all-trans retinoic acid, arsenic trioxide, idarubicin, and dexamethasone. cvvhd was required for acute renal failure. despite maximal respiratory support, she remained hypoxemic, with oxygenation index of , pao /fio ratio of . ecmo was initiated hours after start of induction, hours after admission. coagulopathy resolved on day of induction, ecmo was discontinued after days, mechanical ventilation and cvvhd were stopped after days and she continued to improve, eventually achieving remission with few neurologic side effects. despite relative contraindications to ecmo, this patient was successfully treated with ecmo without significant neurologic side effects. the correction of her coagulopathy was multifactorial: ) restoration of adequate oxygen delivery via ecmo improving endothelial function; ) successful organ support to allow sufficient response to induction chemotherapy with atra leading to the terminal differentiation of leukemic blasts; ) complement and contact system activation through contact with ecmo circuitry. this case illustrates that ecmo can still be considered in patients despite coagulopathy and end organ damage. sinai hospital of baltimore, baltimore, maryland, united states background: primary polycythemia vera is an extremely rare diagnosis in the pediatric patient and is defined by a marked elevation of red blood cells due to erythropoietin-independent mechanisms. presentations of this disorder range from the asymptomatic person to severe thrombotic events, such as budd-chiari syndrome or cerebrovascular stroke. mutations in the jak gene are found in adult and pediatric patients with polycythemia vera; however, the jak v f mutation is less commonly identified in pediatric patients. we describe an otherwise healthy -year-old female who presented with a significantly elevated total erythrocyte count, hemoglobin, and platelets, incidentally discovered upon routine annual blood work obtained by her pediatrician. design/method: this is a report and discussion of a rare case. demonstrated cellular marrow with trilineage hematopoiesis and no dysplasia. cytogenetics were not assessed. his hemoglobin and platelet count recovered but leukopenia and neutropenia persisted. follow-up evaluation at three months revealed fevers, ongoing cytopenias, a one-month of a nodular skin rash on the trunk and extremities resembling erythema nodosum, and hepatitis (peak alt and ast of , and , , respectively). following clinical evaluation, a skin biopsy was performed and was remarkable for atypical lymphocytes within the subcutis with t-cell markers, a high ki- , and positive tia- , perforin, and -f immunoperoxidase stains. negative stains for cd , cd , and ebv were noted. these results are consistent with sptcl. additional evaluation did not support a diagnosis of hlh. a staging evaluation was performed. pet-ct showed widespread hypermetabolic subcutaneous activity in the legs, trunk and skull and diffuse marrow hyperplasia. bone marrow demonstrated involvement with precursor b-cell acute lymphoblastic leukemia, with a mll gene rearranagement. his skin biopsy was retrospectively stained with tdt, cd , pax- , cd a, and cd with negative results, and a blood smear taken at the time of the skin biopsy did not demonstrate leukemic cells. conclusion: this is the first report of a patient with sptcl having a synchronous malignancy. the patient is doing well, currently in the maintenance phase of treatment for his all, and his skin disease has resolved on pet-ct. while it is possible that his presentation was a function of chance, the possibility of an underlying immune dysfunction or cancer predisposition warrants further investigation. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hereditary xerocytosis (hx) is a rare red blood cell (rbc) dehydration disorder, characterized by variable hemolysis and propensity to iron overload. hx is often misdiagnosed as hereditary spherocytosis (hs). while splenectomy is curative for hs, it is relatively contraindicated in hx due to a substantial thromboembolism risk, signifying the importance of delineating these diseases. blood smear abnormalities are variable and often insufficient to make an accurate diagnosis. osmotic-gradient ektacytometry and genetic confirmation are critical in distinguishing these overlapping disorders. objectives: describe a family with hx, initially misdiagnosed as hs. discuss the importance of distinguishing these disorders and the utility of ektacytometry in making this distinction. design/method: a -year-old caucasian male was diagnosed with hs after presenting with prolonged neonatal jaundice starting on the first day of life. he described mild scleral icterus and history of intermittent jaundice and dark urine, without need for transfusions. his father, paternal uncle and paternal grandmother were all diagnosed with hs during childhood and underwent cholecystectomy. additionally, his father underwent splenectomy for abdominal pain. the child's blood counts revealed compensated anemia (hb . gm/dl) and reticulocytosis (arc × /mcl) with increased mcv ( . fl) and mchc ( . gm/dl). blood smear showed increased polychromasia and poikilocytosis with rare spherocytes and few stomatocytes. while the child had normal ferritin, his father had iron overload (ferritin ng/ml) despite no prior transfusions. osmotic-gradient ektacytometry profile of the child and father's rbcs showed a characteristic left-shifted, bell-shaped curve with decreased omin and ohyp, diagnostic of hx. the family is currently undergoing genetic studies. despite clinical similarities between hs and hx, distinguishing these diseases has significant management implications. hx is a disorder of rbc permeability, causing shortened rbc survival. stomatocytes on blood smear can raise suspicion for hx, but are insufficient to make an accurate diagnosis. identifying characteristic biomechanical membrane properties using osmotic-gradient ektacytometry is the gold standard for clinical diagnosis, which can then be confirmed by molecular studies. hs and hx can be easily and reliably distinguished using ektacytometry, as both disorders have very distinctive curves representing different rbc deformability patterns. after hx diagnosis was made, we counseled the family against splenectomy, as the risk of thromboembolism is significantly increased in hx compared to hs, and the father was diagnosed with iron overload. conclusion: hx is commonly misdiagnosed as hs. this case highlights the importance of making this distinction, and the utility of osmotic-gradient ektacytometry in reliably distinguishing these conditions. penn state health children's hospital, hershey, pennsylvania, united states background: relapsed acute myeloid leukemia (aml) presenting as an isolated central nervous system myeloid sarcoma (cns ms) is very rare and its treatment is not well-defined. thiotepa, vinorelbine, topotecan and clofarabine (tvtc) has been successful for re-induction therapy to induce remission prior to hematopoietic stem cell transplant (hsct). objectives: to describe our experience in utilizing tvtc therapy in two children with no extramedullary disease at initial diagnosis who presented with relapsed aml as intracranial myeloid sarcomas. results: case : month-old female was diagnosed with flt negative aml and completed treatment per the children's oncology group (cog) aaml study on the low risk arm without bortezomib. cerebral spinal fluid (csf) negative at diagnosis. fish testing positive for tcf gene deletion of unknown significance. mrd was undetectable after induction i and remained undetectable after each cycle. nine months off therapy, recurrent headaches prompted mri imaging which revealed two posterior fossa masses. csf and bone marrow testing were negative. stereotactic biopsy of the larger mass confirmed recurrence of aml. patient underwent two cycles of tvtc with a total of seven doses of intrathecal cytarabine with almost near resolution of the cns ms. completed cranial radiation and proceeded to allogeneic stem cell transplant with unrelated cord marrow donor and is disease free at approximately day + .case : year-old female diagnosed with flt and mll negative aml and completed treatment per cog aaml study on the low risk arm without bortezomib. csf negative at diagnosis. mrd was undetectable after induction i and completed therapy without complications. two months off therapy, a retrospective analysis of her diagnostic bone marrow by the cytogenetic laboratory to test a new panel identifying novel q partners revealed a cryptic insertional : (mllt /mll(kmt a) translocation. at four months off therapy, acute mental status changes prompted mri imaging which revealed two intracranial ms and lumbar spine involvement. resection of the larger lesion for symptomatic relief confirmed the mllt /mll(kmt a) fusion. csf positive for blasts and marrow negative for relapsed disease. patient completed two cycles of tvtc with a total of seven doses of it cytarabine with near resolution of cns disease (only mm contrast enhancement in the medulla). she received craniospinal radiation and is awaiting improvement in her cardiac function before proceeding to hsct. conclusion: tvtc is a successful reinduction regimen for relapsed aml with cns ms prior to hsct. background: acute severe anemia can be a life-threatening medical condition. the differential is quite broad for possible etiologies of acute severe anemia, including autoimmune hemolytic anemia (aiha) and atypical hemolytic uremic syndrome (ahus). autoimmune hemolytic anemia is an antibody-mediated process that targets the protein antigens located on the surface of red blood cells. treatment options for aiha include corticosteroids, with up to % of patients being responsive, with some requiring splenectomy. atypical hemolytic uremic syndrome is a medical urgency, defined as the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. the etiology is usually due to genetic causes, or less commonly, due to autoantibodies or idiopathic reasons. prognosis is very poor. objectives: differentiating between autoimmune hemolytic anemia and atypical hemolytic uremic syndrome can be a time-sensitive diagnostic dilemma while the patient is in critical condition, but this important delineation can vastly alter therapeutic options. design/method: here we discuss two cases highlighting the diagnostic workup involved in differentiating between atypical hemolytic uremic syndrome and autoimmune hemolytic anemia. patient a is a -year-old male who presented in extremis with severe anemia, uremic encephalopathy, and severe acute renal injury requiring hemodialysis and multiple blood transfusions. patient b is a -month-old male, who also presented in extremis with respiratory failure secondary to adenovirus/rhinovirus/enterovirus, with acute progressive renal failure and microangiopathic hemolytic anemia, requiring hemodialysis and cardiorespiratory support. : patient a underwent a full hematologic and infectious disease workup. subsequent laboratory studies confirmed enteropathogenic e.coli (epec) in the patient's stool; blood cultures remained negative. renal biopsy results were consistent pigment nephropathy. bloodwork indicated positive direct coombs. patient a was ultimately treated with steroids mg/kg/day, with significant improvement. patient b also included a full hematologic work-up, including adamts activity and ahus genetic panel, as well as full infectious disease work-up. subsequent laboratory test-ing revealed blood cultures growing streptococcus pneumoniae, with adamts activity at % (adult ref range: >/ = %), and normal complement levels. imaging findings also supported diagnosis of ahus. the management of a critically ill patient with acute severe anemia requires a thorough hematologic and infectious disease work-up. while molecular and genetic are helpful in definitive diagnosis of ahus, the utility of such results is limited by time. overlapping clinical presentation of a patient in extremis due to acute severe hemolytic anemia with progressive renal failure presents a rather broad differential, with time-sensitive treatment and prognostic implications. the favorable response to steroids delineates aiha from hus. background: d- -hydroxyglutaric aciduria (d- -hga) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in d- hydroxyglutarate dehydrogenase (d hgdh) or isocitrate dehydrogenase (idh ). metaphyseal chondromatosis with d- -hydroxyglutaric aciduria (mc-hga) is a type of d- -hga that has been previously reported in seven patients (omim ; pmid ), three of whom had somatic mosaicism for r variants in isocitrate dehydrogenase (idh ). we describe a -year-old boy with mc-hga who subsequently developed acute myeloid leukemia (aml) and was found to have a r variant in idh in a leukemic bone marrow sample. we report the first case of aml with this metabolic disorder. design/method: a -year-old hispanic boy presented with short stature, developmental delay, abnormal skin pigmentation, and unilateral congenital cataract. workup revealed multiple skeletal enchondromatosis and elevated urine d- -hydroxyglutaric acid levels. he was diagnosed with mc-hga. no pathogenic variants in d hgdh, idh and idh were identified in peripheral blood. germline testing with biopsies of skin lesions was declined by the family. two years later, he presented with streptococcal sepsis and pancytopenia. blasts were noted on peripheral smear. bone marrow morphology was consistent with acute myelomonocytic leukemia (∼ % blasts). chromosome analysis showed normal xy, and molecular testing by pyrosequencing idh and idh revealed a r c variant in idh ( % mosaicism). the patient is being treated as per the cog study aaml . end of induction i bone marrow aspirate was hemodiluted, but there was no obvious residual disease by flow cytometry ( . - . % sensitivity) or morphology. the previously identified idh variant was no longer detectable (limit of detection < %). although targeted therapy for aml with idh mutation is currently in phase i clinical trials in adults, there is no safety or efficacy data for using idh inhibitors in children. treatment with ivosidenib is therefore not currently an option for our patient. conclusion: this is the first case of aml reported with this rare metabolic disorder. somatic r variants in idh have been identified in three other mc-hga cases. this same mutation leads to the accumulation of d- -hydroxyglutarate in gliomas and aml. without any confirmed germline mutation or somatic mosaicism testing of multiple specimen sources, we can only speculate that the patient has an underlying somatic idh mutation associated with mc-hga which subsequently led to leukemogenesis. we present the first case of this association, to increase index of suspicion for development of aml in children with metabolic disorders associated with variants in idh . background: congenital combined deficiency of the vitamin k-dependent coagulating factors (vkcfd) is a rare heterogeneous autosomal recessive bleeding disorder. vkcfd is caused by mutations in the genes of either gamma-glutamyl carboxylase (ggcx) or vitamin k epoxide reductase complex (vkorc), which are responsible for the gammacarboxylation of vitamin k dependent proteins (vkdps) allowing for their activation. the clinical presentation ranges from no bleeding to intracranial hemorrhage. to date, vkcfd has been reported in few patients worldwide. objectives: we report a case of a girl with novel homozygous mutation of the ggcx gene, highlighting her clinical and biochemical characteristics with a review of the literature. a -month-old girl of consanguineous emirati parents, presented to our hospital with a history of bleeding from puncture site after receiving her second-month vaccine. that was associated with episodes of mild mucosal bleeding. review of systems was negative for jaundice, steatorrhea and failure to thrive and physical exam was unremarkable. investigations revealed markedly prolonged pt and aptt with high inr. fibrinogen, hemoglobin and platelets were always normal. activities of vitamin k-dependent factors including fii, fvii, fix, fx, protein c and s were all low. a measurement of proteins induced by vitamin k absence (pivka-ii) was done and came very high. this was associated with a mild elevation in liver enzymes but normal liver function test. the picture was supporting vitamin k deficiency, and as a result, she was started on oral vitamin k supplements of mg/day. she responded partially to vitamin k and required higher doses to stabilize her inr. after excluding acquired causes and due to her requirement of high doses of vitamin k, a mutation in either ggcx or vkorc genes was suspected. genetic analysis was conducted for her which revealed a novel missense homozygous mutation in the ggcx gene (c. a>t) confirming the diagnosis of combined deficiency of vitamin k-dependent clotting factors type . the asymptomatic parents were both heterozygous for the same mutation. results: she is currently stable on mg/day of vitamin k supplements. conclusion: vkcfd is a rare bleeding disorder with an overall good prognosis due to the availability of several effective therapeutic options. the function of the mutated gene is unknown. our patient demonstrated a partial response to vitamin k supplements suggesting presence of a residual carboxylation capacity and a possible role of this gene in the enzymesubstrate interactions. university of alabama at birmingham, birmingham, alabama, united states s of s background: gata is a zinc finger transcription factor that plays a critical role in the regulation of hematopoiesis and lymphatic angiogenesis. mutations leading to gata deficiency (gd) have been linked to a variety of clinical conditions. patients with gd have a striking predisposition to develop myelodysplastic syndrome (mds), acute myeloid leukemia (aml), or chronic myelomonocytic leukemia (cmml). acute lymphoblastic leukemia (all) has not been associated with gd, although the association of bcell all and gd has been previously reported. objectives: to describe a unique association of gata deficiency and t-cell all in a young child. results: an -year-old female presented with a one-week history of fever and malaise. she had a significant past medical history of verruca plantaris and self-resolving leukopenia associated with febrile illnesses. significant family history included sister with neutropenia and human papilloma virus (hpv) infection, and mother with neutropenia, monocytopenia, atypical mycobacterial infections, and hpv infection. peripheral blood revealed hemoglobin . g/dl, hematocrit . %, platelets , /ul, and white blood cell , /ul (neutrophils /ul, lymphocytes /ul, monocytes /ul). patient underwent a bone marrow biopsy demonstrating lymphoblast infiltration. flow cytometry analysis demonstrated monoclonal lymphoid blast population that co-expressed cd , cd , cd , nuclear tdt, cd , however, lacked expression of cd , cd , cd , cd , hla-dr, or myeloperoxidase. findings were consistent with tcell all with aberrant myeloid markers. cytogenetics analysis revealed ,xx,dic( ; )(p . ;p . ). patient began treatment as per children's oncology group aall and achieved remission at the end of induction. course of therapy was complicated by episodes of fever, reciprocating junctional tachycardia, asparaginase-associated thrombosis, viral meningitis, recurrent episodes of verruca plantaris, and resistant streptococcus pneumoniae or haemophilus parainfluenza infections causing chronic cough. later, she was also found to have low igm levels; after completion of therapy, she developed monocytopenia. lymphocyte subset panel revealed absent b cells, decreased number of natural killer (nk) cells, and cd /cd inversion. further work-up included gata sequence analysis that showed heterozygous nonsense mutation (c. c > t/c; reference nm_ ) likely resulting in gata haploinsufficiency. patient continues to be in remission, is receiving monthly immunoglobulin replacement and is on azithromycin for atypical mycobacterial prophylaxis. surveillance bone marrow biopsies have shown no evidence of mds or leukemia, however, have demonstrated persistent hypocellularity. the possibility of undergoing an allogeneic bone marrow transplant is actively being discussed given its curative potential. clinicians should be aware that t-cell all may be associated with gata deficiency. cincinnati children's hospital medical center, cincinnati, ohio, united states background: treatment for severe hemophilia a is centered on factor viii (fviii) replacement therapy. development of an alloantibody (inhibitor) against fviii is a significant treatment complication occurring in as many as - % of patients. high titer inhibitors render treatment with factor viii ineffective, necessitating the use of bypass agents that may not achieve hemostasis with the same efficacy. considering the substantial ramifications of inhibitor development on treatment, eradication of inhibitors is of great importance to achieve adequate hemostasis in this patient population. desensitization by immune tolerance induction (iti) is the primary method of inhibitor elimination. however, not all patients respond to iti. immunomodulation may be considered as the next line of therapy, although controversy remains in regards to agent selection and use. objectives: there is incomplete data on the use of immunomodulation therapy for inhibitor eradication in severe hemophilia a. we present a case of a pediatric patient with severe hemophilia a and high titer inhibitor who failed initial iti therapy to better illustrate potential treatment options for the future. design/method: a retrospective chart review was performed on a patient with severe hemophilia a at cincinnati children's hospital medical center. results: an -year-old caucasian male with severe hemophilia a secondary to intron inversion, was initially diagnosed following extensive bleeding after circumcision at birth. he was identified as having an inhibitor ( bethesda units (bu)) at months of age after exposure days of treatment. he failed multiple attempts of iti, with recombinant and plasma-derived (pd) fviii. he was advanced to immunomodulation therapy in combination with pdfviii, however demonstrated anaphylaxis to rituximab and ofatumumab. he underwent tolerization to rituximab, and received a six month course with a partial response (nadir of . bu). months following last dose of rituximab, a rising inhibitor titer ( . bu) was found. mycophenolate mofetil (mmf) was initiated with subsequent inhibitor stabilization and a decreasing titer ( . bu) over the course of the following year. mmf has been well tolerated without major side effects or infection throughout therapy. conclusion: development of an inhibitor against fviii is a considerable complication in patients with severe hemophilia a. use of immunomodulatory therapies following iti failure remains controversial. mmf has not been well studied in this patient population. we report a case of a patient who is being successfully treated with mmf with minimal side effects. further prospective studies should be considered to further define the role of mmf immunomodulation therapy. background: down syndrome (ds) children with aml (ds aml) have higher cure rates than their non-ds counterparts. outcomes for refractory/relapsed cases, however, remain dismal. somatic mutations of the gene encoding the transcription factor gata in ds aml patients are responsible for the observed hypersensitivity of ds aml blasts to cytosine arabinoside (ara-c). in view of excellent survival rates (approaching %) of ds aml patients, the ongoing children's oncology group (cog) aaml study seeks to determine the feasibility of treating standard risk (minimal residual disease/mrd negative) ds aml patients using a reduced dose ( -fold decrease) ara-c backbone. although results from japanese trials with this approach are promising, north american and european data are conflicting. although chromosome rearrangements in ds aml do not appear to carry the same adverse prognostic significance as in non-ds aml, monosomy in ds aml patients has been associated with a moderately worse outcome. isochromosome q, however, is rare and has only been reported in previous cases of ds aml. objectives: to report our institutional experience of very early relapse involving cases of ds aml patients treated per the reduced dose ara-c arm ( . g/m ) of the aaml study. design/method: we hereby report the disease course and cytogenetics of the above ds aml patients. : patient is a month old caucasian female who had gata mutation negative aml. patient is a -year old caucasian male whose chromosomal analysis revealed isochromosome q ( copies of the long arm of chromosome ). both patients achieved negative mrd (< . %) after induction i chemotherapy with thioguanine, low-dose ara-c and daunorubicin and proceeded per the reduced dose ara-c arm of aaml . patient relapsed immediately after completion of chemotherapy. salvage chemotherapy with mitoxantrone/high dose ara-c (hidac) failed to induce a second remission and the patient subsequently died of disease. patient relapsed within months from end of therapy. the patient underwent salvage chemotherapy utilizing a hidac backbone and remains in disease remission. the noted very early relapse following a reduced dose ara-c regimen in our above ds aml children suggests that testing for gata mutation and chromosome rearrangements may play a useful role in the development of future risk-stratified treatment strategies for ds aml. university of rochester, rochester, new york, united states background: in developed countries in the st century, severe nutritional deficiency is not an often considered differential diagnosis of unexplained childhood anemia. aside from iron deficiency anemia, vitamin deficiency severe enough to impact hematopoiesis is uncommon in the general pediatric population. here we present the unique case of a -monthold infant who presented with intermittent emesis, failure to thrive (ftt), developmental delay, macrocytic anemia, and neutropenia which was initially concerning for a congenital bone marrow failure syndrome. instead, she was discovered to have an underlying, potentially familial deficiency of b . objectives: . to describe the unique case of an infant with b deficiency. . to outline the importance of including b deficiency in the differential diagnosis of unexplained megaloblastic anemia in children. a -month-old exclusively breastfed infant presented for gastroenterology evaluation due to persistent emesis and poor weight gain over the course of months. her history was notable for delayed developmental s of s milestones and hypoactivity. marked pallor prompted hematologic evaluation, which revealed concern for macrocytic anemia (hemoglobin . g/dl, mcv ), reticulocytopenia ( . × ^ / l), and neutropenia (anc . × ^ /l). an otherwise reassuring physical examination and laboratory evaluation was notable only for the discovery of an undetectable b level and marked hyperhomocysteinemia ( mol/l). her hemoglobin (hgb) continued to decline (to . g/dl) over the first few days after presentation, and she required red blood cell (rbc) transfusion. within only a few days of initiation, daily cyanocobalamin injections resulted in a robust reticulocytosis response, improved hgb, immediate normalization in the neutrophil count, and resolution of hyperhomocysteinemia. additional history and laboratory evaluation from the patient's mother revealed a concurrent, asymptomatic maternal b deficiency as well as a history of a need for b supplementation in the maternal grandfather, raising concern for an inherited etiology. despite the rarity of vitamin-deficient hematologic abnormalities in the general pediatric population, b deficiency should be considered as a potential cause of an otherwise unexplained megaloblastic anemia, especially in the setting of concurrent ftt and neurodevelopmental delay. a detailed family history should be obtained in such cases and may have helped to prevent this patient's clinical sequelae had the deficiency been discovered sooner. our patient has experienced a favorable clinical response to b supplementation, attesting to the importance of vitamin b in early childhood growth and development. background: peg-asparaginase is universally utilized in the treatment of pediatric acute lymphoblastic leukemia (all). despite its high efficacy in this disease, it is associated with hypersensitivity and allergy in - % of patients. protracted anaphylaxis has been described in circumstances such as severe food allergy with ongoing allergen exposure; however, it has not yet been described in relation to peg-asparaginase. we describe the first reported case of protracted anaphylaxis after peg-asparaginase administration, provide guidance as to time course and management of protracted anaphylaxis, as well as evidence that erwinia asparaginase may be safely administered even in this high risk population. objectives: to provide guidance regarding the duration, course and management of protracted, severe anaphylaxis after peg-asparaginase therapy. a year old male with very high risk all presented for consolidation therapy with peg-asparaginase (intramuscular) and vincristine. one hour after administration, he developed generalized hives and angioedema, for which he was given diphenhydramine. he then quickly developed progressive hives, angioedema, subjective throat and chest tightness, and wheezing. he was treated with diphenhydramine, epinephrine, albuterol, and methylprednisolone with resolution of symptoms. one hour later, symptoms recurred and the patient became hypotensive; he was retreated with methylprednisolone and epinephrine, and was transferred to the pediatric intensive care unit (picu). in the picu, he was placed on an epinephrine drip, and continued on methylprednisolone, diphenhydramine, cetirizine, albuterol, and ranitidine. the epinephrine drip was successfully discontinued after hours, and his other medications were gradually weaned over the course of two weeks. of note, the patient did have st segment changes in his electrocardiogram during the first hours of anaphylaxis. these were associated with normal ventricular function as per echocardiogram, and resolved within one week. this patient has subsequently tolerated multiple doses of erwinia asparaginase (intramuscular) without premedication. this patient was acutely managed in the pediatric intensive care unit with steroids, anti-histamines, and continuous infusion epinephrine. symptoms consistent with severe anaphylaxis including hives, angioedema, throat and chest tightness, wheezing, and hypotension persisted for a total of four days before finally resolving. he has thus far tolerated multiple doses of erwinia asparaginase without any symptoms of allergy, hypersensitivity, or anaphylaxis. protracted severe anaphylaxis after peg-asparaginase therapy can be successfully managed with multi-agent therapy, including antihistamines, steroids, and continuous infusion epinephrine. re-challenge with an alternate form of asparaginase may be tolerated, even in a patient with protracted anaphylaxis to peg-asparaginase. ucsf benioff children's hospital oakland, oakland, california, united states background: vincristine (vcr) is widely used in pediatric cancers. unlike most cytotoxic agents, hematopoietic toxicity is uncommon. vcr-induced anemia has been observed but its mechanism has not been well studied. vinca alkaloid-induced membrane changes were seen in early studies of hereditary spherocytosis (hs) and anecdotal cases suggest vcr may increase hemolysis in such patients. here we describe a case involving severe vcr-induced anemia in a patient with hs and an explanation as to the mechanism. objectives: to describe the mechanism of vcr-induced anemia in hs. design/method: case report. a year-old female with hs was diagnosed with t-lymphoblastic lymphoma. she had required packed red blood cell (prbc) transfusions as a neonate and thereafter had done well without episodes of acute hemolysis or aplasia. complete blood counts (cbc's) demonstrated a compensated hemolysis, and she did not require further transfusions until she commenced chemotherapy. by the start of maintenance she had received many more prbc transfusions than the average patient. intermittent drops in hemoglobin (hb) did not correlate with any particular agent, and she had stable, mild splenomegaly. a clear pattern emerged during maintenance. her hb was - g/dl at monthly clinic visits, when she received vcr, intermittent intrathecal methotrexate, and corticosteroids. within - days, her hb dropped to . ± . g/dl, and reticulocyte count decreased from . to . ± . %. transfusion at day corrected hb, and the reticulocytes and hb returned to baseline. white blood cell and platelet counts did not change after vcr. blood samples from pre, immediately post, and days post vcr were analyzed and rbc characteristics and markers of hemolysis were not significantly different. ektacytometry showed identical curves, indicating no change in rbc deformability. in vitro incubation of patient blood samples with vcr also did not affect the osmotic deformability, confirming that a change in rbc rigidity was unlikely the reason for the drop in hb. these data indicate that a dysregulation of erythropoiesis was responsible for the anemia after vcr, rather than damage of peripheral rbc's. in most patients, maintenance therapy for lymphoblastic lymphoma does not cause severe anemia, likely because a temporary reduction in erythropoiesis in patients with a normal rbc survival and low reticulocyte count is not noticed. however, in a patient with decreased rbc survival and a brisk reticulocytosis, a disruption in rbc generation is more apparent. in conclusion, vcr administration to patients with an rbc disorder warrants close observation for potentially severe vcr-induced anemia. background: the addition of tyrosine kinase inhibitors (tki) to conventional chemotherapy has improved outcomes for pediatric patients with philadelphia chromosome-positive (ph+) acute lymphoblastic leukemia (all), however there remains an increased risk of relapse compared to other types of childhood all. typically, in relapsed disease the philadelphia chromosome persists and several mechanisms of resistance involving acquired mutations of the bcr-abl chimeric oncoprotein have been reported. objectives: describe a unique case of a pediatric patient with ph+ b-precursor all relapsing with b-precursor all without the philadelphia chromosome. results: an -year-old boy was diagnosed with ph+ bprecursor all with the presence of the t( ; )/bcr-abl translocation by cytogenetics and fluorescence in situ hybridization (fish), respectively. additional abnormalities included gains of runx and loss of one copy of etv . a remission bone marrow with negative minimal residual disease (mrd) was achieved at the end of induction with dasatinib and the esphall chemotherapy backbone. duration of tki therapy was two years post diagnosis. nearly one year after the completion of therapy, cytopenias prompted a bone marrow investigation. relapsed b-precursor all was established by immunophenotyping, however fish analysis did not identify the bcr-abl rearrangement. moreover, quantitative reverse transcriptase pcr was negative for the bcr-abl fusion transcript. again fish analysis of the bone marrow revealed multiple additional copies of runx and mono-allelic loss of etv , similar to the initial diagnostic sample. the patient was re-induced per aall anticipating a ph+ all relapse. however, with confirmation of the loss of the ph+ clone, tki therapy was not re-initiated. due to positive mrd of . % at the end of re-induction therapy, the patient was salvaged with blinatumomab therapy and subsequently underwent an allogenic stem cell transplant with a sibling donor. conclusion: this is the first known report of a pediatric patient with ph+ b-precursor all who developed recurrent b-precursor all without the philadelphia chromosome. the persistent findings of gain of runx and loss of etv makes it unlikely that a second unrelated b-precursor all developed following successful treatment of the original disease. this case highlights the possibility of a genetically distinct subclone present at the onset of disease that shared abnormalities of runx and etv but did not contain the philadelphia chromosome. nevertheless, the subclone harbored leukemogenic potential in the absence bcr-abl expression. it is plausible that the predominant clone present at diagnosis was effectively treated with dasatinib and extinguished, but the bcr-abl -negative clone persisted in the face of tki therapy. background: ligneous conjunctivitis is a rare form of pseudomembranous conjunctivitis that develops specifically in patients with type plasminogen deficiency. lack of plasmin activity in those patients result in defective fibrinolysis and formation of fibrin-rich membranous material/ masses that develops on the palpebral conjunctiva as well as other sites in the body.current management involve surgical excision of the masses that is usually complicated by multiple recurrences. recently, use of topical plasminogen concentrates helped delaying recurrence, but currently, those concentrates are not commercially available. we report on a -year-old omani girl, with hypoplasminogenemia who required optimization of plasminogen level at the time of surgery to delay/ prevent recurrence. objectives: case report on the peri-operative use of ffp versus cryopricipitate transfusion as an alternative replacement of plasminogen during surgical excision of ligneous conjunctivitis. design/method: pharmacokinetic study was performed to assess plasminogen recovery after ffp ( ml/kg) and precipitate ( bag/ kg) transfusion results: plasminogen levels remained subnormal after either ffp or cryoprecipitate administration. with ffp, the maximum concentration reached was almost % of normal. although half-life of plasminogen is known to be - . days, the patient seemed to have a high catabolic rate after receiv-ing cryoprecipitate, with plasminogen levels reaching basal levels within hours. because of the better recovery profile with ffp, we opted to give ffp before and after surgery. peri-operative management included ffp transfusion at ml/kg/ hours one day before and for days post operatively, followed by ml/kg once daily from day - , then ml/kg on th post-operative day. topical treatment was initiated using antibiotic and steroids ed on the day of surgery, followed by heparin ed on the second day. on follow up, she used topical heparin, cyclosporine, prednisolone, and topical lubricant eye drops for variable duration. clinical picture remained stable for almost year post operatively, when she started to develop recurrence of ligneous lesions again. background: ponatinib (inclusig®, ariad pharmaceutical) is a rd generation multi-targeted tyrosine kinase inhibitor (tki) approved for treatment of adults with chronic myeloid leukemia (cml) and philadelphia chromosomepositive acute lymphoblastic leukemia (ph+ all) resistant to or intolerant of other tkis. ponatinib has numerous drug-drug interactions and a black box warning for associated serious adverse vascular events and hepatotoxicity. for this reason, ponatinib use has been confined to specific high-risk populations. however, in patients who prove refractory to other therapies, the potential benefits of ponatinib may outweigh risks. to date, ponatinib has not been studied in the pediatric/adolescent and young adult (aya) population. furthermore, literature describing the use of ponatinib alone or in combination with other agents in pediatric oncology patients is scarce. objectives: to describe a single institutional experience using ponatinib in the pediatric patients with ph+ all. design/method: two cases of ponatinib use in pediatric ph+ patients resistant to other tkis were identified at our institution and are described. peripheral blood samples obtained from both patients identified bcr-abl p fusion transcripts and sanger sequencing was used to identify resistant mutations. results: our first case is a -year-old female who received upfront multi-agent chemotherapy plus dasatinib for ph+ all. relapse was confirmed on end-of-therapy bone marrow evaluation, thus bcr-abl mutation testing was performed and revealed a t i mutation. ponatinib was initiated then discontinued after one week due to clinically significant fluid retention with peripheral edema and bilateral pleural/pericardial effusions. the second case is a lateadolescent female with ph+ all who relapsed -years after stem cell transplant (sct). following relapse, tki therapy included both imatinib and dasatinib. due to persistence of bcr-abl fusion transcript despite tki therapy she was switched to ponatinib. shortly following initiation of ponatinib she developed a diffuse, maculopapular rash, which persisted despite dose reduction, resulting in ultimate discontinuation of the drug. bcr-abl mutation testing identified f l and f v resistance-conferring mutations. to date, there is scant existing literature detailing the use of ponatinib in pediatric patients. appropriate dosing is undefined and side effect profile not well described, particularly when used concurrently with other chemotherapeutic agents. thus, this case series reporting the response to and toxicity of ponatinib in pediatric ph+ all patients has important clinical implications. additionally, this is the first report of a pediatric ph+ all patient with documented t i mutation underscoring the importance of bcr-abl mutational testing, particularly at the time of relapse. cooper university hospital, camden, new jersey, united states background: myh -related disorder is a rare autosomal dominant disease, encompassing several subtypes: may hegglin anomaly, epstein syndrome, fechtner's syndrome, and sebastian syndrome. heterozygous mutations are seen in the gene encoding non-muscle myosin heavy chain iia (nmmhc-iia) which is involved in cell motility as well as functions to maintain cellular shape and integrity. the presentation of myh -rd is mainly characterized by macrothrombocytopenia, but various related expressions exist: nephritis often leading to renal failure, cataracts and sensorineural deafness ( ). a -year-old girl with history of extensive dental caries, hyperactivity, and speech delay due to suspected hearing loss was incidentally found to have thrombocytopenia at the time of genetic evaluation. she did not have any bruising or excessive bleeding. she did not respond to observation, immunoglobulins, or steroid therapy. her platelet count remained persistently low ( - k/ul). she underwent extensive evaluation to rule out platelet disorder vs. coagulation defect. her peripheral smear showed enlarged platelets by giemsa stain but no inclusion bodies were noted in granulocytes. her platelet aggregation and platelet surface glycoprotein by flow cytometry were negative. her coagulation profile was also normal. objectives: this case report summarizes the complexity in diagnosing myh -rd in a pediatric patient. design/method: since a unifying diagnosis for her clinical presentation was not apparent, whole exome sequencing (wes) was undertaken. results: wes revealed the r c heterozygous pathogenic variant, located in exon in the myh gene. myh gene alteration explained the patient's clinical features of macrothrombocytopenia and hearing loss. this mutation was paternally inherited, and her father demonstrates mosaicism. he was asymptomatic with normal platelet count but his morphology showed enlarged platelets with no inclusion bodies in granulocytes. when dealing with patients who have mild or no symptoms of bleeding diathesis but evidence of persistent macrothrombocytopenia, considering a platelet disorder belonging to myh -rd can help delineate certain predisposing syndromes and guide clinical management. patients are likely to benefit from early genetic testing while receiving supportive therapy. wes can highlight syndromes and provide information on recurrence risk for families. the renal and hearing abnormalities are indistinguishable between epstein and fechtner's syndromes, but the pathogenic variants differ ( ). the genotype-phenotype correlation implies that our patient may have either syndrome, although clinical features compatible with nephritis have yet to manifest. patients should be monitored closely for long-term progression of myh disease, and treatments should be initiated accordingly. we present an -year old female evaluated by genetics at birth due to prenatal microcephaly. chromosomes and microarray were normal. at age she developed standard risk pre-b-cell acute lymphoblastic leukemia (all). she completed treatment in and has been doing well in the interim, remaining in complete clinical remission. during and after treatment she exhibited developmental delay and neurocognitive deficits. at age her height and weight were at or below the th centile and head circumference was below the nd centile (approximately standard deviations below the mean and corresponding to the th centile for a -month-old girl). bone age was appropriate. she had a distinctive triangular face with micrognathia and a pointed nose resembling a seckel-like syndrome. the patient also had clinodactyly of the th toes, zygodactylous triradius involving the nd and rd left toes, tendency to sydney line in the right palm and a radial loop in the left middle finger. the patient's unique clinical presentation prompted a more thorough genetic evaluation, which led to a novel finding we feel is clinically significant with regard to the development of malignancy. design/method: whole exome sequencing (wes) was performed on the patient as well as her biological parents (trio). a de novo heterozygous mutation in the gene pcdh with potential relation to the phenotype was discovered. this c. dupa variant causes a frameshift starting with codon asparagine , changing this amino acid to a lysine residue and creating a premature stop codon at position of the new reading frame denoted p.asn lysfsx . this variant is predicted to cause loss of normal protein function via protein truncation or nonsense-mediated mrna decay. conclusion: pcdh is a member of the protocadherins family which is important in cell-to-cell adhesion and synaptic function in the central nervous system and is highly expressed in areas of the brain involved in higher cortical function and speech. aberrant expression of protocadherins has been associated with the development of malignancies in many organ systems. with regards to leukemia, the methylation status of this gene at diagnosis has been implicated in the prognosis of all and could be used as a biomarker to predict relapse. this patient's de novo mutation and clinical presentation are unique to what has been previously presented in the literature. we feel that this mutation is a clinically significant finding that may shed light on the role of this gene in the development of hematopoeitic malignancies. background: acquired hemophilia a (aha) is an uncommon and potentially life-threatening hemorrhagic disease characterized by sudden onset of bleeding in patients with neither personal nor family history of bleeding dyscrasia. it is usually seen in adults with autoimmune diseases, solid tumors, lymphoproliferative diseases, pregnancy or during the postpartum period; occurrence in the pediatric population has rarely been reported. we report a case of an otherwise healthy teenager who was found to have aha when he presented with acute onset of atraumatic soft tissue hematoma. results: a -year old male of middle eastern descent with history of congenital absence of the right external ear, but otherwise in good general health, presented to our emergency department with a three day history of progressive worsening of right lower leg pain, swelling, and paresthesia, without preceding history of trauma. evaluation by the pediatric orthopedics service documented significantly elevated compartment pressures, necessitating immediate four-compartment fasciotomy. pre-operative labs were significant for prolonged activated partial thromboplastin time (aptt) of . ( . - . ) seconds with normal prothrombin time (pt) and international normalized ratio (inr). ptt did not correct on mixing studies, suggesting the presence of a circulating anticoagulant. factors xii and xi were in the normal range; factor ix was elevated, ( - ). factor viii level was % and fviii inhibitor level was . bethesda units (< . ), confirming the diagnosis of aha. work up for autoimmune disease was negative. his bleeding and surgical hemostasis were managed with recombinant factor vii (novoseven) mcg/kg every hours for hours post operatively, with gradual interval prolongation. factor viii antibody eradication was managed with prednisone mg/kg/day. factor viii and inhibitor levels normalized by day of hospitalization. recombinant factor vii was discontinued; steroids were gradually tapered and discontinued at discharge (hospital day ). conclusion: acquired hemophilia is likely an underdiagnosed condition in pediatrics. while it is typically seen in adults with underlying autoimmune disease, solid tumors, lymphoproliferative disease, or during pregnancy or the postpartum period, pediatric cases may have no identifiable etiology. this case highlights the importance of considering this diagnosis in any patient with unexplained bleeding regardless of their age, so as to intervene early and prevent adverse consequences. university of oklahoma, oklahoma city, oklahoma, united states background: myeloid neoplasms associated with eosinophilia is a rare subtype of chronic leukemia characterized by clonal eosinophilia. the true incidence is unknown due to its rarity and possible classification as idiopathic hypereosinophilia syndrome. the most common chromosomal aberrations involve platelet-derived growth factor receptors (pdgfrs). we report one such rare case in a pediatric patient. most of the pediatric management of this entity is derived from adult case reports and case series. objectives: to describe a case of chronic leukemia presenting as eosinophilia results: a previously healthy year old caucasian male presented with a several week history of migrating joint pain, splenomegaly, and abnormal blood counts with leukocytosis, thrombocytopenia and absolute eosinophilia. white blood cell differential showed myeloid precursors suggestive of chronic myeloid leukemia. bone marrow evaluation showed % blasts and % eosinophils. bcr-abl testing was negative, ruling out cml. fish analysis for eosinophilic clonality revealed deletion of chic gene, resulting in fip l /pdgfra fusion gene, diagnostic for myeloid neoplasm with eosinophilia associated with pdgfr abnormalities. treatment was started with tyrosine kinase inhibitor (tki), imatinib mg daily. within months, fish analysis for fusion gene was negative. after approximately months of daily imatinib, he was switched to maintenance dose of mg weekly. he is approximately months since diagnosis and doing well on maintenance imatinib. in , the who revised its classification of some chronic eosinophilic leukemias to myeloid and lymphoid neoplasms associated with eosinophilia and rearrangement of pdgfra, pdgfrb, fgfr . the most common abnormality is the fip l /pdgfra fusion gene. other less common abnormalities include fusion genes kif b-pdgfra and etv -pdgfrb and point mutations in pdgfra . some features of chronic eosinophilic leukemia include absolute eosinophilia, splenomegaly, elevated vitamin b and tryptase levels, and organ damage from eosinophil infiltrates and cytokine release. patients with rearrangements or mutations involving pdgfra are usually very responsive to imatinib. starting doses have not been well studied or established. experts recommend co-administration of corticosteroids during the first few days of imatinib therapy in patients with a history of cardiac involvement and/or elevated serum troponin levels to prevent myocardial necrosis, a rare complication of imatinib therapy in eosinophilic patients. fortunately our patient did not have cardiac involvement and to date has not exhibited signs of chronic tki toxicity. conclusion: myeloid neoplasms with eosinophilia constitute a rare form of chronic leukemias. they are often associated with pdgfr abnormalities and are usually very responsive to tyrosine kinase inhibitor therapy. walter reed national military medical center, bethesda, maryland, united states background: germline samd l mutation is a rare cause of constitutional bone marrow failure with a unique propensity for clonal evolution to monosomy and mds. objectives: previous case series have demonstrated diverse clinical outcomes in patients with a germline samd l mutation. our case presents a novel samd l mutation (p.val leu). additionally, the case highlights the challenges in clinical decision making for a patient with a gene mutation that is known for clonal evolution towards monosomy with risk of progression to myeloid malignancy, but also known for self-correction through uniparental disomy or inactivating mutations which results in disease remission. design/method: a retrospective chart review and review of the literature was performed. dna was isolated from peripheral blood and used for whole exome sequencing. a peripheral blood sample from the patient's mother and father showed no samd l mutation. skin biopsies of the patient and parents were evaluated for uniparental disomy or new mutations. to determine the pathogenicity of this novel mutation, the specific samd l mutant dna was transfected into the human embryonic kidney cell line to assess its role in inhibiting cell proliferation. our patient presented at months of age with pancytopenia and hypocellular bone marrow in the setting of s of s sepsis. he had evidence of dysfunctional immune activation with hemophagocytosis and elevated soluble il with simultaneous severe hypogammaglobulinemia. analysis of the peripheral blood showed no increase in chromosomal breakage, normal telomere length, and normal flow cytometry. gene testing for primary hemophagocytic lymphohistiocytosis and inherited bone marrow failure were negative. after the patient recovered from his presenting illness, a repeat bone marrow biopsy demonstrated improved cellularity with myelodysplasia and cytogenetics significant for monsomy .whole exome testing demonstrated a novel samd l mutation. the patient continued to require intermittent ivig and failed to demonstrate appropriate leukocytosis with intermittent infections. on repeat bone marrow evaluation over the course of months, the patient demonstrated no evidence of evolution towards self-correction and had a persistent monosomy clone. the patient is scheduled to undergo a matched unrelated donor bone marrow transplant. our case highlights the unique clinical picture associated with constitutional marrow failure and clonal evolution secondary to a novel samd l mutation which is thought to cause pancytopenia by inhibiting cellular proliferation and often results in the development of monosomy which rescues hematopoiesis but with a risk for malignancy. background: notable labs developed a flow cytometricbased assay with a custom robotic platform to test fdaapproved drugs for anti-cancer activity against individual patient's tumor cells. this personalized assay is a potential method for identifying novel agents and drug combinations to treat aml patients who have failed standard therapies. objectives: to present the case of a teen who underwent successful treatment of relapsed aml post-sct with bortezomib, panobinostat, and dexamethasone-a regimen selected based upon results of notable lab testing. results: a -year-old male with m -aml had an isolated bone marrow relapse months after completion of scheduled therapy. at relapse, his aml was flt -itd positive. he achieved a second remission with negative mrd and underwent matched sibling donor bmt after busulfan/cyclophosphamide conditioning. bma performed on day + was mrd positive ( . %). repeat bma done on day + showed . % mrd. he started sorafenib on day + . he received donor lymphocyte infusion (dli) on day + , then received cycles of azacitadine (aza) followed by dli. marrow mrd by flow after sorafenib alone, sorafenib with dli, and sorafenib with aza/dli were %, . %, and . %, respectively. treatment was complicated by varicella meningitis, grade i skin agvhd, febrile neutropenia and c. difficile colitis, and metapneumovirus pneumonia. despite extremely low levels of leukemia (marrow mrd . %), notable lab testing performed on the patient's leukemia cells from marrow collected after aza/dli/sorafenib revealed sensitivity of his leukemic blasts to a combination of bortezomib, panobinostat, and dexamethasone. because of prolonged cytopenias, multiple infectious complications, and persistently positive mrd, he discontinued aza/dli/sorafenib and on day + started bortezomib . mg/m iv on days , , , and ; panobinostat mg po on days , , , , , ; and dexamethasone mg po on days , , , , , , , and . chemotherapy cycle started days later. he tolerated treatment without side effects and with resolution of rash and cytopenias. he achieved full donor chimerism, negative flt -itd, and complete remission by morphology and flow after two cycles. notable lab testing is a powerful tool for evaluating the sensitivity of small populations of leukemic blasts to novel drug therapy. results from notable lab testing may serve as a useful guide for treatment selection after failure of standard aml therapy. this patient achieved morphologic and mrd remission post-sct with bortezomib, panobinostat, and dexamethasone-a regimen predicted to be efficacious based upon notable lab results. maria ahmad-nabi, christine knoll, sanjay shah, esteban gomez, lori wagner phoenix children's hospital, phoenix, arizona, united states background: development of inhibitors in patients with factor ix deficiency (fixd) is a well-recognized complication occurring in - % of patients. within this subset a small percentage can develop anaphylaxis to factor. desensitization with cyclophosphamide, an alkylating agent used in the management of various oncologic malignancies, and reported for use in factor viii desensitization has been previously unreported for use in desensitization in patients with fixd. rituximab, an anti-cd antibody, however has been used. objectives: to induce immune tolerance (it) in patients with inhibitors to factor ix with either novel or under reported methods using cyclophosphamide and/or rituximab. we report a case series of patients at phoenix children's hospital with fixd who achieved it with cyclophosphamide and/or rituximab. results: patient one was a year old male with severe fixd, who at the time of desensitization had inhibitor levels of bu. he was desensitized with cyclophosphamide, then admitted for infusion of recombinant factor ix. he experienced a few minor symptoms of intolerance including an urticarial rash which was self-limited, and hemarthrosis of the right elbow on day which responded to novo . he tolerated the remainder of his infusion without issues. he continued recombinant factor ix daily, and returned to clinic for monthly cyclophosphamide for months. he did develop urticaria with hemarthrosis and spontaneous muscle bleeds which were tempered with zantac, zyrtec, solumedrol, and benadryl. he remained without a recurrence of inhibitors, however did have intermittent hemarthrosis of his ankles thereafter requiring prophylactic twice daily dosing recombinant factor ix. patient two was a year old male with severe fixd and a family history of anaphylaxis to factor causing early death in all male relatives with the disease. he had never received factor ix and did not have a detectable inhibitor prior to desensitization. he successfully underwent desensitization to recombinant factor ix with rituximab in the icu, and returned to clinic for weekly infusions x . he experienced no adverse reactions concerning for anaphylaxis. he continued to tolerate factor ix products without evidence of intolerance, development of inhibitors, and continues on as prophylactic dosing of recombinant factor ix every other day. our experience at a single institution proves cyclophosphamide as a novel agent for inducing it in those with fixd and anaphylaxis. it also provides further evidence that rituximab can desensitize patients with severe fixd. differences include longer duration for cyclophosphamide therapy ( months vs month). background: cartilage-hair hypoplasia (chh) is an autosomal recessive chondrodysplasia associated with defective cell-mediated immunity caused by mutations in the ribonuclease mitochondrial rna processing (rmrp) gene. cancer incidence is -fold higher in patients with chh than in the general population, especially non-hodgkin lymphoma. the use of rituximab, an anti cd antibody, results in decreased host b-cell number and impaired humoral function for - months. the safety of rituximab in pediatric patients with cancer and immunodeficiency is not well documented. a diagnosis of underlying immunodeficiency may discourage physicians from using rituximab due to the risk of severe bacterial infection or viral re-activation. objectives: to report a case of burkitt lymphoma in a young adult female with chh and defective cellular immunity successfully treated with rituximab. results: an -year old amish female with disproportionate short stature presented to our center for management of stage iv biopsy proven burkitt lymphoma with myc rearrangement. she had presented a week earlier with cervical, occipital, and submandibular lymphadenopathy, splenomegaly; fevers, night sweats, and weight loss for - weeks. on exam, her height was three feet associated with brachydactyly, mild bowing of the legs, normal size head without frontal bossing, fine and sparse hair. she had normal intelligence. her pattern of dysmorphisms was suggestive of chh (genetic testing not performed at time of diagnosis). pet-ct scan showed stage iv disease with involvement of cervical lymph nodes, spleen, iliac bone and bone marrow. treatment with standardintensity fab/lmb therapy (group c) with the addition of rituximab was initiated. she had an incomplete response to cop (∼ % reduction of tumoral masses) but achieved complete remission after copadam . her course was complicated with severe varicella zoster but she completed therapy and remains in complete disease remission for months after treatment completion. genetic testing subsequently performed proved homozygosity for chh with a n. a>g variant. she had no other opportunistic infections during or after therapy. conclusion: the use of rituximab was both safe and beneficial in our patient despite defective cell mediated immunity secondary to chh suggesting that rituximab may be safe to use in patients with cellular immune deficiencies. background: hemophilia a and b are bleeding disorders characterized by deficiency in factor viii or ix, respectively. spontaneous or provoked hemarthrosis is a known complication of hemophilia. repetitive episodes of hemarthrosis can lead to debilitating hemophilic arthropathy. lyme disease is a tick-born infection which is endemic to increasing parts of the united states. chronic lyme disease, the phase in which lyme arthritis typically develops, occurs months to years after initial infection and is characterized by swelling of one or more large joints generally in the absence of systemic symptoms. objectives: review cases of hemophilia a and b patients with episodes of provoked hemarthrosis refractory to intensive recombinant factor replacement therapy found to have concurrent lyme arthritis. design/method: we report two clinical cases and review relevant literature. results: first, we report a year-old male with moderate hemophilia a with a provoked knee hemarthrosis which failed to improve despite months of intense factor replacement therapy requiring multiple hospitalizations. factor replacement regimens included twice daily standard half-life recombinant factor viii products or daily to every other day extended half-life recombinant factor viii products with trough levels aimed as high as - %. factor viii pk studies were obtained for dosing, to confirm adherence, and to evaluate for subclinical inhibitors (inhibitor testing was negative). given protracted symptoms additional workup for hemarthrosis was pursed. lyme titers were positive for ( )igg, though negative for igm. he was treated with days of doxycycline during which time hemarthrosis greatly improved on examination and imaging, and he was able to recover function through physical therapy. second, we report a year-old male with moderate hemophilia b who required multiple hospital admissions for a provoked knee hemarthro-sis with no improvement in symptoms despite weeks of daily or twice daily factor replacement with standard halflife recombinant factor ix products aiming for % correction. we performed inhibitor testing (which was negative) and pk studies to assess for non-detectable inhibitors, dosing and adherence. lyme testing was positive for ( )igg, though negative for igm. he was treated with amoxicillin for days during which time hemarthrosis significantly improved on examination and imaging. diagnosis and follow-up imaging studies for both patients included mri and serial bedside ultrasounds performed as per uc san diego school of medicine mskus guidelines. background: relapse/refractory aml following allogeneic hematopoietic stem cell transplant (hsct) holds a high mortality rate. current relapse/refractory therapy modalities for younger patients may include re-induction with a clofarabinebased regimen followed by second allogeneic hsct. even for patients who undergo second hsct, the five-year survival rate is dismal. new therapies, including small molecule inhibitors, are being studied in the post-hsct relapse setting or those unfit for hsct with promising results. venetoclax is a small molecule inhibitor that has received breakthrough designation for aml treatment in elderly patients objectives: to report a young adult aml patient with relapse post hsct who was successfully re-induced with topotecan, vinorelbine, thiotepa, clofarabine (tvtc) and has sustained remission with venetoclax maintenance therapy. this approach appears to be unique in terms of reported literature. results: our patient is now a -year-old female noted to have mll rearranged aml at initial diagnosis when she was years old. she underwent chemotherapy consisting of cytarabine/daunorubicin according to standard + . due to persistent disease, she was re-induced with g-csf, clofarabine, and high-dose cytarabine (gclac) which put her in cr. her course was complicated by sepsis, colitis, gastrointestinal bleed, deep venous thrombosis, and transfusionassociated circulatory overload. given her co-morbidities, she received another cycle of clofarabine/cytarabine, and then proceeded to reduced intensity allogeneic hsct, according to bmt ctn . the patient tolerated hsct well and experienced no transplant-related complications, including no acute or chronic gvhd. unfortunately, she relapsed about month's post-hsct. initial salvage therapy consisted of another course of g-clac, but due to persistent disease the decision was made to re-induce her with topotecan, vinorelbine, thiotepa, and clofarabine (tvtc). during this time however, she was found to have extensive infection with a fusarium species requiring a course of anti-fungal therapy. bone marrow evaluation showed no residual disease with an mrd of < . %. once the absolute neutrophil count recovered, the patient was started on single-agent venetoclax for maintenance therapy, which has been well-tolerated. she remains in morphologic remission for over months. we describe herein a young adult with multiply relapsed aml wherein tvtc re-induction, followed by maintenance with venetoclax were safely used in the post-hsct setting. venetoclax therapy in the relapsed aml setting warrants further study. background: vitamin b deficiency is uncommon in children in developed countries, especially in the absence of risk factors like malabsorption or inadequate dietary intake. it often presents with non-specific symptoms and signs and can elude diagnosis. the recognition and treatment of vitamin b deficiency is critical as it can lead to bone marrow failure as well as severe neurological and developmental problems in children. to increase index of suspicion of vitamin b deficiency anemia in children. we report a rare case of vita-min b deficiency anemia in a child who presented with a severe macrocytic anemia, with signs of hemolysis and concern of malignancy. design/method: an almost three-year-old previously healthy girl presented with a few day history of fever, emesis, fatigue and pallor. she had no dysmorphic features, hepatosplenomegaly or lymphadenopathy on exam, growth and development were normal. laboratory findings showed severe macrocytic anemia (hemoglobin . grams/dl; mcv . fl) with reticulocytopenia. signs of intravascular hemolysis were present with elevated lactate dehydrogenase ( , units/l) and haptoglobin below assay limit. immune-mediated hemolysis was ruled out. initial picture of a hemolytic anemia was compounded by other findings of moderate neutropenia, mild thrombocytopenia and peripheral smear showing occasional blasts. further workup was done with a broad differential diagnosis that included leukemias, hemolytic anemias, bone marrow failure syndromes, and specific deficiencies. results: workup revealed abnormally low vitamin b levels along with significantly elevated homocysteine and methylmalonic acid levels indicating functional vitamin b deficiency. bone marrow evaluation showed megaloblastic anemia and dyserythropoiesis consistent with vitamin b deficiency, and ruled out leukemia. vitamin b deficiency can cause a hemolytic anemia like picture secondary to intramedullary hemolysis due to ineffective erythropoiesis. myeloid precursors are also affected which can lead to neutropenia, thrombocytopenia, and abnormal peripheral blood cells. in our patient, initial symptomatic anemia was treated with blood transfusion, followed by intramuscular vitamin b injections with normalizing lab values. so far, workup for an etiology for vitamin b deficiency is negative except for an equivocal range of anti-parietal cell antibodies raising concerns for pernicious anemia; however it is rare in this age group. another rare condition is an inborn error of the cobalamin transporter. she is currently on oral vitamin b supplementation and further workup will be planned based on response. conclusion: this case highlights the importance of early consideration and thorough evaluation of vitamin b deficiency in children with unclear etiology of anemia, so that prompt treatment can be initiated. memorial hospital/ university of miami, miami, florida, united states background: despite great success in the treatment of acute lymphoblastic leukemia (all), the outcomes for patients with relapsed all remain poor. prognostic indicators include timing and site of relapse. blinatumomab, is the first agent in its class that simultaneously binds cd -positive cytotoxic t cells to cd -positive b cells resulting in lysis of malignant cells. however, mechanisms of leukemia resistance to blinatumomab are unclear. objectives: to describe a case with multiple sites of extramedullary (em) relapse during blinatumomab therapy. results: a -year-old hispanic male with philadelphia positive, cd -positive b-precursor cell all refractory to chemotherapy, had failed a bone marrow (bm) and was placed on blinatumomab and imatinib. he achieved minimal residual disease (mrd)-negative systemic remission, but during his fifth cycle developed bilateral periorbital masses. biopsies confirmed cd -negative isolated em relapsed disease, which was treated with radiation therapy (rt). there was notable resolution of em disease and he continued systemic therapy. subsequently, he presented with a painful left scapular swelling. imaging showed muscle and lung parenchymal em relapse with cd -positivity confirmed on histology. he continued on blinatumomab with localized rt while awaiting car-t cell therapy. his bm mrd remained negative until he developed systemic mrd-positivity with cd -positive blasts following the sixth cycle. primary resistance to blinatumomab is poorly understood. it is proposed that expansion of cd -negative clones or downregulation of cd following blinatumomab may play a role. this was observed in our patient's periorbital relapse; but subsequent em and systemic relapses were cd -positive, consistent with the co-existence of multiple clones in relapsed all. it has also been postulated that em relapse could be linked to the failure of blinatumomab or t cells to migrate to em sites of disease or drug inactivation by the microenvironment. the second em relapse in our patient, with cd -positive disease suggests this as a possible mechanism of relapse. this was reported in patients with cd positive non-hodgkin lymphoma (nhl), and higher doses of blinatumomab however, have shown promising results in this population. despite blinatumomab's effectiveness in inducing remissions in patients with refractory/relapsed all, it appears to have limitations in patients with em disease. these may arise either from the multiclonality associated with relapsed all or due to the emergence of resistance to blinatumomab, including failure to migrate to em sites. background: cyclic neutropenia is a rare hereditary disorder, characterized by recurrent neutropenia, cycling at about week intervals, with variable associated symptoms including oral ulcers and fever. there are reported cases of cyclic neutropenia associated with chronic inflammation leading to development of reactive aa amyloidosis. one patient also presented with amyloid goiter. we report a new case of cyclic neutropenia with associated renal and thyroid amyloid. design/method: a -year-old female presented with a month history of thyromegaly, and recurrent aphthous ulcers associated with fevers. laboratory workup showed severe neutropenia, anemia, azotemia, and abnormal thyroid function, with an absolute neutrophil count - / l, hemoglobin - . g/dl, serum creatinine - . mg/dl, and uric acid - . mg/dl. thyroid stimulating hormone was elevated - . iu/ml, and normal free t . urinalysis showed + protein, + blood, and - urine red blood cells/hpf. chest radiograph showed mild narrowing of the trachea from thyroid compression. bone marrow biopsy showed a hypocellular marrow, with tri-lineage hematopoiesis, left shifted myeloid maturation with very rare mature neutrophils. both renal biopsy and thyroid fine needle aspiration revealed abundant amyloid. of note, her father had aa amyloidosis, resulting in end-stage renal disease (esrd) requiring hemodialysis, and recurrent aphthous ulcers. the family history suggested a familial predisposition. genetic testing revealed a pathogenic elane c. a>t gene mutation with autosomal dominant inheritance confirming the diagnosis of cyclic neutropenia. we treated our patient with daily granulocyte colony stimulating factor to reduce the burden of chronic inflammation induced by cyclic neutropenia, and to preserve renal and other end organ function affected by further amyloid deposition. results: proband with elane gene mutation positive cyclic neutropenia, amyloidosis of thyroid and kidney, with a positive paternal history of aa amyloidosis resulting in esrd. cyclic neutropenia may result in chronic inflammatory states leading to secondary amyloidosis. university of kentucky, lexington, kentucky, united states background: overall survival of burkitt lymphoma (bl), regardless of stage, is greater than % in the pediatric population when treated with multi-agent chemotherapy. adenovirus is a common, usually self-limited infection within the pediatric population; however, findings can vary within an immunocompromised host. hepatitis is a rare complication, with very few reports of radiologic findings in this patient population. we discuss a three year old male with history of bl who presented with clinical and radiographic evidence of relapse but was found to have adenovirus hepatitis. design/method: a case report of a patient with bl in complete remission after completion of standard of care chemotherapy, who presented with return of high fever, elevated ldh, transaminitis and hepatic lesions. we describe the hepatic imaging and pathology consistent with adenovirus hepatitis in this immunocompromised host. our patient presented at three years old with a six week history of worsening abdominal pain and fevers. he was found to have a right sided pleural effusion, multiple lesions of the liver, and diffuse abdominal lymphadenopathy; biopsy of lymph tissue was consistent with bl. he completed therapy per anhl arm b and was in a complete remission at the end of planned therapy. one month after completion of therapy, he returned with high fever, abdominal pain and transaminitis, similar to his initial presentation. ct scan showed multiple hypodense discrete lesions throughout the liver and re-accumulation of right sided pleural effusion. ldh peaked at u/l (uln u/l). uric acid remained within normal limits. bilirubin peaked at . mg/dl, conjugated . mg/dl. liver biopsy was performed, showing smudgy nuclei with immunohistochemical staining positive for adenovirus. there was no evidence of lymphomatous involvement. resolution of hepatic lesions and transaminitis, with normalization of ldh and fever, occurred with symptomatic treatment alone. adenovirus is known to cause systemic disease in immunocompromised patients and rarely hepatitis. no pediatric patients with discrete hepatic lesions secondary to adenovirus have been reported in the literature. three cases of discrete hepatic lesions have been reported in adult immunocompromised patients, two with fatal fulminant liver failure and one who required cidofovir. this case demonstrates that a common pediatric viral infection can present with lesions concerning for metastatic disease in a pediatric lymphoma patient. prompt diagnosis is vital in the management of these patients when recurrent lymphoma is in the differential. background: heparin induced thrombocytopenia (hit) is an immunologic process in which antibodies bind a heparin complex and cause a paradoxical hypercoagulable state. ramifications of this process may include a multitude of thrombotic events and bleeding complications secondary to platelet consumption. in our patient, hit manifested as increased bruising, an acute decrease in platelet count, and continual clotting of her crrt circuit. hit, although rare in pediatrics, should be included in the differential for children with thrombocytopenia who have received heparin products. to present a unique case report of a critically ill pediatric patient who developed hit in the presence of multiorgan system failure and to discuss the challenges encountered with identification of an alternative anti-coagulant. results: a yo obese, caucasian female child presented to our facility with bilateral pulmonary emboli (of unclear etiology). initially, she was started on a continuous heparin infusion, but was transitioned to enoxaparin within days without issue. five days after enoxaparin was initiated, the patient developed acute kidney injury (evidenced by increasing creatinine) attributable to her biventricular heart failure. due to her need for continuous renal replacement therapy (crrt), she was transitioned back to a continuous heparin infusion. whereas her initial platelet count on transition was normal, she developed severe thrombocytopenia ( , ul) within hours. due to intermediate risk but low suspicion for hit, pf antibodies were sent which were positive. after much discussion, she was transitioned to an argatroban infusion which was titrated according to ptt levels. within hours, her platelet count normalized. at discharge, she was prescribed apixaban for anti-coagulant management. conclusion: hit is an uncommon presentation in the pediatric population. given its rarity, there is often a delay in diagnosis which increases risk of complications such as bleeding, stroke, and limb ischemia. even if the diagnosis is suspected or proven, there may be challenges in initiating alternative agents as limited data exists on pediatric options. as argatroban remains the treatment of choice for patients with hit, experience in pediatric patients is limited, and dosing recommendations have been extrapolated from adult studies. anecdotal data exists for use of bivalirudin in children, although studies, primarily, focus on use in specific cardiac cases. in our patient's case, choice was further complicated by renal failure. this case study highlights the need for further research regarding the identification of a secondary anti-coagulant agent for use in pediatric patients with hit. background: subcutaneous panniculitis-like t-cell lymphoma (sptl) is a rare form of non-hodgkin's lymphoma characterized by infiltration of cytotoxic t-cells into subcutaneous tissue. sptl occurs in both adults and children and can present in both patient populations as either alpha/beta or gamma/delta subtypes. patients with the gamma-delta phenotype have an overall poorer survival, although the exact etiology is unclear. interestingly, both subtypes of sptl can present with secondary hemophagocytic lymphohistiocytosis (hlh), and this is associated with a worse prognosis. currently, there are no standardized treatment protocols for sptl, and clinical management includes watchful waiting, corticosteroids/immunosuppression, chemotherapy, and stem cell transplant. the primary objective was to compare how two patients with the same diagnosis responded acutely to therapy. we performed a retrospective chart review of two pediatric patients at our institution who were diagnosed with alpha/beta sptl and secondary hlh. we examined each presentation, treatment course, and outcome. we then completed a brief review of the current literature describing treatment of and outcomes for sptl with secondary hlh. results: these two patients presented in a similar manner with signs and symptoms of hlh. each was then subse-quently diagnosed with alpha/beta sptl after biopsy of cutaneous nodules and each had diffuse disease, as measured by pet. however, they demonstrated vastly different acute responses to therapy. one patient was pre-treated with systemic glucocorticoids before receiving definitive chemotherapy and tolerated therapy well as an outpatient. the other patient started systemic chemotherapy without steroid pretreatment and developed severe cytokine storm characterized by hypotension, cardiac dysfunction, multi-organ failure and cytokine elevation. both patients achieved complete remission (cr) after treatment with chop chemotherapy and remain disease-free - months off therapy. in patients presenting with sptl and secondary hlh, we propose that initial treatment with antiinflammatory or anti-cytokine therapy can decrease, or even prevent, the possibility of life threatening cytokine release as a result of cytotoxic chemotherapy. background: congenital dyserythropoietic anemia type ii (cda ii) is a rare autosomal recessive disorder, rarely presenting in the neonatal period. iron overload often occurs as a late sequela of ineffective erythropoiesis and intramedullary hemolysis. objectives: to report the novel use of iron chelation in an infant with cda ii associated with severe iron overload. the patient is a -month-old, former -week infant with prenatal non-immune hydrops and transfusion-dependent fetal anemia who presented with persistent anemia, reticulocytopenia, hyperbilirubinemia, liver dysfunction, and hyperferritinemia. his initial ferritin was . ng/ml, tibc ug/dl, and transferrin mg/dl. his bone marrow biopsy showed trilineage hematopoiesis and erythroid dyspoiesis characterized by binucleation of late-stage precursors. genetic testing revealed a compound heterozygous missense mutation and splice site mutation in the sec b gene, confirming the diagnosis of cda ii. initial liver biopsy revealed mild portal fibrous expansion, and abundant hepatic iron deposition. his ferritin continued to increase, peaking at , ng/ml, along with liver enzymes peaking at an alanine aminotransferase (alt) of u/l and aspartate aminotransferase (ast) of u/l. ferriscan showed an elevated estimated liver concentration of . mg/g dry tissue. repeat liver biopsy months later showed giant cell hepatitis with worsening mild portal fibrosis and hemosiderosis. additionally, tissue liver iron concentration was mcg/g dry weight. cardiac t * mri revealed mild cardiac iron deposition. given his significant degree of iron overload, deferoxamine was used to reduce hemosiderosis and liver morbidity in preparation for bone marrow transplantation. the patient received deferoxamine mg/kg/day iv x days/week for three months, without any clinically significant adverse events. blood counts and hepatic and renal function were monitored weekly without any abnormalities. growth parameters and liver enzymes significantly improved while receiving chelation therapy. as a noninvasive, cost-effective method, serum ferritin levels were monitored monthly to gauge response to treatment. despite receiving blood transfusions every - weeks, serum ferritin decreased to ng/ml and liver enzymes decreased to alt u/l and ast u/l prior to bone marrow transplantation. we report the use of deferoxamine in a patient with cda ii less than years of age, for treatment of iron overload. our patient tolerated deferoxamine well without significant adverse events or organ toxicity. deferoxamine may be a well-tolerated method of reducing iron burden in young patients with iron-loading pathologies. background: low grade gliomas with kiaa- -braf fusions typically have a favorable prognosis with infrequent rates of high grade transformation, low rates of metastasis and even lower rates of extra cns metastasis. while highgrade transformation has been reported for tumors with braf v e mutations and cdkn a deletions, it has not been pre-viously reported in gliomas with kiaa- -braf fusions. while there are case reports of high-grade cns malignancies metastasizing through a ventriculo-peritoneal (vp) shunt, low-grade gliomas metastasizing in this manner are extremely rare. objectives: to describe a unique case of peritoneal tumor dissemination of a braf fusion positive high grade neuroepithelial tumor in a child with a vp shunt placed for multifocal braf fusion positive low grade astrocytomas results: an eight-year-old male was initially diagnosed with multifocal low-grade astrocytomas of the hypothalamus and c -c spinal cord. initial testing revealed the kiaa- -braf fusion, but no cdkn a or braf v e mutation. initial surgical management included a vp shunt and resection of the cervical spinal lesion. he received vincristine and carboplatin, followed by transition to vinblastine given new thoracic metastatic lesions after months of therapy. at months after diagnosis, scans were concerning for diffuse leptomeningeal progressive disease and new intracranial lesions, necessitating craniospinal radiation. following a near cr, he presented months later with acute onset of abdominal pain. a ct scan revealed peri-renal and perirectal soft tissue masses, confirmed by exploratory laparotomy to be peritoneal tumor dissemination of high grade neuroepithelial tumor. a kiaa -braf fusion was noted and confirmed by rt-pcr, identical to that seen in the original cns tumors. additional findings included deletion of chromosome p (without q loss) and heterozygous and homozygous deletion of cdkn a found by fish. brisk mitotic activity justified a high-grade designation. salvage chemotherapy consisted of cycles of ice with subsequent resolution of pet-avid disease and only minimal peri-nephric tissue remaining. given the favorable response, surgical resection and multiple tissue biopsies were performed which documented no residual active disease. the shunt was revised and he started trametinib for maintenance. we present a unique case of peritoneal dissemination of high grade neuroepitheial tumors with the same kiaa- -braf fusion as multifocal low grade astrocytomas in a child with a vp shunt. this raises suspicion for tumor metastasis and transformation to a higher grade malignancy versus two distinct diseases, which may be indicative of an underlying cancer predisposition. texas children's hospital, houston, texas, united states background: polycythemia is a common referral to hematology. it is important to evaluate for a high oxygen affinity hemoglobinopathy, ensuring appropriate testing is performed for early diagnosis and avoidance of additional tests and procedures. a year old mexican female presented with an elevated hemoglobin and hematocrit, symptoms of plethora of her hands and feet, chest pain, palpitations, and fatigue. further confounding the picture, she also had significant menorrhagia and iron deficiency. she was diagnosed with the rare high oxygen affinity hemoglobin new mexico variant, only previously described once in the literature in a year old black boy. objectives: the patient initially presented at age with a hemoglobin of . g/dl and a hematocrit of . %. initial work up consisted of a hemoglobin electrophoresis which diagnosed sickle cell trait, a co-oximetry panel which was normal, and erythropoietin level of mu/ml, also normal. she was then lost to follow up and re-referred at age . she is a competitive basketball athlete, and at that time, she presented with a hemoglobin of . g/dl, and hematocrit of %. erythropoietin level continued to be normal at mu/ml. design/method: cardiology was consulted regarding chest pain and palpitations with a normal evaluation. chest x-ray was also normal. a bone marrow aspirate and biopsy was performed with results significant for mild erythroid hyperplasia and mild reticulin fibrosis. jak mutation, von hippel lindau, bpgm, and hereditary erythrocytosis mutations including phd , hif a, and epor mutation analysis were sent, all of which were normal. testing to mayo clinic for p rbc oxygen dissociation returned low at mmhg ( - mmhg normal range) and subsequently a hemoglobin electrophoresis identified a hemoglobin variant leading to beta globin gene sequencing. results: patient found to be heterozygous for hemoglobin new mexico, with . % hb new mexico and . % hba, and . % hba . there was no evidence of hbs. when evaluating patients with polycythemia, maintaining a high index of suspicion for high affinity hemoglobinopathies may eliminate further unnecessary and invasive testing for patients. caution should be used when using hemoglobin electrophoresis testing since hb new mexico is known to migrate similarly to hbs on hplc with minimal change that may not be detected in regular laboratories. most high affinity hemoglobinopathies are reported to not have significant symptoms. in this case, our patient complains of fatigue, occasional palpitations and plethora of hands and feet. we will need to further follow this patient for possible attributable symptomatology. divya keerthy, simone chang, warren alperstein, patricia delgado, claudia rojas, ofelia alvarez, matteo trucco university of miami jackson memorial hospital, miami, florida, united states background: improved technology is enabling detection of previously unidentified translocations and mutations in otherwise unclassified sarcomas. one such mutation is the bcl- co-repressor -internal tandem duplication (bcor-itd) allowing for the new classification of bcor positive undifferentiated round cell sarcomas (urcs). this sarcoma has a similar appearance to clear cell sarcoma of the kidney (ccsk), potentially representing an extra-renal manifestation of this tumor, but their clinical pathologic features are not identical. objectives: this case highlights how recombinant polymerase chain reaction (rt-pcr) and bcor immunohistochemical staining can ease the diagnosis of this rare sarcoma. results: a month-old female presented for right sided pre-septal cellulitis and a temporal subcutaneous mass. the detection of multiple other subcutaneous nodules on exam raised the concern for malignancy and she was admitted for evaluation. she had two subcutaneous masses on her abdomen, with more cutaneous masses on her legs, back, shoulder, cheek and submandibular areas. she lacked spontaneous lower limb movement and had bilateral clonus. imaging confirmed multiple masses throughout the body including paravertebral area from t to l , bilateral adrenal glands, left kidney and muscles of upper and lower extremities. initial differential included neuroblastoma, infantile myofibromatosis, rhabdomyosarcoma or atypical presentation of a renal tumor. however, synaptophysin and chromogranin stains were negative. with standard immunohistochemistry, the tumor could be only broadly classified as "undifferentiated sarcoma" maintaining the diagnostic challenge. using rt-pcr in the setting of a morphologically primitive round cell neoplasm with strong bcor expression, two external institutes simultaneously diagnosed the tumor as bcor-urcs. the primary lesion is unknown but potentially may have arose from the kidney. bcor-urcs has a heterogeneous histology with tumor cells appearing monomorphic in nests of - cells separated by septa with uniform nuclei. there is frequently an "orphan annie eye" appearance and sparse cytoplasm to the cells. diagnosis cannot be made solely on evaluation of this nonspecific histology. rt-pcr uses the genetic abnormality in undifferentiated sarcomas to narrow the differential and bcor immunohistochemical staining provides further context. bcor has significant diagnostic value given its sensitivity and specificity in urcs. another potential marker includes ywhae-nutm b fusions, which occur in smaller subset of cases, but requires further study. rt-pcr has helped further classify tumors leading to the diagnosis of a rare undifferentiated sarcoma with bcor overexpression. while this technology is beneficial, its availability is limited. if accessibility improves, earlier identification and treatment may be possible maximizing the chance for a positive outcome. background: hematohidrosis is a rare condition that mimics bleeding disorders. cases present with oozing blood tinged fluid from various sites like eyes, ears, nose, skin, etc. reported causes of this condition were stress or fear, physical activity, psychological disorders. the condition is self-limited and don't affect the general condition of the patients, but it may contributes to psychosocial problems and may increases their stress and anxiety. so this condition needs to be promptly treated. to test the response of this disease and the associated headache to propranolol treatment. design/method: our case female patient years old st offspring of non consanguineous marriage, was admitted with recurrent episodes of oozing blood tinged fluid from eyes, ears and nose months before admission, about . - ml from each orifice, lasted - minutes and subsided spontaneously. it could involve the sites simultaneously or - sites. the number of attacks was - times per day then gradually increased to - times per day. later on the patient developed a bleeding attack from umbilicus. these attacks were aggravated by stress and physical activity and decreased with rest and sleep. the condition was associated with severe headache involving the whole head, throbbing in nature of gradual onset, increased by physical activity and relieved by analgesics. the condition was not associated with vomiting, blurring or diminution of vision, ocular pain, eye discoloration. no earache, tinnitus or diminution of hearing. there was no other form of discharge from eyes, ears or nose. no history of ecchymotic patches, bleeding from other orifices or blood product transfusion. no history of trauma, drug intake, fever or rash. no symptoms of other system affection. past history of recurrent attacks of epistaxis and two operations were done that passed without remarkable bleeding. no similar condition in the family physical examination was free, no evidence of psychological problems. complete blood count, coagulation profile, platelets function, factor and c.t brain were normal. oozing fluid from the patient was analyzed showed the same components as blood. results: our case started oral propranolol . mg/kg/day based on its use in similar cases in literature. the frequency of attacks and headache reduced then stopped after months of treatment and didn't recur after stoppage of propranolol. propranolol can treat this condition successfully. further investigations are needed to determine the link between this condition and severe headache our case was suffering from. background: wilms tumor is the most common renal solid tumors of childhood and is derived from primitive metanephric cells located in the kidney. primary extra-renal wilms tumors (erwt) are extremely rare, estimated to comprise . - % of all wilms tumors. despite similar histologic appearance intrarenal and erwts differ in embryologic tissues of origin. erwts arise from the more primitive mesonephric or pronephric origin and, therefore, can develop anywhere along the craniocaudal migration pathway of these primitive tissues, most often retroperitoneal, inguinal/genital, lumbosacral/pelvic and mediastinal. these tumors are typically staged and treated per national wilms tumor study (nwts) guidelines, and, by definition, are stage ii or greater due to location beyond the kidney borders. based on the cases reported in the literature, outcomes for erwt are comparable to renal wilms tumors with an % local recurrence rate and an % two-year event-free survival. we report the first case of a stage iii testicular extrarenal wilms tumor in an -month-old male with an intrabdominal undescended testis who underwent complete surgical excision followed by chemotherapy and inguinal radiation. results: a full term -month old male underwent orchipexy for an undescended left testicle. the testicle was noted to be grossly abnormal with a pea-sized thickened tissue adherent to the upper pole and a separate mass outside of the scrotum on the superior epididymis. both masses were removed, and s of s pathology demonstrated wilms tumor with favorable histology and negative margins. ct imaging of the chest, abdomen and pelvis were negative for a primary renal tumor, local residual disease, pathologic lymph node enlargement or distant metastases. the tumor was classified per nwts as stage iii due to tumor removal in multiple pieces. the patient completed dd- a treatment with vincristine, doxorubicin and dactinomycin per aren with cgy left inguinal radiation. he is currently months off therapy without clinical or radiographic evidence of recurrent disease. primary erwt is an extremely rare malignant neoplasm associated with challenges in diagnosis, staging and treatment. based on the cases reported in the literature, outcomes are similar to that of intrarenal wilms tumor. there are four pediatric paratesticular wilms tumors reported in the literature and, to the best of our knowledge, this is the first case of stage iii testicular wilms tumor successfully treated with dd- a chemotherapy and radiation. in erwt, nwts guidelines for staging and treatment should be applied with evaluation of both kidneys to exclude an intrarenal primary tumor. background: patient is a yo f, with esrd secondary to atypical hus versus ttp, who presented with thrombotic microangiopathy, aki, thrombocytopenia and anemia after a living unrelated donor kidney transplant. patient initially had downtrending creatinine. on post-op day , hematology was consulted for an increasing ldh and drop in platelets. peripheral smear was notable for an absence of schistocytes. yet, biopsy of the kidney revealed microthrombi. the patient was diagnosed with a thrombotic microangiopathy. plasmapharesis was initiated on day # , at which time ms r was noted to have significantly elevated creatinine. plasmapharesis did not yield any correction in labs and significant bruising developed. patient was started on eculizimab; plasmapharesis was stopped. shortly after, creatinine, anemia and thrombocytopenia corrected to levels at which she was discharged. overall, patient was found to have progressive anemia, thrombocytopenia, an increasing creatinine and ldh ( s) concerning for atypical hus, despite absence of schistocytes on peripheral smear. she responded well to eculizimab, with correction of hematologic changes during induction. she was discharged on eculizimab and continued to respond with normalizing platelet counts and hemoglobin. the differential in light of patient's thrombotic microangiopathy and thrombocytope-nia also included ttp. yet, adamts remained normal. dic was unlikely given normal fibrinogen level and d-dimer. objectives: presentations of atypical hus vs ttp. discuss eculizumab as a treatment of atypical hus. highlight atypical presentations of illness in transplant patients. results: despite absence of schistocytes by smear, pt was diagnosed with atypical hus based on presentation and after failing plasmapharesis, she responded well to eculizumab. though her presentation was abnormal, her response to this antibody that blocks the complement cascade suggests that she was experiencing a complement-mediated process. there are rare documented cases in the literature of atypical hus without schistocytes. hemolytic uremic syndrome (hus) is characterized by hemolytic anemia, thrombocytopenia and acute kidney injury. atypical hus is a diagnosis of exclusion, not due common etiologies such as shiga toxin. among atypical causes are complement-mediated forms, caused by an antibody to complement factor. in addition to plasmapharesis, renal transplant and supportive care, the mainstay of treatment for atypical hus is eculizumab (an antibody that blocks the complement terminal cascade). this case describes a patient unique in that, she was diagnosed with atypical hus without any schistocytes by smear. secondly, she responded to eculizumab, with unremarkable gene studies. finally, this case highlights that transplant patients often have unique presentations. nicklaus children's hospital, miami, florida, united states background: synovial sarcoma is a spindle cell tumor categorized as a soft tissue sarcoma. the chromosomal translocation t(x; ) leading to the ss -ssx fusion protein is unique to this sarcoma. it is a slow growing tumor with common recurrences and often, at presentation, with evidence of metastatic disease. if resection is not feasible, then neoadjuvant with adjuvant chemotherapy is recommended. metastasis carries an unfavorable prognosis given synovial sarcoma historically does not respond well to chemotherapy. trabectedin is a well-tolerated alkylating agent currently indicated for the treatment of liposarcoma and leiomyosarcoma. we present a -year-old male with metastatic synovial sarcoma to the lungs that progressed and was refractory to chemotherapy. he was administered trabectedin as a form of palliative chemotherapy, with significant clinical and radiographic response. design/method: pubmed search was done with search for terminology including "synovial sarcoma" and "trabectedin". papers relevant to our case were selected for literature review. a -year-old male patient presented with a large right axillary mass. initial imaging showed a heterogeneous multiseptated mass invading the subscapularis and teres major muscles along with innumerable lung nodules. biopsy confirmed diagnosis of monophasic synovial sarcoma. the patient was started on protocol arst with ifosfomide, mesna, doxorubicin. he completed cycles followed by radical resection and sessions of radiation. due to progression of disease multiple chemotherapy regimens were tried including topotecan and cyclophosphamide, protocol advl with lorvotuzumab, and pazopanib. imaging of the chest continued to show significant progression of metastasis. the patient's clinical status deteriorated with worsening respiratory status, requiring l of oxygen therapy, and inability to ambulate. he was started on trabectedin . mg/m for palliative care. after cycles of treatment patient was no longer requiring oxygen and was ambulating without assistance. radiological imaging showed significant reduction in number and size of lung nodules. trabectedin is a recently approved alkylating agent for the management of sarcomas resistant to first line treatment. response in synovial sarcoma is scarcely documented in the pediatric population. epidemiology places the most common age group in the young adults and children. our case opens the doors to further consideration of the use of trabectedin in the pediatric patient with metastatic synovial sarcoma. background: gata is an x-linked gene that plays critical role in hematopoiesis. mutations of gata gene can be associated to various blood disorders including diamond blackfan anemia, cytopenia, congenital dyserythropoietc anemia and acute megakaryoblastic leukemia. we report a patient with macrocytic anemia and platelet dysfunction who carries a novel gata mutation that has not been reported. results: a now -month-old male with complex medical history including prematurity at weeks, dysmorphic features, global developmental delay, hyperinsulinism, hypogonadotropic hypogonadism, growth hormone deficiency, micropenis, failure to thrive, patent ductus arteriosus status post ligation, and severe hypotonia, was referred to hematology at months old for resolved, transient thrombocytopenia and macrocytic anemia since month of age. chromosomal microarray showed chromosome deletion of q . , which is the rps gene. he doesn't have a family history of diamond blackfan anemia (dba), despite mom having the same rps mutation. he was then diagnosed with dba. his lab workup showed mild macrocytic anemia (hgb . g/dl, mcv fl), normal to inappropriately low reticulocyte count, normal white blood cell and platelet counts, hgf %, erythroid ada . eu/gm hgb (elevated). he has abnormal pfa- , with prolonged closure time of both adp and epinephrine. he had low von willebrand antigen and ristocetin cofactor activity. he has severe pancreatic insufficiency. bone marrow biopsy showed normocellular marrow with trilineage hematopoietic maturation, without ringed sideroblasts. since mother has the same rps gene mutation, maternal labs were done and showed no evidence of macroytosis or anemia. the diagnosis of dba was questioned. whole exome sequencing did not identify any pathogenic sequence changes in the coding regions of rps gene, but detected a gata mutation r w, which was reported variant of uncertain significance. his mother shares the same mutation and is asymptomatic, but she may not be affected since gata iis xlinked. his father doesn't harbor the gata mutation. conclusion: gata gene encodes zinc finger dna binding hematopoietic transcription factor, which is important during erythroid differentiation. gata mutation r w has not been reported in literature and is a novel variant of gata mutation, which might be contributing to this patient's clinical picture. further studies are warranted to confirm gata mutation r w to be a pathogenic sequence change. alexander boucher, tomoyuki mizuno, alexander vinks, greg tiao, stuart goldstein, james geller cincinnati children's hospital medical center, cincinnati, ohio, united states background: hepatoblastoma (hb), the most common pediatric primary hepatic malignancy, can be associated with specific congenital syndromes. recently, chronic kidney disease and genitourinary anomalies have been linked to hb. cisplatin is a key chemotherapeutic agent in treating hb but its renal clearance and toxicity profile can limit its use for those with end-stage renal disease (esrd). objectives: using an institutional case series, we present data using cisplatin for hb in dialysis-dependent esrd and define recommended dosing for future use. design/method: a chart review of patients with concurrent hb and esrd on dialysis treated with cisplatin at our institution was undertaken. demographic data, diagnostic history, tumor pathology, alpha fetoprotein (afp), hearing assessments, dosing schema, treatment outcomes, and therapyrelated toxicities were reviewed. total cisplatin levels were collected at time points within days after each infusion. free cisplatin levels were also collected for infusions, as were dialysate cisplatin levels. pk parameters were generated using bayesian estimation with a published population pk model as a priori information. results: three patients meeting these criteria were identified. each had "low risk" (non-metastatic resectable) disease at presentation and underwent upfront resections. all had congenital renal anomalies with esrd prior to their hb diagnosis. all cisplatin infusions were given over hours, followed hours later by hemodialysis. patients and received cisplatin at % of children's oncology group's ahep weight-based dosing ( . mg/kg). patient received % of ahep body surface area-based dosing ( mg/m ) during cycle but required a second dose reduction ( mg/m ) for cycle due to prolonged cisplatin exposure (total area under the curve mg⋅h/l; average for all seven evaluable cycles mg⋅h/l) and early sensorineural hearing loss at - hz. no other hearing loss in any patient was identified; mild toxicities also included grade - emesis and grade neutropenia and thrombocytopenia. the median (range) of clearance, volume of distribution at steady-state, and elimination half-life at terminal phase for total platinum were . ( . - . ) l/hour/ kg, . ( . - . ) l/ kg and ( - ) hours, respectively. patients and received cycles with rapid afp normalization. patient required an additional cycles, for a likely second primary hb year after initial therapy. cisplatin can be used successfully in pediatric patients with esrd on hemodialysis to treat hb with minimal morbidity using % standard mg/kg-based dosing ( . mg/kg), achieving pharmacologically appropriate cisplatin exposures. background: treatment for immune thrombocytopenia (itp) has been grouped into rescue and maintenance therapy and often is reserved for patients with bleeding, severe thrombocytopenia, or for improvement in quality of life. splenectomy is considered one of the more invasive but definitive treatments with success rates of - %. treatment of itp can be more difficult in the setting of previous treatment with immune modulation or when the patient is immunocompromised and not a candidate for splenectomy. objectives: present an interesting case of a patient with an autoimmune disease that presented with severe thrombocytopenia, un-responsive to rescue therapy, and requiring emergent splenectomy in the setting of acute intracranial hemorrhage (ich). a year old female with a history of juvenile dermatomyositis presented with a fine purpuric rash on her extremities, wet purpura, and a platelet count of k/ l. bone marrow evaluation at that time was consistent with itp. she was on cyclosporine and plaquenil for dermatomyositis. platelets failed to increase after three doses of intravenous immunoglobulin and high dose steroids. following a two week course of oral prednisone and eltrombopag, she presented with persistent severe thrombocytopenia of k/ l, anemia of . g/dl, and a lower gi bleed. she was started on amicar, novo-seven, rituximab, and given platelet transfusions with no improvement in bleeding. subsequently, she developed a subdural hematoma with midline shift. surgery performed an emergent open splenectomy with concurrent continuous platelet transfusion. results: she was monitored closely post operatively and, due to ich, transfused to maintain platelets greater than k/ l. by week post-op she had normal platelet counts off transfusions. all medications were stopped within three days of discharge. she represented eight days later with abdominal pain and thrombocytosis and was found to have a portal vein, splenic vein and mesenteric vein thrombosis. she was started on lovenox therapy and admitted for monitoring due to her history of ich. it is unknown whether our patient's underlying immune dysregulation and history of treatment with immunosuppressive medications may have contributed to her unresponsiveness to multiple therapeutic agents. in addition, her significant bleeding did not allow us to fully evaluate her response to second tier therapy. this adds to the scarcity of literature of itp response in pediatric patients with autoimmune disease, and may support more aggressive therapy upfront in these patients. background: multivisceral organ transplantation involves concurrent transplantation of the stomach, pancreas, liver, and intestine with splenectomy, and has been classically used in the pediatric population for infants with intestinal failure from disorders affecting foregut integrity. while there is some data demonstrating its efficacy in adults with low-grade abdominal malignancies, it has not been traditionally used for hepatocellular carcinoma treatment. to describe a unique pediatric case of multivisceral organ transplantation as definitive therapy for refractory fibrolamellar hepatocellular carcinoma in an adolescent male. a year old male presents with a history of fibrolamellar hepatocellular carcinoma, tumor invasion of the portal vein, severe portal hypertension complicated by bleeding esophageal varices and hypersplenism. he had two treatments with yttrium- radioembolization, without significant response. he completed six cycles of traditional chemotherapy in combination with sorafenib with resolution of petavidity, but minimal decrease in tumor size and continued portal hypertension. since his disease remained relatively stable for over years, he was evaluated and listed for multivisceral organ transplantation. at approximately years and months after diagnosis, he underwent en bloc liver, pancreas, stomach, small bowel, and colon transplant with splenectomy. a single lymph node was positive for malignancy at the time of resection. in addition to expected post-transplant complications, he also developed skin only acute graft versus host disease at weeks after transplant, treated successfully with a thymoglobulin course. he clinically improved and was back to his baseline activity level, on full oral feedings within months post-transplantation. at three and six month post-transplantation, there is no concern for relapsed hepatocellular carcinoma on comprehensive imaging and evaluation. he is maintained on protocol immunosuppression and posttransplant support. we present the first known case of successful multivisceral organ transplantation in the treatment of refractory pediatric fibrolamellar hepatocellular carcinoma. background: hematohidrosis is a rare disorder that presents with spontaneous excretion of whole blood from intact skin or mucosa. diagnosis is based on clinical observation of the occurrence with the proven presence of erythrocytes and other blood components, without other abnormalities to account for the phenomenon. the existing literature is scarce and consists of primarily case studies. most reports describe bleeding from facial sites around the eyes, ears, and nose. the available literature suggests anxiety and physical or emotional stress reactions as the most common inciting events. little evidence exists regarding the ideal therapeutic approach, however propranolol has been used successfully to reduce bleeding frequency and severity in multiple case reports. a specific genetic etiology has not been elucidated, and no familial cases have previously been reported. we present a pair of half-siblings, both of whom presented with spontaneous cutaneous and mucosal bleeding before two years of age, and report on preliminary results of propranolol therapy. tanzania. at months of age, he became ill and developed spontaneous bleeding from his ears, nose, and scalp. he continued to have frequent bleeding episodes, usually related to illness or physical distress. a bleeding diathesis work-up was unremarkable, however some episodes were severe enough to require transfusions. the patient was subsequently diagnosed with hiv and hepatitis b, presumably acquired via unscreened blood product transfusions. patient b is an infant female born to the same mother as patient a, with a different father. she was healthy until two months of age when she developed spontaneous bleeding from the hairline, eyelids, ears and genital/rectal area. bleeding episodes were nearly always associated with irritability and crying. extensive coagulation workup was unremarkable. results: propranolol therapy was started in both patients, titrated to a goal of mg/kg/day. in both patients, the frequency and duration of bleeding episodes significantly improved. patient b continues to have milder occasional bleeding episodes from her eyes, ears and scalp but has significantly less discomfort and irritability during the episodes. conclusion: to our knowledge, there are no prior reports involving two related patients with hematohidrosis. this case series suggests that there may be a genetic predisposition which has yet to be identified. propranolol has shown effectiveness in reducing symptom frequency and severity. background: gliomas are the most common central nervous system tumors in children. they are classified into different grades based on genotype (idh, braf, tsc, etc.). lowgrade gliomas such as oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas are classified as grades i and ii. of the molecular level alterations this case report focuses on the braf v e mutation. braf is a member of the raf family of serine/threonine protein kinases and it plays an important role in cell survival, proliferation and terminal differentiation. objectives: here we discuss two cases where dabrafenib, a braf kinase inhibitor, was utilized in the management of gliomas. the cases focus on the use of dabrafenib late versus early in disease course. design/method: patient jl is a year old female who was diagnosed with a low-grade glioneuronal tumor (c -t with a metastatic lesion to the brain) in . jl was treated with chemotherapy, radiation, and surgical resection. despite treatment, the patient's disease progressed. she developed lower extremity dysfunction, urinary incontinence, poor truncal control, and hydrocephalus. dabrafenib was started after the braf v e mutation was confirmed. patient lg is a year old female who presented in november with left facial and upper extremity weakness. ct and mri scans demonstrated a mixed solid and cystic lesion extending from the optic chiasm and hypothalamus to the right thalamus and posterior basal ganglia with additional involvement of the right cerebral peduncle. neurosurgical intervention was undertaken and dabrafenib was started after the braf v e mutation was confirmed. results: patient jl's mri scans have demonstrated improvement of the spine with diminished areas of enhancement along thecal margins, decreased volume and enhancement within the trigeminal plate cistern and resolution of ependymal enhancement within the right ventricle. the patient's most recent mri exhibits no disease progression in head or spine. jl has shown improvement clinically since starting dabrafenib. patient lg has shown improvement in strength and recent mri of the brain has shown resolution of enhancement along surgical resection margins, decreased hyperintensity along the inferomedial aspect of the right basal ganglia and no new enhancements. conclusion: low grade gliomas can alter a person's quality of life and even lead to life threatening complications. often the standard chemotherapy, radiation and surgery don't prevent these complications. genetic analysis can help clinicians target therapy towards certain mutations such as braf v e. dabrafenib has shown to decrease tumor burden, early utilization as therapy can help prevent morbidity and mortality. children's hospital of pittsburgh of upmc, pittsburgh, pennsylvania, united states background: copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. copper requirements in children over the age of are mg/day, which is readily acquired in a typical diet. copper deficiency is known to occur in patients with the rare x-linked mutation and in older individuals with gastrointestinal bypass surgery; however, it is rarely reported in other conditions. objectives: to highlight individuals with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency, thus a high index of suspicion must exist in order to diagnose the disorder. design/method: a y/o boy with a prior diagnosis of global developmental delay and oral aversion presented with slowly progressive fatigue, weakness, gait instability, and weight loss. his longstanding feeding difficulties were refractory to intensive feeding programs. his daily diet consisted of - oz of milk and - individual servings of butterscotch pudding ( - calories/day, . mg iron/day). initial complete blood count demonstrated white blood cell count of . , absolute neutrophil count of , hemoglobin of . , mean corpuscular volume of < , reticulocyte count of . , platelet count of . review of his peripheral blood smear revealed microcytic, hypochromic red cells without marked fragmentation, anisopoikilocytosis and ringed sideroblasts; there were no morphologic abnormalities of his leukocytes or platelets. iron studies demonstrated ferritin of , total iron binding capacity of , and % iron saturation. he had no evidence of b , folate deficiency or blood loss. additional evaluation revealed a serum copper level of (range - ), and cerulosplasmin of . (range - ). results: once a diagnosis of copper deficiency was made, the patient promptly began a course of parenteral copper repletion. he received iv copper mcg/kg/day x days then weekly intravenous infusions. given his malnutrition, a gtube was placed to begin oral copper repletion and enteral nutrition. within weeks his copper level improved as well as his blood counts. unfortunately, although his blood counts and copper levels normalized, his neurologic status remains below his old baseline although, he has made gains in his gross and fine motor abilities. conclusion: acquired copper deficiency in the pediatric population is a rare event but given the hematologic and neurologic consequences, prompt recognition and treatment is important. this patient's clinical course demonstrates the need to have a high index of suspicion of concomitant nutritional deficiencies other than those routinely evaluated such as iron, b and folate. background: lymphoepithelioma-like thymic carcinoma (lelc) is a rare, aggressive neoplasm with a high rate of invasion, metastasis and recurrence. there are no known curative therapies for metastatic lelc. we report the case of a -year-old male who presented with metastatic ebv positive lelc. sites of disease included a large primary anterior mediastinal mass and metastases to hilar lymph nodes, lungs and liver. he was initially treated with cisplatin and fluorouracil followed by mediastinal radiation. he had a partial response to therapy but his end of therapy scans showed disease progression in lungs, liver, and hilar, supraclavicular and axillary lymph nodes. objectives: molecularly targeted therapies tailored to the patient's genetic profile offer a novel approach to obtain improved survival outcomes. design/method: the patient enrolled on a precision medicine trial, nmtrc : molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancer (nct ). in this study, tumor/normal whole exome sequencing and tumor rna sequencing were performed and a molecular report detailing the results of genomic and gene expression analysis was generated. a treatment plan was designed within a molecular tumor board comprising oncologists, pharmacists, genomicists, and molecular biologists with domain expertise. results: exome sequencing revealed somatic coding point mutations and no structural mutations (focal copy number changes or translocations). candidate somatic driver mutations included tp s x and r w as well as kit n k. both genes have been previously implicated in thymic carcinoma. rna expression analysis demonstrated aberrant activation of biological pathways, including overexpression of kit, hdac , and , tyms, and dhfr. the molecular tumor board selected the combination of pemetrexed ( mg/m ) on day of a day cycle, imatinib ( mg daily), and vorinostat ( mg days - , - , and - ) . on day of cycle , he was admitted with a herpes zoster infection and imatinib was discontinued in order to reduce risk of herpes zoster recurrence. imaging after cycles showed a complete metabolic response on f- fdg pet and a partial response by ct size criteria. as of december , the patient had received cycles of pemetrexed and vorinostat. scans in december showed an increase in the size and metabolic activity of two right lower lobe pulmonary nodules. there were no new sites of disease and imatinib was re-started. background: systemic lupus erythematosus (sle) is a chronic autoimmune disease that affects multiple organ systems and is associated with many different autoantibodies. patients can present with vague constitutional symptoms including fever, rash, fatigue, and weight loss. some of the various hematologic manifestations of sle include anemia of chronic disease, leukopenia, autoimmune hemolytic anemia (aiha), and idiopathic thrombocytopenic purpura (itp). these can be the presenting signs of sle. evans syndrome (es), a disease characterized by itp and aiha, is a rare hematologic manifestation of sle. neurofibromatosis (nf ) is a relatively common neurocutaneous disorder. these patients are at risk of developing benign and malignant tumors. its association with autoimmune disorders, including sle, remains rare. objectives: there are few cases in the literature that have patients with the combination of sle and nf . this is the only case that has a patient with sle, nf , and es. results: a -year-old caucasian female presents with two months of vaginal bleeding, weight loss and petechiae. her exam is remarkable for petechiae and café au lait macules. laboratory findings show severe anemia and thrombocytopenia. she receives blood and platelet transfusions during stabilization, and a bone marrow aspirate is performed to rule out a malignancy which is negative. based on the presence of thrombocytopenia and a positive coombs test, an autoimmune process such as es is considered. screening tests for sle reveal positive antinuclear and anti-double stranded dna antibodies as well as low complement. she receives intravenous immunoglobulin and methylprednisolone and eventually her vaginal bleeding slows and her counts recover. she begins sle therapy with hydroxychloroquine and azathioprine. due to the presence of café au lait macules on her exam, a genetics evaluation is performed and the patient is also diagnosed with nf . to date, there are seven cases of sle with nf reported in the literature, only two of which are pediatric cases. there are no reports of the combination of sle, nf , and es. conclusion: es is a rare hematologic manifestation of sle but can be the initial presentation of this disease. one large study estimates % of childhood-onset sle cases are observed to have es. screening for sle should be considered in all es patients even in the absence of typical clinical findings. association of nf and sle has been rarely described. whether this association reflects a causal relationship or is coincidental needs more investigation. (lube, ped blood & cancer, ) . university of california san diego, la jolla, california, united states background: high grade glioma (hgg) has poor outcomes in adults and children. extraneural metastases are very rare in hgg, and poorly characterized with only a few small case series in adults and only isolated case reports in pediatrics. no genomic data has previously been published for any children with hgg who develop extraneural metastases. objectives: our objective is to describe the natural history of two children with hgg and bony extraneural metastases, comparing their clinical characteristics as well as whole exome sequencing data for both tumors. this information would suggest similar patients should be monitored closely for extraneural metastasis and may benefit from more systemic therapy. design/method: we present a case series of two patients who presented with hgg and had development of bony metastases less than six months after initial diagnosis. both patients had molecular profiling with whole exome sequencing (wes). the first patient was an -year-old male with a tumor found in the left lateral ventricle invading into the fornices, hypothalamus, and left midbrain, who had subtotal resection. bony metastasis were found at . months after diagnosis, and he died months after diagnosis. he initially received radiation, followed by nivolimuab. the second was a -year-old female with a tectal/pineal tumor and multiple spinal cord metastases, who had subtotal resection. she developed bony metastasis at . months after diagnosis and died months after diagnosis. her histologic diagnosis was pineoblastoma, revised to hgg after whole exome sequencing. she received craniospinal radiation followed by chemotherapy per acns (cisplatin, vincristine, and cyclophosphamide) for cycles. when she failed to respond satisfactorily to this therapy, wes of tumor was performed and the findings were consistent with hgg. treatment was transitioned to temodar and lomustine after hgg diagnosis was given. she had ongoing progressive disease despite this therapy as well as trials of nivolumab, everolimus, and vorinostat. neither patient had extraneural metastasis at presentation. in both tumors, whole exome sequencing identified the h f a k m mutation. both tumors also had additional known mutations associated with hgg but no other overlapping mutations. this case series represents the first description of the genetic alterations of pediatric hgg patients who developed extraneural metastases. while h f a k m is a common mutation in pediatric midline hgg, especially dipg, and is associated with more aggressive disease, there has not been an association with extraneural metastasis prior to this series. background: deferiprone-induced agranulocytosis is a well -known albeit rare side effect of the drug. incidence of agranulocytosis varies from . - . %, while milder neutropenia is reported in . % of patients treated with deferiprone. deferasirox is unknown to cause such a complication. clinical trials and post marketing side effect monitoring studied possible correlations between different risk factors and development of agranulocytosis. unfortunately, no studies directly addressed a special risk in a community with background of ethnic neutropenia, like oman. objectives: to report on the incidence of neutropenia among omani children with b thalassemia using different iron chelators design/method: a retrospective study conducted on patients < year-old with b thalassemia treated with different iron chelators. electronic patients records were reviewed to detect episodes of neutropenia either mild (anc . -< . /cmm), moderate (anc . -< ), severe < . , or agranulocytosis anc = ). data were collected including sex, age, personal or family history of ethnic neutropenia, iron chelating agent, infective complications, management and outcome. detailed clinical, laboratory ± radiological information were reported for patients who developed life-threatening agranulocytosis. among young patients with b thalassemia, treated between - in squh, neutropenia, was reported in patients ( . %).severe neutropenia was encountered on occasions in patients ( / : . %) ( on deferiprone including episodes of agranulocytosis, on defersirox, on combined chelation, and off chelation). moderate neutropenia was encountered in patients ( / : . %), on occasions: deferiprone ( ), deferasirox ( ), combined chelation ( ), and episodes off chelation. mild neutropenia was more prevalent, encountered in patients ( . %) on occasions ( on deferiprone, on defersirox, on combined chelation, and off chelation) of patients exposed to deferiprone, patients had neutropenia ( %), higher than previously reported. deferiproneinduced agranulocytosis was encountered in patients ( / = . %). three of them had life threatening complications. one patient developed pneumonia complicated by rupture of pulmonary artery aneurysm-massive hemoptysis, who recovered fully after catheter embolization. the second had facial cellulitis and treatment with gcsf was complicated by frequent ventricular extrasystoles. the third had sepsis, disseminated herpes simplex and required admission to icu for inotropic support. in a community with background ethnic neutropenia, neutropenia is more common to be encountered among thalassemic patients, both on and off chelation therapy. careful monitoring of anc and rational choice/modification of chelating agents is required for optimal management of iron overload and to avoid life threatening complications. objectives: this case control study aimed to evaluate the systolic and diastolic cardiac function in groups of children with ti: non transfused group and a group that received early regular blood transfusion comparing them to healthy controls. design/method: thirteen regularly transfused patients with ti with a mean age of . + . years were compared with eight patients who are non-transfused or minimally transfused (< rbcs transfusion/year); mean age . + . years and healthy controls with a mean age of . ± . years. clinical parameters and standard echocardiographic and tissue doppler imaging (tdi) were compared. results: young non-transfused ti patients had a statistically significant higher peak late diastolic velocity of the left ventricular inflow doppler, a mitral valve a wave duration over the pulmonary vein a wave duration ratio and the pulmonary s of s vein s/d velocities ratio compared to the transfused group with p values of . , . , . respectively. in addition, they have a lower e/a ratio of the mitral valve inflow and a larger left atrial to aortic diameter ratio compared to the control group with p values of . and . respectively. the diameters of the right and left outflow tract were significantly larger in the non transfused group with a trend to have a higher cardiac index compare to the transfused group. systolic function was similar in the studied groups and none of the patients had evidence of pulmonary hypertension. young patients with ti who are receiving early regular blood transfusion have normal systolic function. diastolic function assessment revealed indicators of an abnormal relaxation of the left ventricle in the non transfused group which indicate diastolic dysfunction. the abnormalities affected multiple diastolic function parameters which give an indication that the changes are clinically significant. a statistically significant increase in the diameters of the outflow tracts are likely attributed to high cardiac output status in nontransfused ti patients as they had a trend to have a higher cardiac index. these findings support the early commencing of regular blood transfusion therapy for ti patients to prevent serious cardiac complications in adult life. background: in the -week sustain study, crizanlizumab . mg/kg significantly reduced the frequency of scpcs versus placebo ( . vs . , p = . ) and increased the time to first on-treatment scpc ( . vs . months, p = . ) in patients with sickle cell disease (scd). to evaluate time to first scpc in sustain study subgroups and the likelihood of not experiencing scpc for the duration of the trial using post hoc analyses. design/method: sustain was a randomized, double-blind, placebo-controlled, phase study (nct ). inclusion criteria were: scd patients aged - years; - scpcs in previous months; concomitant hydroxyurea use permitted if ≥ months and stable dose for ≥ months. patients were randomized : : to receive intravenous crizanlizumab . mg/kg, . mg/kg, or placebo. study treatments were administered on days and , then every weeks to week , with the final assessment at week . median time to first scpc after first dose was summarized for crizanlizumab . mg/kg or placebo in these subgroups: - or - scpcs in previous months; scd genotype; and hydroxyurea use at baseline. hazard ratios (hrs) for crizanlizumab . mg/kg versus placebo were calculated based on cox regression analysis, with treatment as a covariate. descriptive statistics were used to summarize the frequency of patients who were scpc event-free for the duration of the study by prior scpc events, scd genotype, and hydroxyurea use at baseline. : patients received crizanlizumab . mg/kg and received placebo. there was a meaningful delay in time to first scpc with crizanlizumab . mg/kg versus placebo observed in the entire study population. the effect was present in both scpc subgroups, and the largest treatment difference was observed in hbss scd versus other genotypes ( . vs . months; hr: . ). in patients taking hydroxyurea who experienced - scpcs in the previous year, time to first onstudy scpc was longer with crizanlizumab . mg/kg versus placebo ( . vs . months; hr: . ). a greater proportion of patients treated with crizanlizumab . mg/kg were scpc event-free versus placebo in each of the analyzed subgroups. one third of patients who were taking hydroxyurea and treated with crizanlizumab . mg/kg were scpc event-free during the study versus . % with placebo, possibly suggesting an additive effect. with crizanlizumab . mg/kg, there was a clinically meaningful delay in time to first scpc and an increased likelihood of being scpc-free versus placebo in all subgroups investigated. cincinnati children's hospital medical center, cincinnati, ohio, united states background: shwachman-diamond syndrome (sds) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (mds) and acute myeloid leukemia (aml). objectives: this multi-institutional retrospective study investigated clinical features, treatment, and outcomes of sds patients who developed mds or aml by central pathology review. design/method: nine individuals presented with aml ( male, female), mds-eb / ( males, females, with mds ( male and female), and one male with isolated persistent somatic tp mutation. one mds-eb and mds patient progressed to aml. median age (years) at diagnosis of mds was (range . - ), mds-eb / was (range . - ) and aml was . (range . - ). complex cytogenetics were noted in / aml cases, with one having normal cytogenetics. complex clonal cytogenetic abnormalities were noted in of mds-eb /eb patients and clonal abnormalities in of mds patients. follow up was available for aml patients; are deceased. received chemotherapy with intent to proceed to hematopoietic stem cell transplant (hsct). four failed to achieve remission and died with disease without proceeding to transplant. one patient proceeded to hsct without prior chemotherapy. four of six transplanted subjects died with relapsed disease. treatment related mortality was largely infectious or gvhd. the sole surviving aml patient had normal cytogenetics, achieved remission with chemotherapy and underwent hscts with separate stem cell infusions due to two primary graft failures. he remains alive in remission more than years after diagnosis. of the mds-eb / patients, underwent ric hsct, three of whom are alive, one died of infection. the fifth patient has stable disease on continued decitabine monotherapy for . years. of mds patients with treatment data, had upfront hsct therapy, upfront chemotherapy and had no therapy. three patients required ≥ hscts all due to graft failure. follow up is available for , of whom are deceased, with relapsed disease. treatment related mortality was largely infectious or graft failure. one individual died of hepatic failure unrelated to mds. seven mds patients are alive in remission. in summary, prognosis is poor for patients with sds who develop aml due to resistant disease and treatment-related complications. better markers for risk stratification are needed to identify patients who would benefit from early transplant. novel therapeutic strategies are urgently needed to improve outcomes of sds patients with mds or aml. background: unlike primary myelofibrosis (pmf) in adults, which is associated with somatic mutations in jak , mpl, or calr, myelofibrosis in children is rare and the underlying genetic mechanisms remain elusive. here we describe families with autosomal recessive congenital macrothrombocytopenia with focal myelofibrosis (cmtfm) due to germline mutations in the megakaryocyte-specific immune receptor tyrosine-based inhibitory motif (itim) receptor g b-b. objectives: to characterize the clinical phenotype, histological features and identify the causative gene for cmtfm. we performed affymetrix snp . genotyping on the index family to identify shared regions of homozygosity by descent. whole exome sequencing (ws) was performed on all three pedigrees to identify potentially causative mutations. we studied affected children from families, with macrothrombocytopenia, anemia, mild leukocytosis and a distinctive pattern of bone marrow (bm) fibrosis centered around clusters of atypical megakaryocytes. affected children had mild to moderate bleeding symptoms and required platelet and red cell transfusions. none showed evidence of extramedullary hematopoiesis, and all were negative for mutations in jak , mpl, and calr. snp genotyping identified multiple statistically non-significant genomic loci, including the region of the major histocompatibility locus (mhc) on chromosome p (lod = . ). we focused on this region because affected individuals in two families shared a common homozygous human leukocyte antigen (hla) type and had congenital adrenal hyperplasia (cah) due to -hydroxylase (cyp a ) mutation; the cyp a and hla loci are located at p . and p . - p . . wes revealed homozygous frameshift mutations in the megakaryocyte and platelet inhibitory receptor g b-b, encoded within the candidate linkage region. we identified two distinct g b-b frameshift mutations (c. _ + dup; p. fs and c. inst; p. fs) in individuals within these three families. no other mutations that segregated with the phenotype were identified. to validate g b-b as a potential disease-causing gene, we evaluated g b-b expression in bm biopsy specimens from affected patient and control samples by immunohistochemical staining using a monoclonal antibody. g b-b was strongly s of s and selectively expressed in megakaryocytes of control samples, but completely absent in clinically affected individuals. a murine knockout that lacks g b-b has a strikingly similar phenotype with macrothrombocytopenia, myelofibrosis and aberrant platelet production and function, further affirming the causality of g b-b mutations. we showed that autosomal recessive loss-offunction mutations in g b-b cause cmtfm, uncovering the molecular basis of this rare disease. loss of g b-b-dependent inhibition of megakaryocyte activation likely underlies the distinctive focal myelofibrotic phenotype and might be important in other forms of marrow fibrosis. cardinal glennon, saint louis, missouri, united states background: intrauterine transfusion is the method of choice for management of fetal anemia due to red blood cell alloimmunization. despite the decrease in prevalence of anemia due to rhesus d alloimmunization with prophylactic administration of anti-rhd immunoglobulin in rh d negative patients, maternal red red blood cell alloimmunization with other type of red blood cell antigens remains an important cause of fetal anemia. newborn who received intrauterine transfusion for hemolytic disease may have prolonged postnatal transfusion requirement. objectives: -to evaluate clinical outcome of fetuses and newborns who received intrauterine transfusions. -to determine the need of packed red blood cell transfusions until months of age. we conducted a retrospective case series study of all intrauterine transfusions due to anemia secondary to red blood cell alloimmunization performed in our regional center ssm in st louis missouri, between april and january . we evaluated the indications, diagnosis, gestational age, and frequency of intrauterine transfusions, along with the infant's gestational age at birth, duration of admission, timing of blood transfusion and monitoring of hemoglobin. results: intrauterine transfusions were performed in patients. the most common causes of alloimmunization were due to d antibodies (n = , %) and kell antibodies (n = , . %). the median gestational age of the first intrauterine transfusion was . weeks, and the median pre-transfusion hemoglobin was . g/dl. the gestational age at the first intrauterine transfusions was found to be significantly correlated with the number of postnatal transfusions (r = . . p = . ). the median gestational age at birth was found to be weeks ( . - . weeks), with a hemoglobin of . ( . - . ). in our population, patients ( %) received postnatal transfusions, of which were during the first weeks of life, and close monitoring follow up with a hematologist was established in patients at their discharge from the nursery/nicu. one neonatal death occurred and severe morbidity due to severe anemia occurred in one infant. despite the continuing risk factor for persistent anemia, only patients had follow up hemoglobin monitored by their primary care provider. conclusion: infants with anemia due to red blood cell alloimmunization treated with intrauterine transfusion should be monitored closely via regular complete blood count for persistent anemia due to suppression of fetal erythropoiesis. sebastian hesse, piotr grabowski, juri rappsilber, christoph klein dr. von hauner childen's hospital, lmu university hospital, munich, munich, germany background: neutrophil granulocytes are the most abundant leukocytes in the peripheral blood. validated diagnostic options for these cells are limited, leaving many patients with functional neutrophil defects without a defined diagnosis. objectives: here we evaluate proteomics as a new diagnostic tool to investigate defects of neutrophil granulocytes. we analyzed neutrophil granulocytes from children with severe congenital neutropenia (scn) associated with elane mutations, children with chronic granulomatous disease (cgd) with cyba ( ) or cybb ( ) mutations and children with leukocyte adhesion deficiency (lad) due to itgb mutations. in addition we collected samples of children with genetically undetermined neutrophil defects. neutrophils from healthy individuals served as controls. cells were isolated from fresh venous blood using negative selection (purity > %). whole cell proteome analysis was done by data-independent acquisition. showed a correlation coefficient of ∼ . . principal component analysis demonstrated unequivocal separation of the proteome of healthy and diseased cells. differential expression analysis showed minimal proteome aberrations in lad with deficiency in cell surface receptors and upregulation of alpl (total downregulated proteins: / total upregulated proteins: ). analysis of neutrophils from cgd patients also showed limited proteome aberration. cyba and cybb were both diminished independent of genotype, whereas protein clusters around a stat / centered network were increased (total down: / up: ). neutrophils with elane mutations showed the gravest proteome disturbance (total down: / up: ) with an upregulated translational apparatus (srpdependent ribosomes and protein folding complexes) and increased mitochondrial proteins. proteins of each granule subset were dysregulated and metabolic pathways upregulated. a detailed analysis of the proteome from patients with genetically undefined diseases is currently ongoing. one patient with clinical phenotype of cgd was found to have no mutations of nadph oxidase members in whole exome sequencing but critically low levels of ncf on protein level. heterozygosity mapping showed autozytocity in the ncf region warranting current efforts to sequence promoters and intronic regions of the gene. mass spectrometry based proteomics promises exciting new insights into monogenic disease of neutrophil granulocytes and may offer new diagnostic options, in particular in synergy with genome sequencing. by virtue of our international care-for-rare alliance, open to new partners, we hope that our proteome focus may lead to better delineation of as yet unknown disease of neutrophil granulocytes. background: warm autoimmune hemolytic anemia (aiha) is an igg mediated disease. although it can be post-viral, it is often idiopathic and can also be a forme fruste for malignancy or an autoimmune disease. initial management includes steroids. it often relapses on steroid wean and can be refractory to the use of second line treatment such as rituximab. objectives: abatacept (ctla- -ig fusion protein, ctla- mimetic) has been used to ameliorate autoimmune manifestation associated with ctla- haploinsufficiency. we used abatacept as a novel therapeutic agent to manage patients with refractory aiha. design/method: a retrospective case series of two patients at phoenix children's hospital with severe refractory aiha. results: patient , a previously healthy year old female, presented with weeks of icterus, fatigue, and hemoglobinuria. spleen was enlarged cm below the costal margin. laboratory evaluation demonstrated: hemoglobin . g/dl, mild leukopenia /microliter, platelets , /microliter, reticulocytosis . %, positive direct coombs' test, mycoplasma igm and igg positive. bone marrow evaluation showed a hypercellular marrow. she continued to need packed red blood cell (prbc) transfusions despite receiving high dose steroids, ivig and rituximab from may-july . in august, she started sirolimus decreasing her transfusion requirement. after starting abatacept ( mg/kg/dose bi-monthly for three doses and then monthly) in october, she maintained hemoglobin of - g/dl without transfusion. patient , a previously healthy month old male, presented with one week of progressive fatigue, jaundice, and poor feeding. splenomegaly was absent. laboratory evaluation revealed hemoglobin . g/dl, leukocytosis , /microliter, platelets , /microliter, reticulocytosis . %, negative direct coombs' test, and non-specific reactivity on antibody screen. evaluation for inherited hemolytic anemia including a next generation sequencing panel was negative. further evaluation by blood bank showed + positive coombs' for c d due to a warm antibody. cold agglutinin disease was ruled out. bone marrow evaluation was normal. he received high dose ivig as a steroid sparing agent but continued to require prbc transfusions weekly. when prednisone did not seem to slow down hemolysis, treatment with abatacept was initiated and he has not required transfusions for two months. steroids are being weaned. we present successful treatment of two refractory aiha cases with abatacept. patient is steroid and transfusion free and continues on monthly abatacept and sirolimus. patient is also transfusion free and continues on a steroid taper. ctla- is crucial for suppressive function of treg cells. abatacept by binding to cd / seems to enhance treg activity ameliorating autoimmune hemolysis. children's minnesota, minneapolis, minnesota, united states s of s background: transfusional iron overload is common in patients receiving chronic red cell transfusions. as a result, iron chelation is required to minimize toxicity from iron overload. chelation with a single agent can be inadequate at controlling or reducing iron burden. when combination therapy is required deferoxamine may be added to oral chelation. deferoxamine is generally given subcutaneous over - hours for - days a week at - mg/kg/day. many patients struggle to remain compliant with this schedule which has prompted trials of intravenous high-dose (hd) deferoxamine. prior reports of short-term hd deferoxamine have shown minimal side effects however, prolonged use of hd deferoxamine has known toxicity. when compliance is a concern, our center has used hd deferoxamine infusions at mg/kg/hr x hours every to weeks. objectives: evaluate the safety and efficacy of hd deferoxamine at our institution to help guide future therapy. design/method: a retrospective review was completed of patients previously treated with hd deferoxamine between april and september at children's minnesota. final sample included patients ages to years with underlying diagnosis of thalassemia ( ) and diamond-blackfan anemia ( ). deferoxamine infusions were given for hours every - days with a mean length of treatment of days. results: all patients were on combination therapy with deferasirox, however deferasirox was held during deferoxamine infusion. mean pre-deferoxamine liver iron concentration (lic) was . mg/g and mean post lic was . mg/g (p = . ). ferritin mean pre-deferoxamine was ng/ml compared with mean post ng/ml (p = . ). two patients had possible allergy, leading to deferoxamine discontinuation. one patient developed hives, eye swelling and cough while the other had emesis and cough. another patient experienced facial nerve palsy of unclear etiology, which did not recur with resumption of deferoxamine. no respiratory complications were seen. results showed significant decrease in iron burden following combination therapy with high dose deferoxamine and deferasirox. no significant pulmonary, liver, renal, vision, or hearing toxicities were observed. three patients reported reactions to deferoxamine infusions. however, one of these was able to successfully continue deferoxamine without further incident. short-term, hd deferoxamine was effective at reducing lic in combination with oral chelation but requires further evaluation to assess for potential increased risk of toxicity. short-term hd deferoxamine may be considered in the setting of poor compliance of subcutaneous administration or inadequate chelation with single agent therapy. further studies are needed to clarify ideal dosing, timing and risk of toxicity. background: immune thrombocytopenia (itp) is the most common cause of symptomatic thrombocytopenia in childhood but remains a diagnosis of exclusion warranting further evaluation if atypical findings are present. two male children ( months and years old) with newly diagnosed immune thrombocytopenia (itp) were found on initial evaluation to have persistent elevations of lactate dehydrogenase (ldh), alanine aminotransferase (alt), and aspartate aminotransferase (ast). these serum enzyme abnormalities cannot be attributed to itp. in the setting of thrombocytopenia, elevated transaminases and ldh create diagnostic complexity for the hematology/oncology provider as their elevation raises concern for malignancy, hemolytic disease, and other systemic diseases. to raise awareness about an unexpected pattern of duchenne muscular dystrophy in patients undergoing evaluation for itp. to expand the differential of a hematologist/oncologist when abnormal labs support a nonhematologic diagnosis design/method: this case-series of two patients with their clinical and laboratory findings were discovered with retrospective chart review. results: after a thorough evaluation for hemolytic anemias, liver disease and infectious etiologies was negative, bone marrow and liver biopsies were considered. eventually, both children were found to have severely elevated serum creatine kinase (ck). skeletal muscle has the highest concentration of ck of any tissue. thus, significant ck elevation is almost exclusively attributable to muscle injury and is the most sensitive and specific enzyme for diagnosis of muscle disease. referral to a neuromuscular specialist and further genetic testing confirmed the diagnosis of duchenne muscular dystrophy in both children allowing initiation of appropriate interventions. to date, there is no clear genetic predisposition to itp in patients with muscular dystrophy although further investigation may be needed. hematology/oncology providers should consider obtaining a serum ck to rule out muscle disease in any male child with unexplained elevations of serum ldh and/or aminotransferases, as it provides an easy and inexpensive, non-invasive approach to screening. additionally, clinical history and physical examination can aid in the diagnosis of muscular dystrophy, with gross motor delay, abnormal muscle bulk, gower's sign, and proximal muscle weakness all possible findings. objectives: to identify the range of cbcs in patients with ds without infections, hematologic or immune disorders and to create more accurate reference ranges for total white blood count; hemoglobin; hematocrit; mcv; platelet count and absolute neutrophils (anc), lymphocytes, monocytes, eosinophils, and basophils. design/method: a retrospective investigation of healthy pediatric patients with ds who received a cbc between and as part of their medical care at a single, large, pediatric teaching hospital. the study group consisted of children with ds (male = , . %; mean age = . years, sd = . ) at time of blood draw. initially children were reviewed for possible participation in the study; however, patients were excluded due to not meeting the study's inclusion criteria. descriptive statistics were performed on demographic and clinical characteristics. kruskal-wallis h tests, anova, and t-tests were run to determine the significant associations between independent means. results: a significant difference in absolute neutrophils between racial groups, f( , . ) = . , p = . , was observed. there was an increase in anc from . +/- . with african americans to . +/- . in the other racial groups and to . +/- . with caucasians. differences were also found in anc in hispanics/latinos versus non-hispanic/latinos. the results were higher in non-hispanics and latinos, a significant difference of -. ( % ci, -. to -. ), t( ) = . , p = . . preliminary kruskal-wallis h tests run determined that there were significant differences between age groups for total white blood cell, hemoglobin, hematocrit, platelets, lymphocytes and anc. further studies are being run to evaluate in which age groups these differences lie and create reference ranges by age, race and sex. conclusion: among patients with ds, there are differences between racial groups and age groups. this data has been compared to previously established reference ranges for cbcs, but we are currently establishing healthy cbc controls which we will use to validate the reference ranges. these ranges will be published to help guide providers in workup and management of patients with ds. background: transfusion is a critical part of the care provided in the neonatal intensive care unit, but it is not without risks. low birth weight and premature infants can become anaemic from an immature haematopoietic system and frequent phlebotomy. these infants often receive multiple red blood cell transfusions. identifying infants more likely to require such intervention is important in ensuring the appropriate usage of this scarce resource. to determine whether birth weight, gestational age, gender, length of stay and mode of delivery can predict red cell concentrate (rcc) transfusion, units required, donor exposure and time to exposure. design/method: a retrospective chart review of all infants born below weeks gestation and/or birth weight less than , g who received a red blood cell transfusion between july and july in the cork university maternity hospital neonatal unit. results: infants met the inclusion criteria, ( . %) received a rcc transfusion. our study showed lower gestational age (p< . ) and lower birth weight (p< . ) infants are more likely to be transfused. donor exposure increases with a lower birth weight (p = . ). multivariate analysis showed infants with a lower gestational age (or - . per day; p< . ); lower birth weight (or - . per g; p< . ) and a longer length of stay (or . per day; p< . ) are more likely to receive a higher number of rcc transfusions. the time to first rcc transfusion is shorter in those with lower birth weight (or . per g; p< . ) and lower gestational age (or . per day; p< . ). gender and mode of delivery were not found to be predictors of red blood cell transfusion in this study. conclusion: low birth weight and premature infants are more likely to receive a rcc transfusion during admission to the neonatal unit. our study highlights predictors of rcc transfusion, donor exposure and time to transfusion. these can be used in identifying at risk infants, counselling parents and in anticipating transfusion requirements. emily southard, r. grant rowe, david williams, akiko shimamura, taizo nakano children's hospital colorado, aurora, colorado, united states background: the mecom locus encodes transcription factors that regulate hematopoietic stem cell self-renewal and maintenance. overexpression of mecom has been noted in - % of acute myeloid leukemia, several solid tumors, and denotes a poor prognosis. mutations that reduce mecom expression or that disrupt protein function, however, have been implicated in the development of bone marrow failure (bmf) through undefined pathways. an association between mecom mutations and radioulnar synostosis with amegakaryocytic thrombocytopenia (rusat) syndrome has been reported, however further characterization of this phenotype has yet to be explored. to characterize the phenotypic spectrum of a cohort of pediatric patients with novel mecom mutations. we performed a retrospective review of five patients with mecom mutations who were referred to hematology at children's hospital colorado or boston children's hospital. clinical, laboratory, and genetic data was collected on subjects and available family members. results: four of subjects were identified in infancy presenting with congenital cytopenias or physical dysmorphisms that prompted broad genetic screening. platforms for genetic detection included microarray, targeted genetic panels, and whole exome sequencing. three of subjects with cytopenias presented with congenital thrombocytopenia, of whom rapidly progressed to severe aplastic anemia. four of subjects presented with congenital anomalies, of whom demonstrated radioulnar synostosis. additional dysmorphic features identified include craniofacial (low set ears x ), cardiac (pda x , vsd x , aortic root dilation x ), pulmonary (pulmonary hypertension x , arteriovenous malformations x ), and developmental delay. one subject presented at age years with acute pancytopenia, hypocellular marrow, no dysmorphisms, and a mecom variant of unknown signif-icance. the identified mecom mutations include one . mb deletion involving several genes including mecom, one variant affecting a splice acceptor consensus sequence predicted to disrupt splicing, and three novel missense mutations, tyr cys, arg thr, and tyr cys, all of which were absent from public databases and were predicted in silico to be deleterious. we describe the phenotypic spectrum of patients with novel mecom variants. a subset of patients lacked radio-ulnar synostosis and had presence of additional systemic anomalies, demonstrating a varied clinical phenotype that is not isolated to rusat syndrome. a centralized publically accessible database to share clinically annotated mecom variants, together with analysis by experts in mecom function would advance our understanding of the clinical interpretation of mecom variants. mecom should be considered in the differential diagnosis of bone marrow failure and we advocate for the inclusion of mecom in targeted sequencing panels. cairo university, cairo, egypt background: beta thalassemia is regarded as a serious public health problem in the mediterranean region, southeast asia, and the middle east. however, very few studies have been conducted to assess the quality of life (qol) among thalassemia major patients. objectives: to assess the quality of life among b-thalassemia major patients using short form (sf)- questionnaire and to determine the factors associated with their quality of life. design/method: a cross-sectional study was conducted among thalassemia major patients who were attending the hematology outpatient clinic at cairo university hospital, during the study period. data were collected between october and march . the quality of life was assessed for patients aged ≥ years. the mean age of the studied group was . ± . years. the majority ( . %) had one monthly blood transfusion. the mean total score of sf- was . ± . . general health perception domain was the most affected domain with mean score, while vitality was the least affected one. there was no statistically significant difference between males and females regarding different quality domains except for vitality where the mean score was significantly higher in males than females (p = . ). age at onset of disease, and at first blood transfusion were the most documented factors positively correlated with the quality of life among the enrolled thalassemia patients. conclusion: the quality of life in thalassemia major patient was found to be compromised. all thalassemia patients should undergo assessment of the quality of life so that interventions focusing on the affected domains can be implemented. background: international adoption of children with special needs has become more prevalent in recent years leading to tremendous growth in the number of u.s. thalassemia patients adopted from foreign countries. currently % of the , thalassemia patients registered in the cooley's anemia foundation (caf) patient database have been adopted from foreign countries, primarily china. as this population continues to grow, further information is needed in order to provide these families with best supportive care. the primary goal of this study is to characterize the socio-demographics and health statuses of adopted children with thalassemia and their families. a secondary goal is to describe adoptive families' motivations, experiences, challenges, and support resources. design/method: a redcap survey was accessed by families of adopted children with thalassemia through the caf website and caf social media from january to august . following a four-question screen, eligible subjects were directed to complete an adoption questionnaire. families who had at least one adopted child with thalassemia receiving care at a participating thalassemia treatment center or hematology office in the u.s. were considered eligible. descriptive statistics were analyzed using sas . . respondents who were ineligible or who provided incomplete data were removed from the dataset prior to analysis. of survey respondents, qualified and completed the survey. these households had adopted a total of children with thalassemia ( . % male), most from china ( . %), where they had been living in orphanages ( . %). legal guardians identified primarily as christian ( . %). the majority had completed post-secondary education ( . %) with reported household incomes greater than $ , ( . %). most adoptive families were connected to an adoption group or community including online groups, local support groups, and adoption networks ( . %). commonly cited challenges were: ) volume of frequent medical appointments, ) insufficient support from their local care centers, and ) financial burdens. the reality of care for the population of adopted patients with thalassemia in the u.s does not seem to match the expectations set by their providers. we are hopeful this data will be used to assist adoptive families navigating the complexities of thalassemia care. the findings suggest that this population would benefit from additional outreach, education, guidance, and advocacy resources -especially in the early stages of adoption and during initiation of post-adoption medical care. background: in many higher-income countries, thalassemia major has become a chronic disorder; many outcomes are different in emerging countries with more limited resources. most analyzes of health-related quality of life (qofl) in thalassemia have been conducted in high-income settings. objectives: to assess the impact of health status on qofl in thalassemia patients in an emerging country. we assessed qofl in randomly-selected patients ( thalassemia major; with hemoglobin e thalassemia; five thalassemia intermedia) at the national thalassemia center in kurunegala, sri lanka where approximately patients are managed. treatment is free, but compared to north america/europe, access to tertiary staff and other resources are limited. overall, control of body iron as estimated by serum ferritin concentration (mean± sem, ± g/l) was not optimal in many patients. to understand the impact of health status on qofl, we used the sf v health survey, analyzing scores of physical function, pain, general health, social functioning, emotional and mental health, to generate overall physical and mental component scores. results: compared to reports from higher-income countries (american journal of hematology ; : - ), physical function scores (mean±sd, . ± . ) were similar in sri lankan patients; indeed, in three categories (physical role, social function, emotional role), sri lankan scores were slightly higher. by contrast, compared to scores from higherincome settings, those estimating bodily pain, general health, and mental health were significantly lower, resulting overall in a significantly lower physical component score in sri lankan patients. male sri lankan patients reported higher scores than females, and somewhat surprisingly, in four categories (physical function, physical role, social function and emotional role) reported higher scores than those obtained in higher-income settings. lower scores in physical functioning, leading to an overall lower physical component score, were recorded by females. patients with hemoglobin e thalassemia reported generally poorer qofl than those with thalassemia major. the lack of differences in qofl in patients with "high" and "low" hemoglobins was likely related to low pre-transfusion hbs (mean±sem, . ± . g/dl) in nearly all patients. these early data in a small cohort of thalassemia patients in an emerging setting suggest that in many patients bodily pain, reduced mental health, and poorer views of general health affect overall qofl. prospective studies in larger cohorts including evaluation of adequacy of transfusions and chelation therapy, complications, and overall accessibility of care may guide approaches to improve qofl in lower-income settings of thalassemia care. geetanjali bora, anand prakash dubey, tarun sekhri, mammen puliyel, aparna roy maulana azad medical college, new delhi, delhi, india background: in the last two decades, the presence of osteopenia has been described in optimally treated patients with transfusion dependent thalassemia, the pathogenesis of which seems to differ from osteopenia in non-transfused patients. the prevalence rate of low bone mineral density (bmd) in pediatric population is highly variable amongst studies done worldwide. furthermore, the role of metabolic and endocrine factors in determining bone mass in this population is not well understood. objectives: to assess bmd in subjects with transfusion dependent beta thalassemia by dual-energy-x rayabsorptiometry and find its co-relation with clinical, biochemical and hematological parameters. design/method: this is a comparative cross-sectional study and includes patients with transfusion dependent beta thalassemia between ages to years enrolled from a thalassemia day care center in the year - . at the time of enrollment age, sex, bmi z scores, pubertal staging, duration and type of chelation therapy were noted. enrolled subjects were scanned for bmd at lumbar spine l - and left femoral neck using dexa scan. the bmd was expressed in mean values and z scores. age, bmi, ethnicity and gender matched historic controls were used to generate z scores. ml of pre transfusion fasting venous blood samples were obtained to test for serum calcium, phosphate, alkaline phosphatase, pth, thyroid function panel, serum ferritin and serum igf- levels. mean values for pretransfusion hemoglobin and serum ferritin over last months were calculated. results: total no of subjects , median age . years, male ( %), female ( %), ethnicity % asian, bmi < rd centile ( %), pre pubertal %, all receiving transfusion and chelation therapy. prevalence of low (z score < - sd) and very low (< - . sd) bmd was %, % at l -l respectively and %, % at left femoral neck respectively. there was trend of lower bmd z scores with advancing age. statistically significant co-relation (p value < . ) was found between low bmd and low mean pretransfusion hemoglobin, serum phosphate, igf - and vitamin d levels conclusion: a sizable proportion of children and adolescents with transfusion dependent thalassemia have suboptimal bone mineral density and this decline may start as early as - years of age despite being on transfusion regimen highlighting the importance of yearly dexa screening and optimization of pre-transfusion hemoglobin, vitamin d and igf levels. vanderbilt university medical center, nashville, tennessee, united states background: it is well described that iron deficiency anemia (ida) can co-present with thrombocytosis or thrombocytopenia, though cases of thrombocytopenia are less frequent than thrombocytosis. prior reports of thrombocytopenia have included adult and pediatric patients with menorrhagia ( - ), menorrhagia due to uterine fibroids ( ), or other gynecologic abnormalities ( ). our cases highlight the pattern of ida, thrombocytopenia, and menorrhagia in the setting of significant menstrual clotting without observed gynecologic abnormalities in african-american adolescents. objectives: to describe the clinical course of three adolescent females with severe ida, menorrhagia, and thrombocytopenia. results: our cases included three female african-american patients ages - who presented with severe anemia and concurrent thrombocytopenia in the setting of menorrhagia. all three patients reported heavy and prolonged menstrual cycle bleeding with significant clots. two of the three were admitted for transfusions at presentation and noted to have significant menstrual bleeding with continued blood loss requiring additional transfusions until bleeding was controlled with estrogen therapy. these two patients were evaluated with pelvic ultrasounds revealing a prominent endometrium in both patients and hyperechoic material consistent with a clot in one patient. average hemoglobin on presentation was . gm/dl ( . - . ), average platelet count was , /mcl ( , - , ), and average mcv was ( - ). all had severe iron deficiency with an average ferritin of ng/ml ( - ) subsequently treated with oral iron. one patient had a prior history of ida that required transfusion and had subsequent normalization of her complete blood count. two patients had subsequent thrombocytosis before normalization of their platelet counts. two patients received platelet transfusions: one due to recent neurosurgical intervention with a higher goal platelet count and the other to help control menstrual bleeding after a nadir platelet count of , . a review of the clinical history and red cell indices pointed to ida and ongoing blood loss from menorrhagia as the reason for the bicytopenias. the thrombocytopenia in these cases may have been exacerbated by consumption of platelets in the significant clots all three patients reported. it is reasonable to treat with iron supplementation and supportive care which may include transfusions or management of menorrhagia with oral contraceptives or other hormonal methods. background: sickle cell disease is one of the most common inherited red blood cell disorders, yet many are not aware of their carrier status. the american college of obstetricians and gynecologists' guidelines recommend that pregnant women of african, mediterranean and southeast asian descent be screened for hemoglobinopathies with a cbc and hemoglobin electrophoresis . however, adherence to this practice and frequency of improper screening with sickledex is unknown. proper screening and counseling can impact families' knowledge, allowing for establishing relationships with pediatric hematology providers earlier. objectives: we sought to assess prenatal hemoglobinopathy screening practice patterns and methods of obstetrics & gynecology (obgyn) and family medicine providers in the nyc regional area. design/method: a cross-sectional electronic survey was administered to obgyn and family medicine practitioners from four nyc institutions. questions focused on prenatal hemoglobinopathy screening practices using case scenarios with variations on parental trait status and ethnicities. chisquare analyses were used to compare the two provider groups on categorical variables. there were total responses; surveys were complete, of which were obgyn and family medicine providers. respondents were mainly from academic medical centers, with the majority being faculty ( % of the obgyns and % of family medicine). no significant difference was found in frequencies of screening patients with a positive family history of a hemoglobinopathy. when asked about screening practices for patients without a personal/family history of a hemoglobinopathy, % of obgyns versus % of family medicine providers "always" screened for hemoglobinpathies (p = . ). when analyzed by ethnic background, there were significant differences by group in screening patients of white ( % vs %), black ( % vs %), mediterranean ( % vs %), and asian descent ( % vs %) (p≤ . for all). however, in cases where the hemoglobinopathy carrier status of both parents was known, there was no difference in screening with a hemoglobin electrophoresis. furthermore, > % of all respondents use sickledex for screening in the case scenarios. conclusion: this pilot survey highlights a difference in the methods and likelihood of prenatal hemoglobinopathy screening based on the type of prenatal care provider. screening differences can lead to variations in prenatal guidance, diagnostic procedures, informed decision-making and knowledge of families referred to pediatric hematology clinics. this is the first study analyzing prenatal screening for hemoglobinopathies in obgyn and family medicine. improving prenatal screening practices by collaborating with hematologists may decrease health care disparities and allow for earlier relationship building with pediatric hematology. . acog, opinion# , poster # hermansky-pudlak syndrome: spectrum in oman background: hermansky-pudlak syndrome (hps) is a rare autosomal recessive disorder, characterized by the triad of oculocutaneous albinism, a hemorrhagic diathesis resulting from storage pool-deficient platelets, and accumulation of ceroid/lipofuscin-like material in various tissues. before , nine different types of hermansky-pudlak syndrome were identified, which can be distinguished by their signs and symptoms and underlying genetic cause. in , a tenth type was defined based on mutations in the ap d gene. hps type is characterized in addition by severe neutropenia and recurrent sinopulmonary infection. the disease is more common in puerto rico, and this is the first report from oman. to describe the clinical, laboratory and genetic characteristics of hps sub-types in oman, including the first cases of hps type . design/method: this is a retrospective study, including cases with hps that had been suspected clinically and confirmed through genetic mutation analysis. clinical data included sex, age at presentation, initial clinical presentation (skin, eyes, development, neurological involvement, bleeding tendency, recurrent infections) and course of disease. laboratory data (complete blood counts, platelet and absolute neutrophil counts, coagulation screening, platelet function tests by platelet function analyzer, and platelet aggregation studies using different agonist had been recorded. pcr and next generation sequencing for genetic confirmation by testing mutations in hps , ap b , hps , hps , hps , hps , dtnbp ,, bloc s , bloc s genes had been done. results: seven omani cases with hps have been identified ( males and females). their age ranged between (at birth) to years. two patients had hps type , patient had type , while the other cases had hps type . no other sub-types were encountered in oman. all patients were products of consanguineous marriage. one patient had adrenal hge, while the others had mild hemorrhagic phenotype, characterized by recurrent bruising and mild epistaxis. laboratory testing confirmed variable platelet aggregation defects with different platelet agonists. all patients had characteristic hypopigmentation, iris transillumination, nystagmus, and foveal hypoplasia. both patients with hps type had the same homozygous mutation in the ap b gene (c. _ delta), and presented with severe neutropenia. early diagnosis and initiation of gcsf on one of them improved outcome and prevented the development of complications. late diagnosis in the other patient resulted in the development of bronchiectasis as a result of recurrent sinopulmonary infections. background: sickle cell disease (scd), a genetic disorder characterized by defective sickle hemoglobin (hbs), triggers red blood cell sickling, hemolysis, vaso-occlusion, and inflammation. ischemic injury from scd starts in infancy and accumulates over a lifetime, causing pain, fatigue, and progressive end-organ damage that culminates in early mortality. voxelotor (gbt ) is an oral, once-daily therapy that modulates hemoglobin's oxygen affinity, thereby inhibiting hemoglobin polymerization. objectives: to assess the safety, pharmacokinetics, and efficacy of voxelotor in pediatric patients with scd. design/method: this ongoing study is being conducted in parts: part a: a single dose of voxelotor mg in pediatric and adolescent patients; part b: multiple doses of voxelotor mg/d or mg/d for weeks in adolescents. part b's primary objective is to assess the effect of voxelotor on modifying anemia. secondary objectives include measuring other markers of disease modification, such as hemolysis; daily scd symptoms, using a patient-reported outcome (pro) measure; and safety. results: as of november , , patients ( females) had received voxelotor mg and patients ( females) had received voxelotor for ≥ weeks. the median age for the patients was years, % were receiving hydroxyurea (hu), and % had ≥ painful crises in the past year. data for hemolysis measures are available for patients who received voxelotor for weeks. six of the patients achieved a hemoglobin (hb) response of > g/dl increase. laboratory markers of hemolysis improved concordantly; the median reductions in reticulocytes and indirect bilirubin were % and %, respectively. ten of patients showed reduction in total symptom scores (tss) at week , with a % median reduction in tss from baseline. there were no treatmentrelated serious adverse events (aes) or drug discontinuations due to aes. voxelotor mg for weeks in adolescents with scd, the majority receiving hu, demonstrated consistent, sustained efficacy on hb levels and measures of hemolysis; > % of patients showed a > g/dl improvement in hb. improvement in tss in mildly symptomatic patients suggests that the pro is sensitive to treatment effect and supports use in the ongoing hope phase study. voxelotor's reassuring safety profile is consistent with results in adults. these interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with scd. supported by global blood therapeutics. background: acute kidney injury (aki) is a common complication in sickle cell disease (scd), and a potential risk factor for sickle nephropathy. aki is associated with acute decline in hemoglobin (hb) during vaso-occlusive pain crisis and acute chest syndrome (acs). it is unclear which pathologic factor plays a stronger role in aki development during hb drop: increase in free heme during vaso-occlusive events secondary to hemolysis or hb decline itself. objectives: to investigate if hb decline alone is associated with aki, we tested if the renal function of patients with scd worsened during parvovirus b -induced transient aplastic crisis (tac), in the absence of accentuated hemolysis. design/method: with irb approval, a retrospective study of patients who had laboratory confirmed parvovirus-b was conducted. serum creatinine (scr), both during and within months from the tac event, was collected. comparisons of the clinical and laboratory characteristics were analyzed using the wilcoxon test for continuous variables. aki was defined as an increase in scr by ≥ . mg/dl or a % increase in scr from baseline. to evaluate differences in change in hb on aki risk, changes in scr during tac were compared to those during pain crisis or acs admissions by fitting a generalized linear mixed model for binary outcome. a comparative sample of acs events and vaso-occlusive pain crisis were used to estimate rates of aki according to hb levels. results: three ( %) of the patients with scd developed aki during tac. no association was identified between change in hb from baseline to tac event (p = . ). no cases of aki were identified until hb decreased < . g/dl or the change in hb was ≥ . g/dl from baseline. next, we developed a model to evaluate the impact of change in hb from baseline for patients admitted with tac, pain crisis or acs on aki. with a g/dl decrease in admission hb from baseline, patients with tac had a % probability of developing aki, while acute chest syndrome and pain crisis would have a % and % probability, respectively. our data suggest that aki is still prevalent during parvovirus b -induced tac. however, the risk of aki during a tac event is and times lower than that from severe anemia induced by acute chest syndrome and vasoocclusive pain events, respectively. hemolysis-induced anemia during scd crisis appears to have a more significant role in the development of aki as compared to agenerative anemia. background: the natural history of hemoglobin e beta thalassemia (hbethal), the commonest form of severe beta thalassemia worldwide, has been examined in very few longterm studies. previously, we reported findings in hbethal patients in sri lanka. objectives: to evaluate longterm requirements for transfusion and splenectomy, complications and death in hbethal patients. design/method: all available patients were reviewed - times annually over years. results: patients ( %) died, aged (mean ± sem) . ± . years; the (known) causes commonly included iron overload ( ) and infection ( ); patients surviving patients are aged . ± . years. of patients originally classified by severity (group the mildest, and group the most severe, phenotypes), ( %) were assessed as mild (groups and ), of whom transfusions had been discontinued in . ultimately, / ( %) resumed transfusions, often following shifts to increasingly severe phenotypes including increasing intolerance to anemia. age at resumption of transfusions (following a transfusion-free interval of . ± . years) was . ± . years; in the more severe groups and , regular transfusions were stopped in / patients and resumed in / ( %), at younger ages ( . ± . years) and after shorter transfusion-free periods ( . ± . years) than in "milder" patients. mid-parental height (mph) was ultimately achieved in %. patients ( %) were splenectomized; updated analysis of responses to splenectomy (originally "group " patients), showed that splenectomy (at . ± . years) was followed by an extended, but impermanent, transfusion-free interval ( . ± . years); % patients resumed transfusions, usually related to exercise intolerance or poor growth. in groups and , complications of anemia and ineffective erythropoiesis, including leg ulcers (in % and %) and gallstones ( % and %), were more frequent than in groups and ; fractures were observed ( - %) across all groups, except for regularly-transfused group patients ( %). pulmonary artery pressures > mm were recorded in % patients. evaluation of patients with hbethal requires observations over years, without which definition of patients as "mild" or "severe" may be misleading. while in many patients transfusions may be withheld or reduced in frequency, troublesome complications may surface with advancing age even in "milder" patients. although individual consideration of transfusion requirements is critical, the availability of effective chelation, where this can be provided without prohibitive cost, may alter the balance of risks and benefits of regular transfusions in hbethal. (premawardhena a. lancet ). background: social determinants of health (sdh) are environmental and socioeconomic factors, such as access to food and housing that affect health outcomes. pediatricians are increasingly screening for sdh as part of primary care visits, however less is known about screening for sdh in pediatric hematology. evidence suggests that sdh play a role in disease severity for children with scd, who face significant socio-economic and racial disparities. the goal of our quality improvement (qi) project was to increase the percentage of patients with scd who were connected to community resources for unmet social needs. design/method: we based our intervention on the successful implementation of wecare in our institution's pediatric primary care clinic. eligible patients were identified at the start of each clinic session. on arrival the parent was given a self-reported screening tool for six sdh (childcare, education, employment, food, utilities and housing). results were entered in the electronic health record by the physician or social worker who then printed a pre-existing resource list for patients with a positive screen. we used a series of plan-do-study-act (pdsa) cycles to study tests of change. we tracked process measures (percentage of patients screened, percentage of patients with an unmet social need who received a resource sheet), outcome measures (percentage of patients with an unmet social need who connected with a community resource) and balancing measures (staff, patient and provider satisfaction). run charts were reviewed weekly and then monthly to inform further tests of change. examples of pdsa cycles include who gave the paper survey to patients (social worker or physician versus medical assistant) and length of time between surveys ( to months). results: between august and december screening rates improved from % to %. of the patients screened, % report at least one unmet social need; of those % received a targeted list of community resources in the first month of the project, and % in the fifth month. finally, % of patients reached by phone had connected with a community resource within weeks of the clinic visit. we have successfully implemented universal screening for sdh for patients with scd in our urban pediatric hematology clinic without requiring extra staff. next steps include further pdsa cycles to connect more patients to appropriate resources, and tracking improvement in health care utilization outcomes from addressing sdh in this vulnerable patient population. background: the clinical manifestations of sickle cell disease (scd), chronic hemolytic anemia, and vaso-occlusion occur as a direct result of sickle hemoglobin (hbs) polymerization. voxelotor (gbt ) is a first-in-class, oral, oncedaily investigational agent designed to modulate hemoglobin's oxygen affinity in a targeted approach to inhibit hbs polymerization. objectives: to examine the pharmacokinetics (pk), safety, and dosing of voxelotor in children (aged - years) and adolescents (aged - years) with scd from part a of the gbt - study. design/method: gbt - is an ongoing, open-label, phase a study in patients aged - years with scd (sickle cell anemia or sickle beta zero thalassemia). part a of this study (the focus of this abstract) is examining pk of singledose ( mg) voxelotor. pk samples to measure whole blood and plasma voxelotor concentrations were collected up to days following single-dose administration. separate population pk (ppk) models were developed to describe the concentration versus time profiles of voxelotor in whole blood and plasma using nonlinear mixed effects modeling (non-mem, version . ). ppk modeling and physiologically based pk (pbpk) modeling were used to simulate voxelotor pk parameters and support dose selection for future evaluation in younger children. : part a included adolescents ( females; median age years [range - ]) and children ( females; median age . years [range - ]). mean weight was . kg (range - kg) and . kg (range - kg) in adolescents and children, respectively. voxelotor was well tolerated with no drugrelated grade ≥ adverse events (ae) or serious aes. a compartment model with first-order absorption best described the pk of voxelotor (and was the same model structure used for adults with scd). voxelotor pk exposures in adolescents were comparable to those observed in adults, but higher exposures were observed in children. ppk and pbpk modeling support the use of a weight-based dosing strategy in younger children (aged < years) in future trials. adult voxelotor doses can be used in adolescents. however, based on higher pk exposures, a lower weight-based dosing strategy is recommended in children. ppk and pbpk modeling provides an innovative approach to minimize experimental dosing in children and accelerate dose selection of voxelotor in ongoing and future clinical studies. this abstract is supported by global blood therapeutics. background: hydroxyurea (hu) reduces rates of acute complications, and improves long term outcomes in patients with sickle cell disease (scd) and is now fda approved for children. through previous work we have increased the number of eligible patients on hu in our clinic, however accessing a compounding pharmacy remained a significant barrier to hu adherence for infants and children who cannot swallow capsules. objectives: the objective of our quality improvement project was to improve adherence to hu among pediatric patients with scd at our urban safety net hospital by addressing barriers to obtaining liquid hu. design/method: to begin we met with the leadership of our outpatient pharmacy which offers mail order delivery. however, like most retail pharmacies, they do not have the necessary protective equipment to compound liquid hu. through a series of discussions, we began a unique partnership with our institution's inpatient chemotherapy pharmacy who compounds the liquid hu and delivers it to the outpatient s of s pharmacy, who then dispenses liquid hu to families. using a series of plan-do-study-act (pdsa) cycles we tracked adherence by calculating the medication possession ratio (mpr), defined as the percentage of days in a given period of time that each patient had their medication on hand. the mpr for liquid hu mpr among enrolled patients was tracked by pharmacy staff and reviewed monthly. additional pdsa cycles included adding automatic refills and reminder calls by pharmacy staff and improving communication about delivery. we also tracked patient satisfaction. results: between march and december , a total of thirty pediatric patients were enrolled in our program for on-site compounding and free mail order delivery of liquid hu. mpr for liquid hu is currently . % among enrolled patients, significantly higher than the mpr of % reported in the literature, and has risen steadily since the beginning of the project. families are highly satisfied with the program, specifically appreciating the convenience of mail order delivery, saving on delivery fees, and reminder calls when refills were due. by compounding and dispensing liquid hu directly from our institution's outpatient pharmacy we have significantly improved adherence to this hu therapy in our high-risk population. next steps include analysis of change in clinical outcomes for patients enrolled in this program. as adherence to hydroxyurea is associated with decreased acute care utilization and cost, programs such as ours could play a crucial role in reducing the excessive costs and ed utilization among this patient population. background: experience with the iron-chelator deferasirox is reported widely in higher-income settings. by contrast, real-life experiences in emerging countries are infrequently reported. objectives: to evaluate, in a non-trial setting, the real-life response to deferasirox in an emerging country. design/method: in sri lanka's national thalassemia center which manages patients without tertiary staff, quantitative evaluations of body iron or estimates of extra-hepatic iron, the records of patients who began deferasirox in / were retrospectively reviewed. results: baseline assessments (mean±sem) indicated substantial iron loading [serum ferritin (sf) , ± ug/l; serum alt ± . u/l (normal ≤ u/l)]. deferasirox was introduced at low doses ( . ± . mg/kg/day); many patients started at < mg/kg and, after months, doses remained ≤ mg/kg/day in % patients. after months, sf in % patients remained > , ug/l; only by months had (mean) sf declined to < , ug/l ( ± ; p< . ). similarly, mean alt normalized (to ± u/l) only by months. death and complications were not systematically recorded by staff who had been charged, without provision of additional resources, with the introduction of this new drug in hundreds of patients. these results contrast to those in sri lanka's tertiary thalassemia center where, in patients following the introduction of deferasirox ± . mg/kg/day, sf declined rapidly, even in relatively less ironloaded patients (from , ± to , ± g/l after months; p = . ). these findings underscore the importance, during the implementation of new drug regimens in lowerincome centers with marginal resources, for investments in methods to quantitate body iron burden, hands-on educational initiatives to guide day-to-day management by competent but non-expert staff, and data systems to record efficacy, effectiveness, toxicity and compliance. such investment is critical to optimising therapy and improving complications in thalassemia patients worldwide: even in sri lanka, where resources directed to thalassemia management are greater than in most of asia, results in the oldest living cohort (born - ) indicate under-treatment [elevated iron burdens (sf , ± ug/l) and high prevalences of diabetes ( %) and hypothyroidism ( %)]. even in a younger cohort (born - ) which has benefitted from improved treatments, the prevalence of many complications exceeds those reported from high-income settings. over the next decade, and two decades after the who declaration that the impact of thalassemia on global mortality and morbidity is underrecognized, increased investments by governmental and nongovernmental sources will be necessary to improve outcomes for asian patients with thalassemia. background: a major barrier to success in hydroxyurea (hu) treatment of patients with sickle cell disease (scd) is non-adherence. objectives: to optimize hu adherence in patients with scd. design/method: a care model was designed by the sickle cell (qi) team at children's hospital to improve hu adherence among scd patients. the original model included bimonthly family phone contact, monthly dispensing pharmacy phone contact and lab monitoring. adherence measures included obtaining hu from pharmacy monthly, completion of monthly labs, hb f percentage and mcv, and mtd achievement. from / - / , several pdsa cycles refined our care model. a one-year follow-up survey gathered feedback on the care model. the first-year data involved ∼ patients. the biggest improvements resulted from making pharmacy calls before patient/family calls, shipping liquid hu to outlying patients, and tracking call time/content. the qi goal was % hu adherence by / . the % baseline adherence rate increased to % by / , and has remained in that range. the completion rate of patient/parent phone calls increased from % the first month to % at six months. pharmacy prescription pick-up has increased from % to % per month. lack of liquid hu availability was overcome by shipping the medication to the patient's home. parental hesitance to share information by phone, especially with qi team members with whom they had no established relationship, was overcome by having the longtime sickle cell nurse do many of the early calls. however, survey feedback showed families became comfortable with several clinic personnel calling. the calls gave families the opportunity to ask questions about their child and/or get additional information about scd. the calls also provided an opportunity for seasonal flu shot or tcd testing reminders. the surveys gave information on the optimal time of day to reach each family, providing individualization and further increasing the percentage of completed calls. two families surveyed said they no longer needed two calls a month because they were now able to remember to pick up hu, administer it, and get labs on their own. this qi project has not only improved hu adherence, but also fostered health education/counseling, increased patient/parent satisfaction, and enhanced service utilization. medical team member and patient/family comments demonstrate that it has helped build relationships and trust between families and the medical care system. based on survey feedback, we will further individualize care to increase adherence rate and sustain improvements. cincinnati children's hospital medical center, cincinnati, ohio, united states background: the thalassemias are a heterogeneous group of genetic blood disorders caused by mutations that decrease or eliminate the synthesis of the -and/or -globin subunits of hemoglobin. the phenotype of thalassemia depends on the interaction of the -and -globin gene clusters, because both loci determine the -/ -chain balance. for example, a -thalassemia phenotype can be more severe than expected when coinherited with -globin gene triplication (copy number gain), which exacerbates the -/ -globin imbalance. objectives: describe four individuals with an incorrect diagnosis of -thalassemia trait who were later properly diagnosed by comprehensive genetic testing to have -thalassemia intermedia caused by heterozygous -thalassemia mutations coinherited with triplicated -globin loci. design/method: sequence analysis of the -globin (hba /hba ) and -globin (hbb) genes, and copy number variation analysis of the -and -globin gene clusters by multiplex ligand-dependent probe amplification. results: four unrelated individuals of northern european ancestry were evaluated for signs and symptoms not explained by a diagnosis of -thalassemia trait (previously made by a pediatric hematologist), including growth delay, splenomegaly, moderate anemia, marked elevation of hemoglobin f, thalassemic facies, reticulocytosis, and/or indirect hyperbilirubinemia. genetic testing revealed that all were heterozygous ( / ) for the same, single -globin mutation [hbb.c. c>t (p.q *)] and also heterozygous for an -globin triplication ( / anti- . ). their previous diagnoses of thalassemia trait had been made by complete blood counts, hemoglobin electrophoresis, and/or sequence analysis of the -globin genes only. these individuals' phenotypes ranged from moderate anemia only to multiple stigmata of thalassemia, demonstrating the phenotypic variation of a thalassemia genotype. correct diagnosis was made at an average age of . years. a trial of chronic transfusions was initiated for one patient for growth failure. all were educated about the potential for exacerbations of anemia, gallstones, osteoporosis, and iron overload (even without transfusions). parental genetic testing was recommended to assess reproductive risk, because inheritance of this complex genotype can be apparently autosomal dominant. conclusion: heterozygosity for a -thalassemia mutation does not necessarily indicate -thalassemia minor or "trait". when coinherited with -globin gene triplication, a symptomatic form of -thalassemia can occur. correct and timely diagnosis of thalassemia requires careful consideration of the degree of anemia and examination for organomegaly, bony changes, and jaundice. sequence analysis and copy number variation analysis of both the -and -globin gene clusters is key. hematologists need to be aware of this diagnostic possibility and how to test for it to prevent inaccurate or delayed diagnosis. background: the burden of healthcare costs for sickle cell disease (scd) is nationally estimated at over $ billion. the major components of these costs are inpatient and emergency center (ec) visits, many of which are potentially avoidable. in several chronic conditions, a subset of patients account for most of the avoidable encounters. identifying these patients is the first step in targeted care delivery. objectives: to measure and analyze scd patient utilization patterns in the ec and inpatient at texas children's hospital (tch). we identified all individuals under years old with any encounter at tch associated with an international classification of disease (icd)- or code for scd, including hgb ss, hgb sc, and hgb s/beta thalassemia. for each patient, we identified all inpatient and ec encounters in the days prior to their most recent encounter. finally, each encounter was classified as associated with pain, acute chest syndrome (acs), or "other" using an algorithm of discharge diagnosis codes and pharmaceutical delivery. the total number of scd-associated ec and inpatient encounters over the prior year was calculated for each patient. we stratified each patient according to their utilization patterns: low ( - encounters), intermediate ( - encounters), and high (≥ encounters). we identified unique patients with scd that had at least one encounter from july until june . there were , scd-related encounters in the days prior to their most recent encounter. most ( %, n = ) patients exhibited low-utilization patterns and % (n = ) were intermediate. finally, a small subset ( %, n = ) demonstrated high-utilization patterns and accounted for % of all encounters. high-utilization was associated with older age and public payment mechanisms. pain encounters were predominantly in pre-adolescents and teenagers with high-and intermediate-utilization patterns. acs was most frequent in pre-teens and younger teens in the intermediate-utilization group. finally, the youngest-aged high and intermediate users presented for other reasons such as febrile episodes and splenic sequestration. our findings reflect national trends in that a significant portion of encounters are attributed to a small subset of patients exhibiting a high-or "super-" utilization pattern. at our institution, scd super-utilization is associated with older age and pain. we also identified a group of infants and toddlers with frequent encounters for fever. to comprehensively address this burden, it will be important to design interventions targeted toward age and specific medical needs. background: background: the rarity of diamond blackfan anemia (dba) has hindered describing the spectrum of disease, identifying predictive correlations, and guiding datadriven recommendations. long-term toxicities from steroid or transfusion therapy that start in childhood remain the major clinical problems in patients with dba who do not receive stem cell transplant. objectives: objective: to define the dba patient population at st. jude children's research hospital including treatment responses and toxicities to help inform recommendations on treatment and monitoring. design/method: method: medical records were reviewed for all patients with dba treated at st. jude between and for diagnostic testing, treatment types and regimens, and outcomes. two-sample t-test or wilcoxon rank sum test was used to compare continuous variables in two groups depending on the normality of the data tested by shapiro-wilk test. results: a total of patients with dba were identified with a median age of . years (range months - years) at last follow up. a ribosomal protein gene mutation was identified in / patients ( %) with an rps mutation / ( %). thirteen different congenital malformations were described in / patients ( %). fourteen of twenty ( %) patients treated with corticosteroids had an initial response and of those achieved full remission. three patients became steroid-refractory and were unable to wean to an acceptable dose. five of twenty patients continue on lower-dose steroids. five patients currently require no therapy. univariate analysis revealed no statistically significant genetic predictors of response or remission, however, / rpl patients responded to steroids with / ( %) in long-term remission. ten patients are maintained on chronic transfusions and have undergone successful hematopoietic stem cell transplant. nineteen of treated patients ( %) had a treatment-related toxicity. patients on steroids were more likely to have short stature than patients on transfusions or in remission (p = . ). severe bone mineral density deficit occurred in / ( %) patients, in before age years. eight patients had hepatic iron overload, in one documented by age years. other severe toxicities included restrictive cardiomyopathy from iron overload, pathologic fracture, diabetes mellitus, and premature ovarian failure in one patient each. this genotypically and phenotypically heterogeneous dba cohort had a high rate of treatment-related toxicities, notably growth retardation, bone density loss, and hepatic iron overload even in very young children. these findings underscore the need for early standardized monitoring. background: patients with sickle cell disease (scd) face worsening morbidity and mortality between ages and , when they must transition from pediatric to adult healthcare.( ) an effective curriculum addressing disease knowledge, educational and vocational skills, self-efficacy, and social supports is critical to a successful transition. traditional didactic approaches have not led to durable knowledge retention. ( ) technology-based methods have been attempted, but the best educational approach remains unknown. objectives: . to understand how adolescent and young adult (aya) patients with scd view existing transition education. . to include patient preferences in improving our transition curriculum. we developed a qualitative survey to assess patient views of existing approaches for learning about scd and their opinions about preferred transition topics. thirty patients with scd aged to years old were recruited between january and december . responses were managed using redcap electronic data tools hosted at the university of rochester.( , ) qualitative and quantitative data analyses were performed, including independent t-testing to compare responses between age groups. results: approximately % of subjects were under years of age, while % were or older. seventy-one percent had a computer, and . % had a cell phone, with most reporting daily use. subjects reported greatest satisfaction with learning from their doctor during clinic visits ( . % agree or strongly agree) and websites on a cell phone ( . % agree or strongly agree); the least popular methods were online chat rooms and microsoft® powerpoint presentations. satisfaction was similar across age groups. recommended transition topics were viewed positively, with subjects ranking highest understanding their bloodwork ( . % agree or strongly agree) and understanding laws protecting students with chronic disease ( . % agree or strongly agree). older subjects ( - years old) agreed more strongly with learning about opioid addiction and understanding differences between adult and pediatric doctors than did younger subjects ( - years old) (p < . ). this pilot study was successful in helping us to understand the educational needs of aya patients with scd. preliminary data underscore the importance of education provided by the pediatric hematologist. our results also suggest that the optimal use of technology-based methods requires further investigation and that tailoring transition education by age group may be useful. background: similar to patients with transfusion-dependent beta-thalassemias (tdt-beta), survivors of hemoglobin barts hydrops fetalis (homozygous alpha- -thalassemia, tdtalpha) will require lifelong transfusions of erythrocytes. we have previously shown that a transfusion strategy that is based on the guidelines developed for tdt-beta (conventional transfusion) is suboptimal for these patients owing to the differences in the pathophysiology of anemia in the two conditions: in tdt-alpha, conventional transfusion strategy will lead to a gradual increase in non-functional hbh with subsequent tissue hypoxia and hemolysis. an aggressive transfusion strategy that was based on reduction of hbh and increase in "functional" hemoglobin level resulted in improvement of tissue oxygenation and reduction of hemolysis but was associated with significant increase in transfusional iron burden [amid et al, blood ] . objectives: to define the optimal chronic blood transfusion targets for hbh% and functional hemoglobin in patients with tdt-alpha. design/method: following research ethics board approval, longitudinal data of patients with tdt-alpha ( males, median age . ( . - . ) were retrospectively collected. variables of interest included total pre-transfusion hemoglobin, hbh%, and "functional" hemoglobin [measured as total hemoglobin x ( -hbh/ )]. outcome variables were lactate dehydrogenase (ldh, marker of hemolysis), and soluble transferrin receptor (str, marker of erythropoiesis). hemoglobin analysis was done using high-performance liquid chromatography and capillary zone electrophoresis. we examined the association of "functional" hemoglobin with str, and hbh% with ldh, using repeated-measures anova to adjust for the effect of multiple testing. we constructed receiver operating characteristic curve and calculated the area under the curve to define the best cut-off values for variables of interests. there was a strong association between functional hb and str, as well as hbh and ldh. the optimal cut-off for "functional" hemoglobin that was associated with str < . mg/l was g/l (auc = . , sensitivity and specificity of . % and % respectively). the optimal cut-off for hbh to supress ldh to < u/l was % (auc = . , sensitivity and specificity of . % and % respectively). the optimal pre-transfusion hbh% for reduction of hemolysis was % and the optimal "functional" hemoglobin to adequately supress erythropoiesis was g/l. to meet these hbh% and functional hb targets by simple blood transfusions, patients with tdt-alpha would require a hypertransfusion regimen with a minimum pre-transfusion total hb of g/l and consequently high transfusional iron burden. an alternative approach using exchange transfusion to reduce hbh% and improve functional hemoglobin would be associated with less volume of transfusion and potentially better long-term outcome. hospital sacre coeur, milot, haiti background: initial results of work developing a pediatric sickle cell disease (scd) clinic at the hôpital sacré coeur (hsc) in milot, northern haiti were presented at aspho . the purpose of this clinic is for a pediatrician with a special interest in scd to provide scd care, advising on trait and managing disease with penicillin prophylaxis (pcn) and hydroxyurea therapy (hu) for select patients. this clinic was started in collaboration with a us based hematologist and support from yale-new haven hospital. objectives: to describe the success and challenges of providing pcn and hu in the scd clinic at hsc through a review of patient records. design/method: since this clinic's inception, a database of patients, with basic clinical information has been kept and made accessible, through 'drop-box', to the us hematologist. the records of those that presented to the clinic were reviewed. the hemoglobin diagnosis was made either by clinical history and sickle cell prep or by hemoglobin electrophoresis through alpha laboratory, port-au-prince, haiti. results: ninety-nine individuals were seen in the first years of the program. fifty-six underwent a hemoglobin electrophoresis. of these , are ≤ years old. thirty-two were started on pcn vk, of which / ( %) were ≤ years old. eleven patients were started hu therapy. all patients on hu have shown progressive increases in hemoglobin. there have been no clinical complications of hu therapy. none of the patients taking hu have required hospitalization or transfusion in . three patients (not on hu) were hospitalized in for complications of scd (osteomyelitis, pain). in , with less than half the numbers in the program, there were admissions for severe anemia, pain, stroke and splenic sequestration. with ongoing external support and a local reputation for excellence in sickle cell care, the clinic at hsc has been able to expand services and improve the health of a growing number of patients with scd. early data suggests that pcn and hu therapies are helping to reduce complications and improve quality of life. challenges to date have included lack of funding for transportation to clinics, for hospitalizations and to cover the cost of electrophoreses. at the same time as continuing providing excellent care and gathering data, it is crucial to explore opportunities for collaboration and cooperation in ways that will assure that the clinic can become independently sustainable while continuing to improve the quality of life for the individuals it serves. background: ykl- is an inflammatory glycoprotein expressed by infiltrating macrophages in various inflammatory conditions. it has been found to be elevated in patients with different pathological conditions like acute and chronic inflammations, increased remodeling of the extracellular matrix (ecm), development of fibrosis and cancer. several studies have found elevated ykl- concentrations in sera of patients with liver diseases such as hepatic fibrosis by hepatitis c virus. it has been suggested that ykl- concentrations reflect the degree of liver fibrosis. to evaluate serum ykl- levels in patients with -thalassemia and its relation to viral hepatitis, liver stiffness as assessed by transient elastography (fibroscan, fs) and hepatic iron concentration. design/method: a prospective study included patients with -tm ( males and females) with mean age . ± . years (range: - years). serum ferritin level, liver enzymes (alt and ast), hbs ag, anti hcv ab and serum ykl- using elisa kit were evaluated. all patients were subjected to liver mri t * to detect liver iron content by the sequence and transient elastography (fibroscan, fs) to assess degree of liver stiffness. results: mean fibroscan value was ( . ± . ) kpa with a median . (range . to ) kpa. ( %) patients were categorized as f - and ( %) were stage f - , ( %) patients had severe fibrosis. their median serum ferritin was ng∖ml, with ( %) patients had values exceeding g/l. median cardiac t * was . with patients had values below ms, and the median lic was . mg/g dw with patients showed readings above mg/g dw. nyl- was evaluated as a marker of inflammation and liver fibrosis and showed mean value . (± . ) pg/ml, and range from to pg/ml. mean ykl- was significantly higher among males (p = . ), patients on chelation therapy (p = . ), patients on dfs (p≤ . ), in those with abnormal liver enzymes, splenectomised patients, patients with hbv sero-positivity, those with moderate elevation of t * and patients with high grades of liver fibrosis (p< . ). ykl- showed positive correlation with the rate of transfusion, lic, ferritin, alt and ast but negative correlation with weight, height and t *. roc curve analysis revealed that the cutoff value of ykl- at pg/ml could differentiate -tm patients with and without viral hepatitis with . % sensitivity and specificity of . %, area under the curve (auc) . , positive predictive value . and negative predictive value . (p< . ). roc curve analysis revealed that the cutoff value of ykl- at pg/ml could detect -tm patients with liver cirrhosis with . % sensitivity and specificity of . %, area under the curve (auc) . , positive predictive value . and negative predictive value . (p< . ). conclusion: serum ykl- levels are elevated in patients with -thalassemia and can detect patients with active viral hepatitis and liver stiffness. background: the most common splenic complication in pediatric patients with sickle cell disease (scd) is acute splenic sequestration (ass), which has often been managed with splenectomy. although splenectomy has been a treatment of choice for years, long-term vascular complications have not been thoroughly evaluated. pulmonary hypertension (phtn) is a severe complication of scd. in adults with scd, phtn has been associated with a -month mortality rate of approximately %. it has been reported that splenectomized patients with hemolytic disorders are at even greater risk of phtn. several medications exist to treat phtn, but with few studies of their efficacy or toxicities in patients with scd. additionally, these patients are often treated with either chronic prbc transfusions or hydroxyurea (hu) to raise hemoglobin, reduce hemolysis, and prevent vaso-occlusive events. objectives: to evaluate effect of chronic prbc or hu vs. no intervention, on tricuspid regurgitant jet velocities (trv) in pediatric patients with scd and history of splenectomy. design/method: retrospective chart review of splenectomized patients with hbss followed at marian anderson center at st. christopher's hospital for children, philadelphia, between and . we analyzed trvs ( hu, prbc, and from control group receiving neither treatment) from patients ( hu, prbc, neither). mean age at echo was . +/- . . data was analyzed with linear correlations and analysis of variance (anova), including the post hoc test of least significant difference (lsd) for all pairs of treatment groups. results: trv was not significantly correlated with age at time of assessment or with time between splenectomy and trv. univariate anova among groups yielded trv means of: . +/- . cm/s (hu), . +/- . (prbc), . +/- . (neither). we found a notable difference as the mean of the hu group was almost cm/s lower than the others, but no overall statistically significant association for any of the groups exists. however, when we performed post hoc tests to adjust for multiple comparisons and looked at all pairings within the anova, we found that the lsd between the hu and the prbc groups was statistically significant (p = . ), and that a trend exists between the hu group and the neither treatment group (p = . ). our data suggests that treatment with hu is correlated with a reduction in trv in pediatric patients with scd who underwent splenectomy. given these promising results, we believe our data warrants further study with larger treatment groups. nancy olivieri, gaurav sharma, susmita nath, rajib de, tuphan kanti dolai, prakas kumar mandal, abhijit phukan, amir sabouhanian, robert yamashita, angela allen, david weatherall, prantar chakrabarti background: hemoglobin e thalassemia (hbethal), which accounts for % of all severe beta thalassemia worldwide, has an estimated prevalence of . / , in west bengal, from which little information about clinical findings has been reported. objectives: to document clinical and laboratory findings in patients with hbethal, ultimately to improve resources for clinical management. design/method: we reviewed records from: a database recording patient names; clinic charts; "special" charts containing additional details; and, in transfused patients, transfusion day-care records. additionally, because in india's public hospitals original lab/imaging reports are commonly retained at home, % of families were interviewed to provide additional information. we excluded records of patients aged < years and patients aged < years who had not been reviewed since . results: while at least one visit had been recorded in , hbethal patients at nrs hospital, most patients are not regularly reviewed there. we examined charts [ ( %) aged ≥ years; ( %) aged - years; % male], representing approximately % of regularly-reviewed patients. most families ( . %) reported monthly incomes (< , indian rupees), below the monthly cost of living ( , rupees) in kolkata. mean (±sem) hemoglobin was . ± . g/dl. % patients were receiving eight or more transfusions per year; from , % had been treated with deferasirox, . ± . mg/kg/day. iron control estimated by serum ferritin concentration ( . ± g/l) was highly variable. a total of % patients were splenectomized. a substantial obstacle to documenting complications was the lack of recording, in any of the five sources, of many relevant parameters: for example, the status of sexual maturation (normal, delayed, or absent) was documented in less than %, and measurements of fasting blood glucose in less than %, of records. where recorded, complication rates were high: delayed/abnormal sexual maturation was recorded in % patients aged > years; in the patients aged > years and those aged - years, respectively, hypothyroidism was recorded in % and %, and elevated serum alt in % and %. in most evaluable patients > years, height was measured between the rd- th percentiles. cardiac findings, rarely documented, included pulmonary hypertension and reduced left ventricular ejection fractions in a few patients. despite dedicated attention to many aspects of thalassemia care, insufficient documentation limited a clear understanding of the current morbidity in hbethal patients. investment in personnel and technology will be critical to record relevant information, ultimately to improve clinical management, over the next decade. children's hospital of richmond at vcu health, richmond, virginia, united states background: sepsis is a common cause of death in children with sickle cell disease (scd). recommendations for care of fever in children with scd include immediate medical evaluation including blood culture and initiation of broad-spectrum antibiotic therapy. the increasing availability of pcr-based respiratory pathogen panels (rpp) provide the opportunity to rapidly identify viral causes of fever. the role for rpps in identifying the source of fever in children with scd and how it affects provider practice is not well studied. ( ) to determine the epidemiology of respiratory virus-associated fever in children with scd and ( ) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all children with scd seen in our emergency department (ed) with temperature ≥ . oc at home or in the ed from january , , through september , , as well as, all febrile children for whom rpps were sent since the introduction of rpps april . we reviewed the results of blood cultures, rpps, chest radiographs, and ed notes and discharge summaries to identify sources of infections. independent t test and chi-square analysis were used as appropriate to compare results using spss©. overall, the rate of bacteremia was %. there were no cases of bacteremia among children with positive rpps. % of children with negative rpps had true bacteremia. a positive rpp did not reduce the likelihood of bacteremia (p . ). patients with bacteremia had higher presenting temperatures than those without bacteremia ( . oc vs . oc, p . ). the most common rpp findings were rhinovirus/enterovirus ( %), human metapneumovirus ( %), and influenza a ( %). sending an rpp did not affect admission rate ( % and % respectively, p . ); however, likelihood of admission was lower in patients with positive rpps ( % vs %, or . [ . - . ], p . ). length of stay (los) was shorter in patients for whom an rpp was not sent ( . vs . days, p . ). as previously reported, bacteremia in febrile children with scd is very low, but remains a serious concern, particularly in the setting of high fever (> oc). a positive rpp did not reduce the odds of bacteremia, but did have a sta-tistically significant impact on both admission rate and los. more work is needed to understand how rpp results impact provider decision-making and care for children with scd. cincinnati children's hospital medical center, cincinnati, ohio, united states background: diffuse myocardial fibrosis is a common, if not defining, feature of the heart in sickle cell anemia (sca) that is strongly associated with diastolic dysfunction. we found diffuse myocardial fibrosis in every patient in a sca cohort (n = ) ranging in age from to years (niss ). the treatment and prevention of this complication of sca has not been studied before. objectives: because diffuse myocardial fibrosis must begin in early childhood, we hypothesized that early initiation and uninterrupted use of disease-modifying therapy for sca can prevent it. design/method: we use cardiac magnetic resonance imaging (cmr) to measure the myocardial extracellular volume fraction (ecv) to quantify diffuse myocardial fibrosis in individuals with sca who have been treated, uninterrupted, with hydroxyurea or chronic transfusion therapy since ≤ years of age. two comparison groups were used: individuals with sca who have not been treated with disease-modifying therapy since ≤ years of age (n = ) and controls without sca (n = ). results: we studied individuals ( m/ f) with a mean age of . years (range - ). mean age at the start of diseasemodifying therapy was . ± . years (range - ). only had evidence of mild diffuse myocardial fibrosis (ecv . ); the other had no detectable diffuse fibrosis (all had ecv < . , the upper limit of normal). mean ecv was . ± . , which was significantly lower than the ecv of individuals with sca who have not received early uninterrupted therapy ( . ± . ; p = . ) and not statistically different from normal controls ( . ± . ; p = . ). none had macroscopic fibrosis by late gadolinium enhancement or evidence of myocardial hemosiderosis by t * imaging. no patient had diastolic dysfunction by echocardiographic classification, right heart catheterization, or both. disease-modifying therapy for sca can prevent diffuse myocardial fibrosis, and possibly diastolic dysfunction, if started in early childhood. prospective trials of disease-modifying and anti-fibrotic therapy are planned to prevent diffuse myocardial fibrosis, which can be monitored noninvasively by cmr, and improve outcomes in sca. (niss, blood, ) . background: a statewide sickle cell surveillance system (sscss) was developed with the goal of determining the prevalence of sickle cell disease (scd) in indiana and the level of care that patients receive throughout the state. persons with scd are at high risk of infection, especially with encapsulated organisms, as well as at increased complications from influenza. utilizing sscss data, the relationship between vaccination status and mortality was explored. to determine if vaccination status is associated with mortality in persons with scd. the project was granted a waiver of consent by the st. vincent irb. death certificates were obtained to identify cause of death. deceased patients (cases) were matched by age, gender, and sickle genotype to living patients (controls). vaccination data were collected from the medical record and the children and hoosier immunization registry program (chirp) through the date of death for each case. cases and controls were assigned a point for completion of the pneumococcus, meningococcus and haemophilus influenza type b (hib) vaccine series and one point if the influenza vaccine was given within a year prior to death of the cases [max vaccine status score (vss): ]. total points were compared between the cases and controls. two tailed t-tests to compare means of continuous data and wilcoxon signed-rank test to compare ordinal data. one thousand forty-eight individuals were included in the sscss. six hundred and seven ( . %) were seen at one institution and included in this analysis (mean age = years). thirty-three of the ( . %) were deceased at the time of analysis. six point one ( . )% of controls and . % of cases received a vss of . the mean vss for cases was . ± . and . ± . for controls. thirty point three ( . ) % of controls had a vss of one or more, compared to % of cases (p = . ). patients who died of infection [streptococ-cus (n = ), pseudomonas (n = ) and unidentified organisms (n = )] were not up to date on vaccination against encapsulated organisms, but two had received the influenza vaccine in the year prior to death. in this sample, mortality occurred exclusively among adult patients, which is consistent with current patterns in developed countries. among these adults, vss and mortality rates were not related. limitations to the study include small sample size and potential incompleteness of vaccine records. vaccination rates and other standard of care indicators should be explored in a larger cohort of patients to determine associations with mortality. background: sickle cell disease (scd) is a genetic disorder resulting in acute and chronic complications, including delayed puberty. delayed puberty can have adverse physical and psychosocial effects on affected children and families. there are no published reports from ghana on pubertal timing in children with scd. the aim of this cross-sectional study was to describe pubertal changes in children with scd at korle bu teaching hospital (kbth), accra, and compare these findings to those in a control group without scd. design/method: children with scd and children with hb aa, ages - years, were consecutively recruited and matched for age, sex and socioeconomic status. investigator-administered questionnaires were used to obtain demographic data for all participants and information on menarche (girls only). pubertal status was assessed by physical examination using tanner staging. testicular volumes were determined in boys using a prader orchidometer. body mass index (bmi) and socioeconomic status (ses) of participants were analyzed to determine if there were any associations with tanner stage. of the with scd, ( . %) were hb ss and ( . %) hb sc. females comprised . % (cases and controls). mean age at onset of breast development was significantly delayed in girls with scd ( . ± . years) compared to controls ( . ± . years) but there was no significant age difference at onset of pubic hair development. mean age at menarche was significantly delayed in girls with hb ss ( . ± . years) and hb sc ( . ± . years), compared to those with hb aa ( . ± . years). in boys, the mean ages at onset of puberty were significantly delayed in those with scd ( . ± . years, for genital development and . ± . years, for pubic hair development), compared to those without scd ( . ± . years and . ± . years, respectively). mean testicular volumes were significantly lower in cases compared to controls, across all age ranges (p< . ). mean bmi in both cases and controls were similar at onset of breast development in girls. however, in boys with and without scd, mean bmi values were significantly different at pubertal onset. in univariate analysis, ses was not associated with tanner stage for both genital and breast development. mean ages at pubertal onset were significantly delayed in children with scd. longitudinal studies are needed to further characterize any associations with bmi and determine potentially modifiable risk factors affecting pubertal onset in scd. background: sickle-cell disease (scd) is a life-threatening genetic disorder associated with multiple chronic and acute complications. specific monitoring and treatment for children is a major part of the medical focus, but there remains a lack of real-world evidence of the disease burden and practice patterns among the pediatric scd population. objectives: to examine the clinical burden and management of scd among pediatric patients. design/method: a retrospective claims study was conducted using the medicaid analytic extracts database from jan - dec . pediatric patients (aged < years) with scd were identified using icd- -cm diagnosis codes ( . - . , . - . ). the first observed scd diagnosis during the identification period was designated as the index date. patients were required to have continuous medical and pharmacy benefits for at least months pre-and months post-index period. patient data were assessed until the earliest occurrence of the following events: disenrollment, death, or the end of the study period. patient demographic and baseline clinical characteristics, clinical outcomes (mortality, incidence of pain crisis, complications), scd management, and healthcare utilization were examined. all variables were analyzed descriptively. results: a total of , patients met the study inclusion criteria, with a mean age of . years. most patients were black ( . %) and had a charlson comorbidity index score of ( . %). mortality during follow-up was . in personyears, and the event rate of pain crisis in the inpatient setting was . in person-years. the three most common complications after pain crisis (highest rates in person-years) were fever ( . ), infectious and parasitic diseases ( . ), and asthma ( . ). rates of life-threatening complications were also examined in person-years, including acute chest syndrome ( . ), stroke ( . ), splenic sequestration ( . ), pulmonary hypertension ( . ), and pulmonary embolism ( . ). . % of patients were prescribed antibiotics during the one-year post-index period. other frequent medications utilized among children were folic acid ( . %), nonsteroidal anti-inflammatory drugs ( . %), opioids ( . %), and hydroxyurea ( . %). . % of patients had a blood transfusion within one year post-index date. patients had frequent health care utilizations in the inpatient ( visit), emergency room ( visits), office ( visits), and pharmacy ( visits) settings during the one-year follow-up period. pediatric scd patients are burdened with a high rate of complications including pain crisis. in addition, patients utilized a substantial amount of health care resources including outpatient office care and acute care visits. background: novel use of hydroxyurea in an african region with malaria (noharm, nct ) is a randomized controlled trial of hydroxyurea for very young children with sickle cell anemia living in uganda. during year , study participants received blinded study treatment of hydroxyurea or placebo; those receiving hydroxyurea had no increased risk of malaria, but had both laboratory and clinical benefits. during year , all study participants received openlabel hydroxyurea treatment. to assess the effects of open-label hydroxyurea treatment in a very young population of children with sickle s of s cell anemia living in uganda. study endpoints included the rates and severity of malaria infections, clinical sickle-related events, and laboratory effects. design/method: all children in the noharm trial were enrolled at mulago hospital sickle cell clinic in kampala uganda. during year , all children received open-label fixeddose hydroxyurea ( mg/kg/day) for months, after previously receiving either hydroxyurea or placebo for months. results: a total of children entered year of the noharm trial and received fixed-dose hydroxyurea, including males and females, at an average age of . ± . years. among children previously on placebo, there were malaria events in children, including with severity grade ≥ , and three deaths (two acute chest syndrome, one sepsis). clinical adverse event rates dropped from . to . per patient year, and hospitalizations were reduced from to . expected hematological benefits of increased hemoglobin, mcv, and fetal hemoglobin, along with decreased neutrophils and reticulocytes, were rapidly achieved. laboratory adverse events were infrequent at . events per patient-year, and only half of those were dose-limiting hematological toxicities. among children previously on hydroxyurea, there were malaria events in children, including with severity grade ≥ , and two deaths (one acute chest syndrome, one sepsis). clinical adverse event rates and hospitalizations were maintained at low rates, the hematological benefits of hydroxyurea continued throughout the extended treatment period, and dose-limiting toxicities remained infrequent. fixed-dose hydroxyurea treatment of young children with sickle cell anemia living in uganda is associated with no increased risk for malaria. clinical and laboratory benefits occur, including children previously on placebo who crossed-over to hydroxyurea treatment. future studies should focus on the optimal dosing and monitoring strategies, in an effort to determine the overall feasibility and safety of introducing hydroxyurea therapy across sub-saharan africa. background: acute chest syndrome (acs) is the second most common cause of hospitalization in patients with sickle cell disease and is a leading cause of morbidity and mortality. in mid- , an algorithm was implemented at cohen children's medical center to initiate transfusions within four hours of diagnosis of acs in order to improve patient outcomes. objectives: the aim of this project was to analyze the effect of early blood transfusion on the outcomes of patients with acs. we focused on the number of total transfusions, need for exchange transfusion, need for intensive care unit (icu) stay, and length of hospitalization. design/method: a retrospective chart review was completed on patients admitted to ccmc with a primary diagnosis of sickle cell disease and a secondary diagnosis of either acs or pneumonia during the years of - . data from the three years directly prior to implementation of the algorithm was compared to data from the three years directly after implementation of the algorithm. a total of patients were analyzed, of which belonged to the pre-algorithm group and to the postalgorithm group. patients from the post-algorithm group had a higher incidence of transfusions ( % with a mean transfusion number of . pre versus % with a mean of . post) as well as exchange transfusion ( % pre versus % post). the post-algorithm group had a shorter overall length of stay (mean of . days pre versus . days post). while the overall percentage of patients requiring an icu admission was similar in each group ( % pre versus % post), the post-protocol group had a lower likelihood of requiring an icu admission for reasons outside of line placement for exchange transfusion, most commonly for icu-level respiratory support ( % pre versus % post). despite a higher total number of transfusions, early recognition and transfusion for acs can lead to decreased lengths of hospitalization as well as decreased need for icu-level respiratory support. further studies comparing different center's clinical practice guidelines are necessary to improve the standard of care. background: novel use of hydroxyurea in an african region with malaria (noharm) was the first placebocontrolled randomized clinical trial of hydroxyurea in sub-saharan africa. in noharm, young children with sca received either hydroxyurea or placebo during year , followed by open-label hydroxyurea for all study participants during year . an ancillary noharm project was designed to determine if hydroxyurea treatment lowers transcranial doppler (tcd) velocities and possibly reduces stroke risk in this very young cohort. objectives: to perform tcd screening on the noharm cohort, measuring the time-averaged mean velocity (tamv) at the end of both year and year . we hypothesized that the maximum tamv would be lower for noharm study participants receiving hydroxyurea compared to those receiving placebo, and that key clinical and laboratory parameters would also influence tcd velocities. design/method: all children enrolled in noharm were eligible to undergo tcd examination at two study time points: month - when they were completing the blinded treatment phase, and again at month - at the end of the open-label treatment phase. tcd measurements included tamv readings from the main intracranial arteries: middle cerebral artery, distal internal carotid artery, and bifurcation on tcd. all tcd examinations were scored and classified as normal (less than cm/sec), conditional ( - cm/sec) or abnormal (greater than or equal to cm/sec), with higher scores correlating to greater risk of stroke. results: at the end of year , tcd exams were conducted of which were suitable for analysis ( hydroxyurea, placebo). based on the maximum tamv, the median velocity was cm/sec (iqr - ) for children on hydroxyurea and cm/sec (iqr - ) on placebo, p = . . maximum tamv values had negative correlations with hemoglobin concentration (- . ), fetal hemoglobin (- . ), and oxygen saturation (- . ); positive correlations were noted with age ( . ) and absolute neutrophil count ( . ). at the end of year , tcd exams were conducted and all were suitable for analysis; the median velocity was cm/sec on open-label hydroxyurea treatment, regardless of previous blinded treatment. all correlations with tamv were maintained except for age. conclusion: compared to placebo, hydroxyurea treatment for young children with sca living in uganda was associated with lower tcd velocities, which have been correlated in other studies with lower risk of primary stroke. tcd velocities were correlated with hematological and clinical parameters that can be improved by hydroxyurea therapy. children's hospital of richmond at virginia commonwealth university, richmond, virginia, united states background: acute chest syndrome (acs), defined by respiratory symptoms and a new pulmonary infiltrate, is a serious complication of sickle cell disease (scd). acs can occur during hospitalization for non-pulmonary conditions, such as a vaso-occlusive crisis or after surgery. nih clinical practice guidelines encourage incentive spirometry (is) which decreases the incidence of acs. it is additionally widely accepted that early, frequent ambulation in post-operative and pneumonia patients decreases the length of stay (los). to decrease acs events in children with scd at our children's hospital, we aimed for is use in % of ageappropriate pediatric sickle cell admissions. design/method: a multidisciplinary team examined inpatient acs prevention practices, including is, at children's hospital of richmond. key drivers were identified, including educational awareness of patients and healthcare staff, order placement, and documentation. we aimed for all scd patients ≥ months of age hospitalized with any admission diagnosis to participate in is with the use of a traditional incentive spirometer or similar age-and ability-appropriate devices (e.g. positive expiratory pressure devices, bubbles, and pinwheels). we secondarily aimed to increase activity events, specifically ambulation and out of bed time. educational and outreach tools included patient informational brochure and incentive program, and staff informational sessions and reference materials at workstations. a disease-specific order set was implemented including desired is and activity orders. data were collected prospectively may through november , during which pdsa cycles were conducted. admissions during the corresponding months of the previous year were reviewed for comparison. independent t-test analysis was performed using graftpad prism statistical analysis software. results: improvements reaching statistical significance included increase in is order placement from % to % of admissions (p < . ), and admissions with documented is use increased from % to % (p < . ). los decreased from a mean of . days to . days (p . ). post-admission development of acs also decreased from % to % of admissions, but did not reach statistical significance (p . ). there was an additional increase in appropriate activity order placement and documentation of activity events. conclusion: improving education and outreach to patients and staff, including implementation of a disease-specific order set, can improve is use and activity events. the decline seen in incidence of acs development during hospitalization, though not statistically significant, and the decreased los are encouraging, and efforts continue to improve on these trends. background: painful vaso-occlusive crises (voc) are a frequent and debilitating complication of sickle cell disease (scd) and are thought to occur due to progressive blockage of the microvasculature with rigid sickle shaped red blood cells. any trigger that decreases the microvascular blood flow (mbf) can promote entrapment of sickled cells in the microvasculature and progression to voc. exposure to cold wind and changes in weather are common triggers of voc and are associated with increased frequency of hospitalizations for pain in patients with scd. there is limited experimental data on the physiologic effects of these factors on peripheral perfusion in scd. to study the effect of graded thermal stimuli on the peripheral mbf in scd. design/method: scd and control (healthy or sickle trait) subjects aging to years were exposed to their individual threshold temperatures for heat and cold detection, heat and cold pain via tsa-ii thermode that was placed on the thenar eminence. mbf was measured on the contralateral thumb using photo-plethysmography (ppg). the vasoconstriction response within the complex ppg signal was detected using cross-correlation technique. mean mbf was derived from the ppg amplitude during each of these stimuli and compared to baseline mbf. cross correlation analysis showed that cold pain caused significant vasoconstriction response in % of the subjects, followed by heat pain ( %), cold detection ( %) and heat detection ( %).there was a significant drop in the mbf during cold pain (p < . ), heat pain (p < . ), heat detection (p = . ) and cold detection (p = . ) when compared to baseline mbf, with cold pain causing the greatest drop in mbf. thermal sensitivity and mbf responses were comparable between scd and controls. conclusion: exposure to graded thermal stimuli causes a progressive drop in mbf with exposure to cold pain eliciting the strongest vasoconstriction response. vasoconstriction occurred in the contralateral hand at an average of seconds after the stimuli, suggesting a neurally mediated mechanism. although there was no significant difference in vasoconstriction responses between scd and controls, the drop in mbf in patients with sickle cell disease can increase the likelihood of entrapment of the sickled red blood cells, leading to vaso-occlusion. these findings are consistent with extensive reports in literature that exposure to cold weather is associated with a higher frequency of voc. this suggests that neurally mediated vasoconstriction is likely an important factor in the pathophysiology behind cold exposure leading to voc in scd. background: vaso-occlusive crisis (voc) is a major cause of hospital admissions in children with sickle cell disease (scd). although the use of clinical biomarkers in voc has been studied, especially with regards to acute chest syndrome (acs), there is less data regarding overall voc severity prediction. in addition new biomarkers such as platelet to lymphocyte ratio (plr), neutrophil to lymphocyte ratio (nlr), and lymphocyte to monocyte ratio (lmr) have been little studied with regards to scd. objectives: to identify whether admission laboratory values, changes from well baseline laboratory values, and new biomarkers such as plr, nlr, and lmr could predict severity of vaso-occlusive crisis in children with sickle cell disease admitted with voc. design/method: this was a retrospective single center observational study of admissions of voc in children aged - years with hbss or hbs-b thal from september to november excluding those on hyper-transfusion protocol or having an admission diagnosis of acs. univariate analysis was done using student's t-test, mann-whitney non parametric test, or fischer's exact test as appropriate depending on the distribution between admission laboratory data of complete blood count (cbc), reticulocyte count, comprehensive metabolic panel, lactate dehydrogenase (ldh), change from well baseline cbc values within months previously, plr, nlr, lmr, and the development of complicated voc. complicated voc was defined as the development of secondary acute chest syndrome, prolonged admission duration > days ( hours), requirement of blood transfusion, and readmission within days. results: a total of admissions were studied. fifty-nine ( . %) were female. of the , ( . %) were complicated with no significant differences in sex (p . ) or age (p . ). univariate analysis revealed significant elevations in total bilirubin (p . ), ldh (p . ), and platelet count (p . ) in those with complicated voc. there is also significant difference in the percentage change of platelet count from baseline with greater decline in uncomplicated voc (p . ). there were no significant differences in plr (p . ), nlr (p . ), or lmr (p . ). conclusion: elevations in total bilirubin, ldh, and platelet count in admission laboratory values are associated with developing complicated voc. in addition, those with complicated voc present with significantly less decline in platelet count from baseline well cbc. plr, nlr, and lmr do not seem to be useful predictive biomarkers for severity of voc. background: sickle cell disease (scd) causes health problems of varying frequency and severity. the only validated biomarker for children with scd is transcranial doppler. if reliable predictors existed for scd severity, children with scd could be treated according to risk category. many patients with scd face psychosocial or economic hardships, but these factors have not been evaluated as risk markers for medical or functional severity of scd. objectives: the goal of this project was to develop and stratify a preliminary list of psychosocial risk factors for health outcomes that could be used as scd severity predictors. st. vincent institutional review board. a list of potential psychosocial risk factors for adverse health outcomes was compiled based on assessment materials utilized by the sickle safe program (indiana's hemoglobinopathy newborn screening follow-up program). this list of items was distributed to child abuse prevention ( ) and scd ( ) experts, who ranked each item on a likert scale of (least important) to (most important). mean scores were calculated using spss version ; assessments were retrospectively analyzed to determine psychosocial risk factor frequency. risk factors occurring in ≥ % of homes were considered high frequency events. overall, there was high agreement among experts on the risk factors that were considered the most important predictors of severe scd outcomes. the risk factor with the highest frequency ( %) was eligibility for public assistance programs. fifteen risk factors were rated ≥ by the experts. four ( . %) were high frequency events occurring in ≥ % of homes: a child with hbss or hbs thalassemia not taking hydroxyurea ( %); parent report that they had treated a fever (> ®f) at home in the past months ( %); tobacco use by someone in the household ( %); and the family reporting significant psychosocial stressors in the past year ( %). tobacco use in the home was significantly correlated with several other risk factors (smoking during pregnancy [r = . ], other health concerns in the child [r = . ], and child having health insurance [r = - . ]), suggesting that it is part of a constellation of health risk. in general, the risk factors that were rated as most important for health outcomes occurred less frequently in the sample. this study represents important progress toward identifying a group of psychosocial risk factors for scd severity, which is a necessary first step for future investigation of empirical relationships between candidate risk factors and scd outcomes. unitversity of cartagena, cartagena, bolivar, colombia s of s background: sickle cell disease is an autosomal recessive disorder characterized by a mutation in the -globin chain, which produces hbs. acute and chronic complications as aplastic crisis, acute chest syndrome, priapism, stroke, leg ulcers and primary/secondary prevention of stroke can be treated with simple transfusion or exchange transfusion. the latter offers advantages as lower iron overload, post-treatment hbs goal control, lower viscosity and improved microvascular circulation. but it is not a widely-used option because is associated with technical difficulties. objectives: standardization of a new partial exchange transfusion protocol in a group of patients with sickle cell disease, within the framework of a chronic transfusion program. design/method: this is a prospective descriptive study, which included patients under years with sickle cell disease ( hbss, hbs-tal), with indication of partial exchange transfusion in a chronic transfusion program, according to the institutional protocol; patients who fulfilled the inclusion criteria were enrolled in the study between february and december . a registry of the medical and technical complications was made in each of the procedures. a database was constructed in excel, and the graph-pad prism® version oc software was used for statistical analysis. the sequence is as follows: isovolemic phlebotomy and transfusion of packed red cells. depending of the recent hemoglobin level ( hrs), we do the phlebotomy there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg; isovolemic solution (ns , %) there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg and packed red cell transfusion there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg. the safety of this exchange transfusion protocol was analyzed in patients with sickle cell disease ( procedures). there were no differences in the sex distribution, and the median age was years. % of the population was homozygous. the indication of transfusion was . %( / ) primary stroke prevention, . %( / ) secondary stroke prevention and . %( / ) was other reason. a low percentage of complications was found ( . %); of which, those of medical origin (hypotension and nausea/vomiting) were only presented in . % of the total procedures. the standardization of this protocol was safe and its use could be extended to other low-income centers that treat patients with sickle cell disease that need chronic transfusion program including patient with hemoglobin level until gr/dl. we suggest do studies for measure the security and efficacy of this protocol in patients with acute complications. background: clinical trials that aim to achieve pain reduction have challenges achieving clinical endpoints as pain has no quantifiable biomarkers and may be unrelated to scd. furthermore, the threshold of seeking medical care differs between patients and vocs that occur at home are missed. we present a non-interventional, longitudinal study to identify vocs in patients with scd. objectives: to examine the longitudinal relationship between pros and biomarkers in subjects with scd before, during, and after a self-reported voc event, in order to build a model of in-home and clinical voc and to collect longitudinal pros and biomarker data from subjects that span voc events in the home, clinic and the hospital. design/method: longitudinal measures of pain, fatigue, function, activity, and biomarkers from scd patients in steady state and voc were studied over a six month period. patients self-reported pain, fatigue, function, and medication use using a novel epro tool. voc was reported in real-time, triggering a mobile phlebotomy team. blood was collected sequentially after self-reported voc (at home or hospital). blood samples were drawn two days after resolution of voc, as reported by the patient. during non-voc periods, blood was drawn every weeks to establish a baseline. biomarkers included leukocyte-platelet aggregates and circulating microparticles, cell and soluble adhesion molecules, cytokines, inflammatory mediators and coagulation factors. patients wore an actigraphy device to track sleep and activity and rest. results: twenty-seven of thirty-five patients experienced a total of days with voc > hr, of which only days resulted in healthcare utilization. voc days had significantly higher pain and fatigue scores. voc days were associated with significantly decreased functional scores, with significantly greater decreases during vocs requiring medical contact compared to at-home vocs. different activity profiles were identified for non-voc, at-home voc and medical contact voc days by actigraphy monitoring. at-home voc days exhibited increased daytime resting compared to non-voc days. medical contact vocs had decreased average and peak activity, and increased daytime resting compared to non-voc days. a sleep fragmentation index trended up for both at-home ( %) and medical contact voc days ( %). significant changes during voc days were observed in: c-reactive protein ( % increase), nucleated rbc ( % increase), monocyte-platelet aggregates ( % increase) and neutrophil-platelet aggregates ( % increase), interleukin- ( % increase), interleukin- ( % increase) and tnfalpha ( % increase). the identification and assessment of at-home vocs through use of epros, actigraphy and biomarkers is feasible as demonstrated by this innovative at-home study design. background: risk-stratifying sickle cell disease (scd) patients and demonstrating response to disease-modifying therapies is challenging due to the phenotypical heterogeneity of scd. a pathogenic role for procoagulant von willebrand factor (vwf) via excess vwf high molecular weight multimers (hmwm) has been proposed, with variable reports of increased vwf and hmwm in crisis vs. steady-state in adults, but less so for vwf in children with scd. moreover, vwf and multimers have not been studied in sickle trait. objectives: our pilot study evaluated the potential for vwf antigen (vwf:ag) and hmwm on densitometric tracings to serve as biomarkers for disease severity or treatment response in children and young adults with scd compared to sickle trait (hbas) siblings. design/method: we evaluated vwf:ag, vwf multimers and retrospective clinical data from hbss, hbsc and hbas subjects at steady state. one hbsc subject also had a crisis sample. median scd age was years ( . - . years). % were female. scd severity was judged by annual vasoocclusive and acute chest events, or stroke/elevated tcd. eight of ( hbss and hbsc) took hydroxyurea. four hbss subjects had severe scd, all of whom were chronically transfused. results: mean vwf:ag (normal - iu/dl) was higher for hbss ( +/- . ) and severe hbss ( +/- . ) compared to hbsc ( +/- . , p = . and . , respectively); however, lacked statistical significance when compared to hbas ( +/- . , p = . and . , respectively). vwf:ag was elevated in / ( %) steady-state, including / ( %) with "severe" disease on chronic transfusion and / ( %) taking hydroxyurea, in hbsc crisis but no hbsc / ( %) at baseline. vwf:ag was high in / ( %) hbas siblings. four ( %) had increased hmwm at baseline: hbss/severe disease/chronic transfusion, hbss/hydroxyurea and hbsc untreated. hmwm were increased only during vaso-occlusive crisis in hydroxyureatreated hbsc subject. no ultra-large hmwm were observed. in this preliminary study, in young scd subjects, vwf:ag trended higher in hbss vs. hbsc and in severe hbss participants at a single time-point, but serial evaluations at baseline, in crisis and with optimized diseasemodifying therapy are needed to determine the potential of vwf:ag and hmwm as biomarkers for severity or treatment response. surprisingly, vwf:ag was high in some sickle trait subjects. since hbas is associated with some health challenges such as increased thrombosis risk, further examination of vwf and endothelial dysfunction in sickle trait may provide novel insights into its role as a biomarker. background: the national heart lung & blood institute(nhlbi) guidelines for acute management of voe recommends rapid evaluation and treatment of pain, including administration of a parenteral opioid within -minutes of triage or -minutes from registration, pain reassessment & repeat opioid delivery within - -minutes. inf use has been increasing in peds due to its rapid onset and ease of administration. objectives: to evaluate ped utilization of inf & its effect on intravenous (iv) opioid administration and pain control for the treatment of voe. design/method: a retrospective review of emr was performed on children with scd± years presenting to a ped with voe (pain scores on a - scale) from jan-june . variables studied were median time (iqr, %ci) from ped arrival to first-parenteral-opioid-administration, time-to-first-iv-opioid, first & final pain score, disposition and readmission rate. time-to-first-iv-opioid was also compared to historical data (jan-dec ,n = ) prior to inf protocol initiation. . additionally, % patients received iv opioids within minutes of ed arrival in the inf+iv opioid vs. % in the iv opioids alone group (p< . ). no differences in -hour-returnrates were found in any of the groups, including inf alone group. conclusion: use of inf in the ped for voe is an excellent strategy to shorten time-to-first-parenteral-opioidadministration, improve pain scores & improve adherence to the nhlbi guidelines. however we had distinct unexpected findings: ( ) delays in iv opioid delivery after inf use & ( ) inf alone appeared to provide sufficient pain control without iv opioids for disposition home in % of voe patients. whether the latter reflects insufficient pain management or that there is a milder subgroup for whom inf alone is sufficient, requires further investigation. this study illustrates our experience with a ped-based inf protocol in terms of unanticipated delays in iv opioids and also discharges after inf alone. efforts are underway to further improve use of inf in voe management. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: folate supplementation is commonly included as standard management in patients with sickle cell disease. however, clear evidence supporting the clinical benefits of this practice is lacking. a single study demonstrated improvement on the occurrence of repeat dactylitis at a higher dose of folic acid. to compare clinical outcomes in pediatric patients with sickle cell disease treated with folate supplementation versus those who were not. design/method: this study was a retrospective chart review that included patients to years old with sickle cell disease type ss and s followed at st. christopher's hospital for children. data collected included information about folate supplementation, red cell indices and the presence or absence of clinical outcomes including vaso-occlusive crisis requiring hospitalization in the last six months, acute chest syndrome, infections, asthma, sleep apnea, nephropathy, cerebral vascular disease, stroke and avascular necrosis. analysis of variance (anova) was used to evaluate mean differences between age, number of infections, number of voc events, hemoglobin, reticulocyte count, and mean corpuscular volumes. additionally, chi square analysis was implemented to evaluate differences in folate and non-folate groups for left ventricular remodeling (lvr), sickle cell nephropathy, asthma, obstructive sleep apnea (osa), nocturnal hypoxia, and avascular necrosis (avn). mean differences between the folate and non-folate groups were compared for patients on and off hydroxyurea therapy. one hundred and seven patients met inclusion criteria following review of clinical data. of the patients included in the study, patients were found to be taking folate ( %), while patients were not ( %). statistical analysis showed that there were no significant differences in the incidence of clinical outcomes between patients on folate versus those who were not on folate. of the patients who were not on hydroxyurea, hemoglobin levels were significantly higher in patients on folate versus those who were not (p = . ), but not significantly different for the patients on hydroxyurea. this study suggests that folate supplementation makes no significant impact on the red blood cell indices of anemia nor on the incidence of adverse clinical outcomes in children with sickle cell disease. however, a larger prospective study is needed to guide future considerations for folate supplementation in sickle cell patients in the clinical setting. background: tanzania ranks rd globally for the number of infants born annually with sickle cell disease (scd) but lacks a national newborn screening program. the prevalence of sickle cell trait (sct) and scd is highest in the northwestern regions around lake victoria served by bugando medical centre (bmc) a teaching and consultancy hospital in mwanza. bmc also houses the hiv early infant diagnosis (eid) laboratory that tests dried blood spots (dbs) from hivexposed infants. dbs can be tested for hiv and then retested for sickle cell trait and disease. to determine the prevalence of sickle trait and disease by region and district in northwestern tanzania using existing public health infrastructure. secondary objectives explored associations between sct, scd, malaria and hiv. design/method: the tanzania sickle surveillance study (ts ) is a prospective year-long cross-sectional study of hivexposed infants born in northwestern tanzania, whose dbs collected by the eid program are tested at bmc and available for further testing of sct and scd. samples from children ≤ months of age were tested by isoelectric focusing (ief) and scored independently by two tanzanian staff as normal, sct, scd, variant, or uninterpretable. dbs samples scored as disease or variant were repeated. over the course of months, ief gels have been run. a total of , dbs samples have been scored, including , from children less than -months old. the overall prevalence of sct is . % and the prevalence of scd is . %, along with . % hemoglobin variants. quality of the laboratory results is extremely high, with only . % dbs samples yielding an uninterpretable result. geospatial mapping of the first , samples revealed a regional scd prevalence ranging from . % up to . % among the regions served by bmc. the prevalence of sct and scd is very high in northwestern tanzania. geospatial mapping will identify high prevalence areas where targeted newborn screening can be started using existing public health infrastructure with minimal start-up cost and training. further data will enhance the accuracy of the map to the district level. background: pediatric patients with sickle cell disease (scd) could develop obstructive, restrictive or mixed abnormalities of pulmonary function (pf). several publications report progressive worsening of pf over time, which could lead to severe morbidity in adult patients with sickle cell disease. in adults with sickle cell anemia up to - % of mortality is related to lung disease. early intervention aimed at improvement of lung function could significantly decrease morbidity and possibly improve life expectancy. among disease modifying approaches commonly used in scd are hydroxyurea (hu) and chronic prbc transfusions. both interventions lead to increase of hemoglobin, decrease of hbs fraction, leading to decreased hemolysis. reports of effect of hu on pulmonary function are conflicting with some suggesting no effect and others proposing a slower decline of pulmonary function. the goal of our study is to evaluate effect of disease modifying therapies, like hu and chronic prbc on change of pulmonary function in pediatric patients with sickle cell disease. design/method: this study utilized a retrospective chart review of children with scd who had multiple pfts. we analyzed pfts from patients done during clinic visits. scd patients were divided into three treatment groups: hydroxyurea, chronic transfusions or neither. data was analyzed with linear correlations and analysis of variance (anova). comparison were made between the three groups specifically observing the changes in absolute numbers on pfts over time using the first and last pft the patient had. results: there were a total of patients with multiple pfts (ranging from - ); control ( ), hydroxyurea ( ) and chronic transfusion ( ). the mean changes of the control, and hydroxyurea for the pft parameters fev (- . the chronic transfusion group demonstrated a small improvement in pfts over time for fev ( . ), fvc ( . ), fef - ( . ), however there was a decline in fev /fvc (- . ). however, there was no statistically significant (p-value < . ) in the difference in any pfts parameters between any of the groups. in children with scd there is a decline of pf parameters over time. although no significant differences were seen between the three groups it appears chronic transfusion may improve or limit the decline in pfts. larger studies need to be done to evaluate difference in pf decline in patients with scd patients. background: the use of mobile technology in health care has been a growing trend. patients with chronic diseases such as sickle cell disease (scd) require close monitoring to provide appropriate treatment recommendations and avoid complications. we conducted a feasibility study for patients with scd hospitalized for pain using our self-developed mobile application (tru-pain: technology resources to better understand pain) and a wearable activity tracker. subjective symptoms such as pain and objective data such as heart rate (hr) were measured. we aimed to ) correlate nursing recordings with mobile technology recordings; ) get feedback from patients about usability. design/method: we enrolled patients with scd > years old and < hours from admission for uncomplicated vasoocclusive crisis, excluding patients admitted to icu. patients were given an ipad and a wearable device. they were instructed to record in the application at least once per day and to keep the wearable on, removing only to charge. prior to discharge, patients completed a feasibility questionnaire. we enrolled patients, % females, median age . (range to ) who were admitted for a median days (range to ) for uncomplicated pain crisis. patients used the application throughout hospitalization and made one entry/day (range to ). pain scores recorded via tru-pain correlated well (r = . , p< . ) with pain scores recorded in emr. there was an average of , data points recorded per day, by the wearable, with a maximum of , data points/day. the median amount of hours of wearable data per day was . (maximum of . ). the hr recorded via the wearable correlated significantly with the hr recorded in emr (r = . , p-value < . ). as for usability, % of patients indicated never having a problem with the technology, % found tru-pain 'very easy' or 'somewhat easy' to use, and % were 'very satisfied' with their participation in the study, indicating that it helped them track their pain. our pilot study during hospitalization shows strong potential for using tru-pain for patients with scd. pain data from application and hr from wearable correlated well to the emr data. according to the feedback received, our application was easy to use and helped patients track their pain. despite limitations of battery life, the use of wearable technology is feasible, providing additional data such as activity. we are optimistic that we can continue to improve our tru-pain system to help improve care in patients with scd. background: hydroxyurea, chronic blood transfusion, and bone marrow transplantation can reduce complications, and improve survival in sickle cell disease (scd), but are associated with a significant decisional dilemma because of the inherent risk-benefit tradeoffs, and the lack of comparative studies. these treatments are underutilized leading to avoidable morbidity and premature mortality. there is a need for tools to provide patients high-quality information about their treatment options, the associated risks, and benefits, help them clarify their values, and allow them to share in the process of informed medical decision making. objectives: to develop a health literacy sensitive, web-based, decision aid (ptda) to help patients with scd make informed choices about treatments, and to estimate in a randomized clinical trial the acceptability and effectiveness of the ptda in improving patient knowledge, involvement in decisionmaking and decision-making quality. design/method: we conducted qualitative interviews of scd patients, caregivers, stakeholders, and healthcare providers for a decisional needs assessment to identify decisional conflict, knowledge, expectations, values, support, resources, decision types, timing, stages, and learning, and personal clinical characteristics, and to guide the development of a ptda. transcripts were coded using qsr nvivo . stakeholders completed alpha and beta testing of ptda. we conducted a randomized clinical trial of adults, and of caregivers of pediatric patients to evaluate the comparative efficacy of the ptda, vs. standard of care. results: ptda (www.sickleoptions.org) was developed per decisional needs described by stakeholders and finalized following alpha testing, and beta testing by and stakeholders respectively. in a randomized trial of subjects considering various treatment options, qualitative interviews revealed a high level of usability, acceptability, and utility in education, values clarification, and preparedness for decision making of the ptda. a median % rated the acceptability of ptda as good or excellent and provided narrative comments endorsing the acceptability, ease of use, and utility in preparation for decision making. the ptda met international standards for content, development process, and efficacy with the exception of having a full range of positive and negative experiences in patient stories. compared to baseline ptda group had statistically significant improvement in preparedness for decision making (p = . ) and informed subscale of decisional conflict (p = . ) but not for decisional self-efficacy, knowledge, choice predisposition, or stages of decision-making. a ptda for patients with scd developed following extensive engagement of key stakeholders was found to be acceptable, useful, easy to use, to improve preparedness for decision making, and decrease decisional conflict. background: painful vaso-occlusive crisis (voc) accounts for the majority of emergency department (ed) visits and hos-pitalizations in sickle cell disease (scd). we are interested in studying mental stress and associated autonomic nervous system (ans) imbalance that cause vaso-constriction as possible triggers of scd pain. to this end, we developed a mobile phone application (app) to record daily pain frequency and intensity as clinical endpoints that might be predicted by ans parameters measured in the laboratory. in particular, we think that the aura may represent ans instability that precedes or even triggers change in blood flow and voc. objectives: to assess the feasibility of using an app to evaluate frequency and severity of voc and its potential association with mental stress and presence of aura. design/method: an app was developed for both ios and android systems to allow patients to track pain, stress, and aura. the idea was to create an app that was easy to use with the intent to only capture pain episodes, rather than detailed description of the pain. all scd patients were eligible and a parent version was available for younger children. de-identified data was automatically transferred to a hipaa compliant database via a cloud-based server interfaced to the main research project database. a feedback questionnaire was implemented after at least a month of utilization to assess usability. of the scd patients enrolled, participants utilized the app and of the participants that provided feedback indicated the app was easy to navigate. the mean pain scale was out of (standard deviation . ) for those that entered they had pain that day. although the mean stress level was out of , there was a statistically significant correlation between increasing stress levels and increasing pain scores (p < . ). aura was reported by patients, with patients reporting more than episodes. moreover, on days aura was present there was greater incidence that pain was present as well (p < . ). however, there was no statistically significant association between pain intensity and presence of an aura (p = . ). conclusion: consistent with prior research, reported pain intensity is significantly associated with reported stress intensity. although there was an association between presence of aura and pain, it did not seem to correlate with pain intensity. this uniquely designed app can monitor scd pain clinically and help understand the role of sickle dysautonomia in the genesis of scd pain. university of florida college of medicine, gainesville, florida, united states background: evidenced-based guidelines recommend the emergent evaluation of fever in children with sickle cell disease (scd). as the prevalence of bacteremia has decreased, outpatient management has become more common. however, fever can sometimes herald other complications of scd, such as acute chest syndrome, vaso-occlusive pain crisis, splenic sequestration, or aplastic crisis. institutional practices regarding fever management in scd remain variable, and little is known about the clinical outcomes of children hospitalized for uncomplicated fever. objectives: the primary objective was to determine the rate of bacteremia or scd-related complications per febrile episode in children with scd admitted to a single institution between january and june for uncomplicated fever. this was a retrospective cohort study of febrile patients up to years of age with scd, any genotype, admitted to the university of florida during the defined study period. eligible patients were identified by a database search using admitting diagnosis codes for scd and fever based on the international classification of diseases th and th revisions. encounters were manually reviewed to confirm eligibility. patients were excluded if they had other indications for hospitalization apparent at the time of admission, such as an acute vaso-occlusive episode requiring parental narcotics, asthma exacerbation, or additional complications of scd. the database search identified encounters, of which were excluded based on confounding indications for hospitalization. sixty-three eligible patients accounted for hospitalizations. the median age was years (range weeks- years); . % were male. mean duration of hospitalization was . days (range - days). eight positive blood cultures were identified; six of these were classified as contaminants. bacteremia or the development of a scd-related complication was identified in ( . %) admissions. these included acute chest syndrome (n = ), bacteremia (n = ), splenic sequestration (n = ), and red cell transfusion (n = ). exploratory analyses of potential predictors of bacteremia or scd-related complications showed no association with the presenting white blood cell count or degree of fever (p = . ). of the patients classified as having a scd-related complication, % had hemoglobin ss disease and % had at least one prior documented complication. % of the patients transfused had at least one prior transfusion. conclusion: while improvements in preventative care have substantially lowered rates of bacteremia in children with scd, fever warrants careful evaluation for other acute scdrelated complications. providers should consider inpatient observation in select cases. additional studies are warranted to define subsets of patients suitable for outpatient fever management. background: children with sickle cell disease (scd) exhibit lower neurocognitive functioning than healthy peers, even in the absence of stroke. among the domains commonly affected, working memory (wm) seems particularly affected by disease processes and wm deficits have significant implications for academic achievement and disease selfmanagement. few interventions to improve working memory in pediatric scd have been evaluated. to determine the effects of cogmed, a homebased computerized wm training intervention, in children with scd using a randomized controlled trial design. design/method: participants (ages - ) with scd completed a baseline neuropsychological assessment and those with wm deficits were randomized to either begin cogmed immediately or enter an -week waitlist. cogmed is a homebased intervention completed on an ipad that consists of increasingly challenging exercises targeting visual-spatial and verbal wm, practiced over sessions. at the end of training, participants completed a post-intervention neuropsychological assessment, including tests of visual-spatial and verbal wm from the wechsler intelligence scale for children-fifth edition (wisc-v). results: ninety-one participants (m age = . , sd = . ; % female; % hbss) enrolled in the study; % (n = ) exhibited wm deficits and were randomized to either begin cogmed immediately or wait - weeks before starting cogmed. among those that have received the intervention and reached the end of their training period (n = ), participants ( %) completed at least cogmed sessions, ( %) finished at least sessions, and finished at least sessions ( %). the mean number of completed cogmed sessions was . (sd = . ). paired samples t-tests revealed significant improvements on the working memory index (t[ ] = - . , p = . ) and on the digit span (t[ ] = - . , p = . ), and spatial span-backward (t[ ] = - . , p = . ) subtests. improvements were especially pronounced for participants completing at least sessions. partial correlations controlling for respective baseline scores indicated that the number of cogmed sessions completed was positively correlated with post-test scores on digit span (r = . , p = . ) and spatial span-backward (r = . , p = . ) subtests. among participants who completed at least cogmed sessions, % scored in the average range or higher on the working memory index at the post-intervention assessment, compared to % at baseline. results support the efficacy of cogmed in producing significant improvements in wm. a dose-effect was observed such that participants who completed more cogmed sessions had greater improvements in wm. home-based cognitive training programs may ameliorate scd-related wm deficits but methods for motivating and supporting patients as they complete home-based interventions are needed to enhance adherence and effectiveness. background: sickle cell disease is associated with myriad complications that lead to significant morbidity and early mortality. hydroxyurea has been used successfully to reduce the incidence of these complications and has led to significant improvements in quality and duration of life. at children's minnesota we recommend hydroxyurea in all patients with hb ss/s thalassemia as early as months of age with a goal of starting all patients before months of age. objectives: the purpose of this study was to evaluate the use of hydroxyurea therapy in young patients with sickle cell disease, with particular attention to those children less than one year of age. design/method: a retrospective chart review was conducted on patients less than years of age with sickle cell disease who began hydroxyurea therapy between january , and december , . the study population was divided into three cohorts based upon age at hydroxyurea initiation: cohort ( - year), cohort ( - years), and cohort ( - years). outcomes included laboratory data, clinical events (hospitalization, dactylitis, pain crisis, transfusion, splenic sequestration, acute chest syndrome), and toxicity occurring in the first years of life. results: a total of patients were included in cohorts (n = , mean age . months), (n = , mean age . months), and (n = , mean age . months). patients in cohort had higher hemoglobin (p = . ) and mcv (p = . ) and lower absolute reticulocyte count (p = . ) when compared to cohort . the wbc (p = . , < . ) and anc (p = . , . ) were significantly lower compared to both older cohorts. however, no patient had therapy held because of neutropenia. the mean baseline hemoglobin f in cohort was . % compared to . % and . % in cohorts and respectively (p = . , p< . ). the mean duration of therapy in cohort was . months, compared to . months in cohort (p = . ) and . months in cohort (p = . ). during this time, hb f levels remained higher in cohort (mean . %) compared to cohorts and (mean . %, p = . and mean . %, p = . ). patients in cohort experienced fewer hospitalizations (p = . ), pain crises (p = . ), and transfusions (p = . ). there was no difference in toxicity between groups. hydroxyurea was used safely in infants to months of age and resulted in more robust hematologic responses and a decrease in sickle-related complications when compared with patients starting hydroxyurea later in life. children's national health system, washington, district of columbia, united states background: children with sickle cell disease (scd) have a significantly greater risk of silent or overt cerebral infarction than the general population. infarcts are associated with declines in cognitive functioning and academic achievement. while infarcts are reliably identified using mri, scans are expensive and occasionally necessitate sedation. moreover, mri's are not recommended for routine monitoring of cerebral infarcts. additional tools are needed for discriminating the presence of a cerebral infarct that are brief, noninvasive, inexpensive, and repeatable. objectives: to evaluate differences in performance on cogstate, a computerized neurocognitive assessment, in patients with scd with and without history of cerebral infarct. design/method: participants included children with scd ages - (m = . , sd = . ; % female; % s of s hbss) enrolled in a cognitive intervention trial. participants completed the cogstate pediatric battery, which measures processing speed, sustained attention, verbal learning, working memory, and executive functioning. history of silent or overt infarct was determined via health record review. participants also completed measures of intelligence (iq) and math fluency. results: participants' standard scores across most neurocognitive measures were lower than expected compared to the standardization sample (mean iq = . , sd = . ). thirty percent of participants (n = ) had a documented history of cerebral infarct. participants with a history of cerebral infarct scored lower on cogstate tasks measuring sustained attention (t[ ] = . , p = . ) and executive functioning (t[ ] = . , p = . ), as well as on a measure of math fluency (t[ ] = . , p = . ). receiver operating characteristic (roc) analyses demonstrated that the cogstate task measuring sustained attention was a fair discriminant of patients with and without a history of infarct (auc = . , ci = . - . , p = . ), whereas iq score was not (auc = . , ci = . - . , p = . ). cogstate processing speed and sustained attention tasks fairly discriminated between patients with at least average or below average intelligence (auc = . , ci = . - . , p = . and auc = . , ci = . - . , p = . , respectively). finally, the cogstate processing speed task was good at discriminating between at least average or below average math fluency (auc = . , ci = . - . , p< . ). multiple tasks in the cogstate pediatric battery appear to adequately identify patients with a history of cerebral infarcts. in addition, cogstate tasks appear to be fair predictors of impairments in iq and academic achievement outcomes. cogstate is inexpensive and can be easily administered in a medical setting with minimal training in approximately minutes. results support the potential for cogstate to be used as a screening tool for medical and neuropsychological abnormalities in children with scd. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: cardiovascular disease contributes to the morbidity and mortality of patients with sickle cell disease (scd). hydroxyurea therapy in scd has known clinical efficacy including improving anemia, decreasing episodes of vasoocclusive crisis and acute chest syndrome, and decreasing mortality. effect of hydroxyurea on cardiac function in children with scd is not well studied. an earlier study suggested the protective effect of hydroxyurea on left ventricular (lv) hypertrophy in scd. we hypothesized that hydroxyurea use would be associated with decreased lv remodeling and improved cardiac function. we aimed to evaluate the association between hydroxyurea use and lv remodeling and cardiac dysfunction in children with scd. design/method: we completed a retrospective study of patients with scd who were to years old, followed at st. christopher's hospital for children and had an echocardiogram completed in the past months. data collected included gender, bmi, scd genotype, hydroxyurea use, chronic transfusion use, and d and doppler echocardiographic parameters. cardiac structure, geometry, systolic function, and diastolic function echocardiogram parameters were included. analysis of variance (anova) tests were performed to assess for statistical significance of differences in cardiac parameters between patients with and without hydroxyurea use. analysis of covariance (ancova) tests were performed to control for age. results: demographic and echocardiogram data was collected on all patients who met inclusion criteria. of the patients included, ( %) were on hydroxyurea therapy. patients on hydroxyurea had significantly lower mean relative wall thickness (p = . ) and significantly higher mean peak early lv filling velocities (p = . ) and peak early lv filling/septal annuli early peak (e/ea) velocities (p = . ); however, only the e/ea velocities remained significant when controlling for age (p = . ). mean peak early lv filling velocities approached significance when controlling for age (p = . ). hydroxyurea therapy resulted in a significantly higher e/ea velocity, suggesting that these patients had worse diastolic function. it is possible that the patients initiated on hydroxyurea already had worse disease manifestations than those not on hydroxyurea, possibly accounting for the decreased diastolic function. when controlling for age, hydroxyurea use did not result in significant differences in cardiac structure parameters, systolic function parameters or cardiac geometry. prospective studies and larger sample size are needed to validate our findings, examine for additional statistically significant differences, and develop preventive strategies for cardiovascular disease in children with scd. background: acute chest syndrome (acs) is now the leading cause of death in children with sickle cell disease; mortality in the u.s. is reported to be - % and is mostly due to respiratory failure. early transfusion improves clinical outcomes. although patients with concurrent asthma are considered at increased risk for poor outcomes, risk factors for respiratory failure in pediatric acs have not been well-defined. to determine whether specific epidemiological and clinical features of children hospitalized with acs are predictive of the need for mechanical ventilation. design/method: data from the kids' inpatient database were reviewed to identify patients age < years with a discharge diagnosis of acs for the years , , , and . outcomes were defined by the international classification of diseases, ninth revision, clinical modification code. data were weighted to estimate total annual hospitalizations according to hospital characteristics in the united states. trends in healthcare costs, length of hospital stay, transfusion, and mechanical ventilation use were analyzed using multivariable linear regression. in addition, multivariable logistic regression was used to ascertain specific clinical or epidemiologic factors associated with mechanical ventilation use after adjusting for patient and hospital characteristics. the total hospitalizations for acs were , in ; , in ; , in ; and , in . reported use of mechanical ventilation ranged from . % to . % and was associated with non-black compared to black children (or, . ; %ci, . to . ) and the fall season (or, . ; %ci, . to . ), but not with age, preexisting asthma or hb-genotype. comorbidities of obesity (or, . ; %ci, . to . ), obstructive sleep apnea (or, . ; %ci, . to . ) and heart disease (or, . ; %ci, . to . ) were associated with mechanical ventilation use. the use of simple and exchange transfusion during all acs admissions ranged from . % to . % and . % to . %, respectively. among pediatric acs patients, those with obesity, obstructive sleep apnea or heart disease were at increased risk for respiratory failure and might benefit from early intervention (e.g., transfusion). surprisingly, asthma in children with acs does not appear to be a distinct risk factor for respiratory failure, and further studies are needed to clarify whether differences in treatment approach (e.g., addition of corticosteroids, bronchodilators) might impact on acs progression and/or severity even in high risk patients without asthma. objectives: to compare pulmonary functions between aa and k children with scd and to assess if a high hb f level contributes to better function. design/method: a cross sectional study was done on children with scd (hb ss disease) followed in comprehensive sickle cell programs. aa patients were followed at brookdale hospital, ny and k patients were followed in mubarak hospital, kuwait. children between the ages of and years who had pulmonary function tests (pft) done as a routine screening were enrolled. pft was done using spirometer and plethysmography. patients with congenital or anatomical lung abnormality, heart disease, pulmonary disease such as acute chest syndrome, acute asthma or pneumonia within weeks were excluded. results: there were children ( in each group) with scd,. restrictive pattern on pft was seen in / ( %) of aa vs. / ( %) of k (p> . ). obstructive pattern was seen in / ( %) of aa vs. / ( %) of the k group (p> . ). in both groups, children ( %) had normal pft. three/ ( %) in the aa group had a hb f> % as compared to / ( %) in the k group (p< . ). abnormal pft was noted in / children ( %) in each group. hbf was > % in / ( %) in the aa group vs. / ( %) in the s of s k group (p< . ). in patients with abnormal pft, mean hbf was . ± . in aa group, compared to . ± in k group (p< . ). conclusion: abnormal pft is highly prevalent among children with scd in both groups. aa children are more likely to have restrictive disease and k to have an obstructive pattern. level of hbf did not seem to protect k patients from abnormalities on pft. this finding should emphasize the importance of performing pft as part of the initial evaluation of all children with scd. background: sickle cell disease (scd) is a life-threatening disease with varied clinical spectrum and severity leading to premature death. there is a lack of validated prognostic marker in scd. recent evidence suggests that inflammation and platelet adhesion plays a critical role in the pathophysiology of vaso-occlusion in scd. elevated mean platelet volume(mpv) values are associated with a higher degree of inflammation in many disease states but it's effect on sickle cell disease or it's severity is unknown. objectives: to analyze the role of mpv in predicting disease severity/mortality in pediatric patients with scd. design/method: this is a single center retrospective study and included patients with sickle cell disease between months and years of age during a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . demographic information, lab data and clinical information including acute chest syndrome (acs), priapism, transfusions, sepsis, pain crisis, avascular necrosis were collected. all laboratory data were collected in steady state with no crisis in the recent past months. the disease severity score/probability of death was calculated using a validated model to predict risk of death in sickle cell disease (sebastiani et al. blood ) . pearson test was used to analyze correlation between mpv and probability of death. results: total no. of patients = ; male ( . %); female ( . %). median age is . years. all patients were of african-american origin. disease severity, hb ss - ( %); hb sc - ( . %) and sickle-beta thalassemia ( . %). patients on hydroxyurea has significantly lower mpv, p = . and this is independent of hb f levels. mpv has a significant positive correlation with the probability of death, p = . and correlation coefficient, r = . . on subgroup analysis, the correlation is even more significant in the age group between and years, p = . , r = . . using linear regression model, with probability of death as a dependent variable and hydroxyurea, mpv as independent variables, mpv maintains a significant association with probability of death (p = . ). conclusion: mpv is an independent biomarker predicting disease severity and probability of death in pediatric patients with sickle cell disease. hydroxyurea a known disease ameliorating agent is associated with lower mpv values. this effect is independent of the levels of fetal hemoglobin and may be due to anti-inflammatory effect of hydroxyurea or effect on the platelets. background: major success with initial qi projects by the sickle cell care team at children's hospital has precipitated ongoing inclusion of the qi approach to many other aspects of patient care. objectives: to optimize scd patient care utilizing qi processes. design/method: success of the scd qi team's initial project on transcranial doppler studies (tcds) and a second more complex project on hydroxyurea (hu) adherence, led to additional projects on completion of key immunizations, rbc phenotyping, and vitamin d level testing. using similar processes and principles from the hu adherence project, plan-do-study-act (pdsa) cycles were used to conduct smallscale tests of change. patient chart prep sheets, created for bi-monthly pre-appointment chart prep meetings, were significantly modified to include these focused care qi objectives. because of difficulty with emr database capability, data collected from the emr was tracked in excel spreadsheets or other unique tracking vehicles for the various parameters. for example, due to the clinic's diffuse, geographically scattered population, many separate non-shared primary care emrs, and lack of a mandatory state immunization registry; immunization records needed to be retrieved from pcps, outlying hospitals, public health departments, and fqhcs, and added to the emr and excel database. starting in / , all such data was collected and updated monthly. in one year's time ( - ) , the average immunization completion rate for seven key immunizations (pcv , pcv , hepatitis a, hepatitis b, meningococcal a, meningococcal b, and hpv) has increased by %. the biggest improvements were a % and % increase in completion for meningococcal a and meningococcal b, respectively. completion rate for rbc phenotyping rose from . % to . %. patients with at least one vitamin d lab test increased from . % to . %. since starting the tcd project in , the percent of patients who have completed their annual tcd has gone from a baseline of % to a sustained value of > %. conclusion: these qi projects have not only increased adherence to national recommendations for care of scd patients, they have helped establish a scd clinic methodology to create and implement sustainable processes. having the focused care initiatives prominently displayed on the patients' chart prep sheet serve as a reminder to medical team members to check the status of that item. this methodology is currently being used to formulate additional qi projects on annual renal function parameters and specialty visits, such as annual eye and dental exams. background: dominican republic has a high burden of sickle cell disease, and - % of children with homozygous hbss (sickle cell anemia, sca) will develop primary stroke. transcranial doppler (tcd) ultrasonography is an effective screening tool for primary stroke risk, but is not routinely available in dominican republic. hydroxyurea and blood transfusions are available, but no prospective screening and treatment program for stroke prevention has been implemented to date. ( ) to screen a large cohort of children with sca living in dominican republic, using tcd to identify elevated stroke risk; ( ) to determine the effects of treatments for stroke prevention (hydroxyurea for conditional velocities and transfusions for abnormal velocities). we hypothesized that both hydroxyurea and blood transfusions will decrease elevated tcd velocities and help prevent primary stroke. design/method: stroke avoidance for children with república dominicana (sacred, nct ) features a research partnership between cincinnati children's hospital and robert reid cabral children's hospital in dominican republic. the protocol, consent forms, and redcap database were prepared collaboratively and translated into spanish, and then irb approval was obtained at both institutions. in the initial prospective phase, children receive tcd screening over a -month period; those with conditional tcd velocities (maximum time-averaged velocity - cm/sec) receive fixed-dose hydroxyurea at mg/kg/day, followed by dose escalation to maximum tolerated dose, while those with abnormal tcd velocities (≥ cm/sec) receive monthly transfusions for stroke prevention. results: a total of children were enrolled in sacred, with an average age of . ± . years. initial tcd screening revealed ( . %) normal, ( . %) conditional, ( . %) abnormal, and ( . %) inadequate velocities. among children ( males, females, average age . ± . years) who initiated hydroxyurea at mg/kg/day for conditional tcd velocities, completed six months of treatment with expected hematological benefits including significant increases in hemoglobin concentration ( . to . g/dl) and fetal hemoglobin ( . to . %). no clinical strokes have occurred in the treatment group. repeat tcd examination after -months of hydroxyurea treatment revealed % ( / ) with previous conditional velocities had normal tcd velocities. the prevalence of conditional tcd velocities in the dominican republic is high, indicating an elevated stroke risk among children with sca. hydroxyurea treatment is associated with improved hematological parameters, lower tcd velocities, and probable decreased stroke risk. sacred is an important prospective and collaborative research trial providing epidemiological data regarding tcd screening, stroke risk, and hydroxyurea effects among children with sca. background: red blood cell aggregation is a rheologic property that explains the shear-thinning behavior of blood. at lower shear rate blood flow, red cells tend to aggregate, s of s whereas in higher shear rate blood flow, these aggregates are dispersed. this property is especially important in the venous system, where low shear rate blood flow predominates. there is inconsistent data in the literature concerning aggregation and aggregability in sickle cell disease (scd). objectives: because the lorrca and myrenne instruments have been shown to be similarly effective methodologies in red cell aggregation measurements, we aimed to determine whether the measurement of aggregation indices in scd, by myrenne and by lorrca, is consistent in our lab. design/method: we measured aggregation in blood samples corrected to % hematocrit. aggregability was measured using kda dextran in the myrenne but not the lor-rca. aggregation index using lorrca was measured in patients with scd and healthy subjects enrolled in a study of blood flow between and . aggregation and aggregability using the myrenne was measured in patients with scd and healthy subjects enrolled in a separate study of blood flow between and . results: using lorrca, we found that aggregation index in patients with scd was less than that of healthy subjects (p< . ). in the myrenne, aggregation at stasis was slightly higher in patients with scd compared to healthy subjects (p = . ) but aggregation at low shear rotation was not different. aggregability was higher in the patients with scd compared to healthy subjects at both stasis and low shear rotation (p< . ). red cell aggregation is an important determinant of low shear blood flow. deoxygenated venous blood is particularly important to low shear blood flow in patients with sickle cell disease. we found that two different aggregometers predict different aggregation results for scd. it is unclear why there is a systematic difference between the two methods, but there are some possibilities. first, the syllectogram in the lorrca is generated by the backscatter of light from the laser, while the myrenne measures transmitted light. second, the distance between the bob and cup in the lorrca is microns, while the gap between plates in the myrenne is microns, which might affect the disaggregation of red cells. further work is needed to understand the differences in red cell aggregation and aggregability when using these instruments, particularly when using aggregation as a predictor of blood flow and tissue perfusion. background: children with sickle cell disease (scd) are at risk of acute splenic sequestration crisis (assc). assc is a life-threatening complication characterized by splenomegaly, pain and severe anemia. assc most often occurs in young children with the most severe forms of scd and one-third of patients will have more than one episode. treatment is based primarily on expert opinion and includes blood transfusion and surgical splenectomy. objectives: we plan to assess the clinical practice patterns of physicians treating children with assc. design/method: a survey study was performed. the survey included six scenarios of severe scd with variation in age, hydroxyurea-use, and episode number of assc; questions focused on the acute and chronic management of assc. the survey was disseminated on three occasions over a six-month period, using an online survey tool, surveymonkey, to pediatric hematologist-oncologists participating in the american society of pediatric hematology-oncology hemoglobinopathy special interest group. the survey had a response rate of % ( / ). most respondents were recent graduates ( %; / ) practicing in academic urban centers with greater than sickle-cell patients. seventy-nine percent ( / ) recommended hydroxyurea initiation in - m/o with severe scd. prophylactic penicillin after surgical splenectomy was continued by % ( / ) after years. for the acute management of assc results did not vary despite patient age, hydroxyurea use, and the number of previous assc episodes. simple transfusion was preferred by % ( / ), with % ( / ) recommending slow transfusion and % ( / ) recommending routine simple transfusion. for the chronic management of assc, results varied based on patient age and the number of previous assc episodes. for a m/o after the first episode, % ( / ) recommended observation and % ( / ) hydroxyurea initiation. for a m/o with any prior episode of assc, % ( / ) recommended chronic transfusion therapy and % ( / ) surgical referral for splenectomy. for a y/o after the first episode, % ( / ) recommended surgical splenectomy and % ( / ) increasing hydroxyurea dose. for a y/o with any prior assc episode, % ( / ) recommended referral for surgical splenectomy. in this survey, we found most providers continue to recommend simple transfusions for assc and surgical splenectomy after two episodes. the majority of providers continue to delay referral for surgical splenectomy until age two, but earlier referral in children under two and use of chronic transfusion therapy were also reported. variability in chronic management highlights the need for further research of splenic sequestration. background: developing therapies for sickle cell disease (scd) is challenging in part because the accepted endpoint, vaso-occlusive crisis (voc), occurs infrequently, does not measure full disease burden, and is a measure of healthcare utilization. in phase / studies of patients with scd, voxelotor (gbt ) has demonstrated increased hemoglobin (hb) levels and reduced hemolysis and has been safe and welltolerated. voxelotor is being evaluated in the ongoing hope phase trial. objectives: to report the innovative phase / hope trial design with novel primary and secondary outcomes to accelerate drug development. design/method: hope (nct ) is a phase , randomized, placebo-controlled, multicenter study of oral voxelotor in patients with scd (aged - years) with baseline hb . - . g/dl and - episodes of voc in the prior year. to accelerate clinical trials to support drug development, the study combines a phase exploratory, dose-selection phase (group ) with a pivotal phase (groups / ). patients in group will be randomized : : to voxelotor or mg/day or placebo. analysis for dose selection will occur when the final patient has received weeks of treatment. group will continue enrollment with randomization : : until dose selection based on analysis of the group cohort. group will allow for a seamless transition into group , which will randomize patients : to the selected dose or placebo. the final data analysis set will include group patients who received placebo or the selected dose and all group patients. the primary endpoint is an objective laboratory measure and surrogate of clinical benefit, increase in hb > g/dl, from baseline to weeks based on voxelotor mechanism of action (inhibition of hb polymerization). this trial is the first to use a patient-reported outcome (pro), the -item sickle cell disease severity measure, as a secondary endpoint. this novel electronic pro, developed specifically for the hope study following fda guidance, will evaluate changes in scd symptom exacerbation and total symptom score from baseline to weeks. additional secondary endpoints include measures of hemolysis, rates of voc, transfusions, and opioid use. the study was designed to enable selection of pro-defined symptom exacerbations or traditionally defined voc as the key secondary endpoint after the group analysis. results: this study is ongoing. the hope trial, expected to complete enrollment by late , will evaluate the efficacy and safety of voxelotor compared with placebo in patients with scd. supported by global blood therapeutics. background: inflammation, coagulation activation, oxidative stress and blood cell adhesion are elements of sickle cell disease (scd) pathophysiology. patients with scd have low levels of the omega- fatty docosahexaenoic acid (dha) and eicosatetraenoic acid (epa) in plasma and blood cell membranes. dha is a bioactive fatty acid with anti-inflammatory, anti-blood cell adhesion and anti-oxidant properties. altemi-atm is a novel dha ethyl ester formulation with a proprietary delivery platform (advanced lipid technology® (alt®)) that enhances oral dha bioavailability. the scot trial investigated the effects of altemiatm in children with scd. objectives: to demonstrate the effects of altemiatm on blood cell membrane omega- index and selected biomarkers of inflammation, coagulation, adhesion and haemolysis associated with scd. s of s design/method: children with scd, aged - years (n = ), were enrolled. subjects were randomized to receive either placebo or one of three daily oral doses of altemiatm ( - , - or - mg/kg/day dha) for two months. the effects of altemiatm on red blood cell (rbc), white blood cell and platelet membrane omega- fatty acids index (total dha + epa levels) were assessed after four weeks of treatment. the effects of altemiatm on markers of inflammation, adhesion, coagulation, and hemolysis were assessed after eight weeks of treatment. cell membrane dha and epa concentration was determined by using lc-ms/ms method. the percent changes from baseline on blood cell membrane omega- index and select scd biomarkers were compared between the three dose groups and placebo using a mixed-model repeatedmeasures (mmrm) analysis with baseline blood cell membrane omega- index, hydroxyurea use, and treatment as fixed effects and patient as a random effect. after four weeks of treatment, blood cell membrane dha and epa levels were significantly increased in all altemiatm doses (p< . ). after eight weeks of treatment, significant reductions were observed in se-selectin (p = . ), and d-dimer (p = . ) in patients exposed to altemiatm dose level vs. placebo. hemoglobin was significantly increased at altemiatm dose level versus placebo. plasma high-sensitivity c-reactive protein, lactate dehydrogenase, soluble vascular cell adhesion molecule- and white blood cell count showed improvement after weeks of treatment in all three altemiatm doses levels but did not reach significance. conclusion: treatment with altemiatm enriches dha and epa in blood cell membranes of patients with scd and improves select sickle cell disease biomarkers of blood cell adhesion and thrombin generation. these findings provide insight into the mechanisms of action of altemiatm in sickle cell disease. brown university -hasbro children's hospital, providence, rhode island, united states background: despite clinical advances in the treatment of sickle cell disease (scd) in pediatric and young adult patients, pain remains a significant source of disease-related morbidity. physical therapy has been shown to be useful for the treatment of pain in children and young adults with various chronic illnesses of which pain is a significant component, however no data exists regarding potential benefits of physical therapy in pediatric and young adult patients with scd. objectives: to query healthcare providers and others involved in the care of pediatric and young adult scd patients regarding possible benefits of and barriers to physical therapy as a potential treatment modality. design/method: we conducted a web-based survey of healthcare providers within the new england pediatric sickle cell consortium (nepscc) in an attempt to identify potential benefits of and barriers to outpatient physical therapy in this patient population. results: nearly % of survey participants felt that physical therapy had the potential to be "somewhat beneficial" or "very beneficial" in pediatric and young adult patients with scd. a majority of physicians reported having referred patients with scd for physical therapy in the past. the most frequently identified perceived potential benefits included improved functional mobility, improvement of chronic pain symptoms, decreased use of opiates, improved mood symptoms, improved acute pain symptoms, and improved adherence with medications and clinic visits. significant perceived barriers identified included lack of transportation, time constraints, patient lack of understanding, and difficulty with insurance coverage. our study indicates that healthcare providers have an overwhelmingly positive view of the use of physical therapy in the management of pediatric and young adult patients with scd. significant barriers exist which need to be addressed. future research should focus on patient and parent perspectives regarding physical therapy, as well as a randomized controlled trial of a physical therapy intervention in this patient population. background: vitamin-d deficiency is fast becoming increasingly recognized in patients with sickle cell disease (scd). while it is estimated that these patients are five times more likely to develop vitamin-d deficiency, the exact clinical significance of this is largely unknown. given that this deficiency can be inexpensively and easily treated, our study sought to establish the prevalence of vitamin-d deficiency in our patient population and its relationship with disease severity. objectives: to estimate the prevalence of vitamin-d deficiency in patients with scd in our institution and to analyze their disease severity in relation to their vitamin-d level. design/method: through retrospective chart review we analyzed subjects that represent a cohort of patients followed at the adult and pediatric hematology services at university of miami with known diagnosis of scd that had a vitamin-d level drawn between january st, and august st, . we conducted a cross-sectional study and recorded the first vitamin-d level during this period. patient demographics, medical and social history information were collected along with laboratory data. the number of admissions for vaso-occlusive crisis (voc) and acute chest syndrome within one year preceding the collection the vitamin-d level was also recorded. results: a total of charts were reviewed, adult charts and pediatric charts. after exclusion, patients were enrolled. subclinical vitamin-d deficiency is only evident on laboratory blood testing of vitamin-d ( -hydroxy) and according to this laboratory result patients were classified as sufficient (≥ ng/ml), insufficient (< to ng/ml) and deficient (< ng/ml). out of the cases, . % ( / ) were deficient, . % ( / ) were insufficient and . % ( / ) were optimal. after statistical analysis two negative correlations were identified, increasing vitamin-d levels with decreasing white blood cell count (ci %- . (- . , - . )and decreasing incidence voc (ci %- . (- . , - . ). conclusion: this study confirms that there is a significant prevalence of vitamin-d deficiency in patients with scd. furthermore, the results of this investigation proved that vitamin-d deficiency is associated with acute pain and leukocytosis in patients with scd. given the multitude of confounding factors that affect vitamin-d absorption and intake, multivariate analyses are required to truly further investigate this relationship. texas children's hospital, houston, texas, united states background: hemophagocytic lymphohistiocytosis (hlh) is a rare but life-threatening condition of hyper-inflammation that is characterized by splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, hemophagocytosis and coagulopathy. although timely diagnosis is imperative, it is often challenging as these individual signs and symptoms may occur in a variety of clinical conditions. to report a case of undiagnosed sickle cell anemia presenting with severe ebv viremia and associated hemophagocytic lymphohistiocytosis results: a -month-old previously healthy male presented with respiratory distress, increased fatigue, and a focal seizure following a two-week history of cough and lowgrade fevers. physical exam was consistent with hypovolemic shock and revealed significant splenomegaly. laboratory testing revealed severe hypoglycemia, acidosis and electrolyte disturbances including hyperkalemia, hyperphosphatemia, and hyperuricemia. labs showed a leukocytosis (wbc , ), severely low hemoglobin ( . ), and platelets of , . coagulation testing revealed prolonged pt/inr and ptt, hypofibrinogenemia and a highly elevated d-dimer. additional workup was completed to determine etiology of acute presentation, given broad differential diagnosis. infectious studies were consistent with an acute ebv infection (plasma ebv pcr > , ). elevated levels of soluble il- and ferritin completed / criteria for the diagnosis of hlh. bone marrow evaluation showed trilineage hematopoiesis with no abnormal blast population or hemophagocytosis. results from hemoglobin electrophoresis sent from the initial cbc sample were notable for hbs . %, hbf . %, and hba of %, confirming the diagnosis of sickle cell disease. the patient was started on hydroxyurea and penicillin and splenomegaly resolved. with supportive care, he demonstrated gradual improvement in symptoms and laboratory abnormalities, including normalization of soluble il- , ferritin, cd , il- levels, immunoglobulins, and declining ebv titers. nk cell function has remained abnormally low, not eliminating the possibility of acquired hlh despite spontaneous improvement. conclusion: splenic sequestration associated with sickle cell disease in combination with acute infectious mononucleosis could have explained many of the presenting symptoms including anemia, thrombocytopenia, and splenomegaly. however, it does not explain the unusually high ebv titer and degree of inflammation meeting diagnostic criteria for hlh, which raises concern for an underlying immunologic abnormality such as x-linked lymphoproliferative disorder (xlp). although testing for xlp was negative, he will require s of s continued monitoring in the future for signs of relapse. this case illustrates the complexity of diagnosing lymphohistiocytic disorders and the significant overlap in presentation between these disorders and other medical conditions. background: vaso-occlusive crisis (voc) is one of the most distressing occurrences in patients with sickle cell disease (scd). patient controlled analgesia (pca) is recommended by nih and expert opinions favor its early use. we aim to review the use of pca in patients with voc and to evaluate if its early use is associated with faster pain control and reduced length of stay (los). design/method: this retrospective single center study included all pediatric patients admitted and treated with pca for a severe voc from to . "early" use was defined as start of pca within hours of arrival in the emergency department (ed) and "late" use after hours. time to reach adequate analgesia was defined as oucher, verbal scale or faces pain scale < / obtained twice consecutively in a -hours interval. time to reach adequate analgesia and los were compared between early-pca and late-pca groups. results: a total of patients presented episodes of voc treated with pca during the study. sixty-one episodes ( %) were treated with early-pca and ( %) with late-pca. both groups were comparable in terms of age ( . vs . years old), gender ( . % female vs . %), hemoglobin phenotype ( . % hbss vs . %), but median pain score at admission was higher in early-pca than in late-pca ( / vs / , median difference ( % ci , ). early-pca was associated with a median reduction in los of . days ( % ci . , . ) (median early-pca los . vs late-pca . days). time to reach analgesia could be evaluated only in a subset of patients ( in early-pca and in late-pca group). although time to reach adequate analgesia tended to be shorter in the early-pca group, it was not statistically different: median . hours vs . hours, difference of . ( % ci - . , . ). side effects were observed during ( . %) pca treatments ( / ( . %) episodes in early-pca, / ( . %) in late-pca group) among which ( . %) were significant adverse events. these were observed in patients who required interventions: desaturations requiring oxygen without intubation, neurologic abnormalities (hallucinations, visual abnormalities, no stroke), urinary retentions. conclusion: early use of pca for severe voc was associated with a reduced length of hospital stay despite that these patients had higher pain score on admission. prospective studies are needed to support these positive outcomes. background: acute chest syndrome is one of the leading causes of death in children with sickle cell disease - . while the cause of acute chest syndrome most commonly is not identified, fat embolism and infectious causes are believed to be most common. with an extremely high mortality rate, rapid identification and initiation of therapy is essential for survival. case presentation: we describe the case of an -year-old female with sickle cell sc disease who was admitted for vasoocclusive pain crisis and quickly progressed to multi-system organ failure due to fat embolism syndrome and parvovirus b infection objectives: the case highlights the presentation and diagnosis so other providers can optimize outcomes for those with this under-recognized syndrome design/method: her parvovirus studies returned after days which showed: parvovirus b dna pcr detected; parvo igg . (positive > . ); and igm . (positive > . ). the patient experienced an approximately . g/dl drop in hemoglobin( . to . g/dl/ hrs) with progressive thrombocytopenia (from , to , /ul) and a peripheral smear showed microcytic,normochromic red cells with nucleated rbcs and occasional nuclear budding, slight polychromasia, schistocytes, and polymorphic cells with toxic granules that suggested leukoerythroblastosis. she was emergently transferred to the regional quaternary care hospital for ongoing ecmo therapy where she experienced a change in her pupillary exam prompting a stat ct scan that showed severe, diffuse cerebral edema with transtentorial herniation. the decision was made to withdraw life-sustaining therapies and her family refused a post-mortem autopsy examination. fat embolism syndrome is a severe and uncommonly recognized complication of sickle cell disease, seen most commonly in those with a non-ss phenotype and previous mild disease course who present with severe, unrelenting vaso-occlusive pain episode and/or acute chest syndrome that progresses to respiratory distress with altered mental status and cutaneous changes. rapid identification and initiation of exchange transfusion therapy should be initiated with clinical suspicion because of the extremely high mortality rate. although previously considered rare, it needs to be considered in the differential diagnosis of more commonly encountered complications of sickle cell disease. background: patients with sickle cell disease (scd) experience vaso-occlusive crisis (voc), which results in extreme pain, often requiring opioids and admission. genetic and environmental factors affect the frequency and severity of these episodes. previous research has born conflicting evidence on whether environmental temperature is contributory. edmonton, alberta is the northern most city with a population over a million in north america. there is an increasing sickle cell population which is exposed to extreme winter conditions. this provides a suitable population and atmosphere to study the influence on cold external temperatures in scd. this study sought to identify if pediatric patients with scd, experience greater morbidity in cold external temperatures. board approved retrospective case control series. patients were identified through a clinical database, and emergency visit, phone call and admission data was collected over a fiveyear period. the average, minimum and change in temperature on day of presentation, and hours prior, was collected from the government of alberta, and was statistically analyzed using descriptive statistics, to determine the relation to vaso-occlusive events. results: one-hundred and eighteen patients were identified, and voc events reviewed. the mean patient age was . years of age with a range from . - years old. the female to male ratio was equivalent with female ( . %) and male ( . %) voc events. eight records ( %) had docu-mented cold exposures. the analysis between the temperature and the frequency of events did not yield significant correlation. average and minimum temperature on day of admission had the largest percentage of voc events occur at mild temperatures, from - . to • c and - . to respectively. change in temperature on day of admission, and hours had the largest percentage of voc events at a mild to moderate change in temperature of - degrees. data at & hours prior to admission showed similar results. secondary data analysis accounting for the lower proportion of extreme weather days in comparison to moderate temperate days showed no significant impact. there was no correlation of average, minimum or change in temperature on day of admission, or hours prior. multiple cofounding factors likely contribute to these results. as it was a retrospective study many confounding and precipitant factors may not be recorded or identified. a prospective study to better record specific cold exposure is warranted. children's national health system, washington, district of columbia, united states background: achieving optimal anticoagulation with unfractionated heparin (ufh) in pediatric patients receiving extracorporeal membrane oxygenation (ecmo) is often challenging due to antithrombin (at)-mediated heparin resistance (hr). intermittent at dosing during pediatric ecmo support does not maintain adequate at levels. continuous at infusion (cati) presents an alternative strategy to achieving consistent goal at levels and optimizing heparinization. however, cati during pediatric ecmo has not been adequately studied. objectives: to describe our center's experience with an ecmo cati protocol. design/method: in , we modified our ecmo anticoagulation protocols to include ufh titration according to anti-factor xa (anti-fxa) levels and cati in patients with at-mediated hr. the cati rate was calculated using baseline and goal at levels while accounting for the circuit volume. cati was administered with ufh into the circuit via a s of s y-infusion set. at and anti-fxa levels were monitored every hours. recombinant at (r-at) concentrate was used at our center until with subsequent transition to a plasmaderived at (pd-at) concentrate. due to the longer half-life of pd-at concentrate, the protocol was modified so cati is stopped once target at and anti-fxa levels are achieved. we conducted a retrospective study of all patients who received cati during ecmo support at our center. data are reported as median and interquartile range and compared using the mann-whitney u test. two-tailed p-value < . was considered statistically significant. since , patients [ males, age month ( . - )] on ecmo support received catis ( rat, pd-at) per our protocol ( patients received pd-at infusions during one ecmo run). the duration of cati was hours ( - ). cati administration led to significant increases in at and anti-fxa levels from baseline of % ( - ) and . units/ml ( . - . ) to the first level within goal of % ( - ) and . units/ml ( . - . ), respectively (p< . ). the respective times to achieve goal at and anti-fxa levels were hours ( - ) and hours ( - ). the respective peak at and anti-fxa levels were % ( - ) and . units/ml ( . - . ). during cati, no patient required circuit change, patient developed cannula thrombosis and patients experienced non-fatal major bleeding. conclusion: cati in pediatric patients receiving ecmo support with close monitoring of at and anti-fxa levels was associated with significant rapid increase in at, optimization of heparin effect, and reduction in thrombotic complications without increase in major bleeding compared to prior reports. a prospective study of this at dosing strategy is warranted. children's hospital of orange county, orange, california, united states background: inherited factor xiii (f ) deficiency is a rare bleeding disorder with wide heterogeneity in clinical manifestations ranging from mild bruising, and mucosal and umbilical stump bleeding to spontaneous, severe intracranial bleeding. the bleeding phenotype is influenced not just by zygosity of the fxiii mutation alone, but also by co-inheritance of variants in other clotting protein genes that also play a major role in clot formation and stability. we present a series of three siblings found with f a gene variant and platelet dysfunction linked to bleeding phenotype. design/method: retrospective chart review of the index case, coagulation studies and whole gene sequencing. the index patient presented at two years of age with a subdural hematoma after a fall, requiring emergent craniotomy. a week after initial evacuation, she re-bled, prompting an extensive work-up for potential bleeding disorders, including f activity, von willebrand profile, comprehensive fibrinolysis panel, pai- antigen level, platelet mapping thromboelastogram (plt-teg), and f genetic analysis. the patient's identical twin and older sibling, who had symptoms of bruising, underwent a similar evaluation. the index patient demonstrated consistently low f activity ( - %), and platelet function testing revealed decreased response to adp agonists. the twin and older sibling had normal f levels, and only slightly decreased response to adp in platelet studies. whole gene analysis of f and other genes on our next generation panel, revealed several intronic deletions in the index patient that were not shared by her siblings, which likely account for her decrease in circulating f levels. her symptoms have responded well to monthly treatment with factor concentrate. all three children shared the f variant, pro leu, previously described as a risk factor for intracranial hemorrhage. the f mutation, pro leu, has been associated with intracranial hemorrhage in young women, but the presence of the variant alone may not be enough to cause a severe bleeding phenotype. family studies identified novel deletions in the index patient which may account for her decreased f levels, which would have been overlooked with standard sequencing. future studies, including evaluation of 'platelet' f levels, should be performed when platelet dysfunction is detected. further laboratory and clinical evaluation is required to delineate the long term implications of the interaction of even mild f deficiency if present with additional clotting disorders such as the platelet function defect in these siblings. background: acquired hemolytic anemia can occur due to mechanical shearing of red blood cells and is classically seen in patients with prosthetic heart valves. there are reports of this same traumatic effect with other repairs, including annuloplasty. following valvular procedures flow disturbances can exist across the valve that lead to shear stress and hemolysis. although von willebrand disease (vwd) is typically seen due to an inherited disorder in the pediatric population, flow disturbances in the setting of valve abnormalities can lead to acquired von willebrand syndrome (avws). von willebrand factor multimers become unfolded and elongated in the setting of shear stress resulting in increased susceptibility to cleavage by adamsts- . specifically, loss of high molecular weight multimers (hmwms) can lead to a syndrome akin to type a vwd. objectives: to describe a case of mechanical hemolysis with acquired type a vwd design/method: a -month-old girl with history of hypoplastic left heart syndrome and severe tricuspid valve insufficiency underwent norwood procedure, blalok-taussig shunt placement and subsequently a bidirectional glenn and tricuspid valve annuloplasty. during the following month she requires weekly red blood cell (rbc) transfusions due to intermittent anemia. she also experienced bloody stools and dark urine. laboratory evaluation was notable for normocytic anemia, reticulocytosis, elevated lactate dehydrogenase, and low haptoglobin consistent with hemolytic process. immune-mediated hemolysis from transfusion reaction or presence of autoimmune or alloimmune antibodies testing was negative. to investigate gi bleeding, work up for vwd revealed normal vw activity and antigen but with loss of high molecular weight multimers consistent with acquired type a vwd. in consultation with cardiology, it was felt her tricuspid valve insufficiency jet could be leading to mechanical hemolysis and avws. a repeat echo showed persistent moderate tricuspid insufficiency but no other significant changes. due to the patient's continued need for weekly rbc transfusions she was subsequently trialed on pentoxifylline which is used in adult patients to decrease blood viscosity and increase erythrocyte flexibility in patients with mechanical hemolysis. her transfusion needs remained the same and the medication was discontinued after two weeks. she required one transfusion a week later but no transfusions since that time. although not commonly seen in pediatric patients, the diagnosis of mechanical hemolysis accompanied by avws should be pursued in a patient with congenital heart disease with significant anemia and/or bleeding. the work up in these patients is difficult as echocardiograms can be inconclusive thus an extensive hematologic evaluation is usually necessary. objectives: our aim was to assess incidence of and potential risk factors for central line-related dvt at our institution between - . additionally, our goal was to analyze if that incidence differed between the three central line types and identification of line-specific risks. design/method: a retrospective chart review of central line placements in pediatric patients at cleveland clinic between - was conducted. data included demographics, potential risk factors, line characteristics and any related thrombotic events. the study cohort consisted of lines in pediatric patients aged - years of age. there were . thrombi ( % ci . - . ) per , line days. statistically significant risk factors for thrombus include diagnosis group (liquid tumor highest rate of %, solid tumor lowest at %), type of line (picc %, broviac %, and mediport %), location of line, greater number of lines per patient, peg asparaginase ( % vs %), sepsis, and history of procoagulant state. line characteristics such as lumen size and number of lumens were not identified as a significant risk. there was a significantly higher rate of thrombus in than in the previous years when pooled ( % in vs . % from - , p = . ). the incidence of dvt in pediatric patients at our institution was highest with broviac lines, and significant risk factors in our patient population included liquid tumor, femoral vein location, peg asparaginase, sepsis, and history of a procoagulant state. the incidence of thrombi was highest in , and therefore highlights the urgent need for improvement in nationwide hospital practices to minimize risk of thrombi formation and early detection in the higher-risk s of s populations. there is still much to be learned regarding the characteristics specific to different central lines, which would influence thrombi formation. nyu winthrop hospital, mineola, new york, united states background: pediatric immune thrombocytopenic purpura (itp) is an autoimmune disorder with platelet counts < causing increased risk for significant hemorrhage. there is increased immunologic platelet destruction due to production of specific autoantibodies along with inhibition of platelet production. few randomized trials exist to guide management and ultimately each patient requires an individualized treatment plan. itp may be acute (diagnosis to m) or chronic (> months). one of the treatments of chronic itp is laparoscopic splenectomy (ls), which is very well tolerated. a rare complication of ls is splenosis, an autotransplantation or implantation of ectopic splenic tissue within the abdominal cavity or in any other unusual body compartment. splenosis is sometimes associated with relapsed itp due to preserved immune activity. the usual management of symptomatic splenosis is surgical resection. objectives: to describe medical management in a young patient with itp relapsed due to extensive unresectable splenosis following ls design/method: our patient was originally diagnosed at years with itp and was treated with ls at years of age for chronic severe thrombocytopenia and persistent bleeding not responding to first line therapies. she tolerated it well and had a complete response (cr) defined as a platelet count of > measured on occasions > days apart and absence of bleeding. she maintained a normal platelet count for twelve years after which she relapsed (loss of response after cr) with severe thrombocytopenia and hematuria necessitating high dose steroids. ct scans showed multiple wellcircumscribed soft tissue masses in the left lower quadrant adjacent to uterus and left ovary, involving left omentum and the anterior abdominal wall partly. findings were confirmed by damaged rbc nuclear scan to be splenosis. during laparoscopy the splenosis lesions were deemed too extensive and were not resected completely to avoid postoperative morbidity. she was started on sirolimus around the same time for treatment of her relapsed itp and steroids were weaned off. results: eight months since beginning sirolimus with therapeutic levels she remains in cr with no bleeding and has not required any steroids, immunoglobulins or anti d immunoglobulin. conclusion: sirolimus is a safe and effective steroid-sparing agent in treatment of chronic itp. this is the first instance of a patient with poorly resectable splenosis responding well to medications for itp. more data is needed regarding the longterm efficacy of such an intervention and whether it will eliminate the need for a second surgery in relapsed itp patients with extensive splenosis. background: storage pool disorders affecting platelets result in bleeding symptoms related to a deficiency or defect in alpha granules or delta granules. in delta-storage pool disorders (dspd,) there is a deficiency of the delta granules and their constituents, which results in the inability of platelets to properly activate as well as lack of proper constriction of blood vessels during bleeding episodes. amongst patients with dspd, females most commonly present with menorrhagia, while males tend to present with epistaxis and easy bruising. the international society on thrombosis and hemostasis (isth) developed a screening bleeding assessment tool (bat) for mild bleeding disorders, shown to be a validated tool in children. diagnosis of dspd is classically made with a platelet electron microscopy (pem) value < . delta granules per platelet (dg/pl), but recently lower diagnostic thresholds of dg/pl or even . dg/pl have been suggested. objectives: evaluate the correlation between pem and bleeding scores, and also examine various cut-off values used to diagnose and risk stratify patients with dspd. design/method: retrospective chart review of pediatric patients followed by hematology with a diagnosis of dspd was performed. clinicians obtained bleeding scores for each patient as standard of care in the hemostasis clinic. quartile ranges were established to appropriate three stages of severity based upon bleeding scores. statistical analysis was performed using software r and exploratory data analysis to evaluate for a correlation. results: amongst all patients, the average bat score was . and pem was . dg/pl. the average bleeding score for pem between . dg/pl and dg/pl was . , while the average bleeding score for pem below dg/pl was . . the correlation coefficient between pem and bleeding scores is . . using a threshold of dg/pl, % of patients would have met diagnostic criteria. quartile ranges for the bleeding scores are as follows: st quartile was - , nd quartile was - , and rd quartile was > . conclusion: patients with a more marked granule deficiency do not exhibit a more severe bleeding phenotype, suggesting proper platelet function is not solely determined by granule quantity in these patients. bleeding severity may be more appropriately assessed with bleeding scores rather than pem values, and using quartile ranges may aide in risk stratification and therapeutic interventions for dspd patients. further work remains to determine the optimal diagnostic threshold of pem dspd in pediatric populations. texas children's hospital, houston, texas, united states background: warfarin management has many challenging aspects including pharmacogenomics, food and drug interactions, lack of standardized dosing, patient compliance, tracking lab results from multiple lab locations, and the potential for significant bleeding or thrombotic complications. a literature review revealed limited data highlighting anticoagulation monitoring workflow and emr documentation and specifically, no data in the pediatric population. historically, the texas children's hospital cardiology and hematology centers were each documenting anticoagulation data within the epic tm system differently. epic's tm original design for anticoagulation documenting resulted in the necessity to duplicate documentation in order to see at-a-glance critical anticoagulation monitoring information. objectives: the objective of this project was to standardize inr documentation across departments to reduce the risk of patient safety events and improve workflow. design/method: a workgroup assembled consisting of nurses from the cardiology and hematology departments, along with staff members from the epic tm is support group. the workgroup identified current documentation practices, available epic tm tools, and brainstormed ideas to streamline and improve both documentation with the current epic tm tools. physician partners were identified in cardiology, hematology and coagulation laboratory to gain their input. a new anti-coag (ac) encounter was developed and first made available in an epic tm practice environment, then once approved, epic tm written education and training session were completed by both departments' staff. results: surveys were sent to health care providers in the cardiology and hematology centers prior to the new ac encounter, and also to health care providers six months after implementing the ac encounter. six responses were received for each survey. the pre-implementation survey showed the most problematic part of the documentation system for anticoagulation was no single place in the emr to find a complete anticoagulation picture. post ac encounter implementation survey results revealed more health care providers using the epic tm inr reminder pool, less time needed to compile a report of three months of anticoagulation information, less time needed to document individual encounters, less locations needed to document ac information and decreased amount of types of documentation used. standardized ac encounters improves workflow with less time needed to document and compile information, less types of documentation utilized and easier access to patients ac information. next steps include retrospective review of patients' inr time in therapeutic range to determine if there was an impact on patient compliance and continue to evaluate and modify the ac encounter to enhance user friendliness. caitlin tydings, jennifer meldau, christine guelcher, carole hennessey, eena kapoor, michael guerrera, yaser diab s of s children's national health system, washington, district of columbia, united states background: venous anatomic abnormalities (vaas) are considered a risk factor for developing deep vein thromboses (dvts) that occur as a result of significant alterations in venous blood flow. identification of predisposing vaas can be challenging. hence, diagnosis can be delayed or overlooked especially in pediatric patients. dvts in children or adolescents with predisposing vaas have been only described in sporadic case reports and small case series. objectives: to describe characteristics and outcomes of dvts in pediatric patients with underlying vaa treated at our center. design/method: we conducted a retrospective chart review of all pediatric patients with objectively confirmed extremity dvt treated at our institution over a -year period from to and identified all patients with underlying vaas. patients were managed according to standardized institutional protocols based on published guidelines. post-thrombotic syndrome (pts) was assessed at our center using the manco-johnson instrument. relevant data were collected and summarized using descriptive statistics. during the study period, of pediatric patients ( %) [ females, median age years (range - )] diagnosed with extremity dvt at our center were found to have an underlying vaa. vaas included may-thurner anomaly ( patients), venous thoracic outlet obstruction ( patients) and inferior vena cava (ivc) atresia ( patients). additional provoking factors were identified in patients at time of presentation. dvt locations included upper extremity veins ( patients), lower extremity veins ( patients) and lower extremity veins and ivc ( patients). the majority of dvts [ patients, ( %)] were completely occlusive. high risk thrombophilia (defined as inherited deficiency of antithrombin, protein c, or protein s, or antiphospholipid antibody syndrome) was present in patients ( %). all patients were treated with therapeutic anticoagulation with patients continuing indefinite anticoagulation. endovascular interventions were performed in patients and included percutaneous pharmacomechanical thrombectomy and/or catheter-directed thrombolysis ( patients), balloon angioplasty ( patients) and stent angioplasty ( patients). surgical interventions included thoracic decompressive surgery ( patients) and surgical thrombectomy ( patient vvas represent an important risk factor for developing extensive extremity dvt in adolescents. this special population is at risk for short-term and long-term com-plications. early identification and correction of vaas may improve outcomes. however, multicenter, prospective studies are needed for developing optimal evidence-based treatment approaches. alexander glaros, roland chu, sureyya savasan, meera chitlur, madhvi rajpurkar, yaddanapudi ravindranath children's hospital of michigan, detroit, michigan, united states background: acute budd-chiari syndrome (bcs) is a rare thrombotic emergency in children, and etiologies/treatment are less well-defined than in adults. in adults, a systematic approach including anticoagulation, relief of venous obstruction, and treatment of the underlying cause has proven successful. more recently treatment has tilted towards aggressive surgical interventions, which carry significant risk and are often not feasible. objectives: review our experience with three different patients with bcs and suggest a mechanistic based approach to treatment. the records of three patients with bcs were reviewed and their presentations, etiologies, treatment, and outcomes were reported. results: patient a was a -year-old female with paroxysmal nocturnal hemoglobinuria who presented with recurrent worsening abdominal pain over several months. narrowing of inferior vena cava (ivc) and hepatic veins was noted on imaging. liver transplant was not considered surgically feasible. she was treated with eculizumab, steroids, and anticoagulation with restoration of hepatic venous flow in weeks. patient b was a -year-old male with several weeks of right upper quadrant pain, fatigue, and pre-syncopal episodes, with a history of blunt abdominal trauma from football scrimmage weeks earlier. he was found to have near complete occlusion of the ivc and hepatic veins. liver transplant was not considered feasible. he was successfully treated with anticoagulation alone. patient c was a -yearold male with acute myeloid leukemia in induction cycle who developed severe pancytopenia; typhlitis was diagnosed and managed medically. days later he acutely decompensated, arrested, and was placed on extra corporeal membrane oxygenation, and imaging showed complete occlusion of the portal vein, hepatic veins, and ivc to the level of the atrium, with bilateral pulmonary emboli. emergency liver transplant or catheter based interventions was deemed not feasible. treatment with eculizumab was considered for presumed inflammation induced complement activation (c mg/dl [normal - ]; ch was u/ml [normal - ]) as a trigger for thrombosis, but the patient progressed quickly and died before it could be initiated. our experience with bcs shows that invasive interventional options and liver transplant may not be feasible in most patients for multiple reasons. rapid diagnosis and aggressive etiology-based medical management are paramount to successful treatment of this rare complication. eculizumab may be considered in treating bcs with complement activation not only due to innate disorders, but also secondary to acute inflammation when proper laboratory evidence is present. background: platelet aggregation studies are the gold standard for the diagnosis of platelet function defects during the evaluation of a patient with bleeding problems. the platelet aggregation test measures how well platelets clot in response to different concentrations of epinephrine, adenosine diphosphate (adp), collagen, arachidonic acid and ristocetin. because platelet function defects are often under-recognized and under-diagnosed in the pediatric patient, the true incidence is unknown. we report our experience in the diagnosis of platelet defects at our institution over a -year period in order to add some clarity to the limited pediatric data available. objectives: our primary objective is to document correlations/trends between less well-known platelet function abnormalities and clinically significant bleeding at our institution over a -year period. design/method: after appropriate irb approval obtained, we performed a retrospective chart review of all children who had platelet aggregation testing done from to . data collected included demographics (age, sex, race), personal and family history of bleeding, screening for coagulation defects and platelet aggregation test results. symptoms examined in our data were limited to epistaxis and heavy menstrual periods. for each of these symptoms, results were further analyzed to those with abnormal responses to adp and epinephrine. patients with existing bleeding diagnoses and those with incomplete medical records were excluded. we identified patients. of the patients with epistaxis, % had abnormal platelet aggregation testing while only % of those with heavy menstrual periods had abnormal results. within our population, abnormal platelet function assay (pfa- ) results or race did not appear to correlate with abnormal platelet aggregation testing. in the cases of epistaxis, sex was also noncontributory. our preliminary results suggest that platelet aggregation testing was more useful in predicting platelet defects in those with a clinical bleeding history of epistaxis as opposed to heavy menstrual periods. for other presenting symptoms, platelet aggregation testing did not offer diagnostic benefit. abnormal response to adp in the platelet aggregation test was the most common finding in our population; the clinical significance of which is not well understood. going forward, we plan to document whether abnormal results correlated significantly with the subsequent final diagnoses of our patients. background: decision making for severe hemophilia a in previously untreated patients (pups) has recently become a significant ethical debate. recombinant factor viii (rfviii) products previously were recommended to avoid transmission of blood borne pathogens associated with plasma-derived fviii (pdfviii) products. however, the increased incidence of fviii alloantibody inhibitors with rfviii products compared to pdfviii products has challenged this former standard of care. despite the support of the medical and scientific advisory council, recommendations considering pdfviii products for a pup remains controversial. design/method: we used a modified utilitarian approach involving clinical, public health, and research ethics. shared decision making permeates the framework to maximize understanding, minimize bias, respect informed consent or dissent, and provide care that aligns with patient and family values when medically and practically feasible. the framework has three tiers. first, it evaluates whether resources are scarce or abundant for equitable resource allocation. if fviii products are scarce, we s of s recommend developing a central supply for emergency use and then evaluating the needs of the severe hemophilia a patients. prioritization of who receives the factor products would be decided by a designated team based on the availability of the factor products and clinical scenarios, with no preference given to those on research trials. however, if resources are abundant, treatment for acute bleeding and standard of care prophylaxis measures, including primary prophylaxis, could continue. the second tier accounts for whether there is a new infectious epidemic or concern where a pathogen cannot be eliminated. if there is, healthcare and public health workers may limit the use of pdfviii products. if not, pdfviii and rfviii products are to be equally considered. the third tier evaluates whether the clinical scenario is emergent or not. if there is acute, emergent bleeding, the immediately available resource should be used, along with bypassing and/or adjuvant resources as needed until the bleeding has resolved or improved. to align with patient and family preferences, attempts to have both pdfviii and rfviii products available at similar costs in institutions would be ideal. this ethical framework endeavors to balance autonomy, beneficence, nonmaleficence and justice in helping guide discussions among providers, pups with severe hemophilia a, and their families. disclaimer: findings and conclusions are those of the author(s) and do not necessarily represent the official position of the centers for disease control and prevention, emory university, or children's healthcare of atlanta. background: von willebrand disease (vwd) is a common bleeding disorder which affects up to % of the population without gender predilection. bleeding associated with this condition results from a deficiency or abnormality in von willebrand factor interfering with formation of primary hemostasis. ehlers-danlos syndrome (eds) is a group of rare inherited connective tissue disorders which may have an associated bleeding manifestation without abnormalities in coagulation testing. bleeding symptoms reported in eds result from capillary and tissue fragility. joint hypermobility syndrome (jhs) is an inherited condition which is nearly indistinguishable from eds iii. reports of coinheritance of vwd and eds or jhs are infrequent. the objective of this retrospective study was to review patients with coexisting vwd and eds or jhs at the indiana hemophilia and thrombosis center in order to describe the type and severity of bleeding symptoms, physical examination findings, and pertinent laboratory data. design/method: the electronic medical record database of the indiana hemophilia and thrombosis center was queried for patients with a diagnosis of vwd and one of the following descriptors: hypermobility syndrome, hypermobility, hypermobile joints, or ehlers-danlos syndrome. the records of identified patients were reviewed for demographics, type and severity of bleeding symptoms, beighton scores (bs), vwd antigen, ristocetin cofactor, factor viii levels, vwd multimer pattern, vwd subtype, genetic testing for eds, and family history of eds. results: a total of patients with dual diagnoses of vwd and eds and patients with vwd and hypermobility were identified with this query. two patients had completed genetic testing for eds, and one had a col a gene mutation identified. significant bleeding symptoms in the vwd and eds group included hematuria and postoperative hemorrhage. two of these patients had delayed wound healing postoperatively. seven of the patients identified to have type i vwd and jhs had moderately severe and somewhat unusual bleeding episodes reported including hematuria, hematemesis, and hemoptysis; of these patients had significant perioperative bleeding. females composed % of the vwd and eds group and % of the vwd and jhs group. conclusion: coinheritance of vwd and eds is an uncommon phenomenon. patients with vwd and eds or jhs may have atypical and moderately severe bleeding, especially with procedural intervention. incorporation of bs into the assessment of patients with bleeding disorders is useful to identify potential inherited collagen disorders, as diagnosis of these conditions may impact clinical management. in the year-long phase ii study (ro fd ), / khe patients responded. patients were followed for years after study completion, collecting data on growth and development, complications of therapy, unexpected toxicities, and need for continuing sirolimus. objectives: after study therapy treatment of one year, objectives include: . assess long term toxicity over the - year period after study therapy completion . assess unexpected toxicity . assess overall condition of the patient . assess need for restart or continuation of sirolimus therapy design/method: prospective follow-up of patients with a diagnosis of khe from institutions. inclusion criteria: follow-up for - years post-study. results: follow-up included data at year (n = ) and - . year (n = ) time points. average age at the start of treatment was months. of patients were available for follow up. four patients are no longer on sirolimus: one patient completed study therapy and remains off treatment (ot) ( years), required years of treatment and is now . years ot and required an additional treatment course prior to successful discontinuation now and months ot. of the patients still on sirolimus, all restarted medication for symptoms of pain, swelling and/or edema interfering with quality of life and have made an average of . attempts to discontinue sirolimus. no patient had reoccurrence of kmp. all patients had improvement in clinical and radiologic appearance of khe but all have residual lesions noted on imaging and/or clinical exam. no unexpected toxicity, growth delay, developmental issues or other long term toxicity of sirolimus was noted. conclusion: this is the first prospective data on long-term follow up of khe patients treated with sirolimus. although numbers are small, sirolimus is well tolerated; however, over half the patients were still on medication at - year follow up. this stresses the need for continued long term follow up in these young patients and investigation of the mechanism of sirolimus effect. nationwide children's hospital, columbus, ohio, united states background: recent studies have identified that adult persons with hemophilia (pwh) have a higher prevalence of hypertension and renal disease than the general population. while hematuria is a known complication of hemophilia a and b (ha, hb), its long-term impact on pwh is not currently known. by annually screening our patients with urinalysis, our pediatric center identified that just under half of our patients demonstrated hematuria over a four-year period. motivated by a desire to identify early markers of hypertension and renal disease, we sought to determine if this finding is reflected in the pediatric hemophilia population as a whole. objectives: establish the population-wide prevalence of hematuria in pediatric pwh. design/method: we used the pediatric health information system (phis) database, which contains clinical and resource utilization data for inpatients from hospitals nationwide, to analyze the prevalence of hematuria, hypertension, renal disease and related diagnosis codes in pediatric pwh who were admitted from january to september . results: during the five-year period, , unique pediatric pwh accounted for , admissions. while the majority of admissions were for bleeding or infectious concerns, ( . %) patients had an affiliated admission code for hematuria. for admissions as a whole, the median age was years with % of those admitted being infants, % toddlers, % children, % adolescents, % older than . we identified % of admissions were for ha with the remaining % were for hb. there were ( %) admits in which a bypassing agent was administered. the median length of stay for persons with hematuria was days compared to days for nonhematuria/other bleeding. there were ( . %) admissions with hypertension reported; though, only patients received an antihypertensive medication during that admission. additionally, only ( . %) admissions reported a diagnosis code of renal disease. our study demonstrated that pediatric pwh are experiencing hematuria. in general, only patients with persistent hematuria require hospital admission so we suspect this data underrepresents the numbers of pwh experiencing hematuria that is managed in the outpatient setting. we also suspect that hypertension is grossly underreported and undertreated in pediatric pwh. additionally, there are a low number of patients experiencing renal disease requiring hospital admission among this cohort. given that there is little research into the long-term impact of hematuria in hemophilia, we feel these findings support the need for further vigilance of our pediatric pwh. background: gla and gsd can aggressively destroy bone, with significant impact on morbidity and mortality. the mtor inhibitor, sirolimus has been shown to be effective in the treatment of these diseases. based on the addition of mtor inhibition to bisphosphonate therapy in metastatic cancer therapy, regimens have been used for refractory or high risk gla and gsd but there is heterogeneity of diagnosis, and variability of drug regimens and assessment of effectiveness. objectives: . assess the variability of clinical features of gla and gsd . assess the heterogeneity of diagnosis . assess drug regimens and response assessment across multiple institutions design/method: we conducted a retrospective review from institutions of cases of gla and gsd treated with sirolimus and a bisphosphonate for at least months with assessment of clinical features, treatment protocols, response regimens and side effects. results: patients included gla (n = ) and gsd (n = ). the average age at diagnosis was years. clinical features included effusions: gla (n = ), soft tissue lymphatic malformations: gla (n = ), gsd (n = ), multiple splenic lesions: gla (n = ), and soft tissue swelling at the site of bony lesion: gsd (n = ). the presenting symptom in patients was pain with patients (gla) presenting with shortness of breath. fracture was noted in patients: gla ( ), gsd ( ). diagnostic and/or response imaging included mri, ct, bone scan, skeletal survey and dexa scan. treatment consisted of: initial sirolimus use with the addition of bisphosphonate secondary to worsening disease (n = ), initial therapy with other agents (interferon, chemotherapeutic agents, radiation) and change to sirolimus and bisphosphonate secondary to toxicity (n = ), sirolimus and bisphosphonates (n = ) and sirolimus, bisphosphonates and interferon (n = ). seventeen patients had stable disease and patients had improvement of disease. sirolimus protocol was standard; however, bisphosphonate protocol varied in dosing and frequency. side effects were tolerable and expected with no grade iii or iv toxicity. sirolimus and bisphosphonates are a safe and effective therapy for gsd and gla. a consistent medication regimen, redefined response and an improved radiologic classification will be important for the development of a prospective clinical trial. background: hemophilia a is a bleeding disorder from the deficiency of clotting factor viii. the most significant sequelae of hemophilia a is the tendency to develop hemarthrosis that incites joint destruction. the prevalence of overweight and obesity has been increasing in the general and hemophilia population and leads to several morbidities including arthropathy. this is a particular concern for hemophilia a as arthropathy is a consequence of joint bleeding. objectives: the purpose of this study was to detect the relation between body mass index (bmi) and joint health endpoints in a pediatric hemophilia population. design/method: participants in this study included patients from the hemostasis and thrombosis center at children's hospital los angeles. participants were pre-screened and approached for this study during routine follow-up appointments. patients aged - years old who have been diagnosed with hemophilia a, including mild, moderate, and severe, qualified for the study. informed consent was obtained from the patients or parents before enrollment. joint health was objectively measured by physical therapists from children's hospital los angeles using the hemophilia joint health score (hjhs). an hjhs total score is calculated by assessing: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and muscle strength in major joints. subjective data was also obtained by patients recording their annual bleed rate within the past year. of the patients, ( %) were normal weight, ( %) overweight, and ( %) obese. we used chi-square analysis to compare joint scores across bmi classifications (chi square = . , df = , p-value = . ). although, this did not approach statistical significance, the average hjhs score in patients who had a hjhs > shows an increasing trend among bmi classifications: . in normal bmi patients, . in overweight bmi patients, and . in obese bmi patients. the average number of annual bleeds in those with positive values show: in normal bmi patients, in overweight bmi patients, and in obese bmi patients. although a positive effect of adiposity was found in the joints of hemophilia a pediatric patients, the effect shows there was not enough evidence to conclude a difference. future studies are needed to address whether obesity has an effect on hemophilia and to determine whether overweight/obesity can lead to further complications in hemophilic joints. background: stagnant blood flow in slow-flow vascular malformations (vm), particularly in their venous components, can lead to localized intravascular coagulation (lic) that is characterized by elevated d-dimer levels, low fibrinogen and decreased platelet count this coagulation derangement can lead to localized thrombosis or bleeding which can result in pain, functional limitations, and possible progression to disseminated intravascular coagulopathy (dic). the treatment of vm and their associated coagulopathy has proven difficult. patients with complex vm are frequently managed with sirolimus, an mtor inhibitor, and have clinical benefits, including reduction of pain and improvement in functional impairment. it is possible that some of these improvements from sirolimus could be secondary to improvement in the coexisting lic. objectives: this study assessed the use of sirolimus to manage the coagulopathy seen in slow-flow vm. design/method: we reviewed charts of patients with vm who are followed in the vascular anomalies center at arkansas children's hospital and were started on sirolimus. efficacy was objectively assessed through improvement of ddimer, fibrinogen and platelet count. three sets of lab values (pre-sirolimus, - months post-sirolimus, and most recent) were obtained for each patient when available. we identified a total of patients who had been prescribed sirolimus. eighteen were excluded based on underlying condition other than slow-flow vascular malformation and for inadequate medical records. a total of patients ( combined vascular, venous) were included in the study. all had elevated d-dimer levels (mean . mcg/ml feu, median . mcg/ml feu, range ( . - . )) prior to treatment. two patients had an associated low fibrinogen (below mg/dl), indicating severe lic. with treatment, ( . %) patients showed an overall decrease in d-dimer levels with an average decrease of . mcg/ml feu between pre-and post-sirolimus labs, and an average decrease of . mcg/ml feu between pre-sirolimus and most recent values. the two patients with low fibrinogen prior to treatment showed a decrease in d-dimer levels (mean decrease of . mcg/ml feu) and an increase and normalization in fibrinogen (mean increase . mg/dl) after beginning sirolimus. no patient had thrombocytopenia. we report that treatment with sirolimus was effective in improving coagulopathy associated with slowflow vm as evidenced by decreased d-dimer levels and increased fibrinogen and/or platelets. long-term use of this medication in this population may decrease the bleeding and thrombotic complications that these patients experience, especially following invasive vascular procedures. background: safety and efficacy of bay - , a sitespecifically pegylated b-domain-deleted recombinant factor viii, in previously treated adolescents and adults aged - years with severe hemophilia a was demonstrated in the phase / protect viii study and ongoing extension. objectives: this subanalysis examines the efficacy and safety of bay - in adolescents in protect viii and the ongoing extension study (data cutoff, january ). design/method: in protect viii, patients (including adolescents) received bay - on demand or as prophylaxis for weeks. prophylaxis regimens for weeks - were twice-weekly ( - iu/kg), every- -days ( - iu/kg), or once-weekly ( iu/kg) infusions based on bleeding during a -week run-in period of iu/kg twice-weekly prophylaxis. patients continued their prophylaxis regimens in the extension or changed regimens at any time. results: twelve patients aged - years were included in the protect viii intent-to-treat population; s of s additional patient discontinued after dose (included in safety population). for patients receiving prophylaxis before study enrollment, median (range) number of total and joint bleeds in the months before study entry was . ( - ) and . ( - ), respectively. ten patients ( . %) had target joints at baseline (median [range], [ - ] per patient). during weeks - of protect viii for the entire time patients remained on their designated prophylaxis dosing frequency, the median (quartile [q] ; q ) annualized bleeding rate (abr) for patients receiving twice-weekly (n = ), every- -days (n = ), and once-weekly prophylaxis (n = ) was ( ; . ), . ( ; . ), and . ( ; . ), respectively (overall prophylaxis [n = ], . [ . ; . ]). two patients switched from once-weekly to twice-weekly (n = ) or every- -days prophylaxis (n = ), and number of bleeds decreased from to in one patient and to in the other. all patients from the main study continued in the extension; mean abr in the extension was . and varied by dosing regimen (twice weekly [n = ], . ; every days [n = ], . ; once weekly [n = ], . ). two patients changed from every- -days to once-weekly prophylaxis during extension (mean abr, . ). one patient had a nonneutralizing antibody to bay - at baseline; end-of-study titers were negative. no patient developed anti-peg antibodies or factor viii inhibitors or experienced a serious adverse event related to bay - during the main study or extension. in previously treated adolescents with severe hemophilia a, bay - prophylaxis was effective in prevention of bleeds, with less bleeding overall versus prestudy, and was generally well tolerated. funded by bayer. cincinnati children's hospital medical center, cincinnati, ohio, united states background: vascular malformations (vms) consist of a heterogeneous group of congenital disorders characterized by the abnormal development of blood and/or lymphatic vessels, which cause a broad spectrum of clinical manifestations. although considered benign, vms are frequently associated with cutaneous complications that can cause significant morbidity such as nodular overgrowth, skin thickening, pruritus, oozing or bleeding of lymphatic blebs and secondary infection. oral sirolimus has shown to be effective in the treatment of complicated vascular malformations but has known side effects and need for frequent laboratory monitoring. currently, there are limited studies on the use of topical sirolimus for the treatment of cutaneous manifestations of vascular malformations. objectives: to evaluate the efficacy and safety of topical sirolimus in vms with cutaneous complications and propose indications for use. design/method: this is a retrospective review of medical records of patients with vascular malformations treated with topical sirolimus from january to december . response was determined by subjective and objective improvement. results: twenty-four patients, ( %) females and ( %) males, with vascular malformations and cutaneous manifestations were treated with topical sirolimus. age ranged from - years. indications for treatment were: blebs ( %, n = ) causing either leaking, bleeding, pain, pruritus, swelling or recurrent infection; nodular overgrowth % (n = ); pyogenic granuloma % (n = ); bleeding % (n = ) and cosmetic % (n = ). treatment course ranged from - months. no major side effects were reported. one patient reported burning and itching sensation. regarding clinical response: % (n = ) patients had improvement in cutaneous lesions; % (n = ) had a stable lesions; and % (n = ) stopped treatment due to side effects. for prior/concomitant treatment: % (n = ) had prior surgery, laser or sclerotherapy; % (n = ) had concomitant oral sirolimus. of the patients not receiving concomitant systemic sirolimus, only % (n = / ) had been on oral sirolimus. of these patients, % (n = / ) had a very good response to topical treatment. : topical sirolimus appears to be beneficial and well-tolerated with a minimal side effect profile for the treatment of cutaneous manifestations of vascular malformations as a single agent or as adjuvant therapy with systemic sirolimus when symptoms are not adequately controlled. further studies are needed to prospectively analyze efficacy and safety of topical sirolimus in this patient population. objectives: to evaluate the safety and efficacy of long-term romiplostim in children with itp. design/method: all patients received weekly sc romiplostim from - g/kg to target platelet counts of - × ( )/l. median (min-max) treatment for the patients was ( - ) weeks for a total of patient-years, or . years per patient. at baseline, median (min-max) age was ( - ) years; % were female; . % had prior splenectomy. median (min-max) average weekly dose was . ( . - . ) g/kg, including escalation to a stable dose; patients started on g/kg. reasons for discontinuing romiplostim (n = , %) included consent withdrawn (n = ), required other therapy (n = ), and ae (n = ) (asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other; none treatment related). fifty four serious aes occurred in patients but were treatment related in one (concurrent grade thrombocytopenia, grade epistaxis, and grade anemia). anti-romiplostim neutralizing antibodies were detected in one patient who discontinued to receive other therapy; antibodies were absent on retesting. from week on, median platelet counts remained > × ( )/l; median platelet counts were > × ( )/l from weeks - . nearly all ( %, / ) patients had ≥ platelet response (platelet counts ≥ × ( )/l, excluding ≤ weeks after rescue medication). most ( %, / ) patients had a platelet response ≥ % of the time and % ( / ) did ≥ % of the time. sixty ( %) patients (or caregivers) self-administered romiplostim. fifteen ( %) patients had treatment-free periods of platelet counts ≥ × ( )/l for ≥ weeks (ie, remission); these patients ( girls, boys) had had itp for a median (min-max) of . ( . - ) years, none had prior splenectomy, and had received romiplostim for . ( . - ) years. all had platelet counts > × ( )/l for ≥ months and / for ≥ months; the median (min-max) duration of being ≥ × ( )/l was ( - ) weeks. of baseline characteristics such as sex, platelet counts, itp duration, and number of past itp treatments ( , , , > ), only age < years was predictive of developing treatment-free periods ≥ weeks (p = . ). in this seven-year open-label extension, > % of children with itp achieved a platelet response and romiplostim was well tolerated. importantly, % of patients were able to discontinue all itp medications for ≥ months. funded by amgen inc. background: sirolimus is an immunosuppressive drug that is widely used in solid organ and bone marrow transplantation, and more recently for the treatment of vascular and lymphatic anomalies. sirolimus has been associated with decreased immunity in the transplant setting in patients that have received other immunosuppressive drugs or were immunosuppressed from previous chemotherapy. the effects of sirolimus on the immune system in chemotherapy naïve children who have not received other immunosuppressive agents are not well understood, and there is variability in the approach to fever and pcp prophylaxis. to understand the effects of sirolimus on the immune system of patients with non-complicated vascular or lymphatic anomalies by evaluating anc, alc prior to and after sirolimus therapy. design/method: multi-institutional retrospective review was done to include patients with non-complicated vascular or lymphatic anomalies. those with effusions/ascites, multiorgan involvement, or history of vascular-anomaly-related infections prior to treatment were excluded. results: twenty patients with kaposiform hemangioendothelioma (n = ), generalized lymphatic anomaly (n = ), cloves syndrome ( ), and simple vascular malformation (n = ) were included. age at initiation of sirolimus treatment ranged from . - years. male to female ratio was : . sirolimus was initiated due to extensive disease, lack of response to steroids or bisphosphonates, pain, dment, lymphatic drainage, and prevention of ongoing overgrowth. prior to the start of sirolimus (sir- ) the mean anc was and alc was . the target level of sirolimus varied by indication and patient, and ranged from to . after the st steady state level, month after sirolimus (sir- ) the mean anc decreased to and alc was . at months after sirolimus (sir- ) the mean anc was and alc was . the first sirolimus levels (sir- ) mean was . ; and sir- level was . . nine patients were placed on pcp prophylaxis at the start of sirolimus. none of these patients had an infectious complication while on sirolimus at a median f/u of months. one patient had mild neutropenia (anc > ) which normalized after discontinuation of pjp prophylaxis. conclusion: in this small cohort of patients we found that the anc and alc level in patients with non-complicated vascular or lymphatic anomalies at sir- was not different from the sir- or sir- . prospective studies that specifically track anc, alc, igg, and lymphocyte function should be conducted to better understand the effects of sirolimus in the immune system. this data will allow for uniform recommendations regarding prophylaxis and management of febrile episodes. background: acute infections and the associated systemic inflammation can increase the risk of venous thromboembolism (vte) and in certain well-defined clinical scenarios may be the primary trigger of vte in pediatric patients. pediatric data on vte in the setting of acute infection are sparse. objectives: to describe characteristics and outcomes of vte in pediatric patients with acute infections. we conducted a retrospective chart review of all pediatric patients with objectively confirmed vte treated at our institution since and identified all patients in whom an acute infection was identified as a vte trigger. patients were managed according to standardized institutional protocols based on published guidelines. relevant demographic, clinical and laboratory data were collected and summarized using descriptive statistics. since , acute infection was identified as a trigger in of vtes ( %) diagnosed at our center. the median age at time of vte diagnosis in this group was . years (interquartile range . - ). males were more commonly affected than females, representing % of cases. neonatal vte events accounted for % of cases. sepsis was the most common acute infection to be identified as a vte trigger [ / cases ( %)]. most vte events ( %) associated with acute infections were considered hospital-associated vtes. at time of vte diagnosis, % of patients were critically ill. extensive vte (defined as completely occlusive thrombosis involving > venous segment) occurred in % of patients. acute infection was deemed to be the primary trigger for vte in / patients ( %). infection-associated vtes in this cohort included cerebral sinus venous thrombosis due to sinus or cns infection ( patients, %), septic throm-bophlebitis ( patients, %), lemierre's or lemierre's-like syndrome ( patients, %) and osteomyelitis-associated deep vein thrombosis ( patients, %). systemic anticoagulation was prescribed in / patients ( %). anticoagulationrelated major bleeding occurred in / patients ( %). vte complications included vte recurrence ( patients, %), vte progression ( patient), acute pulmonary embolism ( patients) and arterial ischemic stroke ( patients). our study indicates that acute infection is a common risk factor for pediatric vte, especially in critically ill children, and can be the primary trigger in a significant proportion of vte cases associated with acute infections. anticoagulation appeared to be overall safe in this population and was associated with low rates of serious vte-related acute complications. however, our study also suggests that this population may be at increased risk for vte recurrence and anticoagulation-related major bleeding. background: epithelioid hemangiomas (eh) are rare benign vascular tumors that occur in soft tissues and bone and present between the third and sixth decades of life. a subset ( %) of eh harbor fos rearrangement. eh has been described in children, but little is known about the long-term outcomes of pediatric eh. the main objective is to obtain data to be used for improved understanding of this rare disease in order to provide standardization of care and development of future research studies. board-approved retrospective review of clinical, pathologic, and radiographic characteristics, and treatment outcomes in patients diagnosed with eh between and . results: eight patients were male; mean age at diagnosis was . years (range: - ). lesions involved the lower extremities (n = ), cranium (n = ), pelvis (n = ), and spine (n = ). multifocal disease was identified in five patients. the most common presentations involved significant localized pain and neurologic symptoms: headache, cranial nerve injury, loss of consciousness. radiographic studies identified variable features, such as multifocal lytic bony lesions with sclerotic margins, enhancing soft tissue component, and surrounding inflammatory edema. histologically, all specimens were composed of vascular channels lined by epithelioid endothelial cells without significant cytologic atypia; solid cellular areas (n = ). endothelial cells were positive for cd and egr, and negative for camta . fos rearrangement was assessed in only one specimen and detected. mean follow-up time was days (range: - ). patients were treated with surgical resection, intravascular embolization, bisphosphonates, propranolol, interferon, and sirolimus. one patient treated with interferon and one with sirolimus exhibited partial response for mean follow-up of . days. although eh is a benign neoplasm, it is difficult to manage without standard protocols and portends considerable morbidity. our findings suggest medical management, particularly sirolimus, may benefit these patients; however, long-term follow-up is needed in treated children. novel fos inhibitors are in development and may benefit patients with fos rearrangement. penn state health children's hospital, hershey, pennsylvania, united states background: central venous catheters (cvc) are often required in critical care settings in order to provide a secure point of access for life sustaining care. clinical studies identify cvc presence as the single most important risk factor for deep vein thrombosis (dvt) in children. venous thromboembolic event (vte) incidence rates in critically ill children with a cvc range from . - % and . - . per catheter days depending on the population studied. per institutional protocol, the penn state health children's hospital picu (hershey, pa) utilizes a low dose continuous infusion of unfractionated heparin (ldufh) at units/kg/hr as prophylaxis against cvc-related vte and to maintain line patency. the efficacy of this approach has never been evaluated. to determine if ldufh for prophylaxis results in lower incidence of cvc-related vte, catheter dysfunction and central line associated blood stream infection (clabsi) without increasing morbidities. to determine if the incidence of catheter related vte is lower than historical published data, a retrospective chart review was conducted utilizing the institutional electronic medical record for all patients in , aged - . years, who had a cvc during a picu admission. secondary objectives such as the incidence of catheter dysfunction, clabsi, and any associated bleeding complications are also being analyzed. results: interim data analysis revealed cvcs ( nontunneled cvc, totally implantable devices, tunneled lines, peripherally inserted central catheters [picc] ) in total patients with a median age of . years. overall vte incidence was . % ( / ) with vtes associated with non-tunneled cvc and with piccs. sixty one percent of non-tunneled cvcs received ldufh and % ( / ) of the patients with vtes associated with non-tunneled cvcs did receive ldufh prophylaxis. vte incidence rate of nontunneled cvcs with ldufh was . % ( / ) and . per picu catheter days. the only other vte events identified within our study cohort were in the picc group where two patients experienced vte, one of which was receiving ldufh. clabsi incidence was . % ( non-tunneled cvc, tunnel cvc, picc). no major bleeding complications were associated with ldufh. preliminary data demonstrates ldufh is efficacious in preventing cvc-related vte in comparison to published reports. further analysis will compare another similar sized and acuity level picu which does not practice the same method. background: fibroadipose vascular anomaly (fava) is a rare, challenging disorder associated with pik ca mutations. fava often causes painful replacement of muscle and soft tissues with fibrotic and adipose tissue and is associated with ectatic draining veins. treatments for focal lesions are surgical excision, cryoablation or sclerotherapy and the role of medical therapy is unclear. some fava lesions are too extensive or directly involve neurovascular structure, resulting in refractory pain. objectives: to retrospectively evaluate the efficacy of sirolimus in patient with residual symptoms after procedural therapies for fava design/method: retrospective review of individual cases from institutions of fava refractory to other therapies treated with sirolimus for at least months. cases were s of s identified by polling member of the aspho vascular anomalies special interest group. results: all seven patients report improvement on sirolimus therapy. all patients had received prior procedures, including sclerotherapy ( patients), cryoablation ( patients) and/or resection ( patients). mean age at sirolimus initiation was y (range - y). mean length of therapy is . months (range - months). six patients were treated with bid dosing and one adult received daily dosing. goals of sirolimus were improvement in pain or musculoskeletal dysfunction. pain and function improved in all patients, including discontinuation of narcotic use and resumption of participation in sports. time to symptom improvement ranged from - weeks. in four patients for whom dose was lowered, pain recurred in all four and responded to restarting or increasing sirolimus dose. while all patients do not have pre-and postsirolimus imaging, decrease in fava lesion size is seen in cases with available imaging. sirolimus side effects are similar to prior reports, most commonly mouth sores, elevated lipids and acne. we report the first known data supporting a role of sirolimus in refractory fava cases. sirolimus is welltolerated and initial improvement is rapid, within weeks of initiation. whether sirolimus has a role in upfront therapy to reduce lesion size prior to procedures deserves further study. objectives: to assess platelet responses in children with itp receiving romiplostim. design/method: eligible children had itp for ≥ months, ≥ prior therapy, and screening platelet counts ≤ × ( )/l or uncontrolled bleeding. weekly dosing was from - g/kg to target platelet counts of - × ( )/l. bone marrow biopsies were evaluated in europe at baseline and after or years (cohorts and ). as of mar , patients received ≥ dose. at baseline, median (min-max) age was ( - ) years, itp duration was . ( . - . ) years, and platelet count was ( - ) × ( )/l; patients ( %) had had prior splenectomy. the median (q , q ) % time with a platelet response (platelet count ≥ × ( )/l, no rescue medications past weeks) in months - was % ( %, %) (primary endpoint). over the course of the study, % ( / ) of patients had a platelet response. four patients maintained platelet counts ≥ × ( )/l with no itp medications for ≥ weeks. median (min-max) treatment duration was ( - ) weeks for patient-years in total. median (min-max) average weekly romiplostim dose over the course of the study was . ( . - . ) g/kg; the median dose was g/kg at year (n = ) and g/kg at years (n = ). most ( %) patients initiated self-administration. sixty-four patients ( %) discontinued treatment, most frequently for lack of efficacy (n = ), patient request (n = ), and adverse event (ae) (n = ). fortyone ( %) patients had serious aes (saes) including epistaxis ( %) and decreased platelet count ( %). five patients had treatment-related saes: headaches, abdominal pain, and each of presyncope and neutralizing antibodies (ab). there were cases of neutralizing ab to romiplostim (of patients tested), but none to tpo; / had continued elevated platelet counts and in / cases ab were not found on retesting. for cohort , of patients with baseline bone marrow biopsies, had evaluable on-study biopsies scheduled for year; patient had an increase from grade to . there were no findings of collagen or abnormalities. in this interim datacut of a romiplostim openlabel study in children with itp, % of children had a platelet response. overall, the median dose was . g/kg; the median romiplostim dose over time reached g/kg. no new safety signals were observed over patient-years. funded by amgen inc. background: hepatic hemangiomas are benign vascular tumors without a medical home, managed by multiple specialties. the diagnosis has been assigned historically to various vascular lesions affecting the liver with completely different clinical presentations, resulting in difficult standardized management. objectives: the consensus steering committee identified an acute need of clear definitions and evaluation guidelines using the updated international society for the study of vascular anomalies (issva) classification. the goal was to formulate recommendations that will be adopted by all specialties involved in the care of children with hepatic hemangiomas. design/method: we used a rigorous, transparent consensus protocol, with input from multiple pediatric experts in vascular anomalies from hematology-oncology, surgery, pathology, radiology and gastroenterology. in the first section, we precisely define the subtypes of hepatic hemangiomas seen in children (congenital and infantile) using clinical course, histology and radiologic characteristics. inclusion and exclusion limits to the diagnosis are noted. the following two sections describe these subtypes in further detail, including complications to be considered during monitoring and respectively recommended screening evaluations. conclusion: while institutional variations may exist for specific clinical details, a clear understanding of the diagnosis of hepatic hemangiomas affecting the pediatric population and the possible complications that require screening during the monitoring period should be standard. as patients with hepatic hemangiomas are managed by different medical and surgical specialties, a multidisciplinary consensus based on current literature, on the data extracted from the liver hemangioma registry and on expert opinion was required and was accomplished by this manuscript. objectives: to investigate the association between routine prophylaxis with bay - and bleeding outcomes after adjusting for key patient and pharmacokinetic (pk) characteristics. design/method: the leopold kids study evaluated safety and efficacy of bay - prophylaxis in previously treated boys aged ≤ years with severe hemophilia a. patients received bay - - iu/kg x/wk (n = ) or > x/wk (n = ) and were followed up for - months. prophylaxis dose and frequency were assigned by investigators. pk parameters, including area under the curve (auc), half-life, and clearance, were derived from a population pk model and reflect predicted pk values with a -iu/kg dose. patient characteristics were compared between the x/wk and > x/wk groups using wilcoxon rank sum or chi-square tests. negative binomial regression was used to model the association between prophylaxis frequency and annualized bleeding rate (abr) for total bleeds, first without adjustment and then adjusting for age, pk parameters, and bleed history. results: mean ± sd age for patients in this analysis was . ± . years. patients receiving prophylaxis x/wk had more bleeding episodes in the months before study entry (mean ± sd, . ± . [median, . ] for x/wk vs . ± . [ . ] for > x/wk; p = . ) and were more likely to have been treated on demand ( % vs %; p = . ). pk parameters were similar between the x/wk and > x/wk groups. without adjustments, abr during the study was % higher in the x/wk group compared with the > x/wk group (rate ratio [rr], . ; % ci, . - . ; p = . ). abr was % lower in the x/wk group (rr, . ; % ci, . - . ; p = . ) after adjusting for age, auc, and number of bleeds in the prior months. conclusion: abr was numerically lower but not significantly different between the x/wk and > x/wk groups after adjusting for age and pk parameters. these findings suggest that even among patient groups that are homogeneous with respect to age, pk, and bleed history, further individualization of bay - prophylaxis based on other characteristics may help reduce bleeding episodes even at a lower treatment frequency. larger real-world studies are needed to verify these findings. funded by bayer. stanford, palo alto, california, united states s of s background: vascular malformations may be of lymphatic, arterial, venous or capillary endothelial origin. they may be simple or complex, with complex malformations being a combination soft tissue and skeletal overgrowth. although likely present at birth, these malformations often become symptomatic with puberty or infection, and range from little or no clinical impact to life threatening symptoms. in malformations primarily of venous origin, pain may be significant and hypothesized to be caused by phlebolith development (intra-malformation thrombi), inflammation, consumptive coagulopathy, vascular engorgement, and endothelial proliferation. anti-angiogenic and anti-platelet therapies have been reported to relieve pain. however, the use of anticoagulation for pain is not well described. objectives: to report clinical features and outcomes of patients with vascular malformations of venous origin treated with anticoagulation for pain. we performed a retrospective review of patients with vascular malformations followed by the hematology service between january and december who were treated for pain with anticoagulation. pain relief was determined both by wong-baker pain scales and patient report. clinical data were extracted from electronic medical records. we identified five patients with venous malformations (vm) who had received anticoagulation for pain. four patients were female and median age was years old (range to years old) at time of initiation of anticoagulation. all five patients had vm of the extremity, two with vm of the lower extremity, and three patients had vm of the upper extremity. two patients had concomitant coagulopathy and demonstrated decreased d-dimer after initiation of anticoagulation. four patients received enoxaparin, and one adult patient received rivaroxaban. all patients reported improvement in pain after administration of anticoagulation. one patient exhibited mild epistaxis and bruising at the injection site. there was no significant bleeding or other complications. pain is a significant complication in patients with venous malformations. our case series suggests that anticoagulation is a safe and effective therapy for pain relief in this population. further investigation is indicated to compare the effect of anticoagulation to other therapeutic interventions such sclerotherapy, surgery, and sirolimus in the treatment of pain associated with venous malformation. maria ahmad-nabi, christine knoll, sanjay shah, lucia mirea phoenix children's hospital, phoenix, arizona, united states background: estimates of the incidence of dvt in patients with osteomyelitis range widely from %- %, however risk factors and outcomes of dvt in this cohort have not been thoroughly established. objectives: this study aims to estimate the incidence of dvt in patients with osteomyelitis, and to assess risk factors and outcomes of dvt in this cohort. design/method: after irb approval, a retrospective chart review was conducted for patients aged - years seen at phoenix children's hospital between - with icd / codes for osteomyelitis. exclusion criteria included chronic recurrent multifocal osteomyelitis, and chronic dvt. demographics, clinical factors and outcomes were compared between osteomyelitis patients with and without dvt using the fisher-exact and wilcoxon-rank sum tests, as appropriate for the data distribution. results: a total of study subjects with osteomyelitis had a mean (standard deviation) age of . ( . ) years. dvt was present in ( % of ) patients, and ( %), ( %) and ( %) patients received anticoagulation for < , - and ≥ weeks, respectively. patients with vs without dvt were more likely to be male ( % vs %; p-value = . ), and had significantly higher rates of bacteremia ( % vs %; p-value = . ). rates of central lines were comparable between dvt and non-dvt patients ( % vs %; p-value = . ); however patients with dvt vs without dvt had significantly longer mean length of stay ( vs days; p-value < . ) and higher rates of icu admission ( % vs %; p-value < . ). the incidence of dvt among osteomyelitis pediatric patients was estimated at %, with risk increased by male sex and bacteremia. patients with dvt had significantly higher rates of icu admission and longer length of hospital stay. many of these patients had standard practice management of their dvt with - weeks of anticoagulation. our data highlights the need for recognition of high risk patients, and the need for future efforts targeting dvt prophylaxis. baylor college of medicine, houston, texas, united states background: lymphatic malformations (lm) frequently occur in the head and neck and can often be disfiguring and even life-threatening. management options include observation, surgery, sclerotherapy, and sirolimus. the optimal sequence of therapeutic interventions has not been determined due to the lack of comparative clinical trials or established guidelines. thus, prenatal planning with a multidisciplinary team is beneficial. we present a case series of ten children with head and neck lms evaluated in at our multidisciplinary vascular anomalies center. a chart review was performed to assess treatment modalities and recent trends. results: seven of patients ( %) with head and neck lms were diagnosed prenatally. six patients required an ex utero intrapartum treatment procedure. all patients were started on sirolimus at a median age of . months (range days - years). four patients most recently started on sirolimus were less than months of age at the time of initiation. six patients underwent partial excision of lm during the first year of life; none of whom received sirolimus prior to surgery. sirolimus was discontinued in one patient given chronic clostridium difficile infections, and non-compliance in another patient. five patients received sclerotherapy. tracheostomy was necessary in six patients; one patient was de-cannulated after months on sirolimus. all patients have had radiographic and clinical improvement of lm with varying treatment modalities. current clinical observations show improved response with sirolimus and demonstrate tolerability of sirolimus at a young age. conclusion: treatment of pediatric head and neck lms is challenging and a multidisciplinary approach is necessary. as the majority of patients are diagnosed prenatally, prenatal planning and discussion of potential use of sirolimus is beneficial. availability of vascular anomalies experts in the prenatal/neonatal period offers the best management results, and early initiation of sirolimus should be considered for complex lesions. long-term follow up is warranted to investigate the efficacy and timing of treatment options. yale school of medicine, new haven, connecticut, united states background: to mitigate transfusion of pathogencontaminated platelets, amotosalen, a synthetic psoralen compound, is added to sdp components. exposure to uv-a light activates amotosalen and crosslinks dna/rna base pairs, preventing replication of a broad spectrum of viral, bacterial, and other pathogens that may contaminate platelets. pr-sdps were fda approved for clinical use with no age restrictions in . we initiated use of pr-sdps in november of for all patients. we retrospectively analyzed usage of pr-sdp vs conventional (non-pr) platelets (cp) in neonatal and pediatric patients with thrombocytopenia to compare hemostatic efficacy and the incidence of transfusion reactions (tr) for these products, after one year of a dual platelet inventory. design/method: since pr-sdp were fda-licensed, no irb approval was required; pr-sdp and cp were both considered standard of care. we evaluated transfusions for all pediatric patients age - years who received any platelet transfusion between november and november . we determined the volume (mean ml ± sd) of each type of platelet component transfused, the number of platelet transfusion episodes, and reported trs based on cdc hemovigilance guidelines. a subgroup analysis was performed for thrombocytopenic neonates ( - months). results: patients - years who received only cps (n = ) received a total of , ml of platelets ( ± ml/patient) over transfusions ( . ± . episodes/patient). for comparison, in patients who received only pr-sdp, a total of , ml of platelets ( ± ml/patient, p = . ) were infused over transfusions ( . ± . episodes/patient, p = . ). for neonates ( - months, n = ) who received only cps, , ml of cps ( ± ml/ patient) were transfused over episodes ( . ± . episodes/patient). for comparison, those who received only pr-sdp (n = ), received , ml of pr-sdp ( ± ml/patient, p = . ), transfused over episodes ( . ± . episodes/patient, p = . ). for all recipients - years (n = ), including additional patients who received both cp and pr-sdp, there were three reported allergic trs over transfusion episodes, while no allergic reactions were reported with pr-sdp transfusions. one febrile tr was reported to cp transfusion, while three were reported for pr-sdp. in conclusion, pr-sdps, in our pediatric population age - years, were comparable to cp products in regards to volume and episodes of platelet transfusions, and incidence/type of transfusion reactions. pr-sdp were safe and effective for use in this pediatric patient population. background: vascular anomalies are classified as either vascular tumors or vascular malformations. fibro-adipose vascular anomaly (fava) is a newly described entity which presents with distinct clinical, radiographic and histopathologic findings. we present a case in which the diagnosis of fava was complicated by a persistent low platelet count secondary to immune thrombocytopenia (itp). to describe a challenging diagnosis of a novel vascular anomaly (fava) complicated by severe thrombocytopenia. a year old male presented to hospital with bruising and left thigh pain related to a remote sports injury. blood work revealed a platelet count of × /l, but with an otherwise normal complete blood count. the following were also normal: aptt and fibrinogen; d dimer levels were slightly increased. he was treated with one dose of ivig ( . mg/kg) for presumed itp and responded well with his platelet count increasing to × /l. he returned to hospital weeks later with recurrent thrombocytopenia and worsening leg pain. an ultrasound of the left thigh revealed a . cm x . cm x . cm lesion within the vastus medialis. the diagnosis of an intramuscular hematoma secondary to persistent thrombocytopenia was made. the patient presented with multiple episodes of thrombocytopenia over the next several months. his itp did not respond to oral prednisone ( mg/day for days). he continued to have short-lived responses to ivig requiring infusions every other week as his platelet count would fall below × /l. his leg pain progressed, restricting him to a wheelchair. further imaging by mri brought into question the diagnosis of a hematoma and a biopsy of the thigh lesion was performed. the results were consistent with a diagnosis of fava; this was subsequently excised. conclusion: this is a unique case where a vascular anomaly was misdiagnosed as a hematoma due to a patient's persistent thrombocytopenia and history of an injury. fava is a newer entity which, unlike other vascular anomalies, has not been linked to thrombocytopenia or a localized consumptive coagulopathy. after excision of the fava, the patient's chronic pain, and mobility resolved, though his itp persisted. objectives: this preliminary, exploratory analysis of realworld administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with a currently marketed shl or ehl rfix product. design/method: de-identified claims data from the commercially available truven health marketscan® research u.s. claims database were used to identify direct expenditures and number of international units (ius) dispensed for all patients aged - years with a diagnosis code of icd- . /icd- d who used nonacog alfa or eftrenonacog alfa during the study period (june , to july , ). reference weight measurements from the centers for disease control and prevention national center for health statistics' (cdc nchs) anthropometric data were used to estimate product dispensation on an iu per kg basis. the nonacog alfa and eftrenonacog groups comprised and patients, respectively. the median [iqr] age in the two groups was . [ . ] and . [ . ] years, respectively. while of the patients in the eftrenonacog alfa group had > calendar quarter of available data, only of the patients in the nonacog alfa group had > available quarter. the median rfix product dispensation per quarter was , ius (iqr, , ius) in the nonacog alfa group and , ius (iqr, , ius) in the eftrenonacog alfa group. incorporating attributed weight values, the median rfix product iu dispensation per kg per week was . iu/kg/wk (iqr, . iu/kg/wk- . iu/kg/wk) in the nonacog alfa group, and . iu/kg/wk (iqr, . - . iu/kg/wk) in the eftrenonacog alfa group. applying wac prices (eftrenonacog alfa = $ . /iu; nonacog alfa = $ . /iu), the calculated estimates of $/kg/week were $ and $ in the nonacog alfa and eftranonacog alfa groups, respectively. conclusion: preliminary real-world data derived from a large u.s. claims database revealed differences in product dispensation and factor product-related expenditures among pediatric patients with any severity of hemophilia b to whom an shl or ehl rfix product was prescribed. refinements of these data, potentially to exclude instances of sporadic usage, may shed light on real-world dispensation of rfix products among pediatric hemophilia b patients. background: vascular malformations can be classified as simple (including capillary, venous, lymphatic, arteriovenous), combined, malformations of major named vessels or associated with other anomalies. multiple modalities including laser treatments, sclerotherapy, embolization, surgery and pharmacological intervention (with mtor inhibitors like sirolimus) have been used for treatment of vascular malformations. these interventions have been used alone or in combination with varied outcomes. we present our institution's experience with a multimodal approach to simple and combined vascular malformations. design/method: we performed a retrospective chart review of patients with vascular malformations who were referred to our center for an interventional radiology evaluation from june -july . we included patients (age at presentation: months - years), referred initially for interventional radiology procedures (irp) for vascular malformations. all patients had symptoms of pain and/or swelling/deformity. diagnosis of was based on vascular imaging (doppler ultrasound, mri/a/v). nine patients had venous malformations (vm), five had macrocystic lymphatic malformations (lm), six had lymphatic-venous malformations (lvm), and two arteriovenous malformations (avm). patients initially underwent interventional radiology procedures. all the vm patients responded to sclerotherapy alone. three patients with lm responded to sclerotherapy alone, remainder required surgical intervention. one avm patient responded well to embolization, the other needed surgical resection after embolization. four lvm patients underwent irp with minimal improvement in symptoms ( - procedures attempted), surgical resection was attempted in patients with poor response and patients were started on sirolimus ( . mg/m /dose twice a day). all lvm patients started on sirolimus have responded well (decreased pain and swelling); time to initial symptom response ranged from weeks - month from starting medication. in this case series, patients with simple vm responded well to sclerotherapy alone, avm and lm patients needed irp and/or surgery for complete response. complex lvm did not respond well to surgery or irp; . % had improvement in clinical symptoms with addition of sirolimus to the treatment regimen. response to various modalities of treatment varied based on the type of vascular malformation. a multidisciplinary approach to management of vascular malformations is essential to provide multimodal therapeutic options for rapid symptom relief and improve the quality of life of these fragile patients, especially those with complex malformations. background: von willebrand disease (vwd) is the most common bleeding disorder in humans, affecting ∼ % of the united states' population. desmopressin (ddavp) is a longacting vasopressin analog that induces vasoconstriction and release of vwf. ddavp is used in patients with vwd and as a surgical prophylaxis, but carries anti-diuretic properties. to avoid electrolyte imbalance and hyponatremia, fluid restrictions are recommended in the hours post-ddavp administration. objectives: this study sought to examine perioperative practices and outcomes following ddavp administration and a fluid restriction protocol in a population of pediatric patients with von willebrand disease. design/method: a retrospective chart review was conducted for patients with von willebrand disease who underwent surgical procedures at children's hospital of pittsburgh of upmc between january , and december , . patient age, sex, weight, diagnosis, surgical procedure, total fluids administered, and post-operative sodium level were recorded. the primary outcomes noted were the proportion of patients exceeding % of the recommended fluid consumption for the -and -hour periods post-ddavp s of s administration, as defined by local guidelines. secondary outcomes were the presence of any bleeding requiring an er visit or readmission or hyponatremic seizures within hours of ddavp administration. results: data was compiled for patients ( females, males). the mean age was . years (sd . years), median age was years (range to years). procedures included dental ( ), otolaryngology ( ), orthopedics ( ), gastrointestinal ( ), plastics ( ), neurosurgery ( ), ophthalmology ( ), dermatology ( ), general surgery ( ) and gynecology ( ). % of patients exceeded % of the fluid volume recommended for the first -hour period post-ddavp administration while still in the surgical setting. no patients exceeded % of the fluid volume recommended for the total -hour period post-ddavp administration. post-operative sodium levels were obtained in only of patients. no patients returned to the er or were admitted for bleeding in the hours post-ddavp administration. no patients returned to the er or were admitted for hyponatremia or seizures in the hours post-ddavp administration. maintenance of a fluid restriction protocol effectively deterred negative outcomes in this cohort. however, a significant fluid volume was administered in nearly a third of patients despite the restrictions. given the risk of hyponatremia, and limited compliance with fluid restrictions, postoperative sodium levels should be recorded in following ddavp administration to assess the possibility of a hyponatremia and to reinforce the importance of fluid restrictions and their communication. results: a male fetus required in utero insertion of a pleuroamniotic shunt for bilateral pleural effusions diagnosed antenatally by ultrasound. shortly after delivery at term, he developed respiratory distress and was found to have reaccumulation of the pleural effusions. blood work on day of life showed a platelet count of , / l, which then decreased precipitously. he demonstrated schistocytes on blood-smear, signs of consumptive coagulopathy with hypofibrinogenemia and high d-dimers, and compensatory reticulocytosis. he required multiple transfusions and admissions to the intensive care unit for respiratory support. investigations ruled out congenital ttp, neonatal alloimmune thrombocytopenia, and noonan syndrome. given high clinical suspicion for an underlying vascular lesion causing kmp, a full body mri without contrast was undertaken. this showed a focal area of suspicious signal intensity in the upper paraspinal musculature. an ultrasound and mri with contrast demonstrated an extensive infiltrative vascular lesion involving the paraspinal musculature, prevertebral space, posterior extrapleural space, mediastinum, and neck. the child was commenced on prednisone ( mg/kg/day) and rapamycin ( . mg/m twice/day). there was no clinical or laboratory improvement after one month. a biopsy was performed which confirmed khe. in the second month of rapamycin therapy, the platelet count gradually normalized and the patient was discharged from hospital at . -months of life. prednisone was weaned off at . months of life. a repeat mri at months showed significant reduction in the khe. he is now almost years into therapy and doing well. conclusion: this is a unique case of khe with kmp that initially presented with extensive and recurrent pleural and pericardial effusions. this case demonstrates the importance of suspecting an underlying vascular malformation in the presence of kmp. our patient had a delayed but overall good response to rapamycin. further studies investigating duration of rapamycin therapy is key for the optimal management of these patients. rosa diaz, donald mahoney, lakshmi srivaths, donald yee texas children's hospital, houston, texas, united states background: since von willebrand disease (vwd) is the most common inherited bleeding disorder, it must co-exist with other less common bleeding disorders in some dually affected patients. however, reports of combined deficiencies in factor viii (fviii) and von willebrand factor (vwf) are rare. objectives: to study the prevalence and bleeding phenotype of combined deficiencies of fviii and vwf in males with hemophilia a in a hemophilia treatment center. design/method: we retrospectively reviewed the electronic medical records of males with hemophilia a followed at our institution during the past years. the primary and secondary outcomes for the study were ( ) the prevalence of combined fviii and vwf deficiencies and ( ) the bleeding phenotype of these patients. we identified vwf deficiencies in % (n = ) of the patients with hemophilia a. most (n = , %) patients were tested for vwf deficiency as part of the initial hemostatic evaluation, but one-third were tested due to clinical concern for inadequate response to fviii concentrate. the median duration of follow up was . years (range . to . ). patients were referred to our clinic at a median age of months (range to years) for evaluation of easy bruising (n = , %), mucosal (n = , %) and surgical bleeding (n = , %). primary diagnoses included with severe, moderate and mild discrepant hemophilia a. secondary diagnoses included with low vwf activity, type vwd and with type unclassified. patients experienced episodes of musculoskeletal (n = , %), mucocutaneous (n = , %) and cns bleeding (n = , %). a total of patients received factor prophylaxis. half of the patients were initially treated with fviii concentrates but subsequently changed to combined fviii/vwf products due to the frequency of breakthrough bleeding despite good compliance. all patients are on combined fviii/vwf products at the time of this review. a total of ( %) of this cohort developed chronic joint disease manifest as decreased range of motion and/or abnormal mri findings. combined deficiencies of fviii and vwf were present in % of our center's hemophilia patients. these patients exhibited a severe bleeding phenotype as evidenced by the high frequency of hemarthrosis, need for prophylaxis and high prevalence of chronic joint disease. while the optimal treatment strategy remains to be elucidated, early recognition of a combined deficiency may have important clinical implications, particularly in patients who demonstrate a suboptimal response to fviii concentrate alone. background: childhood neutropenia is heterogeneous and may be congenital or acquired. cerebral cavernous malformation (ccm ) is a neurovascular malformation disorder where lesions consist of low flow, dilated capillary endothelial channels with increased permeability, predisposing to hemorrhage and thrombosis. programmed cell death protein (pdcd ) activity has been implicated in glia and neuron migration, and recently linked to the dysregulation of the actin and microtubule cytoskeleton, thereby affecting cellular morphology and migration. variants of pdcd encoding pdcd have been associated with ccm . ccm causes a greater and earlier disease burden than other ccms, with % presenting younger than years. some patients have associated extra-neuronal manifestations, suggesting that pdcd plays a role in other tissues. we describe a patient with significant blood cytopenias associated with ccm . design/method: retrospective chart review to obtain patient data. results: an -month old female presented with seizure and was found to have multiple intracranial cystic lesions and abscesses due to s. pneumonia serotype f. during her treatment, she developed anemia (hemoglobin . - . g/dl), thrombocytopenia (platelets , - , cells/l), and profound neutropenia (absolute neutrophil counts of zero). initial bone marrow evaluation revealed a normocellular marrow but with marked granulocytic hypoplasia and % hematogones on flow cytometry. florescent in situ hybridization excluded cytogenetic changes characteristic of myelodysplastic syndrome. further evaluation included testing for neutrophil antibodies, chromosome breakage, and telomere length and results were normal. whole exome sequencing excluded mutations affecting congenital neutropenia genes, but detected a de novo pdcd variant (c. + g>a), thereby diagnosing ccm . the neutropenia has responded well to granulocyte colony stimulation factor (gcsf), which is still needed at months of age. moreover, the thrombocytopenia has progressed, requiring periodic platelet transfusions. over time, the bone marrow hematogone population has decreased to % at months of age, though the granulocytic hypoplasia persists. conclusion: our case describes the first patient with neutropenia and thrombocytopenia associated with ccm . we hypothesize the pdcd variant is the etiology of bone marrow dysfunction due to its role in actin and microtubule cytoskeleton formation, akin to the pathophysiology of xlinked neutropenia. supportive features of an underlying genetic cause of marrow dysfunction include the persistence of cytopenias beyond infection resolution as well as presence of hematogones. hematogones were previously reported to occur in patients with other congenital neutropenia disorders, indicating they could be a feature of congenital neutropenia and may be reactive to surrounding cell apoptosis. further testing of pdcd role in hematopoiesis should be explored. background: - % of adult women will suffer from heavy menstrual bleeding (hmb) during their lifetime. % of women with inherited bleeding disorders suffer from hmb. there is a paucity of data about hmb among adolescents and young adults (aya), a population in which hmb may have large social and educational effects. objectives: to study the social and academic implications of hmb in an aya population. design/method: this is a questionnaire based survey conducted in a medium-sized city in california. we recruited females - years of age from one high school and from local university. the questionnaire was set up in research electronic data capture (redcap) at our institute which allowed us to obtain objective data about the respondents' menstrual cycles. a link was sent to the high school students via their online portal schoolloop and to the university students via social media and word of mouth. data was collected over weeks from may to august . we received replies, some were not complete. using regression analysis, data was analyzed from respondents in the age group of - (with a mean age of ) years. we developed a composite score for hmb based on factors including saturation levels, number of pads, duration of bleeding, soaking of a pad within two hours, passage of clots, size and number of clots, and gushing sensation. we conducted statistical analysis of the drivers and implications of hmb based on the composite score. results indicate that having a relative with hmb, having other bleeding problems, and having anemia are drivers of higher hmb score. the results also indicate that hmb adversely affects quality of life as measured by participation in sports, social activities, after-school activities, tiredness, absenteeism, and gpa. hmb is also associated with increased rates of anemia and use of anti-depressants. hmb-driven anemia further adversely affects gpa. under-represented minorities are more likely to have a higher hmb score, as well as an increased adverse effect of hmb on gpa. the results suggest that the social costs of hmb are pervasive in the aya population, and especially pronounced among minorities. a relative with hmb is a significant driver of heavy menstrual bleeding. a hemostatic screen should be included when assessing the aya population with hmb. johns hopkins all children 's hospital, st. petersburg, florida, united states background: propranolol is a non-cardioselective beta blocker medication frequently prescribed for hemangiomas and hyperthyroidism. propranolol inhibits types i and ii iodothyronine deiodinases, enzymes that convert bioinactive thyroxine (t ) into bioactive triiodothyronine (t ). hypothyroidism is a well-recognized complication of diffuse hepatic hemangiomas that produce type iii deiodinase, an enzyme that converts t into bioinactive reverse t and t into diiodothyronine. thyroxine is typically selected for replacement in this population, even though doses up to % above physiologic may be necessary. we hypothesized that low dose, nearly physiologic t would be safer and equally effective because it bypasses propranolol's impact on the pituitarythyroid axis. we report an infant with diffuse hepatic hemangiomatosis and acquired hypothyroidism successfully treated with propranolol, prednisone, and triiodothyronine. design/method: a mo healthy female presented with abdominal distension, poor oral intake, and hepatomegaly. mri confirmed diffuse hepatic hemangiomatosis, the largest lesion measuring . cm by . cm. thyrotropin (tsh) was elevated at . (reference range* . - mcgiu/ml), total t # (rr - ng/dl), and total t ^ . (rr - mcg/dl). treatment was started with prednisone ( mg/kg/day) for three weeks, propranolol ( mg/kg/day) and t ( . mcg/kg/day). the t dose was slowly titrated to a maximum of . mcg/kg/day. thyroid hormone levels rapidly improved on t replacement. after two weeks, the tsh was . , tt , and tt . . after eight months, the tsh was . , tt , and tt . . at twelve months, the tsh dropped to . , tt , and tt . , suggesting decreased tumor production of type iii iodothyronine deiodinase. liver mri confirmed fewer hemangiomas, largest being . cm by . cm. the patient's t dose was reduced. both propranolol and t were discontinued after twenty-four months of treatment. one year off all therapy, this child has normal growth and development, only two < . cm hepatic hemangiomas and no evidence of hypothyroidism (tsh . ; tt ; tt . ). conclusion: t at near physiologic doses corrects the consumptive hypothyroidism associated with diffuse hepatic hemangiomas. t replacement is preferable to thyroxine due to its lower risk of rebound hyperthyroidism as the hemangiomas involute and type iii deiodinase production declines. there are two prior case reports describing t use without t , one employing propranolol and the other utilizing steroids for hemangioma management. this is the first case report with long term follow-up of a child treated with multimodal therapy including propranolol, prednisone, and triiodothyronine. *rr = reference range; #tt = total t ;^tt = total t background: multifocal lymphangioendotheliomatosis with thrombocytopenia (mlt) is a rare congenital disorder first described in that is characterized by multiple vascular abnormalities commonly involving the skin and gastrointestinal tract as well as consumptive coagulopathy often resulting in gi bleeding in infancy( ). to describe an unusual presentation and successful management of mlt in a neonate. design/method: baby h was born at full term after a pregnancy complicated by maternal sinus venous thrombosis requiring anticoagulation beginning at weeks. at birth, she was diagnosed with multiple hemangiomas based on clinical exam. at two weeks of age, she developed melena and hematemesis. cbc revealed platelet count of and she was referred to the ed. abdominal ultrasound was concerning for abnormal hepatic waveform; cxr showed multiple pulmonary nodules. workup revealed no other lesions and no further hematologic abnormalities. biopsy of presumed hemangioma ultimately revealed a smooth muscle-lined vascular proliferation without glut- immunoreactivity, consistent with mlt. her early course was complicated by an acute hemodynamically significant gi bleed; esophagogastroduodenoscopy identified six bleeding vascular malformations within the stomach that were injected with epinephrine and sclerosed with successful hemostasis. she received multiple prbc and platelet transfusions. central access was obtained and she was started on oral sirolimus based on previous reports of successful use in management of vascular malformations given its antiangiogenic and immunosuppressive effects ( ). she has tolerated it well with no evidence of toxicity and has achieved a partial response with stable of hemoglobin > and platelet count > . cutaneous lesions have diminished in intensity and she has had no further signs of gi bleeding. she receives pentamidine for pcp prophylaxis. she continues to have appropriate growth and development. we describe here an unusual presentation of an already rare disease. while cutaneous and gi lesions are typical of mlt, pulmonary involvement is not well-described in the literature. early identification of tissue-based diagnosis enabled timely stabilization and treatment of the patient. five months later, she continues to tolerate sirolimus and has shown significant response with diminished coloration of cutaneous lesions, stable blood counts, and no further bleeding. mlt is a relatively newly-recognized disorder with significant phenotypic variability. given that bleeding secondary to a kasabach-merritt-type consumptive thrombocytopenia is the major cause of morbidity and mortality in the first year of life in children with mlt, it is essential to recognize the diagnosis and initiate appropriate treatment as early as possible. north, arch background: patients with generalized joint hypermobility (jhm) may experience easy bruising or bleeding given the association between these symptoms and abnormalities in collagen, a required component of primary hemostasis. heavy menstrual bleeding (hmb) is a common initial presentation for females with underlying hemostatic defects and may be the sole manifestation of a bleeding disorder. however, limited reports describe jhm as a cause of hmb, leading to under recognition. objectives: to describe the clinical characteristics and management of young women presenting with hmb in the setting of jhm. design/method: this study utilized our hmb research registry. we included subjects - years, seen in the nationwide children's young women's hematology clinic between february and november with both hmb and jhm. medical records were retrospectively reviewed for history of presentation, menorrhagia impact questionnaire (miq): a validated quality-of-life tool for females with hmb, medication profiles and relevant laboratory studies. results: twenty-five patients met inclusion criteria (median age years, range - ) with an average beighton score of . (range to ). participants presented an average of . years (range months to years) after menarche despite % of patients reporting heavy to very heavy menses since menarche. according to the miq responses, most participants expressed hmb-associated limitations in physical activities ( %), social activities ( %), and work or school activities ( %). of the participants, % reported bleeding symptoms in addition to hmb, most commonly easy bruising ( %), epistaxis ( %) and cutaneous bleeding ( %). forty percent of young women presented with anemia due to chronic blood loss. results of hemostatic testing were unremarkable, with the exception of one patient who was also found to have type von willebrand disease. additionally, % of females reported arthralgia, with knees and ankles the most commonly affected joints. at time of presentation, % of participants reported failure of initial therapies and most patients ( %) were managed long-term with oral hormone therapy. in a small population of young women found to have jhm who initially presented with hmb, patients were likely to have prior bleeding symptoms as well as substantial delays from menarche to timing of presentation at our young women's hematology clinic despite limitations in activities of daily life. greater awareness of the associations between bleeding symptoms and jhm, despite typically normal hemostatic laboratory results, is necessary so that patients can more easily be identified and receive appropriate therapy. the objective is to determine the impact of cl care practices involving the home environment on ambulatory clabsi rates. design/method: information for the pi was collected through a comprehensive survey that was completed annually by the ccbdn member hospitals. responses to the questions about cl care practices involving the home environment were selected from the pi for . ambulatory clabsi rates and ambulatory total bloodstream infection (bsi) rates were obtained from another ccbdn database. the proportion of hospitals that did or did not employ a particular cl care practice was tallied. the mean ambulatory clabsi rate and mean ambulatory total bsi rate of the hospitals that did or did not employ a particular cl care practice were compared using generalized linear model techniques assuming an underlying negative binomial distribution. results: twenty-five hospitals submitted responses to the questions about cl care practices involving the home environment. one hospital was excluded for lack of bsi data. sixty-three percent of the hospitals programmatically educated parents about all aspects of the cl care bundle. the mean ambulatory clabsi rate for the hospitals that educated parents was significantly lower than that of the hospitals that did not ( . infections/ cl days vs. . infections/ cl days; p = . ). the mean ambulatory total bsi rate was also significantly lower ( . infections/ cl days vs. . infections/ cl days; p = . ). the mean ambulatory clabsi rates and mean ambulatory total bsi rates were not significantly different for the other cl care practices. conclusion: an analysis of cl care practices involving the home environment reveals that parental education of all aspects of the cl care bundle is associated with a lower ambulatory clabsi rate and lower ambulatory total bsi rate. this finding highlights the importance of systematically teaching family members the proper method of handling cl. background: children undergoing chemotherapy are at a high risk for developing nausea. dr. amy baxter in collaboration with pediatric oncology patients and nurses, developed and validated a pictorial nausea rating scale for children aged - years, called the baxter retching faces (barf) nausea scale. staff nurses at a large, academic, pediatric hospital located within washington, d.c., have identified variability in nursing assessment and documentation of chemotherapy induced nausea and vomiting (cinv) in pediatric oncology patients. the purpose of this quality improvement project was to utilize the barf scale to standardize assessment and documentation of nausea in pediatric oncology patients receiving chemotherapy. the primary aims of this project were to: assess feasibility of the barf scale in clinical practice; increase nursing knowledge about cinv through education sessions; increase documentation of nausea assessments through the use of the scale. the secondary aim of this project was to: increase the recognition of nausea through the use of a standardized assessment tool. design/method: the pdsa model was used to guide the design and implementation plan. in the first phase of the project data was collected to identify the prevalence of nausea in patients admitted for chemotherapy in the prior three months. education sessions discussing cinv and the utilization of the barf scale were conducted. pre and post assessment of nurses' knowledge of cinv and documentation were assessed. in the second phase the barf scale was implemented into practice. nurses were asked to utilize the barf scale to assess and document nausea scores in patients, aged to years, receiving chemotherapy. at the end of the implementation period nurses were surveyed about the feasibility of the scale. post data was collected to identify the prevalence of nausea documented in the electronic health record. this project was undertaken as a quality improvement initiative at children's national and it does not constitute as human subjects research. as such it was not under the oversight of the institutional review board. results: all data has been collected; however complete data analysis will be conducted in the upcoming weeks. background: sickle cell disease (scd) is the most common inherited blood disorder in the united states (us); however, there are few quality measurements to evaluate scd practice. in , the nhlbi published guidelines that include two key interventions for children with sickle cell anemia (sca): the use of transcranial doppler (tcd) screening for stroke prevention and hydroxyurea (hu) to prevent scd pain crisis. we conducted a national survey of scd management sent to providers in over institutions in the us to better assess knowledge of the guidelines and barriers to hu counseling and tcd screening guideline implementation. it was hypothesized that the barriers to tcd screening are different than barriers to hu counseling and prescribing. a -question anonymous survey was sent to providers by mail (follow-up by email). survey themes included nhlbi guidelines knowledge and comfort with understanding and implementing both tcd screening and hu use. the response rate was % ( / ) however one survey was incomplete. thus, were analyzed in the final data set. all of the respondents are in active practice, % s of s in academics and all care for children with scd. the majority of providers ( %) felt "very" or "extremely" confident in their knowledge of tcd screening and interpretation. similarly, % of providers felt "very" or "extremely" familiar with hu dosing and management. for tcd screening, % of providers estimated their screening rates were > % and % providers felt their annual screening rates were - %. the two biggest barriers to tcd screening noted by providers (of moderate to extreme significance) included: lack of support staff ( %) and lack of time during a patient visit ( %). regarding hu prescribing practices, % of providers offered hu to at least % of children with sca over nine months of age. the biggest barrier to hu prescribing noted by % of providers was concerns about patient adherence or access to the medication. only % providers felt that lack of support staff was a moderately significant barrier to hu prescribing. the pediatric scd providers surveyed all have access to the nhlbi guidelines. despite widespread guideline knowledge, there are different barriers for tcd screening versus hu prescribing, which prevent optimal implementation. as a result, although both recommendations are from the same nhlbi guideline, they likely will require different implementation strategies (systems-based interventions for tcd screening; interventions to improve patient adherence for hu counseling) to improve outcomes. background: invasive fungal disease (ifd) is a major cause of mortality and morbidity among pediatric immunocompromised patients such as those who receive chemotherapy or hematopoietic stem cell transplantation. the current diagnostic 'gold standard' of ifd remains culture of infected tissue obtained by biopsy. noninvasive biomarker testing for galactomannan or , -beta-d-glucan (bg) can have low sensitivity and does not provide species-level identification. nextgeneration sequencing (ngs) of cell-free plasma is a promis-ing noninvasive approach to providing species-level identification of ifd via a blood test and can further guide specific treatment. objectives: describe the incidence of positivity for fungal specific pathogens on ngs analysis in a high-risk immunocompromised pediatric population and correlate results with other 'standard' infectious studies if performed. design/method: immunocompromised pediatric patients with suspected ifd were enrolled and plasma was collected at time of enrollment. ngs was performed on extracted dna in cell-free plasma (karius, redwood city, ca). after removing human reads, remaining sequences were aligned to a curated database including pathogens. organisms present at a significance-level above a predefined threshold were reported. results: twenty-seven samples from enrolled patients have been processed thus far. of these subjects, were enrolled for prolonged febrile neutropenia (≥ hours) despite broad-spectrum antibiotics, for recrudescent febrile neutropenia, for abnormal imaging, and with other findings. after evaluation of routine studies performed, patients met criteria for proven ifd, for probable ifd, and for possible ifd using eortc/msg guidelines. the ngs plasma test identified the same pathogen as cultured from infected tissue or blood in % ( / ) of the proven cases. in the probable cases, pneumocystis jirovecii was identified in a patient with a positive bg ( pg/ml) and pneumonia. among the possible cases, toxoplasma gondii was detected in a patient with prolonged febrile neutropenia and lung imaging suggestive of ifd. additionally, candida glabrata was isolated in a patient with prolonged febrile neutropenia but no other criteria for ifd. numerous pathogens were also identified that could explain the above clinical parameters, including hsv , cmv, vzv, hhv , ebv, bk polyoma virus, and ureaplasma parvum. the cell-free plasma ngs test can detect invasive fungal infections from blood. the test identified fungi from proven ifd, detected pathogens in both probable and possible ifd cases, and is a useful diagnostic tool in the evaluation of ifd. supplies and sample shipment and processing supported by karius, inc. baylor college of medicine, texas children's hospital, houston, texas, united states background: practicing medicine is a lifelong learning process. as noted in the institute of medicine's seminal report, 'to err is human,' adverse outcomes do not typically result from individual recklessness; rather, they result from faulty systems, processes, or conditions that provide an environment conducive to making a mistake, or failing to prevent one. learning to systematically review errors and translate lessons learned into quality improvement (qi) initiatives is a critical component of practice-based learning and improvement for practitioners at all career levels. objectives: to develop a methodical, self-reflective and nonthreatening approach to incident analysis and translation of lessons learned into qi initiatives. design/method: we used a validated, structured case audit approach, modified from szostek et al: ) review all documentation relating to the case and identify all health care providers involved; ) interview stakeholders, including those who directly provided and supported care; ) use a qi tool to conduct a root-cause analysis; ) identify a systems issue that contributed to the outcome; and ) propose systems-level interventions and prioritize initiatives based on effort-yield projections. results: pdsa cycle : plan: establish a committee to ) identify potential cases, ) triage cases for conference presentation, ) determine timing and frequency of conferences, ) develop a training manual, ) record identified qi initiatives. do: we established a quarterly section-wide meeting to which all members of the pediatric hematology/oncology service are invited, including administrative and nursing leadership. we developed a training manual and structured presentation template. prioritized cases were discussed in advance during multidisciplinary case review sessions, and presented by senior fellows who were instructed to focus discussion on potential opportunities for qi. study: we identified cases, meeting criteria for mmi presentation. qi initiatives identified from this conference resulted in a number of systemic practice changes; however, we encountered challenges to sustaining these changes over time. act: objectives for the next pdsa cycle are to ) establish a method for tracking the adherence to recommended changes in practice, ) maximize sustainability by integrating qi initiatives into institutional qi leadership and practice standardization committees. we have successfully implemented an mmi conference that meets out of institute of medicine quality domains: safety, effectiveness, patient-centeredness, timeliness, and efficiency. a standardized, consistent approach to mmi presentations that includes identification of contributing factors and specific qi implications has the potential for improving both provider education and patient care/safety. johns hopkins university, baltimore, maryland, united states background: receiving a cancer diagnosis is a life-changing event for patients and caregivers, although little is known about the experience. while some oncologists receive dedicated training in delivering this bad news, the initial conversation is often with a primary pediatrician, and these providers often feel they do not receive adequate training in the communication of a cancer diagnosis. objectives: our objectives were two-fold: first, to better define the experiences of caregivers/patients when told of a cancer diagnosis, and to query how caregivers/patients believe providers can improve the disclosure of this bad news. secondly, to assess what, if any, training primary pediatricians received in this skill, and to assess how comfortable providers in various settings and stages of training are with communicating cancer diagnoses. design/method: from november - , semistructured, in-depth interviews were conducted with pediatric oncology patients and caregivers of patients (n = ) diagnosed in the past year regarding their experiences receiving the diagnosis at our institution. in addition, pediatric residents (n = ), outpatient pediatric primary care physicians and pediatric emergency medicine physicians (n = ) were interviewed regarding their experiences delivering cancer diagnoses. interviews were analyzed following principles of thematic analysis. interviewers with patients and caregivers had two common themes: ) all emphasized their wish for direct and thorough information; ) both patients and caregivers emphasized the gratitude they felt for physicians who gave them hope by emphasizing the good prognosis of their child's cancer. lack of training in this area, as well as lack of comfort delivering this news was common will all providers. additionally, providers report variable approaches to giving bad news, including ) whether to tell caregivers separately or tell the child and parents together, and ) whether to give favorable prognostic information. additionally, attending physicians also differed significantly in their approaches to teaching residents. while some believed residents should give the news to gain experience, others felt that this is not appropriate if residents are inexperienced. only one resident reported ever receiving feedback on his communication skills in this type of discussion. conclusion: we plan to build on these interviews to develop a national survey of patients, caregivers, and providers to better understand the issues surrounding this discussion. we will use the findings to develop a communication curriculum for pediatric residents, focusing on the discussions that occur in the outpatient setting by primary pediatricians. background: human papilloma virus (hpv), common in both females and males, is responsible for pathologies ranging from benign genital warts to cervical and penile cancer. hpv strains and are responsible for , malignancies each year in the united states, and one third of them arise in men. pharmaceutical companies have now developed a vaccine that will help prevent the virus-associated malignancies. the cdc initially recommended that females ages - years receive the vaccine series, then starting in they expanded the eligibility to males ages - years. despite being widely available and highly publicized, only % of eligible females receive the full vaccine series. objectives: this study aims to assess the knowledge of hpv, the attitudes towards the hpv vaccine, and identify barriers preventing its full utilization. once identified, we aim to overcome the barrier(s) in order to improve vaccination rates in eligible adolescents. we distributed a standardized questionnaire to the parents of eligible female and male patients in our pediatric hematology-oncology clinic. it assessed the parents' knowledge of hpv and the vaccine, their views of the vaccine, and reasons why they may oppose it. results: approximately % of parents claim they have been educated about hpv, mostly by their primary care physician. however, % did not know what disorders hpv caused; % felt the vaccine should not be added to the typical vaccine schedule; % of parents do not intend to vaccinate their child. of those that opposed the vaccine, one-third were concerned about potential side effects and nearly % feel they do not have enough information. additionally, % of parents are not aware that the vaccine is available at their child's doctor and only % of parents have discussed the hpv vaccine with their child's doctor. the largest barrier to the utilization of the hpv vaccine that we have identified appears to be lack of educa-tion. as a result, we have begun distributing the cdc's hpv and vaccine patient guide to our patients' families as an intervention. we are currently in the process of re-administering our survey to these families after implementing the intervention to assess its success in increasing both knowledge and utilization of the hpv vaccine. cancer institute, chennai, chennai, tamilnadu, india background: rasburicase is a recombinant urate oxidase enzyme approved for use in tumor lysis syndrome (tls) and it acts by reducing serum uric acid levels. using rasburicase at the recommended dose of . mg/kg/day for days is expensive and it is not known whether this extended schedule is clinically beneficial compared to a single fixed dose of . mg. the aim of the present study was to evaluate the efficacy of single dose rasburicase . mg in prevention and management of tls. design/method: rasburicase is available as single use . mg vial. at our institution a single dose of rasburicase . mg irrespective of bodyweight has been used in adults and in children a dose of . mg/kg (maximum . mg) has been used since for prevention and management of tls and subsequent doses are given based on biochemical response and clinical condition. we retrospectively analysed the case records of patients who had received rasburicase from january to january . the study included patients with hematological malignancies who received rasburicase. children accounted for . % (n = ) patients and males comprised % (n = ). rasburicase was used prophylactically in ( . %) patients, for laboratory tls in patients ( . %) and for clinical tls in ( . %) patients. single fixed dose rasburicase prevented laboratory/clinical tls in % of the prophylactic group and prevented clinical tls in % of the laboratory tls group. none of the patients in prophylactic and laboratory tls group developed clinical tls. however, majority of the patients with clinical tls required more than one dose rasburicase. single dose of . mg ( vial) rasburicase is efficient in preventing and managing laboratory tls and is economically viable in resource constrained settings. nicole wood, lauren amos, nicholas clark, chris klockau, karen lewing, alan gamis children's mercy kansas city, kansas city, missouri, united states background: medication reconciliation for newly diagnosed oncology patients is complicated and cumbersome. these patients are often admitted on no medications, and leave on multiple. chemotherapy and supportive medications are crucial. despite numerous individuals overseeing this process, prescribing errors or omissions still occur. when reviewing the literature, improvement occurs when there is an interprofessional and standardized process to medication reconciliation. objectives: this project's aim was to improve the accuracy of the discharge medication reconciliation process from % to % from february -august . the process measure was the percentage of patients discharged with an accurate checklist. additional time for staff spent in completing the checklist and avoiding an increased error rate by changing the prescribing process were followed as balancing measures. we created a discharge medication checklist which included a list of required home medications prescribed by the resident, ideally hours prior to discharge. it required fellow or attending review and pharmacy to review the list and educate the family. checklists were collected monthly and reviewed against the electronic medical record (emr) for accuracy. results: six pdsa cycles were completed. there were errors during the data collection time frame. in pdsa cycle , a patient received acetaminophen for pain control which is avoided at home. in addition, this patient received diphenhydramine instead of ondansetron, which is preferred as an antiemetic. in pdsa cycle , a patient with a pending diagnosis was sent home with acetaminophen. of note, this patient did not have a checklist completed upon discharge. this project provides a novel and important method to standardize the discharge medication reconciliation process in a complex patient population. it clarifies which types of medications these patients need, provides pharmacy teaching to families which was not done previously, and prescribes discharge medications to families sooner. after the first medication reconciliation error, the checklist was revised. no further errors were made following revision, with the exception of one patient without a completed checklist at dis-charge. our accuracy rate increased from % at baseline to % following implementation. we are in the process of making the checklist electronic and accessible in the emr. in the interim between the end of data collection and implementation into the emr, a leukemia patient was sent home without an epinephrine pen, further demonstrating the importance of this standardized discharge process. for this reason, we have re-instituted the checklist until the electronic version is available. background: survivors of pediatric cancer are at risk of losing pre-existing protective antibodies to vaccine preventable diseases. in a prior study, % of children < years lost humoral immunity to measles as a result of chemotherapy induced alterations in immune system. measles in recipients of immunosuppressive chemotherapy has mortality rates up to %. because of volitional vaccine refusal, there has been a dramatic increase in measles infection from cases in to in , including several statewide outbreaks. small pediatric oncology practices frequently share floor/clinic space with the general pediatric patients putting them at risk for measles since virulence starts hours prior to symptoms. there is no standard protocol for revaccinating post-chemotherapy patients. to assess measles risk based on serial humoral immune status in a cohort of pediatric oncology patients receiving intensive chemotherapy design/method: patients < years age with known vaccination status receiving intensive chemotherapy between july -june at our institution's pediatric oncology practice were included in this prospective study. serial measles igg antibodies were measured at diagnosis, months and months after initiation of chemotherapy using elisa. measles immunity was defined per lab standards. a comparison of pre-chemotherapy and serial post-chemotherapy immunization titers was made for all patients by diagnosis. the study population consisted of children ( male); patients had all, non-hodgkin lymphoma, sarcoma and other solid tumors. two patients ( . %), both unvaccinated had non-protective measles antibody levels at s of s baseline. of the remaining patients, . % patients ( leukemia, lymphoma and sarcoma) lost protective antibody titers at months after initiation of chemotherapy and . % ( leukemia, lymphoma and sarcoma) at months after initiation of therapy. % of the remaining patients who retained measles antibody titers within protective range at months also demonstrated a steady decline in antibody titers at and months from therapy initiation. the loss of protective measles humoral immunity occurred significantly more often in patients with leukemia compared to other malignancies. oncology patients in our practice undergoing intensive chemotherapy demonstrated progressive waning of protective measles igg titers. our data suggests that it should be standard practice to check all patients for measles humoral immunity prior to starting chemotherapy and at completion. larger studies need to be performed to establish guidelines for revaccinating post-chemotherapy pediatric patients, an intervention that is easily applicable and of low cost. background: the accurate determination of glomerular filtration rate (gfr) is important to screen for acute kidney injury, to dose chemo-therapy, and to identify risk for chronic kidney disease.being correlated with inulin clearance, measured gfr by iohexol plasma disappearance (igfr) is a new gold standard for measurement of gfr in pediatric cohort studies. igfr is based on the clearance of an exogenous marker and is unaffected by endogenous compounds or a patient's muscle mass. we compared igfr with -hour urine creatinine clearance ( crcl) and gfr estimating equations using serum creatinine (scr) and serum cystatin c (cystc) in pediatric patients with cancer. we recruited participants who were ages to yrs, continent of urine, and diagnosed with a malignancy in the past years. eligible subjects had stable kidney function for at least two weeks prior to the assessment of igfr. consented subjects had baseline assessments including height, weight and vital signs. blood samples were obtained for serum chemistry, and time zero iohexol. igfr determined by ml iohexol solution infused over - minutes followed by ml of sterile saline. blood was drawn at , , and minutes.at the same time of igfr, the crcl was collected. igfr was calculated using a two-compartment model and area under the curve. we compared igfr to published gfr equations (schwartz et al, kidney int ). results: ten subjects ( female/ male) agreed to participate. the distribution of diagnoses for the subjects: all = , lymphoma = , brain tumors = and hepatocellular carcinoma = . six patients were off therapy. the lower gfrs are noted in patients who had malignancies other than leukemia, likely due to the use of cisplatin based therapy. the average igfr was ml/min/ . m^ whereas crcl was . ml/min/ . m^ ; demonstrating the crcl overestimates gfr compared to igfr. comparing igfr to univariate equations using scr, cystc, and the multivariate equation with both, the univariate cystc equation correlated well with igfr; the others overestimated igfr. we found that crcl overestimated igfr. the univariate cystc equation better correlated to igfr than equations with scr. the poor performance of scr based methods to assess gfr might be due to decreased muscle mass and inadequate nutritional status. creatinine-based determinations of gfr alone, may not be accurate in this population. further study is needed to determine if igfr should be a standard of care to assess gfr in children with cancer particularly who are receiving nephrotoxic medications and incontinent of urine. background: pediatric oncology patients undergoing chemotherapy through indwelling venous catheters are at increased risk for severe sepsis especially when neutropenic due to chemotherapy. rapid triage and early recognition are essential because delayed initiation of antibiotics and fluids in these patients or delayed transfer to higher level of care after initial stabilization is associated with poor clinical outcome. our pediatric oncology out-patient clinic is designated as an article unit whereby the providers can initiate and give treatment such as intravenous fluid, antibiotics, chemotherapy and blood products. objectives: global aim-optimize management of early sepsis and decreased morbidity, mortality and hospital length of stay in the high risk pediatric oncology patients. smart aim-improve timely management with initiation of fluids and antibiotics and transfer of septic patients to higher levels of care by % in months in above patients design/method: multidisciplinary team with physicians and nurses was created. retropective chart review of sepsis patients treated at the clinic from april to october was done using an audit sheet to identify the barriers in the delivery of care. three patients were identified and data analyzed prior to intervention; two were analyzed post interventions. a key driver diagram was created by the group to drive intervention. a process map was designed to identify the different steps in the care of these patients to pinpoint areas needing improvement. different timed data points were used starting from time of arrival to clinic, time to antibiotics and fluids and time to transfer to higher level of care. rapid pdsa cycles were done to improve the processes and delivery of care. run charts were created. there was an improvement close to the goal of % for all data points used. pdsa cycles for improvement included conducting frequent mock codes with appropriate feedback real time coaching and process planning with nursing staff. we partnered with pharmacy for close loop communication with clinic staff and we improved communication between physicans at different levels. conclusion: sepsis in neutropenic pediatric oncology patients is deadly and can be reversed with timely management at different levels. given the promising results of the above project, we want re-inforcement of the processes to be a part of the daily practice of first line clinical staff. eventually we will extend the principles learnt in management and triage of sepsis to other outpatient emergencies chemotherapy related anaphylaxis background: chemotherapy-induced nausea and vomiting (cinv) is a common side effect in children receiving antineoplastic chemotherapy. recommended prophylactic antiemetic medications are based on the classification of chemotherapy emetogenicity. however, despite appropriate use of these antiemetic agents, some patients will still experience nausea and/or vomiting. children's oncology group clinical practice guidelines recommend the addition of olanzapine to prophylactic regimens for management of breakthrough cinv. objectives: our pediatric hematology oncology center implemented a quality improvement (qi) project aimed to increase the use of olanzapine in pediatric cancer patients years of age and older receiving moderately or highly emetogenic chemotherapy and experiencing breakthrough cinv over a month period. design/method: this qi project was conducted utilizing plan-do-study-act (pdsa) cycles. for the first pdsa cycle, baseline data was collected through chart review to determine the rate of olanzapine use for breakthrough cinv over a month period from july to december . breakthrough cinv was defined as use of or more doses of antiemetic agents other than those given for cinv prophylaxis. guidelines for treatment of breakthrough cinv were reviewed with pediatric hematology/oncology attending physicians and fellows. flyers were created that listed chemotherapy regimens considered moderately and highly emetogenic. if a patient experienced breakthrough cinv, a flyer was to be placed in the patient's roadmap binder to signal olanzapine should be added to the next chemotherapy block. data was collected over a month period in september following this first intervention. the second pdsa cycle consisted of didactic education and training of pediatric oncology nurses as well as pediatric residents regarding the addition of olanzapine for breakthrough cinv. rates of olanzapine use were then collected from october through november . results: olanzapine use increased from . % at baseline to . % after the first pdsa cycle ( = . , p = . ). after the second pdsa cycle, olanzapine use increased another . % to . % ( = . , p = . ). the administration of olanzapine was successfully increased by modifying patients' roadmaps after patients experienced breakthrough cinv as well as with education and training of pediatric oncology staff, fellows, residents, and nurses. background: venous thromboembolism (vte) is increasingly affecting children. according to an administrative database study, there was a % increase in the incidence of vte among children admitted to free-standing children's hospitals in the united states from to . risk factors for hospital-acquired vte are well-known and well-studied in adults, with evidence-based preventative measures available. similar guidelines are lacking for children. objectives: there is an ongoing national-initiative to develop and institute methods for screening and preventing hospitalacquired vte in children. in / , nationwide children's hospital instituted an electronic screening form required for all patients admitted ≥ hours. patients were scored and riskstratified based on eight risk-categories. a summated score was used to determine the vte risk level, and used to make prophylaxis recommendations for patients ≥ years; as well as patients ≥ years who were admitted to an intensive care (icu), surgical, or trauma unit. the purpose of this irb exempt, quality improvement initiative was to retrospectively review our experience with this risk-stratification tool. results: hospital-acquired vte events occurred in unique subjects. median age at vte diagnosis was years. only ( %) vte occurred in children ≥ years of age. ( %) vte were deep vein thrombosis (dvt), and ( . %) involved pulmonary embolism. vte was most common in subspecialty units including the pediatric and cardiac icus ( . %); neonatal icu, ( . %); and hematologyoncology, ( . %). ( %) vte were associated with central venous catheters (cvc) and events ( %) were associated with altered mobility. congenital heart disease/heart failure was the most common chronic medical condition associated with vte ( ( . %) events); whereas infection and trauma/surgery were the most common acute medical conditions associated with vte ( ( . %) and ( %) events, respectively). during ( %) events, subjects scored a summated score ≥ . in summary, in this single institution, prospectively maintained database, cvc remains the most common risk factor for vte, followed by cardiac disease, infection and trauma/surgery. most subjects who developed vte scored high (score ≥ ) on our screening tool. only a small proportion of vte occurred in patients older than years and thus eligible for thromboprophylaxis. our results indicate that future vte prevention endeavors should include these age groups in addition to exploring more aggressive prophylactic modalities including pharmacological prophylaxis. background: pediatric fellows are required to have active engagement in quality improvement (qi) activities, and yet a national acgme review found most trainees had "limited knowledge of qi methods" and "limited participation in interprofessional qi teams". the twenty fellows in our pediatric hematology/oncology training program identified blood culture utilization as their qi priority. our institution recently introduced a hospital-wide decision algorithm to guide providers regarding when to obtain blood cultures. there is often a low threshold to obtain blood cultures in immunocompromised pediatric oncology patients, but these are often low-yield or result in falsepositives. our fellows spearheaded a project to implement the algorithm in the inpatient pediatric oncology population and improve the proportion of appropriately drawn blood cultures. we investigated how appropriately the algorithm was being utilized on the inpatient pediatric oncology floor prior to and after several educational steps aimed at disseminating the algorithm to members of the care team. our primary endpoint was to quantify the proportion of culture episodes drawn "inappropriately", with a goal of reducing inappropriate episodes to ≤ %. the algorithm was initially introduced to the nursing staff and residents covering the twenty-bed inpatient unit in september . qi project planning took place with upper level fellows in january . fellows and faculty received intensive training on the algorithm in july-august . we then conducted a retrospective chart review of blood culture episodes drawn between august and november . upper level fellows scored ∼ culture episodes as to whether the decision to culture and number of cultures drawn were "appropriate" or "inappropriate", and catalogued the indications for culture episodes and if applicable, why the episode was found to be inappropriate. additionally, fellows discussed inappropriate culture episodes with the team onservice, to provide direct feedback on where the algorithm failed. results: between august -december on average cultures/ patient-days were drawn. forty-nine percent of culture episodes were inappropriate. from january -october , following targeted education on the algorithm, the rate of blood cultures drawn decreased to cultures/ patient-days. the average proportion of inappropriate culture episodes fell to . %, representing a % decrease in inappropriate culture utilization. correct application of a decision algorithm for blood culture utilization can reduce total cultures drawn on an inpatient pediatric oncology unit. fellow-led education of the multi-disciplinary team decreases the rate of inappropriate culture episodes as well as provides active engagement in qi. background: inadequate understanding of sickle cell disease (scd) is common and can affect patients' compliance and therefore their morbidity and mortality, especially after transition to adult care. optimal clinical care for scd includes disease education, which can be difficult given the breadth of possible topics and limited time in clinic. it is unclear how best to provide personalized, efficient education for adolescents with scd. this quality improvement (qi) study aimed to implement a questionnaire-based system to improve patients' knowledge of their scd and documentation of education by the nurse or physician. the study objective was to improve provider documentation and patient knowledge about their scd by identifying patients' gaps in comprehension. by january , the study aimed to increase education documentation from % to %. by april , the study aimed to increase use of a smart phrase for education documentation from % to %. by june , the study aimed to increase patients' knowledge about their disease by %. design/method: twenty-one scd patients enrolled on an irb approved qi study, with twenty active patients. our comprehensive team generated a questionnaire with knowledgebased questions for two age groups: - and - years old. at each comprehensive visit, a questionnaire was distributed, with at least -month intervals. the provider scored questionnaires and reviewed two educational topics, with wrong answers taking priority. plan-do-study-act (pdsa) cycles included pdsa# : patients completed questionnaire. pdsa# : a smart phrase addressing questionnaire topics was created and shared with providers. pdsa# : patients received education handouts during clinic education. documentation in clinic notes was the process measure and questionnaire scores was the outcome measure. results: pdsa# is complete, pdsa# has four patients remaining, and pdsa# is ongoing. due to variable visit frequency, there are multiple concurrent cycles. after pdsa# , free text documentation was completed an average of % over the course of months. after pdsa # documentation increased to % within months and questionnaire scores increased from an average of % to %. of the questions that patients got wrong on their first visit, they were significantly more likely to improve on retesting if the topic was taught to them than if it was not addressed ( % vs. %, p = . ). we are currently completing pdsa# and collection of post pdsa# data. questionnaire-based scd education coupled with standardized smart phrases improves patients' scd knowledge and documentation by providers. further improvement in knowledge is expected with the addition of handouts. background: exposure to suffering can have a profound impact on the wellness of caregivers, often referred to as the "cost of caring". this cost is especially high in pediatric hematology/oncology. repeated exposure to suffering has the potential to negatively impact resilience and increases the risk of burnout, thus impacting quality of care and patient satisfaction. we have developed a peer support team utilizing the critical incident stress management (cism) model. this model has been successfully used in other professions that frequently face traumatic events such as fire fighters, police and emergency medical technicians. the h.o.p.e.s. team (helping our peers endure stress) consists of volunteer multidisciplinary staff members who have received training to provide both group and peer support following any 'critical incident' that may impact one or more staff members. we hypothesize that implementation of the h.o.p.e.s. team will improve staff resilience, decrease overall rates of burnout and improve compassion satisfaction. s of s design/method: we are using both empiric metrics and anecdotal reports to assess the impact of the h.o.p.e.s. team. prior to the activation of the team, all pediatric hematology/oncology clinical staff members were surveyed using validated tools to assess their levels of resilience, burnout, secondary trauma and compassion satisfaction (proqolv and brief resilience scale). they were also asked to rate the number of times they had experienced critical incidents, as well as their perceived level of distress after dealing with traumatic events. after the h.o.p.e.s. team has been functional for months, we will send the same survey to staff members to measure changes, paying special attention to resilience and rates of burnout and compassion satisfaction. results: enthusiasm for development of the team has been high. of people approached to volunteer their time to participate in the multidisciplinary team agreed, including attending physicians, fellows, nurses, nurse practitioners, child life specialists, social workers, clergy and psychologists. all volunteers participated in a -day training conducted by an instructor from the international critical incident stress foundation. engagement in the first staff survey has been high, with of responding to date. data collection is ongoing. clinical staff in pediatric hematology/oncology may be particularly vulnerable to burnout and decreased resilience by repeatedly witnessing suffering and trauma. peer support interventions following critical incidents may lead to increased resilience and compassion satisfaction while decreasing rates of burnout. enthusiasm for the development of a peer support team has been high. background: monthly blood transfusions are an indicated therapy for pediatric patients with sickle cell disease with certain complications. maximizing transfusion efficiency in a busy infusion clinic requires: ensuring that appropriate blood units are available in the hospital blood bank; laboratory specimens are obtained from patients in advance; and coordination of clinic appointment and nursing availability. we sought to improve clinic efficiency through identifying ways to better communicate with patients/families regarding upcoming laboratory and transfusion appointments, and to assess the efficacy of implementing a web-based personalized text reminder (pinger.com). we measured the baseline frequency with which transfusion appointments were missed by families, moved to later within the week, or delayed due to late labs. a convenience sample of patients receiving monthly transfusions received a questionnaire about patient/parent preferences for appointment reminders and barriers to keeping appointments. those patients/parents who did not opt-out of an additional text reminder received personalized texts from their care team reminding them of lab and transfusion appointments. rates of missed/moved/delayed appointments were compared between the group receiving the additional text messages and the group only receiving standard, hospitalgenerated appointment reminders (telephone call). results: forty-one families ( patients) responded to the survey, capturing information on % of patients receiving chronic transfusion therapy. thirteen families ( %) declined the additional text reminders. families reported a preference for text reminders ( %), more often than email ( %) or telephone ( %), and % of families wanted to receive reminders for both transfusion and laboratory appointments. the majority ( %) of families reported competing work/life priorities as the reason for missed/late appointments. other families noted transportation/travel ( %), fear/illness/pain ( %), and lack of reminders ( %) as the reason for missed appointments. at baseline (twelve weeks), . % of appointments were missed on a weekly basis (range - of available per week), . % were moved, and % of appointments were delayed. during our intervention period (twelve weeks), % were missed, . % were moved, and . % were delayed (combined, both groups). there was no difference in missed ( . % texted vs . % standard), moved ( . % texted vs . % standard) or delayed ( . % text vs . % standard) appointments. though families at our center reported a preference for a text-based reminder, personalized text reminders for appointments did not improve clinic efficiency as measured by missed, moved or delayed transfusion appointments. there was no improvement in appointment adherence in the group receiving personalized texts in addition to standard hospital reminders. university of utah, salt lake city, utah, united states background: childhood cancer outcomes have improved significantly, in large part due to multi-institution collaborative clinical trials run by the children's oncology group (cog). approximately half of eligible children with cancer will enroll on a therapeutic trial, but little is known about the factors affecting caregiver decision-making regarding enrollment or how well the required elements of informed consent are conveyed during the consent process. objectives: . assess coverage of ten of the required elements of informed consent for cog therapeutic trials. . describe factors affecting caregiver decision-making regarding therapeutic trial enrollment. we surveyed families of children who were offered enrollment onto a phase cog therapeutic study for an initial cancer diagnosis in the previous months. fisher's exact or wilcoxon rank-sum tests were utilized to compare demographic and other motivating factors related to enrollment decision-making. results: seventy participants were surveyed. regarding of the basic required elements of informed consent, % knew the trial involved research, % knew consent was required, % knew the enrollment length for the trial, % knew they could continue care independent of enrollment, % knew who to contact with questions, % knew there were options besides enrollment, % knew they could withdraw at any time, % knew the information was confidential, % knew there were risks associated with the trial, and % knew there were benefits. of all participants, % (n = / ) enrolled onto a therapeutic study. among enrollees, % (n = / ) of the primary caregivers had completed college compared to % (n = / ) of those not enrolled (p = . ). when asked about factors impacting their decision, % (n = / ) of those enrolled said they felt there were no risks or did not know if there were risks associated with the study compared to % (n = / ) of those choosing not to enroll (p = . ). of those enrolled, % (n = / ) reported the physician recommendation "somewhat" or "strongly" affected their decision to enroll compared to % (n = / ) of those not enrolling (p = . ). of those who enrolled, % (n = / ) reported feeling pressured to enroll while % (n = / ) of those not enrolled reported pressure (p = . ). of enrollees, % (n = / ) reported they did not have enough time to decide compared to % (n = / ) of those not enrolled (p = . ). failure to convey all required elements of informed consent highlights possible deficiencies in the consent process for cog therapeutic trials. caregivers' perception of being pressured and lack of time to make an informed decision may impact clinical trial enrollment. background: abnormal uterine bleeding (aub) is a frequent adolescent gynecologic complaint. however, limited research exists to guide management, and acute care varies. we sought to improve emergency care for adolescents with aub by developing a clinical effectiveness guideline (ceg) and assessing its impact on quality of care. design/method: a stakeholder engagement group consisting of members from the departments of hematology/oncology, adolescent medicine, general pediatrics, and emergency medicine designed a ceg algorithm for emergency aub management. pediatric residents received ceg training and their knowledge and attitudes were assessed using pre and post intervention surveys. icd- and codes identified electronic health record data for patients presenting to the pediatric emergency department (ed) for aub months before and after ceg implementation. pre-pubertal patients and those with vaginal bleeding from trauma were excluded. a weighted, -point scoring system consisting of prioritized aspects of history, laboratory studies and management was developed to quantify the quality of care provided. t-test, chi square test, wilcoxon rank sum test, and a run chart were used for analysis. of the patients identified, met inclusion criteria. there were % of patients currently using some form of contraception, while . % had bleeding related to a current or recent pregnancy. median aub quality care scores were pre-and post-intervention (p = . ). run chart data showed no shifts or trends (overall median score, -points). both pre and post-implementation, points were deducted most frequently for not assessing personal/family clotting disorder history and inappropriate use/dosing of oral contraceptives. we successfully designed and implemented a ceg and educational intervention for aub management in a pediatric ed. these data suggest our ceg may be an effective tool to improve emergency aub care for adolescents, though additional cycles are needed. background: high-dose methotrexate (hd-mtx) is a common chemotherapy administered inpatient at most centers. its administration is particularly susceptible to error due to the need for frequent drug levels with resulting changes in supportive care. errors can prolong patient stay and cause patient harm. objectives: global aim-to reduce the length of stay (los) of hd-mtx admissions. smart aims-to increase the percentage of patients whose pre-hydration fluids are started by am from % to % by / / , and to increase the percentage of patients who receive hd-mtx by pm from % to % by / / . we used rapid process improvement methods to target earlier methotrexate administration. a key driver of prolonged los was hypothesized to be drug levels returning overnight rather than in the day time due to delayed hd-mtx start. changes implemented have included scheduling hd-mtx patients as the first patients of the day for their exam in clinic and scheduling labs to pass for hd-mtx on the day prior to admission. there are ongoing pdsa cycles to change the location of pre-hydration start from the inpatient room to the clinic exam room in order to meet hd-mtx administration time goals. we are piloting two different education materials to improve patient experience. one explains hd-mtx levels in a red/yellow/green stoplight format and the other reminds patients how to prepare for the admission. other interventions regarding how we test urine ph and safety checks in the ordering process for history of delayed clearance are in the planning stage. the project is ongoing, but as of / / , we start methotrexate by pm % of the time which is improved from a baseline of %. when the project was started, pre-hydration was never started before am. now, fluids are started by am % of the time. pdsa cycles are ongoing and we have yet to sustain reductions in los, but some months have shown decreased los by as much as hours from baseline measurements. rapid cycle improvement can be utilized to decrease los hd-mtx admissions. this has important financial implications as well as the potential to reduce secondary harm from unnecessary time in the hospital. pediatric cancer centers should schedule hd-mtx admissions first thing in the morning so that data regarding kidney injury and drug clearance can be interpreted by the day team and children are not cleared for discharge in the middle of the night. background: education and training for interdisciplinary pediatric oncology providers requires training in principles of palliative and end-of-life (eol) care. the experiences of bereaved parents can inform and enhance palliative care educational curricula in uniquely powerful and valuable ways. the objective of this study is to present an innovative palliative care educational program for oncology providers facilitated by trained bereaved parents who serve as volunteer educators in local and national palliative care educational forums and to describe how incorporation of bereaved parents in these educational forums affects participant comfort with communication and management of children at the eol. design/method: survey tools were adapted to determine how bereaved parent educators affected participant experiences in different educational forums: institutional seminars on pediatric palliative and eol care, role-play based communication training sessions, and an international symposium on pediatric palliative oncology. pre-and post-session surveys with incorporation of retrospective pre-program assessment item to control for response shift were used in the evaluation of institutional seminars and communication training sessions. results from feedback surveys sent to all attendees were used to appraise the participants experience in the international oncology symposium. results: involvement of trained parent educators across diverse, interdisciplinary educational forums improved attendee comfort in communicating with, and caring for, patients and families with serious illness. importantly, parent educators also derive benefit from educational with interdisciplinary clinicians. integration of bereaved parents into palliative and eol care education is an innovative and effective model that benefits both interdisciplinary clinicians and bereaved parents. background: poorly controlled chemotherapy-induced nausea and vomiting (cinv) significantly impairs patients' quality of life and contributes to ongoing medical costs through increased length of stay in the hospital or readmissions and outpatient visits for control of nausea, vomiting or dehydration. lack of adherence to national evidenced-based guidelines that dictate antiemetic prescribing for variably emetogenic chemotherapy leaves patients vulnerable to increased cinv and its ensuing complications. objectives: to review our institution's antiemetic prescribing practices and their consistency with the antiemesis guidelines from the national comprehensive cancer network (nccn) and children's oncology group (cog)-endorsed supportive care guidelines and to further develop tools to increase adherence to these national-based guidelines to improve control of cinv. we performed a retrospective chart review of inpatient chemotherapy encounters. we evaluated emetogenicty of chemotherapy (high, medium, low), initial antiemetic regimen ordered, number of as needed medications required and adherence to national evidenced based guidelines tailored to each level of emetogenicity in the prescription of antiemetics. results: fifty-five total inpatient chemotherapy encounters were reviewed over months. eighteen of these encounters were considered to have been highly emetogenic chemotherapy (hec) with the remaining of these considered to be moderately emetogenic. only out of hec encounters completely included all guideline-recommended agents. there was a demonstrable lack of consistency across providers with dosing of aprepitant and most as needed medications. there was significant variation in order of first, second and third line anti-emetics ordered -with lorazepam and promethazine being used most frequently. with an aim of improving antiemetic prescribing practices for our patients, we are currently rebuilding chemotherapy treatment plans in our electronic medical record to incorporate antiemetic drug order sets that follow evidenced-based guidelines for variably emetogenic chemotherapy. this will be used in conjunction with an education initiative about best practices in supportive care for all prescribers of antiemetics. review of our department's recent inpatient chemotherapy encounters show we are falling short in following nationally recommended standards for appropriate antiemetic coverage during chemotherapy. identification of these deficiencies allows for implementation of quality initiatives to improve prescriber adherence to evidenced-based guidelines for better control of cinv. background: there are currently no consensus guidelines for the management of pediatric oncology patients presenting with fever without neutropenia. historically, these patients had been treated similarly to neutropenic patients with empiric antibiotics. while there has been a shift towards reducing unnecessary empiric treatment, there has been limited research into the outcomes associated with withholding empiric iv antibiotics in this patient population. we assessed the safety and efficacy of our institution's current protocol of observing well-appearing patients who present with fever without neutropenia and compared the outcomes of the patients who did and did not receive empiric iv antibiotics. design/method: this was a prospective, single-institution cohort study. patients were included if they were currently undergoing chemotherapy for an oncologic diagnosis and presented initially as an outpatient with fever and nonneutropenia (defined as anc ≥ cells/mm ). for each episode we recorded lab and blood culture results, signs and symptoms of initial presentation, and clinical outcomes, including antibiotic administration and hospital admission. results: a total of episodes of well-appearing patients with fever without neutropenia were identified. compliance with the institutional protocol was high; . % of patients were observed without receiving empiric iv antibiotics. the majority of patients were discharged home and there were no serious complications or infectious deaths. the incidence of positive blood cultures was low ( . % including several likely contaminants), despite the presence of central venous catheters in the majority ( . %) of patients. there were no significant differences in age, oncologic diagnosis, central s of s line access, anc value, or incidence of bacteremia between patients who did and did not receive empiric iv antibiotics. patients who were admitted to the hospital were significantly more likely to have received iv antibiotics (p < . ) despite documentation of a reassuring exam. however, admitted patients who initially received iv antibiotics were just as likely to discharge within hours compared to patients who were observed. we propose that empiric iv antibiotic administration in febrile, non-neutropenic, otherwise well-appearing patients is unnecessary. our study demonstrated no adverse consequences of observation and no significant differences in clinical outcomes between patients who did and did not receive iv antibiotics aside from rate of hospitalization. this supports the practice of observation without empiric antibiotics for such patients. background: children with hepatoblastoma (hb) undergo repetitive computed tomography (ct) scans to determine response to treatment and assess for relapse. this imaging exposes children to radiation, anesthesia, and imposes financial and emotional burden. objectives: review our institutional experience to determine if afp measurements are sufficient to assess response to treatment and detect relapse. we conducted a retrospective chart review of all patients diagnosed with hb at our institution between - . data collected included serum afp, total number and type of imaging studies during and post treatment, and how relapse or progressive disease was detected. results: thirty-one patients were diagnosed with afp positive hb. during therapy, ct scans were performed: to assess for response to therapy or surgical planning (average scans/patient) and due to concern for progression with rising afp. off therapy, surveillance ct scans were performed (average of . scans/patient) and ( %) included the chest in patients with no lung metastasis at diagnosis. relapsed patients averaged . surveillance scans, . of which were done before relapse was noted on imaging. there were no cases of radiographic evidence of relapse without a prior increase in afp. during treatment, response to therapy based on imaging correlated with a decline in afp in all patients, arguing that repetitive scans are not needed in this setting unless required for surgical planning. only of scans performed during off therapy surveillance displayed evidence of relapse, all of which were preceded by rise in afp. our study represents the largest cohort of hb patients. prior studies suggest similar results, but included fewer patients, lower stage of disease and less than years of surveillance monitoring. at our institution, the cost of a ct c/a/p is $ , with reimbursement varying from - %. in comparison, the cost of an afp measurement is $ . . many scans also require anesthesia and result in emotional toil for families concerned about this procedure as well as the results. thus, afp demonstrates greater sensitivity, with significant cost savings and decreased emotional burden, and should be used for monitoring both during and off therapy, replacing routine serial imaging. background: we observed that our practice of drawing daily blood cultures in hospitalized patients with fever and neutropenia was wasteful; it resulted in excessive negative cultures that did not add to patient care. the smart aim of this quality improvement project was to reduce the number of negative blood cultures drawn on hospitalized patients with fever and neutropenia by % in months. design/method: after reviewing published evidence suggesting drawing daily blood cultures in febrile neutropenic patients was unnecessary, a new blood culture guideline was implemented: cultures were drawn at presentation for fever with neutropenia and, if negative at hours, repeat cultures were not drawn except for clinical change, new fever after being afebrile > hours, or antimicrobials were being changed/broadened. to impact key drivers, we educated staff and changed blood culture order sets to require providers to select a reason for ordering the culture and to eliminate a nursing order to draw daily cultures with fever. we compared the number of blood cultures drawn per central linedays (/ -cld) and the proportion of positive versus negative cultures pre-guideline (july -may ) and postguideline (june -december ). we calculated the cost savings from reducing cultures. to assess patient safety, potential septic events without a corresponding positive blood culture were reviewed. data were analyzed by service (oncology and stem cell transplant). a chi-square test was used to compare rates. in stem cell transplant patients, pre vs. postguideline, there were vs. total cultures drawn/ -cld; vs. positive ( % decrease, p = . ) and vs. negative cultures/ -cld ( % decrease, p< . ). in oncology patients, pre vs. post-guideline, there were vs. total cultures drawn/ -cld; vs. positive ( % decrease, p = . ) and vs. negative cultures/ -cld ( % decrease, p< . ). the decreased positive culture rate among oncology patients may be due to decreased culture contaminants and/or the effect of a concurrent initiative to decrease clabsi in that group. there were safety concerns; however, chart review concluded that the guideline did not lead to missed infections in these patients. for the first months of the guideline, the total cost savings in blood cultures was $ , . . the implementation of our new blood culture guideline successfully led to a substantial reduction in the collection of negative cultures and a cost savings without compromising the detection of bacteremia in hospitalized pediatric patients with fever and neutropenia. background: there are various evidence-based guidelines for treatment of adult cancers, such as the nccn guidelines. previously, care was standardized for most new diagnosis pediatric cancer patients through enrollment on a clinical trial. with decreasing clinical trial availability and enrollment and few, if any, evidence-based guidelines for pediatric cancer, care standardization is challenging for pediatric cancers. objectives: to assess consistency of care, as determined by plan of treatment by diagnosis, for pediatric patients receiving chemotherapy for newly diagnosed cancer at a single center. design/method: patients with a new cancer diagnosis at a large, tertiary care pediatric oncology center in calendar year were identified through reports from the chemotherapy order entry (coe) system. reports included diagnosis (recorded through standardized options) and the plan of treatment. chart review was used to exclude patients who started treatment elsewhere and patients being treated for relapse, to clarify diagnosis if the standardized options in coe were unclear, and to clarify treatment plan if needed. data was entered and analyzed in a redcap database. specific diagnoses were clustered into higher level disease groups and the distribution of treatment plans for patients within each was determined. this project was deemed exempt from irb approval for human subject research as a qualifying quality improvement project. of the patients with a first chemotherapy order in , were excluded due to one or more reasons: stem cell transplant ( ), transfer of care ( ), relapse ( ), and other ( ). an additional patients were excluded because < patients/year/diagnosis. there was no cns tumor disease group with > patients. thus, patients with hematologic malignancies or non-cns solid tumors are the focus of this analysis. for patients with intermediate risk rhabdomyosarcoma, the plan of treatment was the standard arm of a cog protocol, arst for patients and arst for subsequent patient after protocol activation. for all other diseases including lymphoblastic leukemia/lymphoma (excluding infants), classical hodgkin lymphoma, aml (excluding trisomy and apml), stage iii/iv burkitt lymphoma/diffuse large b-cell lymphoma, posttransplant lymphoproliferative disease, wilms tumor, rhabdomyosarcoma, ewings sarcoma, osteosarcoma, neuroblastoma, and retinoblastoma, only one treatment plan per risk category was used. conclusion: this analysis demonstrates highly consistent chemotherapy treatment at a single center for patients with hematologic malignancies and non-cns solid tumors. next steps include exploring strategies to group diagnoses for cns tumors and assessing the quality of evidence supporting the treatments given. background: rapid initiation of empiric antibiotics in patients with fever and neutropenia has been shown to reduce morbidity and mortality. current practice guidelines call for the initiation of antibiotics in these patients within sixty minutes and time-to-antibiotic (tta) has been suggested as a quality-of-care measure. many institutions, including our own, face barriers to meeting this time limit. objectives: utilizing a quality improvement model, determine barriers and implement an intervention to reduce the time-to-antibiotics for pediatric febrile patients with suspected neutropenia who present to the emergency department (ed) at our institution. we have identified and implemented an intervention utilizing the plan-do-study-act model for quality improvement. a twelve-month retrospective review was conducted to evaluate the efficacy of the current practice algorithm at our large, academic tertiary-care hospital. subjects identified were pediatric oncology patients undergoing active chemotherapy who presented to the ed with febrile neutropenia. we identified two specific barriers, triage level assignments and delay in ordering antibiotics. to address these barriers, we have created a wallet sized "fever card" that patients were instructed to show upon arrive to the ed. in collaboration with the ed staff, efforts were also made to educate all pediatric staff on the use of the fever card. post-intervention data collection is currently underway and pre-and post-intervention antibiotic delivery times will be compared. the pre-intervention cohort consisted of thirty-three encounters with a mean time-to-antibiotic delivery of minutes, or seventy-five minutes greater than the accepted standard of care. only one patient received antibiotics within sixty minutes of arrival. post-intervention data collection is currently underway. since identifying two barriers to meeting the standard of care at our institution, we have implemented a quality improvement measure that empowers patient families to direct appropriate triage in the ed as well as simplifying the treatment protocol for ed providers. we expect to identify an improvement in time-to-antibiotics from the pre-intervention to the post-intervention period. background: sickle cell disease (scd) is a genetic disorder in which sickle hemoglobin (hbs) triggers multiple downstream effects, including red cell sickling, hemolysis, vaso-occlusion, and inflammation. scd, a lifelong disease initiated at birth with injury that accumulates over time, causes significant end-organ damage and clinical complications that are undertreated and associated with early death. homozygous mutation (hbss) causes the severe form of scd. individuals with scd are at increased risk of infection, stroke, and retinopathy. clinical guidelines for pediatric patients with scd recommend prophylactic penicillin use (ages - ), annual screening for stroke with transcranial doppler (tcd) imaging (ages - ), and annual ophthalmology exams to assess for retinopathy (ages ≥ ). there are limited real-world data on implementation of these nhlbi-based recommendations. objectives: to describe utilization of penicillin, tcd screening, and ophthalmology care in children with hbss disease. medicaid administrative claims databases were used to identify us patients aged - years at first indication of hbss recorded in each calendar year from to . patients were required to have medical and pharmacy benefits for the calendar year in which they were identified and for months prior to their first recorded hbss indication. prior year utilization of penicillin, tcds, and ophthalmologist visits was measured for each annual cohort. annual cohorts included - commercial (mean age . years, % female) and - medicaid (mean age . years, % female) patients with hbss disease. fewer than half of all patients had received a tcd scan in the previous year, with similar rates seen across all age groups for both payers. ophthalmologist visits increased as patients aged, and while patients aged - years had the highest proportion with an ophthalmologist visit in both payer populations, the overall implementation remained low. in contrast to the low use of tcd and ophthalmology visits, penicillin use was highest in the - year age group: > % use in any given year for both payers. conclusion: although our data demonstrated high penicillin use in the - year age group, consistent with guidelines there is an opportunity to improve implementation of other guidelines-based recommended screening. for example, tcd screening can identify children at risk of scd-related stroke in order to initiate preventive therapies. further research to understand potential barriers to proper screening and to evaluate strategies to improve awareness, adherence, and implementation of recommended screenings in children with scd is warranted. supported by global blood therapeutics. background: childhood cancer therapy has improved where there are many long-term survivors. while psychosocial difficulties in pediatric cancer survivors are recognized, the prevalence of these problems at initial survivorship presentation is unclear. objectives: to examine the prevalence of overall internalizing symptoms (e.g., depression/anxiety) in pediatric cancer survivors presenting to a survivorship clinic and to examine how this is mitigated by receiving psychological services and by evidence of parental depression/anxiety. design/method: pediatric cancer survivors attending their first visit at the reach for survivorship clinic at vanderbilt (ages - ) were included. survivors' parents ( % female) completed the child behavior checklist (cbcl), beck depression inventory-ii, and beck anxiety inventory. survivors > years completed a self-report. the wilcoxon rank-sum and pearson's test were used for univariate analyses. the effect size and % confidence intervals (ci) estimated from the multivariable linear regressions were reported. results: childhood cancer survivors a median of years old and . years off therapy were included. thirty one survivors ( %) showed at least borderline clinical internalizing problems (t score > ) on the cbcl, but only of these patients ( %) reported receiving psychological services. nine other survivors with normal t score ≤ also reported receiving psychological services. parental depressive and anxiety symptoms were correlated to the parental report of survivor overall internalizing symptoms (spearman = . , p = < . and = . , p = < . respectively), however they were not correlated to survivor selfreports. furthermore, parents with mild to severe depressive symptoms or mild to severe anxiety symptoms were more likely to rate their child as having higher overall internalizing symptoms (p = . ; p = . , respectively). multivariable linear regression showed that when adjusted for age, gender, cancer diagnosis and time off treatment, reported utilization of psychological services ( = . , % ci [ . , . ],p = . ), and parent depressive symptoms ( = . , [. , . ],p< . ) were significantly associated with child overall internalizing symptoms. in an otherwise identical alternate model substituting parental anxiety for parental depression, parental anxiety was also a significant risk factor ( = . , [. , . ], p< . ). alternatively, parent anxiety/depressive symptoms were not significantly associated with child self-report of internalizing symptoms. childhood cancer survivors have an elevated prevalence of experiencing internalizing symptoms but seldom report receiving psychological services. childhood cancer survivors' parents with anxious/depressed symptoms are more likely to rate their children as having more internalizing problems, compared to patient self-reports. ongoing longitudinal analyses will help clarify the best timing for potential interventions. background: life expectancy for adults with sickle cell disease (scd) has remained unchanged over the past years despite improvements in pediatric scd survival. at greatest risk are the adolescents and young adults (ayas) transitioning from pediatric to adult care. allen county ranks rd in scd incidence among the counties in indiana, and has board certified pediatric hematologist-oncologists. when children "age out" of the pediatric system, there are few providers knowledgeable about managing adults with scd in the region. a novel partnership between hematologists and the family medicine residency program in allen county was initiated to educate family medicine residents (fps) about scd, hydroxyurea (hu), and management of scd-related complications with the goal to increase the number of knowledgeable providers to care for adults with scd. to determine the effectiveness of online learning modules in educating fps about hu, best practices for aya scd care and transition. three online learning modules about scd (comprehensive care of ayas with scd, hu, best practices in aya transition) were developed and cme-accredited. electronic pre-and post-tests were distributed to fps with five questions for each module covering: contraception; screening tests; hu indications, dosing and monitoring; developmental milestones and scd knowledge assessments. the st vincent irb reviewed the protocol and granted a waiver of consent. results: twenty-six fps ( %) completed the pre-and posttests. over two-thirds correctly identified the clinical benefits of hu on both assessments. knowledge about the rationale for hu therapy increased after the completion of the hu module ( % correct on pre-test vs. % on post-test, p = . ). the proportion of correct responses increased for all comprehensive aya scd care post-test questions, but only the leading cause of death and the priapism-related questions reached statistical significance ( % vs. %, p = . ; % vs. %, p = . , respectively). the proportion of correct responses for of the transition-focused questions was unchanged ( % for both), while the proportion of correct post-test responses on the self-care assessment question significantly increased ( % vs. %, p = . ). after module completion, fps were able to correctly identify common scd complications and why hu is an effective treatment for individuals with scd. the best practices of transition clinic module may need modification to improve physician understanding of the intricacies in establishing and maintaining a scd transition clinic. overall, online training is effective at educating fps and could be used to increase the number of providers knowledgeable about scd care. background: survival rates for pediatric hodgkin lymphoma (hl) exceed % with contemporary therapy. studies of pediatric hl survivors treated in the s- s have shown increased risk for treatment-related chronic health conditions. risk-adapted therapy, including tailored radiotherapy, has been developed to reduce long-term morbidity while maintaining excellent survival. little is known about chronic conditions associated with contemporary therapy presenting during the first years from therapy completion (early outcomes). objectives: to analyze survival and early outcomes of pediatric hl patients treated with contemporary therapy. we conducted a retrospective review of hl patients diagnosed < years of age at our institution from - . three-year overall (os) and event-free (efs) survival were calculated with kaplan meier statistics using sas . . results of standardized screening for targeted toxicities that developed between - years from therapy completion were identified and graded per ctcae criteria. censoring occurred at date of death, years from therapy completion, or december , . data from the last collection point were used for prevalence calculations in cases with multiple evaluations. we identified patients ( % male; % non-hispanic white; mean age at diagnosis . ± . years) with a median time since therapy completion of . years (range . - . ). initial treatment included: ( %) chemotherapy only and ( %) multimodality treatment. all patients received anthracyclines (median dose mg/m ) and % received alkylating agents (median cyclophosphamide equivalent dose [ced] mg/m ). the -year os was % with an efs of % ( % chemotherapy only, % multimodality treatment; p = . ). patients with relapsed/refractory disease received salvage treatment including chemotherapy only (n = ), multimodality therapy (n = ), or multimodality treatment including stem cell transplant (autologous n = ; autologous+allogeneic n = ). no patients developed thyroid dysfunction, cardiac dysfunction, subsequent neoplasm, or male gonadal dysfunction during the study period. pulmonary dysfunction was limited to ctcae grade . anti-mullerian hormone (amh) below the normal range was found in / pubertal females who received ced ≥ mg/m compared to / females who received ced < mg/m . two of the females with low amh also had follicle stimulating hormone > iu/ml. this study is the first to evaluate early outcomes in pediatric hl survivors. the results indicate contemporary chemotherapy and a lower rate of radiotherapy utilization lead to excellent -year survival rates with minimal early toxicities. females exposed to ced ≥ mg/m are at increased risk for gonadal dysfunction and should be prioritized for fertility preservation approaches prior to initiation of cancer therapy. background: cancer is one of the leading disease-related causes of death among individuals aged < years in the united states. recent evaluations of national trends of pediatric cancer used data from before , or covered ≤ % of the us population. objectives: this study describes pediatric cancer incidence rates and trends by using the most recent and comprehensive cancer registry data available in the us. design/method: data from us cancer statistics were used to evaluate cancer incidence rates and trends among individuals aged < years during - . data were from states and covered % of the us population. we assessed trends by calculating average annual percent change (aapc) in rates using joinpoint regression. rates and trends were stratified by sex, age, race/ethnicity, us census region, county-based economic status, and county-based rural/urban classification, and cancer type, as grouped by the international classification of childhood cancer (iccc). we identified , cases of pediatric cancer during - . the overall cancer incidence rate was . per million; incidence rates were highest for leukemia ( . ), brain tumors ( . ), and lymphoma ( . ). rates were highest among males, aged - years, non-hispanic whites, the northeast us census region, the top % of counties by economic status, and metropolitan counties. the overall pediatric cancer incidence rate increased (aapc = . , % ci, . - . ) during - and contained no joinpoints. rates increased in each stratum of sex, age, race/ethnicity (except non-hispanic american indian/alaska native), region, economic status, and rural/urban classification. rates were stable for most individual cancer types, but increased for non-hodgkin lymphomas except burkitt lymphoma (iccc group ii(b), aapc = . , % ci, . - . ), central nervous system neoplasms (group iii, aapc = . , % ci, . - . ), renal tumors (group vi, aapc = . , % ci, . - . ), hepatic tumors (group vii, aapc = . , % ci, . - . ), and thyroid carcinomas (group xi(b), aapc = . , % ci, . - . ). rates of malignant melanoma decreased (group xi(d), aapc = - . , % ci, - . -- . ). this study documents increased rates of pediatric cancer during - , in each of the demographic variables examined. increased overall rates of hepatic cancer and decreased rates of melanoma are novel findings using data since . next steps in addressing changing rates could include investigation of diagnostic and reporting standards, host biologic factors, environmental exposures, or potential interventions for reducing cancer risk. increasing pediatric cancer incidence rates may necessitate changes related to treatment and survivorship care capacity. background: while childhood cancer treatment modalities have improved, the delayed effects of cancer treatment continue to compromise the quality of life in survivors. metabolic syndrome (ms) is diagnosed based on the presence of three of the following findings -obesity, dyslipidemia, hypertension and insulin resistance per the world health organization (who) criteria. the increased risk of ms among childhood cancer survivors was first reported in the 's and is known to increase the incidence of cardiovascular disease in these individuals. objectives: assess the frequency of ms in childhood cancer survivors at our institution. . we conducted a retrospective chart review on pediatric cancer survivors, - years of age, who had been treated at sri ramachandra medical institute and research foundation between august and august . patients who received at least one year of treatment with s of s chemotherapy and/or radiation and surgery were included. medical history, family history of diabetes, cardiovascular diseases, and hypercholesterolemia, tanner staging, weight for height (< y per who criteria), bmi (> y per indian academy of pediatrics iap), blood pressure (nhlbi criteria), fasting blood sugar levels and lipid profile were obtained from the charts. statistical analysis of the data was done using ibm spss statistical software (version ). results: patients were studied, . % were male. . % were under years of age, . % between - years and . % above years. leukemia survivors comprised . % of the sample and non-leukemic's were . %. . % were treated with chemotherapy alone, . % with radiotherapy and chemotherapy, and . % underwent surgery with radiotherapy and chemotherapy. hypertension was found in . % of the study group, dyslipidemia in %, impaired fasting blood glucose in . % and . % were found to be obese. % of the study group was diagnosed with ms based on who criteria. conclusion: % of our study population was found to have ms per who criteria. individual metabolic complications were detected in % of the population. acute lymphoblastic leukemia (all) survivors appeared to be at high risk in our population. ms has been known to increase cardiovascular complications in cancer survivors. a multidisciplinary team approach to management of these patients is important to closely monitor and manage the long-term complications related to ms such as type diabetes and atherosclerosis. such an approach is essential to decrease long term morbidity and mortality from ms in this vulnerable population. background: the -year survival rate for childhood cancer exceeds %. however, up to % of these children require admission to the pediatric intensive care unit (picu) within three years of diagnosis. these children account for approximately % of all picu deaths, with mortality being higher for those post-hematopoietic stem cell transplant (hsct). national guidelines recommend that providers share informa-tion regarding prognosis and treatment options within the first hours of icu admission. these prognostic goals of care conversations (pgocc) are critical to the care of children with malignancies, a subpopulation at risk for increased mortality. to determine the frequency of pgocc as well as describe differences in patient characteristics and critical care therapies by pgocc status. design/method: a retrospective cohort study was conducted using the university of michigan virtual picu system database. picu admissions lasting longer than hours for patients ages to years between july , and june , with an oncologic diagnosis and/or hsct were identified. data on pgocc, patient demographics, diagnoses, picu interventions, and outcomes were recorded and compared between children with pgocc and those without using chi square test for categorical variables and kruskal-wallis test for continuous data. of picu admissions, % were male; the mean age was . years. the leading diagnoses were acute lymphoblastic leukemia ( %), acute myeloid leukemia ( %), lymphoma ( %), neuroblastoma ( %), and brain tumors ( %), and % of patients were post-hsct. pgocc was documented in ( %) patients. in comparison with patients who did not have a pgocc, children with a pgocc were more likely to be readmitted to the picu ( % vs. %, p < . ) and more likely to have had relapse of disease ( % vs. %, p< . ). patients with a pgocc had higher severity of illness scores (p = . ), higher use of non-invasive ( . % vs. . %, p = . ) and invasive conventional ventilation ( . % vs. . %, p< . ), and high frequency ventilation ( . % vs. . %, p < . ). also, patients with pgocc were more likely to receive continuous renal replacement therapy ( . % vs. . %, p< . ), arterial catheterization ( . % vs. . %, p< . ), and cardiopulmonary resuscitation ( . % vs. . %, p< . ). in only in critically ill children with hematologic-oncologic disease is pgocc held. children with pgocc were sicker and received more critical care interventions. future research is needed to evaluate the content of pgocc. background: central nervous system (cns) tumors and autism spectrum disorder (asd) represent significant disease cohorts in the pediatric population. asd diagnoses in children have a prevalence of %, in every children in the united states. additionally, more than , cns tumors are reported in children age to years in the united states with brain tumors being the most common solid tumor and the leading cause of death among all childhood cancers. the genetic etiology of autism and cns tumors is complex. specific gene alterations present in certain cancers have similarly been described and suspected to play a role in asd subtypes. targeted therapy panels, like foundation one (fo), have been beneficial in guiding treatment for some cancers based on distinct gene alterations. given the genetic overlap, the potential for therapeutic benefit and crossover from such actionable gene target panels merit further exploration in asd and cns tumors. we aim to identify and describe genetic alterations with known actionable targets in cancer therapy from fo as potential diagnostic, therapeutic and research targets for neurodevelopmental diseases. we plan to discuss the common genetic alterations between our cancers and neurodevelopmental diseases described in the literature. fo data was extracted and compared to the literature. each reported gene alteration from fo plus the keywords "autism", "psych" were used on pubmed to search for a suspected association if any with a neurodevelopmental disorder. results: twenty-one patients representing a cohort of six unique (astrocytoma-five, ependymoma-six, gbm-four, glioma-three, nerve sheath tumor-one, etmr-two) cns tumors were investigated. fo produced eighty total with sixty unique gene alterations. thirty-one ( %) of these yielded at least one published, suspected association to a neurodevelopmental disorder. the most common gene alterations were tp -four, cdkn a/b-five and braf-four. the main functional categories were cellular: proliferation, structure, differentiation and degradation; chromatin modeling; histone transcriptional modification; dna methylation and repair; strna; and neural signaling. sixty unique gene alterations were found in our cns tumor set using foundation one. thirty-one ( %) of these discrete alterations paired with at least one description in the literature as having been similarly altered in an asd subtype. many of these alterations have actionable targeted therapies presented through foundation one for our cns tumors and may be a relevant guide in the future of targeted therapy and research in asd subtypes. monoclonal antibody therapy usage is associated with significantly improved survival in b-cell nhl aya patients. although the usage has increased in the aya population from to , the magnitude of the increase is low. factors that affect the use of mab include race and insurance s of s type. further research is warranted to identify why privately insured patients are less likely to receive these drugs. background: prevention of chemotherapy-induced nausea and vomiting (cinv) remains a challenge despite advances in pharmacotherapy and the development of cinv clinical practice guidelines by the pediatric oncology group of ontario (pogo) that have been endorsed by the children's oncology group. achieving control of cinv in pediatrics further is complicated by the difficulty young children have vocalizing their symptoms. use of a validated nausea-assessment tool in conjunction with improved adherence to evidence-based guidelines may result in better quantification of symptoms and reduction of both nausea severity and vomiting frequency for pediatric patients undergoing chemotherapy. the pediatric nausea assessment tool (penat) has been validated for children ages - , and its integration into clinical practice may help optimize cinv control. objectives: this single-institution study sought to improve control of cinv in patients admitted for chemotherapy by standardizing the antiemetic regimens prescribed by all providers according to an institutional cinv algorithm developed from the pogo guidelines. we hypothesized that treatment using a standardized guideline would improve cinv control in patients admitted for chemotherapy. a baseline cohort of admissions for chemotherapy completed penat assessments and cinv diaries prior to receiving chemotherapy, four times daily during each admission, and daily for days following completion of chemotherapy from may , to january , . providers then were provided an institutional cinv treatment algorithm based on the pogo guidelines and received education at departmental meetings on appropriate implementation of this algorithm. a second cohort of admissions completed penat assessments and cinv diaries in a similar fashion from july , to december , . results: complete control of vomiting markedly improved following cinv guideline implementation ( % vs %, p <. ) with treatment failure also significantly reduced ( % vs %, p <. ). after controlling for the degree of emetogenicity of chemotherapy received, a patient was . times more likely to vomit prior to guideline implementation (or . , ci . - . ). there was no difference in nausea control, even after adjusting for the emetogenicity of chemotherapy. conclusion: control of chemotherapy-induced vomiting (civ) improved following widespread implementation of an institutional cinv treatment algorithm at a single institution. the severity of nausea reported remained unchanged which may reflect the difficulty of assessing nausea or an inadequate sample size. future research may focus on cinv treatment management through the use of guidelines specifically for breakthrough cinv and delayed cinv. background: aspho's professional development committee (pdc) recognized pediatric hematologists-oncologists (phos) serving in the united states (us) military have unique professional development needs that may not be addressed by aspho or a similar professional society. these individuals may also encounter challenges when transitioning to a civilian career. however, barriers to professional development have not been systematically characterized. the objectives were to characterize the number of phos with current or prior military service (mphos) and to identify any unmet professional development needs. design/method: a working group consisting of pdc members and both senior and early career mphos was formed. initial comments were solicited by email from known mphos regarding potential gaps in professional development and interest in working with aspho to improve support of mphos. a survey was developed and piloted with four members of the advisory group, questions were revised based on their feedback, and a final version was distributed via the aspho website and online community forum. targeted emails were sent to mphos identified through aspho and military databases. eligibility to complete the survey included ) completion of a fellowship in pediatric hematologyoncology, and ) current or prior service as an active duty military provider. quantitative and qualitative information were collected, including demographic data and perceived barriers to professional development. responses were summarized using descriptive statistics. results: sixty-five mphos were identified and surveys were completed for a % response rate. respondents were engaged in a variety of professional activities; % were male, % were serving active duty commitments, and % felt there were professional development gaps. areas of concern were categorized into nine themes with the most concerning being ) limited civilian knowledge of mpho practices ( % of participants), ) inability to attend professional society meetings ( %), and possibility of deployment ( %). participants expressed a desire for educational products to meet their specific needs and for networking opportunities with civilian colleagues. qualitative analyses identified concerns about low patient numbers and practice size. a subset of mphos perceive significant gaps in professional development. additional research is needed to better define areas for intervention, but many of the concerns align with those of similarly sized civilian programs and may be addressed through professional society networking opportunities, such as an aspho special interest group. background: infertility is an established cause of distress and has a negative impact on quality of life among childhood cancer survivors. the american society of clinical oncology has established guidelines on fertility counseling for individuals of reproductive age diagnosed with cancer, with the goal of improving reproductive and psychosocial outcomes. studies have shown that instituting a fertility team that can provide counseling and discuss fertility preservation (fp) options results in improved patient satisfaction in patients with cancer. objectives: the goal of this study was to examine predictors of referrals to the multidisciplinary fertility team, and documented fp interventions among these patients. design/method: an irb-approved retrospective medical record review was performed at a large pediatric academic center. all patients with new cancer diagnoses receiving chemotherapy were included from january (when the fertility team was established) to present. a standardized abstraction form was used to collect information about: age at diagnosis, gender, cancer type, whether a fertility consult was placed, and documented fp interventions. data were summarized descriptively and comparisons were made using nonparametric statistical methods. results: patients met inclusion criteria, of which ( %) were male. cancer types were as follows: leukemia/lymphoma, cns tumors, sarcomas, embryonal tumors, and langerhan's cell histiocytosis (lch). the mean age was . years, (range < - years). overall, % of all patients had a consultation with the fertility team. patients were significantly less likely to have a fertility consult if they were younger (p< . ). further, there were differences in the consultation rate between diagnoses, with % of sarcoma patients completing a consult, compared to % of those with cns tumors, % of those with embryonal tumor, % of those with leukemia/lymphoma and none of the patients with lch. our findings show that many children, adolescents, and young adults newly diagnosed with cancer are still not receiving fertility counseling despite: ) an expanding body of literature supporting the need to provide this counseling, ) guidelines published by several organizations recommending discussions about infertility risk and fp options, and ) presence of a multidisciplinary fertility team. specific strategies need to be developed to improve access for younger children, and for disease groups in whom fertility consults are underutilized, such as youth with cns tumors, embryonal tumors, and leukemia/lymphoma. background: socioeconomic status (ses) has on impact on overall survival in the pediatric oncology population. unfortunately, data are insufficiently detailed to explain the mechanism behind this phenomenon. how parents handle the health management demands placed on them at the time of a child's cancer diagnosis may represent a point of differentiation in health outcomes. objectives: determine the association between socioeconomic factors, cancer literacy, and parents' understanding of home emergency management and their responses to instances of pain, nausea, and fever. in a prospective observational study of parents whose children were newly diagnosed with cancer, we obtained demographic information and, using a validated instrument, (dumenci, ) we evaluated cancer literacy. we tested understanding of the education parents received about home emergency management with a -item multiple-choice vignette-based questionnaire focused on actions needed in home scenarios. we then followed parents' actual behavior through periodic phone calls assessing instances of nausea, pain, and fever and their responses to these episodes. results: preliminary analysis of participants showed an average score of on the -item parental understanding questionnaire (range - ). variables associated with increased score were college-level education by . points ( % ci [. to . ]), private insurance by . points [. to . ] and adequate cancer literacy by . points [. to . ]. actual behavior reported by families indicated that married parents and those with income above $ , were less likely to treat instances of pain by % ( % ci [ to ]) and % [ . to ], respectively. white parents, those with college-level education, and those with adequate cancer literacy were less likely to treat instances of nausea by % [ to ], % [ to ] and % [ to ], respectively. no associations were found between socioeconomic markers and parental responses to instances of fever. our findings suggest an association between demographic and socioeconomic markers and improved parental understanding of home emergency management. paradoxically, the same markers show a decrease in treatment response to pain and nausea. larger prospective studies are needed to link this behavior pattern to health outcomes, and help inform the extent of ses impact on home emergency management. emory university/children's heathcare of atlanta, atlanta, georgia, united states background: cardiovascular disease is a leading cause of morbidity and mortality in childhood cancer survivors (ccs). previous research showed wide practice variation in referral patterns to cardiology from the survivor clinic and in recommendations from cardiologists about the need for further testing or exercise restrictions. to develop a cardio-oncology algorithm in order to standardize referrals to cardiology and provide guidelines for cardiologists evaluating pediatric ccs. design/method: survivorship and cardiology experts developed a weighted scoring system for pediatric ccs who received cardiotoxic therapy based on time since treatment and risk factors identified by the children's oncology group (cog) and american heart association (aha). the cardiooncology algorithm assigned a score of - . the score range was categorized to guide cardiology referral: screening echo only ( - ), consider cardiology referral ( - ), recommend cardiology referral ( - ), and regular cardiology follow-up (≥ ). the algorithm also provides recommendations to cardiologists for screening and exercise modifications based on the score. after establishment of the algorithm, a convenience sample of institutional survivor clinic patient charts were retrospectively reviewed from the first month of each quarter from april -march to validate the algorithm, evaluate referral patterns to cardiology, and assess cardiology recommendations. the retrospective chart review evaluated patients ( % male; % non-hispanic white; % leukemia survivors; median age at diagnosis . years [range - . ]; median time off-therapy . years [range . - . ]). patients ( %) received anthracyclines (median dose mg/m , range - ) and ( %) received cardiac radiation. assigned cardio-oncology scores resulted in: % echo only, % consider cardiology referral, % recommend cardiology referral, and % regular cardiology followup. when evaluating detection rates of late effects by cardiooncology score, survivors ( %) had an abnormal echo: / echo only, / consider referral, / recommend referral, and / regular cardiology follow-up. assessing referral patterns prior to initiation of the algorithm revealed forty-two survivors ( %) referred to cardiology: / echo only, / consider referral, / recommend referral, and / regular cardiology follow-up. of the patients seen by a cardiologist at our institution, had further diagnostic testing ordered (i.e., stress test) and received exercise restrictions. a cardio-oncology algorithm and guidelines will standardize cardiac care for survivors by assigning a score to guide referral and cardiology practice after referral. prospective clinical use has begun and review will occur in one year to determine changes in detection rates of cardiac late effects, referrals, and recommendations from cardiologists. oregon health and science university, portland, oregon, united states background: delirium affects - % of patients (pts) in pediatric intensive care units (picu) and is associated with increased length of stay, decreased attention in school, and post-traumatic stress disorder. the diagnostic and statistical manual of mental disorders (dsm v) defines delirium as a "disturbance of consciousness […] with reduced ability to focus, sustain or shift attention" due to an underlying medical condition. despite the medical complexity of the hospitalized pho population, there are no published prospective studies looking at delirium in these pts. hypothesizing that delirium is under recognized in the pho population, we designed a year-long prospective study using a validated screening tool to determine the frequency of delirium in hospitalized pho pts and to identify associated clinical factors. design/method: baseline frequency of pts with symptoms suggestive of delirium was determined through retrospective chart review using a data mining program of electronic medical records (emr). for the prospective study, pho and picu nurses were trained to use the cornell assessment for pediatric delirium and to record scores within the emr on all pho pts once every -hour shift. predetermined demographic and clinical variables were entered daily into a red-cap database on all hospitalized pho pts. results: baseline frequency of delirium, without active screening, was determined to be . % of hospitalized pho pts. in the first months of the prospective study, consecutive admissions occurred among unique pho pts: oncology, hematology, and stem cell transplant pts. pts had at least positive delirium screen, for a prevalence per admission of . %. statistically significant variables associated with delirium, at p < . by univariate logistical regression, included prolonged length of stay, pt location (picu vs pho unit), and fever. adjusting for length of stay, administration of benzodiazepines and opiates were also significantly associated with delirium, p = . and . , respectively. on average, nurses completed delirium screening in % of each pts' -hour shifts. study accrual ends in jan and final data analyses will be reported in the abstract presentation. conclusion: delirium does occur in the pho hospitalized population and screening by trained nursing staff is feasible. pts at highest risk appear to be pts with prolonged hospital stays, picu admissions, or frequent use of benzodiazepines/opioids. routine screening should improve our recognition of delirium and allow us to promptly intervene, or prevent delirium in an effort to avoid potential acute and long term consequences. background: with high survival rates for children and adolescents with hodgkin lymphoma (hl), treatment regimens are now designed to maximize cure while decreasing risk of long-term health outcomes associated with chemotherapy and radiation therapy. within contemporary treatment regimens, the comparison of toxicities experienced by patients receiving chemotherapy plus radiotherapy (crt) versus only chemotherapy (co) has not been studied extensively. objectives: this study examines select self-reported adverse health outcomes in survivors of contemporarily-treated pediatric hl to better understand the balance between efficacy and toxicity associated with chemotherapy and radiation therapy. (cog) ahod that evaluated a response-based treatment paradigm in pediatric hl. patient who received initial chemotherapy were randomized based on early response to continued chemotherapy, chemotherapy plus radiotherapy or augmented chemotherapy plus radiotherapy. patients completed self-report questionnaires on health problems at , , , and years following therapy. we examined selected patient-reported pulmonary, gastrointestinal (gi), cardiac and endocrine outcomes. kaplan-meier survival curves were used to determine probability of survival without the selected adverse health outcome. log-rank tests were used to compare the co versus the crt group. results: a total of , enrolled patients, patients in the co group and patients in the crt group, completed , questionnaires at a median of . years after s of s completion of therapy (q , q : . , . ) which were analyzed. the cumulative -year incidence of endocrine dysfunction was significantly greater in the crt group versus those in the co group ( % versus %; p< . ), driven by the incidence of hypothyroidism ( % versus %; p< . ). there were no significant differences in cardiac ( % versus %; p = . ), pulmonary ( % versus % p = . ), and gastrointestinal dysfunction ( % versus %; p = . ) between the co and crt patients. conclusion: this study demonstrates low cumulative incidence overall of organ dysfunction early post completion of contemporary therapy for hl. the addition of radiation therapy significantly increased risk for hypothyroidism, but with no higher risk noted for cardiac, pulmonary or gi dysfunction. limitations include self-report status, potential selection bias, and relatively short latency period following end of therapy. longer follow-up is needed to determine more delayed risks for organ dysfunction in order to best define the balance between therapeutic efficacy and long-term adverse health outcomes related to chemotherapy and/or radiation therapy. background: identification of an organism via bronchoalveolar lavage (bal) or respiratory tract biopsy (rtb) has historically been considered the gold standard for diagnosis of invasive fungal infection (ifi); however, data previously published by our group showed that these procedures infrequently lead to a change in management in children with an oncological diagnosis or undergoing hematopoietic stem cell transplant (hsct). there is also a paucity of data on the cost of ifi in this population. to compare the costs of work-up and management of pulmonary ifi diagnosed based on ct scan alone versus ct scan or chest x-ray prompting a bal or rtb. design/method: we collected cost data on patients at ann & robert h. lurie children's hospital of chicago undergoing chemotherapy or within months of hsct who were suspected of having an ifi between and . in order to include sufficient time to account for post-procedure compli-cations but avoid including costs unrelated to ifi, data were included for days from the day of their diagnostic scan or procedure. cost data was available for of the patients previously studied. thirty-six of these patients were diagnosed with suspected ifi based on ct only and patients underwent bal or rtb. when evaluating specific costs, inpatient beds costs were higher in the bal and rtb group (median $ , versus $ , , p = . ), yet there was only a trend towards higher costs for antifungal agents (median $ , versus $ , , p = . ) and respiratory support (median $ versus $ , p = . ). many of the initial ct scans were not captured in the -day evaluation period for the bal or rtb group based on the study design; however, even when accounting for ct scans up to a week prior these procedures, the total cost of ct scans was higher in the ct only group (median $ versus $ , p = . ), as they had more scans. despite this, total costs were significantly higher for patients who underwent bal or rtb versus ct scan only (median $ , versus $ , , p < . ). combined with our previous data that bal and rtb infrequently leads to a change in management in children with an oncological diagnosis or undergoing hsct suspected to have an ifi, the significantly higher costs associated with these procedures makes these invasive diagnostic techniques even less desirable. batra, pediatr blood cancer, . background: while infants > months of age with acute lymphoblastic leukemia (all) have a poor prognosis, infants with acute myeloid leukemia (aml) fare better despite more intensive therapy. there are limited data on this difference, particularly differences in supportive care requirements during induction therapy for infants. objectives: to compare induction mortality and resource utilization in infants relative to non-infants aged < years, separately for all and aml. design/method: we used previously established cohorts of children treated for new onset all or aml at children's hospitals in the us contributing to the pediatric health information system. patients with down syndrome were excluded. follow-up started on the first day of induction chemotherapy and continued until the earliest of: days after commencement of chemotherapy, start of the subsequent course, or death. high acuity of presentation, defined as icu requirements involving or more organ systems within the first hours following initial admission were compared using log binomial regression. -day inpatient mortality was compared using cox regression. resource utilization rates (days of use per inpatient days) were compared using poisson regression. results: a total of all ( infants, non-infants) and aml ( infants, non-infants) were included in the analyses. infants were more likely to present with high acuity compared to non-infants for both all ( % and %, rr = . , % ci: . , . ; p< . ) and aml ( % vs %; rr = . , % ci: . , . ; p = . ). infants with all had higher inpatient mortality compared to non-infants even after accounting for differences in acuity of presentation ( . % vs . %, adjusted hr = . % ci: . , . ; p = . ). in contrast, inpatient mortality was more similar for infants and noninfants with aml ( . % vs . %, adjusted hr = . % ci: . , . ; p = . ) and comparable to rates among infants with all. infants with all and aml had higher rates of utilization of fresh frozen plasma, cryoprecipitate, diuretics, supplemental oxygen, and ventilation relative to non-infants. infants with all also had higher rates of total parenteral nutrition, ecmo, and patient controlled analgesics compared to noninfants. infants with all experienced significantly higher induction mortality compared to noninfants, a difference not entirely explained by acuity at presentation. differences in ru among infants may reflect higher presentation acuity and greater treatment related toxicity. further work is needed to elucidate the contribution of treatment related toxicity to early mortality in infants with all. background: fever in a child with cancer is a medical emergency due to the significant risk of a serious bacterial infection. many attempts have been made to risk stratify these patients. the respiratory pathogen panel (rpp) is a panel of polymerase chain reaction tests that identify seventeen common respiratory viruses and three bacterial infections. samples are taken via nasopharyngeal swab. rpps are frequently sent, but we do not have data to determine whether a positive result can lead to stratification to a lower risk of bacterial infection. ( ) to determine the epidemiology of respiratory virus-associated fever in pediatric oncology patients ( ) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all pediatric oncology patients seen in our emergency department (ed) with fever from the introduction of the rpp in april to september , . we reviewed the results of blood cultures, rpp, chest radiographs, and discharge summaries to identify sources of infection. we also identified the patients' cancer diagnosis, age, absolute neutrophil count (anc), and absolute lymphocyte count (alc). results: positive rpps were found among pediatric oncology patients who presented to the ed with fever. the most common positive rpp findings were rhinovirus/enterovirus (rev) ( %), parainfluenza ( %), influenza ( %), coronavirus ( %), and polyviral ( %). among patients with a positive rpp, % had bacteremia compared to % bacteremia among all pediatric oncology patients with fever (or . [ . - . ], p . ). all cases of bacteremia were associated with rev. there was no bacteremia identified in patients with rpps positive for other viruses (or . [ . - . ], p . ). rev positivity did not confer a lower risk of bacteremia than rpp negative patients ], p . ). anc (p = . ) and alc (p = . ) less than , and number of patients with severe neutropenia (p = . ) were not statistically different between the rev and non-rev positive rpp groups. rpps positive for viruses other than rev reduced the likelihood of bacteremia in febrile pediatric oncology patients in the ed setting. patients with bacteremia may have concurrent infection with rev. a larger study is warranted to determine if positive rpp results can inform clinical management of a child with febrile neutropenia. emily mueller, anneli cochrane, seethal jacob, aaron carroll s of s background: the usage of mobile health (mhealth), which refers to the application of mobile or wireless communication technologies to health and healthcare, has grown exponentially in recent years. mhealth tools have been used by caregivers of other vulnerable populations, but little has been focused on caregivers of children with cancer. objectives: to conduct a survey to understand the mobile technology usage, barriers, and desired mhealth tools by caregivers of children with cancer. we conducted a mailed cross-sectional paper survey of caregivers of all children who were diagnosed with cancer at riley hospital for children between june, and june, . the survey contained questions, both fixed and open-ended, in both english and spanish. up to three rounds of surveys were sent to those who did not respond. of the respondents, they were primarily parents ( . %), median age was . years (range - ), and most were white ( . %) and non-hispanic/latino ( . %). the top three annual household income brackets included $ , to $ , ( . %), $ , to $ , ( . %) and under $ , ( . %). the majority had an education: . % college graduates, % graduate degree, and . % high school education or ged. nearly all respondents owned a smart phone ( . %) and . % owned a tablet. the majority used an ios operating system ( . %), while . % reported use of a device with an android operating system. all caregivers reported use of at least one mobile website/app regularly for their personal use. while . % of respondents reported no barriers to mobile technology use, the top barrier selected was "data limitations" ( . %). overall, . % wanted at least one medical managementrelated website/app: medical knowledge ( . %), healthcare symptom tracking/management ( . %), and medication reminders ( %). healthcare system-related desires were high, as . % wanted access to their child's medical record and . % wanted a website/app to facilitate better communication with medical providers. there were no significant associations between socioeconomic status (income or education) with barriers or types of websites/apps desired by caregivers. since the vast majority of caregivers use mobile technology with minimal barriers, future research should focus on designing an mhealth tool to address the medical management needs by caregivers of children with cancer. by supporting caregivers through this type of mhealth tool, it could positively impact patient clinical outcomes through greater adherence to medications and treatment protocols. background: in children with fever and neutropenia, early initiation of targeted antibiotic therapy improves outcomes, yet there are no standards for choice of empiric antibiotics. in our institution implemented an early empiric ceftriaxone (eec) protocol to reduce time to antibiotic administration in febrile hematology-oncology patients who are potentially neutropenic when the absolute neutrophil count is not yet know. ceftriaxone is given immediately after obtaining blood for culture and lab studies. in patients found to be neutropenic, ceftriaxone is discontinued and cefepime is initiated. the purpose of this retrospective study was to evaluate our eec protocol in neutropenic patients by assessing ceftriaxone sensitivity of positive blood cultures and comparing rates of adverse outcomes with a cohort of patients treated prior to implementation of the protocol. we are now conducting a prospective study to more thoroughly investigate antibiotic sensitivities of organisms isolated from blood cultures of neutropenic patients. design/method: hematology-oncology patients with at least one positive blood culture between january and december were identified. patient demographics, neutrophil count, antibiotic treatment, isolated organisms and sensitivities, and adverse outcomes (increased respiratory support, hypotension requiring intervention, and icu admission) were obtained by retrospective chart review. fisher exact test was used to compare dichotomous variables between patient groups. we are now prospectively identifying febrile neutropenic patients with positive blood cultures and performing antibiotic sensitivity testing to several antibiotics commonly used as empiric therapy for febrile neutropenia. results: retrospectively, we identified neutropenic patients with a total of bacterial isolates from blood cultures. of organisms isolated, were tested for sensitivity to ceftriaxone and ( %) were not sensitive, / ( %) of gram-positive cultures and / ( %) of gram-negative cultures. ten of ( %) eec patients had an adverse outcome versus / ( %) of non-eec patients (p = . ). notably, % of eec patients required icu admission versus % of non-eec patients (p = . ). thus far our data obtained prospectively is revealing similar rates of ceftriaxone resistance with / cultures not sensitive to ceftriaxone ( %, ci . %- . %). in our retrospective study, no statistically significant difference was seen in overall adverse outcome rate between the two cohorts, though icu admission rates were significantly higher in eec patients. ceftriaxone resistance rates were high in tested isolates, which is further supported by preliminary data from our ongoing prospective study. given these data, eec may not be effective at improving outcomes in febrile neutropenic pediatric hematology-oncology patients. background: approximately in children diagnosed with cancer will die of their disease, despite advances in treatment. results: two focus groups of six parents each met in june . the parents were predominantly female ( female, male) and had lost their children an average of . years prior (range - . years). two parents were in the same family. nearly all patients were offered palliative care ( / ), all were offered hospice and most died at home ( at home, in the icu). parent discussion uncovered six broad themes: beneficial provider qualities, optimal communication, helpful systematic supports, struggles to feel like a good parent, struggles with a loss of control and unmet needs. parents appreciated providers who were consistent, reliable and honest. parents desired communication that was sensitive to the needs of the patient and family with a balance of hope and realism. parents appreciated the tangible supports pro-vided by social work and the emotional support of child life both for the patient and their siblings. some parents struggled to define and advocate for their child's quality of life, especially when it led to disagreeing with the medical team. several parents expressed frustration with unfamiliar caregivers in the hospital, especially trainees. they expressed a strong desire for more anticipatory guidance about the end of life including how to discuss it with their children. they also wished for a cancer-specific support group for bereaved parents. conclusion: bereaved parents of pediatric oncology patients in our focus groups appreciated consistent, reliable providers who communicated with a balance of realism and hope. they appreciated the tangible and emotional support they received and wanted more anticipatory guidance at the end of their child's life. these results can help guide clinical care, especially in communities without strong palliative care support. further research is needed to develop interventions to improve end of life care. background: clinical trials involving human subjects depend on informed consent (ic) to ensure ethical protections for participants. parents of children with cancer often lack full understanding of the basic elements of ic for clinical trials. additionally, the stress of their child's cancer diagnosis may affect their decision-making capabilities. this is especially problematic as these children rely on parents to fully comprehend clinical trials and weigh their benefits and risks. physician communication is critical for effective family-centered care. the acgme mandates that training programs teach and assess trainees' communication skills. however, there are currently no published curricula aimed at training pediatric hematology/oncology fellows to deliver ic effectively for cancer clinical trials. to develop and pilot-test a simulation-based curriculum to enhance communication skills of pediatric s of s hematology/oncology fellows in the delivery of ic for cancer clinical trials. we developed, tested, and implemented the curriculum from to in two phases. in phase- , we reviewed literature on simulation-based curricula and completed a needs assessment to create a clinical scenario and full curriculum using standardized patients. using miller's pyramid model, fellows' assessments included: immediate de-brief, surveys to assess pre/post confidence and knowledge of the basic ic elements ("knows" and "knows how"), and -degree summative assessments compiled from fellow self-assessments, faculty, and standardized patients ("shows how"). after initial testing and refinements done with fellow, in phase- , we implemented the curriculum with our fellows. likert scale ( strongly disagree- strongly agree) and basic p values are reported. results: fellows gave high mean ratings for training relevance ( . ) and standardized patients' preparedness ( ). almost all ( . ) reported they have used the knowledge gained in their clinical practice. increase in self-reported confidence (pre/post) was noted in all domains: general -describing possible benefits of the clinical trial . / vs. . / (p = . ), risks and potential side effects . / vs. . / (p = . ), and explaining alternatives . / vs. . / (p = . ); research -discussing purpose of the clinical trial . / vs. . / (p = . ), and randomization . / vs. . / (p = . ); and family-centered -addressing emotions during ic . / vs. . / (p = . ), and delivering bad news . / vs. . / (p = . ). summative evaluation mean ratings for all fellows were . (range . - . ). our novel simulated-based ic curriculum, significantly increased fellows' self-reported confidence and skills during ic delivery. importantly, our ic curriculum addressed not just research-related content but also management of parental emotional needs during the ic discussion. next phase includes kirkpatrick model program evaluation and dissemination across other training programs in our institution. national kaohsiung normal university, kaohsiung, taiwan, province of china background: taiwan's childhood cancer foundation reported in that the -year survival rate of childhood cancer was %. as a result, many childhood cancer survivors were back in school after treatment. however, childhood cancer survivors' educational outcomes suffered because of their long-term absence from school and late effects of cancer and cancer treatment. a few school reentry protocols have been developed by the nursing professionals in taiwan to facilitate students' return to school but remained experimental in nature and hardly accessible. parents, students, and teachers were left to their own devices to make individual school reentry plans. objectives: this study aimed to examine and uncover the commonalities among three middle school students' successful school reentry experiences from their teachers' perspectives and to analyze the factors contributing to their success. design/method: this is a qualitative interview study. indepth semi-structured interviews were conducted with three middle school teachers in december about their perceptions, observations, and experiences working with adolescent childhood cancer survivors. the students were two boys with leukemia and one girl with bone cancer. they were diagnosed in the first year of middle school when they were - years old and returned to school for the third and the final year. these students met the following criteria for successful school reentry: regular school attendance, average/above average academic performance, friendship maintenance, and high school diploma. the theme -bring the class to the hospital was found to be the key to the adolescents' successful return to school. without a prescribed school reentry protocol and in the face of limited bedside education services, the homeroom teachers, as links between school, home, and hospital, brought the class to their hospitalized students. they doubled as bedside teachers conducting lessons at the hospital or students' homes, became friends with the parents, witnessed firsthand the students' pain and triumph during treatment, brought the students back to school for visits and celebrations, delivered the classmates' wishes and news to the students, encouraged and welcomed classmates' visits to the hospital, and, together with parents and other teachers, developed flexible school reentry schedules for the students. this on-going study demonstrated the critical roles and functions of homeroom teachers in successfully bringing the students back to school during and/or after cancer treatment. further analysis will be focused on how and why these three homeroom teachers were able to carry out this unexpected task on top of their already full workload. jennifer kesselheim, shicheng weng, victoria allen, collaborative group fellowship program directors dana-farber/boston children's cancer and blood disorders center, boston, massachusetts, united states background: a novel, -module, case-based curriculum entitled "humanism and professionalism for pediatric hematology-oncology" (hp-pho) aims to foster pho fellows' reflection on grief and loss, competing demands of fellowship, difficult relationships with patients and families, and physician well-being and burnout. in small group facilitated sessions, fellows work to identify coping strategies and explore how the challenges of fellowship influence both their own doctoring and the patient experience. objectives: to administer the hp-pho curriculum in a prospective, cluster-randomized trial, measuring whether exposure to this educational intervention, compared to standard conditions, fosters humanism and professionalism and improves satisfaction with training. design/method: pho fellowship programs (n = ) were cluster-randomized to deliver usual training in humanism and professionalism (control) or the novel curriculum (intervention) during the - academic year. the primary outcome measure was the pediatric hematology-oncology self-assessment in humanism (phosah). secondary measures included a -point satisfaction scale, the maslach burnout inventory (mbi), the patient-provider orientation scale, and the empowerment at work scale. participating fellows were pre-tested in summer and post-tested in spring . a change score was calculated for each study instrument. we compared each outcome between arms using mixed effect models adjusted for pre-test score as a fixed effect and site as a random effect. results: randomization yielded intervention and control fellows. the two arms did not significantly differ in distribution of fellow age, gender, or post-graduate year. the intervention sites successfully administered of ( %) modules. change scores on the phosah were not significantly different between the control and intervention arms (adjusted mean difference = . ; % confidence interval [ci] - . , . ; p = . ). compared to the control arm, fellows' exposed to the curriculum gave significantly higher ratings on several items within the satisfaction scale including satisfaction with their training on "physician burnout" (adjusted mean difference = . ; % ci . , . ; p< . ), "physician depression" (adjusted mean difference = . ; % ci . , . ; p< . ), "balancing professional duties and personal life" (adjusted mean difference = . ; % ci . , . ; p = . ), and "humanism overall" (adjusted mean difference = . ; % ci . , . ; p = . ). change scores on other secondary measures were not significantly different between study arms. conclusion: exposure to the hp-pho curriculum did not alter fellows' self-assessed humanism and professionalism. however, the curriculum proved feasible to administer and intervention fellows expressed higher levels of satisfaction in their humanism training, indicating the curriculum's positive impact both for fellows and their learning environment. background: recent work has documented significant levels of unmet needs among adolescents and young adults with cancer, particularly psychosocial challenges during the transition to adulthood, (e.g., abrupt disruption to school and social life, and social isolation). given that adolescents and young adults drive mobile app use, a mobile-phone may be an ideal way to deliver a psychosocial intervention to adolescents and young adults with cancer. to use a patient-centered approach to inform a mobile-based mindfulness and social support intervention for adolescent and young adult patients with cancer. design/method: participants were ten aya with sarcoma ( % female; % adolescents); parents of the five adolescents, and six healthcare providers (n = ). formative research involved three steps: ( ) in-depth interviews were conducted with ten aya with sarcoma; parents of the five adolescents, and six healthcare providers (n = ). ( ) adaptations were made to an existing mindfulness app which offers a program for youth. modifications included creating a -week "mindfulness for resilience in illness" program, with relaxation exercises, and the addition of videos featuring two sarcoma survivors as program hosts. content was informed by the mindfulness curriculum for adolescents, learning to breathe. ( ) a private facebook usability group was organized to (i) elicit beliefs about the mindfulness app and potential future enhancements, and (ii) promote social support. results of the in-depth interviews revealed themes around adolescents' functioning and coping, including body image concerns; recurrence-related anxiety; anger over loss; and being overwhelmed by medical information. themes from the interviews were incorporated into a demonstration version of the mobile app. a patient-centered approach is widely recommended in the development of mobile-based health behavior change interventions and may be a useful way to inform development of a mobile-based mindfulness and social support intervention for adolescents and young adults with cancer. background: medical trainees consistently report suboptimal instruction and poor self-confidence in communication skills. despite these deficits, few training programs provide comprehensive pediatric-specific communication education, particularly in the provision of "bad news." an in-depth survey to examine the historical experience and communication needs of pediatric fellows was conducted at a large academic pediatric center as the first step towards the development of a comprehensive communication curriculum. to determine the previous educational and clinical experiences of pediatric subspecialty fellows, assess their levels of comfort in the context of various communication topics, and query potential modalities and topics for future communication training. design/method: the needs assessment survey was developed using previously developed and validated questions and review of the literature. the survey was reviewed by internal and external pediatric oncology and palliative experts and pre-tested with a subset of trainees to enhance content validity. results: thirty-two out of a total of fellows completed the survey ( % completion rate), of which % were pediatric hematology-oncology or subspecialty fellows. most fellows had participated in previous teaching sessions ( %), including those involving role play or simulation ( %). however, few fellows had received feedback from senior clinicians on their communication skills ( % of fellows had received feedback ≤ times). on a scale of -x, with indicating "not well prepared," the mean score for of communication items was < . fellows felt least prepared to lead discussions around informed consent for experimental therapies, end of life care, and autopsy. fellows indicated that didactic educational sessions and additional coursework were less useful strategies for improving their communication skills, whereas small group role play sessions with faculty and/or bereaved parent educators were most useful. fellows' overall communication preparedness score was not correlated with post-graduate year but was positively associated with the number of times they previously had delivered bad news to patients and families. fellows requested additional training on many topics, with greatest interest in learning skills to optimize communication with an angry patient or family. additional topic requests included placing limitations on resuscitation, withdrawing/withholding further therapy, and ageappropriate inclusion of patients in difficult discussions. despite self-report of prior communication skills training, pediatric subspecialty fellows felt underprepared to participate in difficult discussions with patients and families. learners identified role-playing and coaching with real-time feedback from other physicians and bereaved parents as more useful training strategies as compared to didactic sessions. background: when children die of cancer, parents must adjust to their child's absence amidst the lingering turmoil of what preceded their death: witnessing their child undergo painful treatments, making difficult decisions, and anticipating a devastating loss, all the while hoping for a recovery. adjustment to a child's death, as depicted by current bereavement literature, necessitates making meaning of one's loss. professional care staff can help parents make sense of their child's illness, and in turn, of their own parental experience during treatment. however, the extent to which relationships with professional care team members influence parents' ability to make sense of, and successfully cope with, their loss has not been examined. objectives: to examine how bereaved parents' interactions with their deceased child's pediatric oncology professional care team have impacted their grief symptoms design/method: to better understand how interactions with professional care staff relate to parents' grief outcomes, we conducted a mixed-methods study examining staff impact on parental grief. thirty participants whose children died of cancer one to three years ago completed an in-depth interview and psychometrically validated surveys measuring meaningmaking, depression, and grief symptoms. results: correlational analyses of the measures found that an increase in meaning making was associated with lower depressive and grief symptoms. a content analysis of the interviews found that many participants regarded staff "like family," had on-going relationships with staff after their child died, and described various ways staff interactions during treatment and after the child's death helped them make sense of their loss. in particular, participants described how interactions with staff have helped them find benefits in their loss and learn to create a new relationship with their child despite their physical absence. quantifying the interview data and statistically analyzing it along with the measures found that participants' increased frequency of describing staff's positive impact on their grief correlated with higher meaning-making scores and lower grief symptom scores. our study found that bereaved parents who lost their children to cancer were articulate in sharing their experiences of staff engagement and communication during treatment, offering numerous examples of how staff aided them in making meaning of their loss that were reliably associated with their subsequent grief. we hope the results of this mixed methods research encourage further study of the importance of staff interaction with families during the critical period of their children's care, and the lasting impact this can have regardless of the treatment outcome. memorial sloan kettering cancer center, new york, new york, united states background: although resiliency has been recognized as necessary for healthcare professionals, trainees feel unprepared for the emotional challenges inherent in caring for sick and dying patients. compounded by long hours, challenging work environments, and lack of formal training on handling emotionally difficult situations, many institutions are recognizing the need for interventions to reduce trainee distress. the goals of this fellow-led quality improvement initiative were: ) to determine whether there is a need for emotional support amongst pediatric hematology and oncology fellows, ) to provide formal resiliency and debriefing sessions, and ) to measure feasibility, acceptability and effectiveness of implemented curriculum. design/method: an anonymous survey to determine need for resiliency and debriefing sessions following a traumatic event was distributed to active pediatric hematology & oncology fellows at memorial sloan kettering cancer center in january . once need was established, an intervention consisting of a formal curriculum was developed and initiated in june , involving: ) scheduled and ad hoc debriefing sessions in response to traumatic events (including patient death, codes, interpersonal conflicts, end-of-life care); led by a psychiatrist and social worker with fellows and a pediatric oncologist mentor in attendance, and ) a resiliency didactic curriculum, led by a palliative medicine specialist, focused on skills such as contesting cognitive distortions and mindfulness. the effectiveness of these sessions will be measured using follow-up anonymous surveys at months (currently underway) and months post-initiation of intervention. the initial survey demonstrated most trainees ( / ) were present at or more deaths during their training, while less than half of respondents had attended a post-event debriefing session. % of respondents felt there was not sufficient emotional support from the institution for physicians caring for dying patients. a separate pre-intervention survey found all respondents ( / ) expressed a need for regular debriefings, and nearly all anticipated that they would benefit from such debriefings. concerns identified by trainees that would preclude participation in the curriculum included preference to deal with emotional situations privately and time constraints. trainees identified a need for formal debriefings and resiliency skill development. the program was easily implemented, and is both feasible and acceptable with good attendance. feedback received at the -month mark will determine deficits and possible improvements to the curriculum. the -month survey will measure effectiveness of the program and whether it should be continued. background: acute kidney injury (aki) is a common but under-recognized complication among patients with leukemia. it is associated with prolonged hospital stays, increased mortality, progression to chronic kidney disease, and delays or changes in cancer therapy which may affect a patient's prognosis. however, data on aki in pediatric patients with cancer is still lacking overall. we investigated the incidence of aki in patients who were newly diagnosed with all at our center from january to september . we performed a retrospective chart review of all patients who were newly diagnosed with all from neonate to years in our facility. we determined the incidence of aki in our population using the kidney disease: improving global outcomes (kdigo) diagnostic criteria. we also assessed for nephrotoxic exposures, nci all risk stratification and risk of aki, and tumor lysis syndrome (tls). we identified patients diagnosed during the study period who met inclusion criteria. median follow-up time was . months (range . - . ). the cohort was predominantly male ( . %) and hispanic ( . %). our analysis showed . % had aki by kdigo criteria ( % grade , . % grade , and % grade ), . % had aki on presentation, and % had multiple aki episodes during the study period. older age and longer length of hospitalization were associated with aki (p = . and p = . , respectively). there was no association between aki and nci all risk classification, contrast exposure, hyponatremia, elevated white blood cell count, uric acid levels, antimicrobial therapy, or diuretic use in this study. conclusion: aki was a common finding in our study population. the majority had grade aki by kdigo criteria. however, aki was associated with older age and a longer length of stay. further study is needed to determine the short-and long-term impact of aki on pediatric patients with all. st. jude children's research hospital, memphis, tennessee, united states background: in some regions, the availability of trained pediatric oncologists is a limiting barrier for the care of children with cancer. in , the unidad nacional de oncología pediátrica (unop) and the universidad francisco marroquín school of medicine in guatemala established a pediatric hematology/oncology fellowship program sponsored by st jude children's research hospital to provide central america and the caribbean with well-trained specialists. a systematic analysis of the impact of fellowship programs in pediatric oncology has never been done, especially in the context of a regional education program. objectives: this study sought to analyze the impact of the unop fellowship program based on the regional number of providers, pediatric cancer centers and patient volume. in addition, it sought to characterize the jobs and scientific output of the graduates. the impact will be evaluated in the context of a cost analysis. to define the volume of providers, pediatric cancer centers and patients, the directors of pediatric cancer centers in central america were sent an online survey to obtain these data. all the centers contacted maintain an updated hospital-based patient registry. in addition, the graduates of the fellowship program were also sent an online survey, asking about their job at graduation, current role and scientific productivity. the cost analysis will include assessment of direct costs including salaries and stipends for away rotations, as well as the indirect costs of faculty time spent teaching. since the establishment of the unop fellowship program, the region has more providers for pediatric cancer (p< . ) and centers treat a larger volume of patients (p< . ). two new centers have opened with graduates of the program. all but one graduate practice pediatric oncology ( / ) and the majority do it in their country of origin ( / ). no graduate practices outside of this region. almost half of the graduates ( %) hold a leadership role at their institution. the majority of their time is spent in the public sector (> %). the majority of graduates participate in clinical research ( %) and have participated in the creation or implementation of therapeutic protocols ( %). on average, the graduates have published peer-reviewed articles since completion of training. the unop fellowship program has had a favorable impact on pediatric cancer care in the region, contributing to the capacity to treat a larger volume of patients. graduates practice pediatric oncology in the region in the public sector, frequently hold leadership roles and are scientifically productive. background: abandonment of treatment is a major cause of treatment failure and poor survival in children with cancer in low-and middle-income countries. the incidence of abandonment in peru has not been reported. objectives: the aim of this study was to examine the prevalence and associated factors of treatment abandonment in pediatric patients with cancer of peru. we retrospectively reviewed the sociodemographic and clinical data of children referred between january and december to the two main tertiary centers for childhood cancer, located in lima, peru. definition of treatment abandonment was used from the siop (international society of paediatric oncology) podc (paediatric oncology in developing countries) abandonment of treatment working group recommendation. results: data of children diagnosed with malignant solid tumors and lymphomas were analyzed, of which ( . %) abandoned treatment. univariate logistic regression analysis showed significant higher abandonment rates in children living outside the capital city, lima (p< . ); prolonged travel time to a tertiary center (> hours; or . , p = . ); living in a rural setting (or . ; p< . ) and lack of parental formal job (or . ; p = . ). according to cancer diagnosis, children with retinoblastoma were more likely to abandon compared with other solid tumors. in multivariate regression analyses, rural origin and lack of formal parental employment were independently predictive of abandonment. conclusion: treatment abandonment prevalence in our country is high and closely related to socio-demographical factors. treatment outcomes could be substantially improved by strategies that help prevent abandonment of therapy based on these results. st. jude children's research hospital, memphis, tennessee, united states background: to improve the quality of a pediatric hematology/oncology fellowship program, a systematic assessment must be performed that can evaluate its current state and identify areas of opportunity, as well as modifications over time. unfortunately, widely agreed-upon metrics of quality for pediatric hematology/oncology fellowship programs currently do not exist. this is particularly important in this field due to the global shortage of specialists. for this reason, an assessment instrument that is applicable throughout the world must be created. objectives: the st. jude global education program assessment tool (epat) is a novel instrument that seeks to evaluate pediatric hematology/oncology fellowship programs around the world in systematic and objective way. epat will help determine key performance indexes that are relevant for quality education in pediatric hematology/oncology fellowship programs and establish the framework for improvement. design/method: firstly, key domains to be evaluated for program assessment were identified a priori based on the continuum of pediatric hematology/oncology fellowship programs in the context of geography and educational structure. subsequently, questions were formulated to evaluate these key domains, seeking to assess elements involved in ensuring competence in clinical practice, academic productivity and regional impact. due to the novelty of this tool and the lack of defined metrics of quality, epat relies on expert opinion in a two-step process: internally in the department of global pediatric medicine at st. jude children's research hospital and, subsequently, from a panel of experts in global pediatric oncology and medical education from around the world. ten key domains were identified to evaluate all aspects relevant to training programs around the world, regardless of educational and geographic context. questions have been created to assess these domains and, to make epat quantitative, these have assigned weights with a value reflective of their relative importance. this grading system allows for a score in each key domain, permitting monitoring of changes over time. epat is currently at the stage of external expert review, and subsequently will be piloted in five fellowship programs around the world to provide different geographical and patient care contexts for its validation. once epat is finalized, it will be distributed to pediatric hematology/oncology fellowship programs around the world to be applied. epat proposes a novel strategy to assess training programs in a systematic way that includes all aspects relevant for a training program in a global context. this tool will help guide improvements in pediatric hematology/oncology fellowship programs and assure a well-trained workforce. background: with the improvement in pediatric oncology patient survival and outcomes in the past several decades, monitoring for recurrence and long-term effects of therapy has become even more important. the utilization of personalized treatment summaries and survivorship care plans (scps) is one way to communicate this information with patients and families. the american college of surgeons commission on cancer (coc) created a standard regarding provision of scps to % of eligible patients by december , as a metric for accreditation of all cancer centers. the standard applies to all patients with stage i, ii, and iii cancer diagnoses and requires creation of the scp within one year of diagnosis or six months of completing treatment. during implementation at our pediatric cancer center, we identified barriers to use of the guidelines in the childhood cancer setting. objectives: define eligibility for an scp for pediatric oncology patients to include all patients with curative intent and to deliver scps within six months of finishing therapy. design/method: using chart review and a cancer center registry query, we identified childhood cancer patients potentially eligible for an scp by collecting stage, goal of therapy, and dates of treatment. all patients with curative intent were deemed eligible for an scp regardless of stage i-iv. patients being followed in the oncology clinic for posttreatment surveillance and care were included even if they had received an scp in the survivorship program or were greater than six months off therapy at time of implementation. as expected in the pediatric oncology population, acute lymphoblastic leukemia (all) was the most common diagnosis comprising . % of patients. all is stratified into risk groups instead of surgical staging categories, and treatment duration is greater than one year, unlike many adult-onset malignancies. these differences required interpretation of the guidelines to apply to our pediatric population for all and other pediatric diagnoses with non-surgically based staging. our pediatric oncology clinic has to date provided scps to of eligible patients by adapting the guidelines to focus on patients with curative intent to receive an scp by six months off therapy. cancer staging guidelines and goals for curative intent as well as lengths of treatment vary between the pediatric and adult populations. the coc guidelines require adaptation for optimal applicability to the pediatric oncology population. background: education in communication for fellows in fields that require difficult discussions with families are few in nature. adult learning pedagogies such as role play are under-utilized in medical education, and have been shown to be as effective as traditional teaching methods such as lecture. an -module course for fellows in hematology/oncology, hospice and palliative medicine, radiation oncology, and pediatric hematology/oncology was implemented in january/february . fellows participated in the program. topics covered including fundamentals of communication, coping and spirituality, delivery of bad news, communicating with families, sexual dysfunction during treatment, palliative care/death and dying, and burnout. objectives: overall goal of this course is to foster holistic physicians who views their patients as people with cancer, not cancer patients, and physicians that can communicate effectively with their patients throughout the disease continuum. by the end of the course, learners should be able to practice the fundamental principles of good communication. design/method: fellows initially participated in a pre-course osce to establish baseline skills. osce was facilitated by the center for learning and innovation at northwell, and included actors portraying a pediatric patient and family member to whom the fellow had to break bad news. two months later, the course was carried out over the span of eight weeks and included didactic sessions followed by minutes of role play scenarios. five of the eight modules included role play, with faculty members serving as simulated patients. after the course, a second breaking bad news osce was held. both osces were filmed, and feedback was given by the on-site actors. additionally, faculty members were given access to the videos in an on-line format and were given an evaluation tool to assess the fellows' performance pre-and post-intervention. fellows were given subjective surveys pre-and post-course as well. results: subjective data from participants showed a noticeable increase in comfort level in all areas on the pre-and post-course survey. data obtained from osce videos showed improvement in communication skills as assessed by sps and faculty members using a new evaluation tool developed by faculty. initial first-run data shows that this course is successful in improving communication skills as well as increasing fellows' comfort level across several domains of communication. future directions for our course include improving and validating our assessment tool, expanding our topic base to include more aya and pediatric scenarios, faculty development for improved role play, and investigating impact on practice after course completion. background: acute lymphoblastic leukemia (all) is the most common form of childhood cancer with approximately children diagnosed each year. survival rates have improved significantly over the past several years. children with all are at risk for developing musculoskeletal complications during and after completion of treatment, which can contribute to impaired activity, elevated body mass index (bmi), and risk for complications. interventions involving physical activity could improve musculoskeletal strength as well as overall health in these children. the aims of this study are to examine the feasibility of a directed physical activity program for children with newly diagnosed all during the initial intensive phase of therapy and to evaluate the overall health and quality of life of children participating in the directed physical activity program. design/method: all subjects will receive education materials about the importance and safety of physical activity and a nutrition handout. all subjects will also participate in the directed physical activity program under the supervision of a trained physical therapist for at least minutes every week for weeks. the program will entail four stations including a cardiovascular, balance/proprioception, strength and flexibility, and coordination and cardio. feasibility will be assessed by tracking the participation rate throughout the study period. other assessments will be made at study entry, at the end of weeks of physical activity initiative and months after completion of the intervention. assessments include overall strength and flexibility, weight, height, bmi, blood pressure and performance scores. descriptive statistics will be used for this study. results: a total of patients, male and female, enrolled in the study over a . month period. patient ages ranged from - years. half of the patients enrolled have completed the week program and all patients had stability or improvement of their physical functioning scores. further data collection and analysis is ongoing. patients in the early intensive phase of all therapy are at risk for complications that can affect their physical functioning. a directed physical activity protocol may improve their overall physical functioning. patients may not need specific physical therapy; however a directed physical activity program appears to be beneficial for these patients. the main roadblocks to successful completion of the program were difficulty with scheduling, strain on the parents and patient from treatment, unplanned admissions for fever, as well as nausea and fatigue at time of visit. albany medical center, albany, new york, united states background: communication skills are a core competency highlighted by the acgme. increasing resident confidence in delivering difficult news has been shown to lead to more s of s effective communication. currently, the majority of residency programs lack formal training in communication skills. our objective was to demonstrate feasibility and efficacy of integrating a standardized-patient based training program for communication skills into the curriculum of pediatric residents design/method: to date, pediatric and medicine/pediatric residents have participated in the program during the intern year. the program consists of three, two-hour long sessions, in which each resident is given several opportunities to act out case scenarios with a standardized patient. scenarios included informing a parent of their child's new cancer diagnosis and disclosure of a positive hiv test to a teenager. residents received post hoc peer to peer, and preceptor to learner feedback. pre and post-program surveys were completed by residents. results: following course completion residents reported an increase in confidence in multiple areas of communication including giving a difficult diagnosis (p< . ), discussing a poor prognosis (p< . ), responding to different patient/family member emotional responses i.e. crying or anger (p< . ), and organizing vital information to be relayed (p< . ). in conclusion, communication skills training of pediatric residents is feasible and provides a platform for developing valuable skills not taught elsewhere within the curriculum. background: for children with cancer, transitioning back to school during or after treatment can be challenging. literature supports the need for school re-entry programs to ease this transition. however, these programs vary widely among pediatric cancer institutions with little data addressing their program components. data from this study provides information on current school re-entry programs across these institutions. objectives: one objective of this study was to assess for correlation between the presence of a school re-entry program and other factors, such as geographic location and institution size. a second objective was to establish a list of differences between institutions' school re-entry program components. finally, we aimed to describe current school reentry practices, as well as program benefits and perceived areas for improvement. states with membership in the children's oncology group were offered enrollment in this study. a member of each institution was invited to participate in a survey established by the research team. this person was closely associated with the institution's school re-entry practices. each interview queried institution demographics, as well as program components (e.g., participants, target audience, resources). comment was also collected on program benefits and potential for improvements. analysis of transcripts was performed using pearson's correlation to assess for relationships between institution size, geographic location, and program presence. grounded theory was used for analysis of benefits and improvements. results: thirty-nine of forty-one pediatric institutions who were offered enrollment participated in this study. twentynine institutions ( %) indicated the presence of a school reentry program, and ten ( %) stated they had none. no correlation was found between institution size and the presence of a school re-entry program (p = . , ns). there was also no correlation found between institution location and the presence of a school re-entry program (p = . , ns). a major theme surrounding the benefits of having a program included education for the returning student's peers. for those with programs, perceived improvements included increasing staffing and the ability to offer more services. the results do not support the hypothesis that the presence of a school re-entry program is influenced by the size and geographic location of the treating institution. however, data seem to suggest that available staffing may influence the presence of a program. future studies are needed to address other potential influences, as well as to take an evidence-based approach to determine the effectiveness of the interventions present in these programs. cohen children's medical center/ zucker school of medicine at hofstra-northwell, new hyde park, new york, united states background: genetics/genomics is evolving at an extremely rapid pace. current advances lead to individual algorithms toward disease treatment for each disease with multiple branch points. fellows learn only a fraction of the knowledge and there is no formal approach to teaching critical analysis of information and application algorithms toward disease. additionally, as knowledge evolves extremely rapidly, any approach must teach self-acquisition and application of evolving discoveries. objectives: to create, implement and evaluate a novel curriculum for genetics/genomics targeted toward pediatric hematology/oncology fellows design/method: the curriculum includes four components: ) genetic and genomic medical knowledge, with one initial team-based learning session and weekly online multiple choice questions; ) essential pathways, which will teach molecular pathways common in oncogenesis and relevant to targeted therapy in microteaching sessions with using auditory, visual and tactile learning; ) knowledge acquisition and clinical judgment, to allow learners to gain experience into researching data available, then developing and prioritizing potential treatment plans using problem-based learning sessions in which they will stage a patient, research treatment options, prioritize and present findings; and ) synthesis to demonstrate independent ability to research and recommend therapy through an independent project in which the learner, given a case, will present the case and research findings, genetics/genomics, molecular pathways and make recommendations for therapy in molecular tumor board for faculty and fellows. to evaluate, we plan to recruit to institutions, match for size of programs and implement in half and evaluate nd and rd year fellows in both groups by mcq exam and satisfaction surveys. the creation of a multi-module, adult-learning based curriculum for genetics and genomics in pediatric oncology is feasible. implementation and evaluation are necessary to demonstrate efficacy. background: neuroblastoma is the most common extracranial solid tumor in children. chimeric anti-gd antibody ch . (dinutuximab) therapy has improved the survival of children with newly diagnosed high-risk, neuroblastoma patients as well at the time of first relapse/progression. acute neuropathic pain is a well-documented side effect of dinutuximab administration. however, additional adverse effects including sensorimotor neuropathy, ocular symptoms, and behavioral changes have been described. the incidence and severity of these effects are currently not well-documented in pediatric patients. with improved long term survival of patients receiving this modality, it is important to look for the potential late effects of dinutuximab. objectives: to determine the incidence and severity of neurologic, ophthalmologic, or behavioral changes after dinutuximab administration at our institution. we performed a retrospective chart review using our electronic medical record. we included all patients with high-risk neuroblastoma between the ages of and years at our institution diagnosed between and who received dinutuximab. patients with history of opsoclonus-myoclonus syndrome or gross sensorimotor neuropathy prior to receiving dinutuximab were excluded. we examined clinical documentation for subjective reports and objective exam findings of neurologic, ophthalmologic, or behavioral changes. we also looked for referrals made to neurology, ophthalmology, physical medicine & rehabilitation (pm&r), and psychology. : twenty-two patients met inclusion criteria. at the time of chart review, patients were alive and were deceased. eighteen patients received dinutuximab per anbl ; patients received dinutuximab per anbl . of these patients, patients reported symptoms of interest and reported multiple symptoms. six patients reported symptoms that began at least months after completing dinutuximab. nine patients had objective findings on exam, including decreased deep tendon reflexes, abnormal pupils, and nearsightedness. for patients, referrals were made to ophthalmology, pm&r for neuropsychologic testing, or neurology. two patients who reported symptoms of interest were not referred to a specialist. conclusion: neurologic, ophthalmologic, and behavioral symptoms were commonly reported and demonstrated on exam among pediatric patients with high-risk neuroblastoma who received dinutuximab. it is important to identify these effects so that appropriate specialist referrals can be placed for adequate management of these changes. we recognize that these symptoms may not be solely due to dinutuximab as these patients receive other agents including opioids, so a prospective trial is needed to further evaluate the long-term effects of dinutuximab and to determine how best to screen for these effects. akron children's hospital, akron, ohio, united states background: pediatric cancer is the leading cause of diseaserelated death in children in the united states (u.s.). in , over fifteen thousand children were diagnosed with cancer in the u.s. this population is at high risk for malnutrition due to the multimodal therapies they receive: surgery, chemotherapy, radiation therapy, antibody therapy, and/or bone marrow transplant. adverse effects of these therapies include taste changes, loss of appetite, diarrhea, vomiting, and/or mucositis, making it difficult for the children to be able to consume adequate amounts of nutrition during therapy. there is no "gold standard" measurement tool for identifying patients at risk for malnutrition. nutritional status is not frequently evaluated as a component of clinical trials. assessment of anthropometric measurements (weight, height, z-scores) at diagnosis, as well as over the duration of treatment, can assist in the early identification of malnutrition. the incidence and prevalence of malnutrition in this population is unknown at akron children's hospital. the purpose of this study is to describe the nutritional status and provision of nutritional support therapies in pediatric patients during their first year post new oncologic diagnosis. objectives: identify the incidence and prevalence of malnutrition across oncologic diagnostic categories over the first twelve months post diagnosis. we performed a retrospective records review of all patients newly diagnosed with cancer in at akron children's hospital. demographic and anthropometric data was collected at time of diagnosis and nutritional status categorized by z score. anthropometric and nutrition support data was then collected every two months for the first year after diagnosis along with incidence of unplanned inpatient admissions. results: a total of patients were included in the analysis, with . % malnourished at time of diagnosis; . % developed malnutrition the first year. patients with solid tumors represented % of patients with pre-existing or acquired malnutrition. overall, % of patients received at least one nutritional support modality. patients with pre-existing or acquired malnutrition had a non-significant increase in unplanned admissions (p = . ). our study demonstrated that patients with solid tumors were found to be at increased risk of pre-existing and acquired malnutrition, followed by leukemias, and experienced higher incidence of unplanned admissions in the time period observed. prospective, multi-center replication of this study, including detailed collection of nutrition therapies is recommended to guide development of diagnosis specific nutrition support guidelines. background: pediatric and young adult oncology patients treated with intense chemotherapy have a high incidence of transfusional iron overload. iron deposition can lead to heart failure/arrhythmias, liver abnormalities, endocrine dysfunction, ineffective erythropoiesis, and increased cancer and mortality risk. however, there is a paucity of data regarding recommendations for management of transfusional iron overload in these cancer survivors. consequently, long-term complications of transfusional iron overload specific to these patients have not been assessed. objectives: to assess screening and phlebotomy-based treatment algorithms for this population. design/method: a retrospective chart review of pediatric and young adults who completed oncology management, had iron overload, and initiated phlebotomy treatment was conducted. tiered screening occurred in patients that received at least packed red blood cell (prbc) transfusions. patients were recommended for evaluation and possible phlebotomy if: ( ) liver iron concentration (lic) > mg of iron/gram dry weight liver tissue by ferriscan and/or ( ) cardiac mri t * < ms. during phlebotomy, iron status was assessed quarterly and phlebotomy discontinued with lic < or normalization of ferritin/imaging lic verification. descriptive statistics were employed to report the characteristics of the study population. spearman correlations were utilized to describe associations between transfusions, lic, ferritin, iron saturation and number of phlebotomy sessions. results: twenty five survivors underwent phlebotomy. the mean age was . years (sd . ) and ( %) were female. oncologic diagnoses: all ( %), aml ( %), nhl ( %), ewing sarcoma ( %), osteosarcoma ( %), neuroblastoma ( %) and cns ( %). patients received a median of . (iqr - ) transfusions. median number of phlebotomy sessions was (iqr - ) over . years (iqr . - . ). prior to phlebotomy, median lic was . mg/g (iqr . - . ) and ferritin was . ng/ml (iqr - ) . no patients demonstrated abnormal cardiac t * mri (n = ). ( %) patients completed phlebotomy. one discontinued due to poor vascular access. no patients developed iron deficiency. lic was reduced by a median of . mg/g (iqr . - . ) and ferritin by ng/ml . correlation between number of transfusions and phlebotomy sessions was poor (r = . ). conclusion: management guidelines are lacking for transfusional iron overload in pediatric and young adult survivors of cancer. we demonstrate a phlebotomy algorithm that is effective and tolerated. correlation between number of transfusions received and phlebotomy treatments was poor, necessitating serial assessments. using this management algorithm, prospective studies can evaluate the effect of iron removal on iron overload complications in this patient population. penn state children's hospital, hershey, pennsylvania, united states background: cancer therapy leads to an impaired immune system that takes time to recover. it is important to ensure that these survivors have adequate immunity to prevent common yet potentially severe childhood illnesses. no validated guidelines currently exist for surveillance testing or re-immunization in this population. retrospective analysis involving a small cohort of pediatric cancer patients treated at penn state children's hospital showed % of patients screened for varicella immunity after therapy completion did not have adequate disease titers. to determine the proportion of pediatric cancer survivors who have lost humoral immunity to previously received vaccines; to determine the rate of response to single dose boosters or full vaccine series in seronegative subjects after one booster. design/method: pediatric cancer survivors treated at the children's hospital who are at least months from completion of cancer therapy are prospectively tested for antibody levels to hepatitis b, tetanus, varicella, measles, and strains of pneumococcus ( , b, v, c, f, and f). samples are analyzed by the cdc for measles and varicella avidity. seronegative subjects by commercial studies, are eligible to receive booster vaccines. titers are rechecked at least weeks after boosters to re-evaluate immunity; if still seronegative, subjects will receive the entire vaccine series. titers are finally tested at least weeks after the final dose of the vaccine series. immunity analyzed after therapy, after boosters, and after vaccine series. results: of pediatric cancers survivors who completed therapy, % were non-immune to hepatitis b, % nonimmune to > % of pneumococcal strains tested, % nonimmune to measles, % non-immune to varicella, and % non-immune to tetanus. of subjects who received mmr vaccine after therapy and prior to study enrollment did not have protective antibodies to measles. of the subjects who received varicella vaccine after end of therapy and prior to study enrollment, did not maintain protective antibody levels. cdc results for measles and varicella are pending, as well as repeat studies after vaccine boosters and series. conclusion: a significant percentage of pediatric cancer survivors do not retain immunity to hepatitis b, pneumococcus, measles, and varicella. after one booster, a high percentage of subjects did not develop protective immunity to varicella. only subject did not have immunity to tetanus, which is consistent with the high immunogenicity of tetanus toxoid. formal guidelines are needed to protect this population from vaccine-preventable illness post-therapy. children's hospital of richmond at virginia commonwealth university health system, richmond, virginia, united states background: childhood cancer survivors are at risk for being overweight. diet and physical exercise are important in maintaining a healthy lifestyle and weight; however, it has been reported that cancer survivors are less active than their peers. one reason for this may be that there are no clearly established risk-based exercise recommendations for cancer survivors. another reason may be that providers tend to focus s of s recommendations for exercise more towards patients who are overweight. objectives: to describe changes in physical fitness of childhood cancer survivors who exercise. design/method: 'moving forward' is a wellness and physical fitness program that the center for care beyond the cure at chor offers in partnership with the ask childhood cancer foundation and the ymca. the program is available for any childhood cancer survivor between y and y age, being seen at our center. survivors define their fitness or wellness goals and then work with a trainer once a week (at least) for min sessions throughout the year to achieve these goals. baseline and ongoing measurements for core strength, endurance, overall strength and balance were collected. the average of each of the parameters of all participants were compared from the beginning to the end of the program. over the year, there was a % increase in endurance as measured by the average of the miles walked in minutes, % increase in core strength as measured by the average number of sit-ups in secs, an % and % increase in overall strength as measured by the average weight lifted by leg press and the average weight lifted by chest press, and a % increase in balance as measured by the average number of seconds balancing on a single leg. in addition, each child had actually gained weight in the process with an approximately % increase in the average of the weights of all children. there are benefits to regular exercise beyond weight control, and improvements in physical fitness can be seen even without weight loss. regular physical exercise results in improved physical fitness and should be universally advocated to all patients. determining insulin resistance, measuring changes in fatigue and wellness perception following exercise are future directions that we intend to explore. dana-farber cancer institute, boston, massachusetts, united states background: improvements in adolescent and young adult cancer patient (aya) survival rates and quality of life outcomes have lagged behind those of children and older adults, highlighting a need for research targeting this unique population. current literature supports the value of strong ayaclinician communication, notably in facilitating therapeutic alliance, however little is known about aya communication priorities during cancer care and barriers to optimal ayaclinician communication. objectives: to explore aya and oncology clinician communication priorities and to identify barriers and facilitators to aya-oncology clinician communication. design/method: semi-structured interviews were held with aya cancer patients and survivors (ages - years) from a single large academic institution and oncology clinicians (physicians and nurse practitioners) from academic institutions in the northeastern united states. interviews were conducted in english by phone or in person. all interviews were audio-recorded and transcribed verbatim. analyses were aided by nvivo software. ayas identified a wide range of topics as important to discuss with clinicians. the most frequently identified topics were ) side effects of treatment (with an emphasis on physical appearance and function, n = ), ) social issues (including friendship, family, and school, n = ), ) looking ahead to the future (n = ), and ) sexual & reproductive health (including future fertility, contraception, and romantic relationships, n = ). clinicians prioritized ) cancer treatment and side effects (n = ), ) emotional and psychological health (n = ), and ) sexual and reproductive health with a focus on fertility risk and fertility preservation (n = ). aya reported facilitators to good communication including an open and long-established relationship with the clinician (n = ) and clinician engagement in age-appropriate and patient-directed conversations (n = ). barriers included parental presence during visits (n = ). clinicians reported barriers including ) clinician discomfort (not feeling wellequipped to discuss psychosocial topics such as sexual health, spirituality, and relationships with peers, n = ), ) presence of parents/family (n = ), and ) perceived patient discomfort discussing specific topics (such as sexual health, n = ). clinicians acknowledged the need for collaborative efforts with additional team members (i.e. nurses, psychosocial providers) to assist in meeting aya communication needs. conclusion: aya and clinician-reported communication priorities are largely aligned. however, ayas emphasize some topics, such as social function, appearance, and sexual health that are not highly prioritized by clinicians, which may result in gaps in care for ayas in treatment and in survivorship. these data identify opportunities for intervention, including clinician education, patient and family education, clinic-based intervention, and systems-based changes that can be developed and tested. background: primary care physicians (pcps) cite lack of knowledge and inadequate communication with the oncology team as major barriers to providing recommended surveillance for late effects of treatment to childhood cancer survivors. a standardized telephone handoff to pcps posttherapy is a potential strategy to increase survivorship care by pcps through interactive communication. to determine the feasibility of a structured telephone communication using the situation, background, assessment, and recommendation (sbar) communication tool delivered by a trained oncology nurse to increase pcp knowledge and willingness to provide survivorship care. design/method: from / / to / / , a registered nurse expert in childhood cancer survivorship attempted to contact by telephone the pcps of the most recent patients attending yale's childhood cancer survivorship clinic that were < years old, english-speaking, and ≥ years posttreatment. all pcps had been previously sent an individualized survivorship care plan (scp) that listed the patient's previous treatment history and recommended surveillance tests. upon successful contact and after confirming receipt of the scp, the nurse explained the definition of late effects, description of patient's diagnosis and treatment history, and associated potential late complications and schedule of recommended surveillance tests. the pcp was also asked about his/her ability and willingness to provide needed surveillance for late effects in the future. overall, of pcps were successfully contacted with a median of phone call (range: - ) that lasted a median of minutes (range: - ) after a median of business day (range: - ). no pcps ended the call mid-conversation. all pcps were receptive and expressed appreciation for the call. twenty-five of ( %) pcps expressed an understand-ing of the material discussed and endorsed belief in their ability and willingness to provide late effects surveillance for their patients. no pcps questioned discussing their patient's care with a nurse versus a physician. interactive, structured communications between nurses and pcps by telephone are feasible and are associated with high-levels of pcp confidence in providing survivorship care. background: childhood cancer (cc) admissions account for % of non-newborn pediatric hospitalizations. these hospitalizations are longer and more expensive than other hospitalizations. admission payer (medicaid or commercial) reflects both health policy and sociodemographic status. the objective of this study was to determine if length of stay (los) or cost of cc admissions differed by payer. we used the kids inpatient database, a sampling of all pediatric hospital discharges in the united states. analysis for this study was limited to admissions containing a cancer diagnosis in any discharge icd- codes. admissions were further subcategorized by discharge codes according to diagnosis (leukemia, lymphoma, solid tumor and brain tumor) and reason for admission (chemotherapy, procedure, infection, non-infectious toxicity or "other"). charges were converted to costs using cost-to-charge ratios. multivariable linear regression models were performed to control for age, gender, race, reason for admission, and diagnosis. results: there were , weighted admissions for children with a cancer diagnosis in . of these admissions, . % had medicaid, . % had commercial insurance, and less than % had other payers. the mean los for medicaid admissions was . days ( % ci . - . ), compared with . days ( % ci . - . ) for commercial insurance. surgical admissions accounted for the largest difference in length of stay with medicaid admissions being . days longer than those covered by commercial insurance ( . days vs . days), however, the difference was significantly different for all reasons for admission. in multivariable analysis admissions associated with commercial insurance were % shorter s of s (p< . ), accounting for approximately one hospital day, than admissions associated with medicaid after controlling for other variables including race. the mean overall cost for medicaid admissions was $ , ( % ci - ), compared with $ , ( % ci - ) for commercial insurance. in the multivariable model, cost was collinear with race. conclusion: los and cost of admissions associated with medicaid differed from those associate with commercial payers. medicaid admissions were % longer on average than commercial insurance, accounting for a difference in length of stay of approximately one day although the difference varied with the reason for hospitalization (chemotherapy, surgical procedure, infection, other toxicity, other). costs of admissions were not independent of race. further investigation into potential explanations for this difference including differential access to home care needs, outpatient reimbursement differences, social indications for prolonged hospitalization, and provider biases, is warranted. background: pediatric cancer is a major cause of morbidity and mortality among children surpassed only by accidents. despite improved outcomes in high income countries (hic) survival rates remain poor in the developing word. there are various diagnostic and therapeutic limitations contributing significantly for the survival gap. the main objective of the study is to to evaluate the outcomes of pediatric cancer in armenia and identify diagnostic and therapeutic limitations in the country. we conducted a retrospective study among (≤ years old) children with cancer (solid tumors and hematological malignancies), who were diagnosed and treated at the clinic of chemotherapy of muratsan hospital complex of yerevan state medical university between and . those patients, who didn't receive chemotherapy for any reason were not included in the study cohort. epidemiological, social, medical information was collected through the patient charts review. this included patient age at diagnosis, sex, place of residence (city vs village), the educational level and employment status of parents, type of cancer, stage, presentation of symptoms, first medical specialty consulted and the time consulted, initial work-up, the type of treatment received, information on the diagnosis/treatment received abroad. results: at our clinic during the mentioned period of time the majority of patients presented with hematologic malignancies- %. ( . %) patients had information on diagnosis delay. average delay in diagnosis was about days. in % of cases the first contact with "healthcare system" was through pediatrician, and in % with surgeon. out of relapsed patients received salvage treatment in armenia and abroad. from those who stayed for treatment in armenia patients survived. majority of relapsed patients had acute lymphoblastic leukemia. from leukemia patients immunophenotyping and cytogenetics were available for ( . %) patients; the majority of missing cases were between and , when these diagnostic modalities were not available or affordable in the country. ( %) patients received part of diagnosis and/or treatment abroad. the most frequent reason for going abroad was bone marrow transplantation, otherwise none available in armenia. out of patients were lost to follow-up, patients had a fatal outcome. patients were in remission at a median follow up of . years. conclusion: unavailability of cancer registry and several essential diagnostic/treatment modalities, luck of multidisciplinary care and palliative support, high rate of out-of-pocket expenses were among the main challenges of pediatric cancer care in armenia. background: adverse drug reactions (adrs) are increasingly recognized as important and sometimes irreversible complications of cancer treatment. anthracyclines and cisplatin are effective chemotherapeutic agents, but their use can be limited by cardiotoxicity (anthracyclines) and ototoxicity (cisplatin) in up to % of patients. genetic variants that can be used to predict who is most at risk of developing these adrs have been discovered and replicated. objectives: to create pharmacogenetic risk prediction models for anthracycline and cisplatin toxicities and discuss results with oncologists to facilitate incorporation into treatment decision-making when appropriate. design/method: risk prediction models were developed from the linear regression of strongly-predictive genomic variants (odds ratios ≥ ) discovered and replicated in at least three patient populations. these models were used to assess an individual patient's genomic risk of developing cardiotoxicity from anthracyclines or hearing loss from cisplatin. risk results were returned to oncologists showing where the specific patient's genetic risk of toxicity lies on a continuum between the lowest and highest risk groups across all studied patients using a multi-gene model. interviews were conducted with patients, families, and oncologists to determine how results were valued and utilized. results: patients have been genotyped and had their genetic risk results returned to their oncologists. the first patients have been characterized to determine the impact these test results have had on their clinical care. results were described as being useful in decision-making by patients and/or oncologists in % of cases. additionally, for patients in the most extreme risk groups (highest and lowest risk), a change in treatment plan was ordered % of the time for cisplatin patients and % of the time for anthracycline patients. this included increased cardiac and audiological monitoring, the addition of a protective agent, or choosing an alternative treatment protocol if the risk outweighed the benefits of remaining on the current treatment plan. in interviews, patients indicated that they felt more involved in decision making, and felt reassured by understanding their genetic risk of toxicities. genetic risk prediction models for anthracycline cardiotoxicity and cisplatin ototoxicity were highly utilized by patients and oncologists in decision-making. results were found to be an important tool for informing patients of the risk of adrs during cancer treatment, and resulted in patients and their families feeling more involved in decision-making. background: childhood cancer survivors are at increased risk of developing executive dysfunction, and low socioe-conomic status (ses) has been identified as one of the mediators of executive functioning. previous studies have used traditional measures of ses, such as parents' education level, family annual income and occupation. but more recently, area based socioeconomic measures like block group poverty status are deemed to be more useful in monitoring of social inequalities in health in the united states. block groups are statistical divisions of census tracts and generally contain between and , people. the current study aims to understand the association of block group poverty status (percentage of households in family's block group of residence living below the federal poverty level) with executive functioning among cancer survivor children. design/method: we used a retrospective cohort of childhood cancer survivors. relevant information was collected from the medical record, administrative data sets and parent-filled surveys. address information was geocoded using arcgis . to obtain data on the block group poverty status. a priori cut-points were set to represent block groups with families living below poverty level at %, . % to . %, and ≥ . %. executive functioning were assessed through a parent-rated instrument, the behavior rating inventory of executive functions (brief). multiple linear regressions were used to determine the relationship between block group poverty status and the brief scores. results: data was examined from families of childhood cancer survivors, ranging in age from to years. in this sample, . % families reported an annual income <$ , , . % reported income between $ , and $ , while . % reported annual income ≥$ , . primary care giver of . % of cancer survivors had more than more high school education, and . %, . % and . %, of families were living in a block groups with %, . - . % and ≥ % poor households respectively. block group poverty level was not significantly associated with annual income levels (spearman's rho = . , p = . ), or parental education level (spearman's rho = - . , p = . ). in a step-wise multiple linear regression, there was no statistically significant association seen between block group poverty status and executive functioning after adjusting for co-variables in the final model. future prospective study with a bigger sample size, longer follow up period and more robust measures of the executive functioning like a clinician administered test are needed to understand the effect of block group poverty status on executive functioning. to d completion was . days (range - ). all parents strongly agreed/agreed that d was helpful and would recommend d participation to another family. ten parents ( %) reported time spent on d was "just right." no parent felt more worried due to the intervention, though parent found d participation stressful. this interim analysis suggests that parents have a favorable d experience and recommend the intervention. to date, < % of enrolled parents fail to participate. d shows promise as an acceptable interdisciplinary communication intervention targeted to the early treatment period for childhood cancer. children 's hospital and research center oakland, oakland, california, united states background: screening echocardiograms are recommended by children's oncology group (cog) guidelines to assess for anthracycline-induced left ventricular (lv) systolic dysfunction. the yield of screening echocardiograms during chemotherapy and in the immediate post-therapy period is uncertain. objectives: to assess the incidence of lv dysfunction detected by screening echocardiograms during chemotherapy and in the immediate post-therapy period, defined as - months off-therapy. design/method: children diagnosed with cancer between january -march who received anthracycline chemotherapy were identified. echocardiograms were performed as per protocol, institutional and cog guidelines, and were reviewed retrospectively. lv dysfunction was defined as fractional shortening (fs) < % or ejection fraction (ef) < % ( ) results: in this cohort (n = , median age years), the most common diagnosis was all ( . %), followed by aml ( . %). of echocardiograms, ( . %) were performed during treatment and in the immediate posttreatment period. thirty-eight ( . %) patients had a > % decrease in fs compared to their pre-treatment echocardiograms. none of these patients required any treatment modification or cardiac medications. only patient ( . %) had echocardiogram-proven lv dysfunction discovered on a screening echocardiogram during her treatment course. she eventually died due to multi-organ failure following septic shock. this patient was receiving treatment for aml and had received mg/m of doxorubicin-equivalent anthracyclines at the time of the abnormal echocardiogram. one patient with metastatic ewing sarcoma had borderline lv dysfunction with a fs of % detected a month before completion of therapy. she had received mg/m of doxorubicin equivalent anthracyclines at the time of the abnormal echocardiogram. she did not require any therapy modification or additional cardiac medications. serial echocardiograms done on this patient have shown stable ventricular function. no off-therapy screening echocardiograms identified lv dysfunction. in our experience, the yield of echocardiograms to detect anthracycline-related cardiac dysfunction during treatment and in the immediate post-therapy period is very low. one patient developed lv dysfunction during treatment and one had borderline fs, while no lv dysfunction was identified within months of completing chemotherapy. though fs decreased in % of patients, none required intervention. further study is needed to optimize the use of echocardiography screening in children treated with anthracyclines. references: . landier w et al. jco . background: platinum-based chemotherapy increases the risk of sensorineural hearing loss in children with cancer. little is known about the impact of hearing loss on cognitive and emotional functioning in survivors. to determine the association of severe/profound hearing loss after platinum-based chemotherapy with ) cognitive impairment and ) emotional distress (i.e. anxiety and/or depression). cross-sectional study of all patients attending yale's childhood cancer survivorship clinic ≥ years off therapy for cancer diagnosed at < years and treated with cisplatin and/or carboplatin, but with no history of cns tumor, cranial radiation, congenital hearing loss, or developmental delay. hearing loss severity and hearing aid data were abstracted from audiograms and detailed clinical history. cognitive impairment was defined as behavior rating inventory of executive function t score ≥ , assessment by neuropsychologist, and/or history of special education. emotional distress was determined by brief symptom inventory t score ≥ (global or two subscales) or behavioral and emotional screening system t score ≥ , psychologist interview, and/or history of psychotropic medication/psychotherapy. the most recent available patient data were used. logistic regression with sas software, version . was performed. results: overall, patients ( % female, % white) met eligibility criteria with a median age of . years (iqr = . ) at diagnosis and . years at evaluation (iqr = . ) after a diagnosis of sarcoma ( %), neuroblastoma ( %), or other ( %) for which % received cisplatin and % received carboplatin. fifteen patients ( %) had severe/profound hearing loss in at least one ear. patients with severe/profound hearing loss had a significantly increased risk of cognitive impairment (or = . ; % ci = . - . ), but not emotional distress, compared to patients without severe/profound hearing loss. there was no significant association between age at diagnosis, current age, time since diagnosis, sex, race, ethnicity, or diagnosis with either cognitive impairment or emotional distress. similarly, there was no significant interaction between ) age at diagnosis and hearing loss or ) sex and hearing loss with either cognitive impairment or emotional distress. ten of the ( %) patients with severe/profound hearing loss in at least one ear were recommended hearing aids, of which ( %) reported compliance most of the time. we conclude that severe/profound hearing loss is significantly associated with cognitive impairment, but not emotional distress, in childhood cancer survivors. our data supports the need for interventions to improve hearing in these patients, including compliance with hearing aids. background: who grade anaplastic astrocytoma is a high grade glioma dependent on vascular endothelial s of s growth factor (vegf) mediated angiogenesis for its growth and infiltration. bevacizumab is a recombinant humanized monoclonal antibody which binds vegf-a and inhibits angiogenesis. common adverse effects of bevacizumab are hypertension, proteinuria, thrombosis and bleeding. while animal model based studies have shown that bevacizumab may impair ovarian function the effects of bevacizumab therapy on human fertility are not clear. since the physiology of pregnancy involves neovascularization/angiogenesis it is recommended that conception be avoided for at least months following exposure to bevacizumab. to describe the course of a young adult who became pregnant after receiving bevacizumab and radiation therapy for treatment of an anaplastic astrocytoma. a year old woman diagnosed with a localized hemispheric who anaplastic astrocytoma was treated with chemotherapy and radiation (temozolomide/ . gy) followed by cycles of bi-weekly bevacizumab/temozolomide. patient opted not to pursue fertility preservation prior to initiation treatment. she experienced bevacizumab-associated proteinuria and hypertension during treatment but received all protocol mandated doses (cumulative doses: bevacizumab = mg/kg; temozolomide = . gm/m ). she had a spontaneous unassisted pregnancy months after completing treatment. her pregnancy was uneventful and she was normotensive throughout. fetal ultrasonography at , , , weeks revealed no abnormality of the brain, heart, great vessels, kidney, extremities, placenta and umbilical cord. at weeks she delivered a female infant via cesarean section (birth weight: grams, apgars: and ) excessive post-partum hemorrhage was not reported. placenta was bi-lobed and weighed g. histological analysis revealed normal placental villous development and maturation and two small infarcts. conclusion: exposure to bevacizumab in our patient had no detrimental effect on fertility and on placental/fetal vascular development. we hope this report will add to the existing data on the effects of bevacizumab therapy on fertility. children's healthcare of atlanta, emory university school of medicine, atlanta, georgia, united states background: reports of malnutrition incidence and prevalence in young cancer patients are variable and not well established. previous research suggests children, especially less than years old, treated with intensive cancer-directed therapy are at higher risk for malnutrition. however, no standardized assessment has been used to evaluate risk in this population. objectives: we aim to assess the trends of weight-for-age for patients following cancer diagnosis. this study will be the first to use a standardized measure of treatment intensity (intensity treatment rating scale, itr- ) and will assist in targeting interventions for identification and treatment of malnutrition. design/method: this observational, retrospective study obtained data through the center's pediatric cancer registry and electronic medical record. patients were classified by tumor type (brain or non-brain tumor) and treatment intensity (itr- ). itr- incorporates diagnosis, chemotherapy, radiation, and surgery, beginning with lowest intensity ( ) to highest intensity ( ). inclusion criteria included new cancer diagnosis - at less than years old, with weight obtained and available within days of therapy start date. incomplete data, alternate growth charts, or treatment intensity of , were excluded. weight was obtained at start of therapy and through years after treatment initiation (approximately days) and converted to z-scores adjusted for age and sex. weight trajectories were modeled using generalized linear mixed models with subject-specific random intercepts and spline functions. separate functions were constructed for subgroups of interest (tumor type and itr). results: there were patients included: patients with brain tumors ( . %) and with non-brain tumors ( . %). of included patients, had treatment intensity of ( . %), of ( . %) and of ( . %). over the observation period, , valid weights were recorded. at initiation of treatment, no difference existed between z-score by tumor type (p = . ) or by intensity ( vs. , p = . ; vs. , p = . ; vs. , p = . ). tumor type did not affect z-score through the follow up period. z-scores were higher for intensity rating vs. and vs. (p = < . and p = . respectively) at days after the start of treatment and persisted through days (p = . and p< . respectively). higher treatment intensity is associated with decline in z-score and failure to return to baseline. future directions include further analysis on specific risk factors and timing of weight loss, longer-term follow-up of weight trends, and targeted interventions for identification, prevention, and treatment of malnutrition. objectives: asses the pt requirements for bleeding episodes in a prospective cohort of pcp using a < × e threshold compared to a < × e /l threshold in a historical cohort. we collected pt data in all pcps treated at our center between january/ through december/ . diagnosis, prescription for pt (prophylaxis vs bleeding disorder), plt count and transfused units were assessed for each pt. pcps treated from january/ through june received prophylactic pt with a < × e threshold (cohort a), and pts treated from july/ through december/ received prophylactic pt with a < × e threshold. pts done for procedures and pts with concomitant hemorrhagic pathology were excluded. we compared the number of pts prescribed as prophylaxis vs bleeding episode between cohorts. data analyzed: graphpad prims . ®. statistical analysis: percentages with confidence interval (ci); t-student test (parametric variables) and mann-whitney test (nonparametric variables). statistical significance: p< . . we reviewed pts ( in cohort a, cohort b) in patients. % had acute leukemia, % received and auto or allo hsct. diagnoses and the proportion of patients undergoing hsct was comparable in both cohorts. the average number of pts per patient was , in cohort a and , in cohort b (p = ns), but a significant difference was found when hsct patients were excluded from this comparison ( , pt per patient in cohort a vs , in cohort b, p = , ), which resulted in an estimated , % reduction in pts prescription. furthermore ( , %) pts were prescribed for bleeding episodes in cohort a versus ( , %) in cohort b (p = ns). patients receiving hsct in the entire group ver-sus those not receiving hsct had similar pt requirements for bleeding episodes ( % vs , % p = ns) conclusion: a < × e plt count threshold for prophylactic pts is safe in pcp in chemotherapy and hsct. it can result in a significant reduction in pt usage. key words: platelets, transfusions, prophylaxis, cancer, childhood. ucsf benioff children's hospital oakland, oakland, california, united states background: transition of care for adolescent and young adult (aya) survivors of childhood cancer from pediatric to adult-oriented long-term follow-up (ltfu) is complex. loss to follow-up is common, and little is known about the success rates among different models. the survivors of childhood cancer program (sccp) at ucsf benioff children's hospital oakland employs a community-based model for transitional care. our multidisciplinary team provides aya survivors a comprehensive treatment summary and recommendations, then facilitates transition to primary care or adult oncology ltfu programs. evaluate the success rate for transition of care among aya survivors of childhood cancer in our ltfu program, and identify barriers to successful transition. design/method: aya patients seen from november to august in the sccp with intent to transition were asked by email or telephone if they had followed up with their designated provider. the primary outcome was successful transition, defined as establishing care within months of their visit. patients were also asked about barriers to transition and to rate the new provider's familiarity with their cancer history and ltfu needs. results: transition was intended for patients. eightyseven were contacted and responded. of these, ( %) successfully transitioned, while ( %) were lost to followup. ages ranged from to years, at to years since completion of therapy. ten ( %) transitioned to a primary care provider, ( %) to an adult oncology ltfu program, and ( %) to a pediatrician. patients rated their new provider's knowledge above average ( . ) on a -point scale from poor ( ) to excellent ( ). survivors lost to follow up indicated the following barriers to transition: loss/change of insurance ( ), inability to find a provider ( ), too busy/forgot ( ), problems with transportation ( ), concerns about cost/copay ( ), and s of s other ( ). twelve patients requested further assistance with transition. conclusion: two-thirds of responding patients successfully transitioned. more work is needed to overcome various barriers to transition for one third of aya survivors. albany medical center, albany, new york, united states background: the transition from active treatment, to offtherapy follow-up, is a stressful event for parents of children with cancer. the psychosocial needs of parents after therapy have received limited attention in the united states with only published quantitative studies, the largest with parents. we have secured funding for and recruited a transition care coordinator (tcc) to investigate this further. objectives: our objective is to assess and screen parents at the end of their child's treatment, and to develop interventions to support parents during this time and thereafter. design/method: after informed consent, a standardized questionnaire, the psychosocial assessment tool (pat . ), was administered to parents at end of therapy (t ), months later (t ) and year later (t ). the tcc provided "universal" intervention to all families with an end of therapy binder containing a treatment summary, follow-up roadmaps, information on late effects, and survivor scholarships. based on their pat . scores, some parents were provided intervention specific to symptoms (targeted intervention for scores - . ) or referred to a behavioral health specialist through the clinic social worker for counseling (for scores > ). results: analysis of pat data showed that % of parents (n = ) scored in the targeted or clinical ranges; % of parents scored in those ranges at pat . significant gender differences were revealed with the mean score for men of . and for women of . . this was confirmed by showing statistical significance (p = . ) when analysis was conducted for only a subgroup of data composed of couples (n = ). analysis of pat data by couples (n = ) showed the mean score for men was . and for women was . (p = . ). gender differences were most apparent in caregiver stress reaction questions that focused on ptsd symptoms. when the subgroup of couples' scores (n = ) for caregiver stress reaction at pat was analyzed, there was a significant difference (p = . ) in caregiver stress reaction with a mean of . for men versus . for women. [note: subcategory scores range from to ]. this study was initiated in october using a tcc and the pat . screening tool. the results suggest greater stress on mothers after therapy, with a substantial proportion of parents having symptoms of ptsd after therapy. background: hodgkin lymphoma (hl) is a common childhood cancer characterized by an inflammatory microenvironment. chemotherapy and radiation may exacerbate this inflammation and contribute to the development of late effects (pneumonitis or pulmonary fibrosis). in a heterogeneous cohort of childhood cancer survivors exposed to pulmonarytoxic therapy, no association between pro-inflammatory cytokines and late pulmonary dysfunction was observed. our objective was to test this association in a relatively uniform cohort of survivors of hl, given the well-recognized proinflammatory background of this disease. objectives: to characterize off-therapy pulmonary function in survivors of hl treated with contemporary therapy, and to investigate its association with persistent systemic inflammation. design/method: blood samples, clinical data, and pulmonary function tests were obtained from survivors of hl ≥ months off therapy. lung function score (lfs), a validated method for assessing degree of pulmonary dysfunction on a scale of i to iv, was determined from diffusion capacity and forced expiratory volume in one second (fev ). for a control group, blood samples from patients with benign, noninflammatory hematologic conditions were used. plasma concentrations of inflammatory cytokines were measured on a luminex platform (emd millipore). associations between clinical features or cytokine levels and lfs i (normal) vs. ii-iv were evaluated using logistic regression or wilcoxon rank sum tests, respectively. results: of survivors (mean age at diagnosis: years, range: - ; mean time off therapy: . years, range: . - ), % were categorized as lfs ii (mild dysfunction), % as lfs iii (moderate dysfunction), and no survivors as lfs iv (severe dysfunction). higher lfs was associated with female sex (p = . ) but not other demographic, disease, or treatment factors. forty-eight survivors had blood samples collected at a mean age of . years (range: - ) with a mean time since treatment completion of . years (range: . - . ). of controls, the mean age at time of blood collection was years (range: - ). survivors did not have significantly elevated cytokine levels compared to controls. female survivors of hl ≥ months off therapy are at increased risk of pulmonary dysfunction. neither evidence for pulmonary dysfunction, as measured by lfs, nor duration of time off therapy were related to systemic inflammation in this study. pulmonary function deterioration and clinical pulmonary symptoms are rarely observed immediately following therapy but increase over time. future studies may consider exploring the contribution of systemic inflammation to pulmonary late effects in survivors farther off therapy, when risk for this late effect is greater. background: thyroid carcinoma is a very rare tumor in pediatrics, accounting for . - % of childhood carcinomas in the united states and europe. we aim to detect the risk of second malignancies among pediatric thyroid cancer survivors. the cohort analysis consisted of pediatric cancer patients aged less than years diagnosed with a primary thyroid cancer and identified by site code icd- - : c , reported to a seer database between and . they were followed up by death or the end of the study period (december , ) . out of patients diagnosed primarily with thyroid carcinoma, there were patients who had incidences of subsequent malignancies. the mean age of patients at initial diagnosis of thyroid cancer was years. females ( . %) had significantly higher incidence of second malignancies (sm) than males ( . %). the overall standardized incidence ratio (sir) of sm in thyroid pediatric patients was higher than expected (sir = . ). some specific sites showed significantly higher incidences: salivary gland (sir = . ), gum and other mouth (sir = . ) and kidney (sir = . ). the overall risk of sm in patients received radioactive iodine was higher than expected (sir = . ). the cumulative inci-dence of sms from the initial diagnosis of thyroid cancer was calculated with the survival methodology of competing risk, death treated as a competing event. cumulative incidence of sm was . % [ % ci ( . , . %)] at years and substantially expanded after years, reaching . % [ % ci ( . , . %)] at years. the cumulative incidence of each tumor type at years was . % [ % ci ( . , . %)] for breast cancer, . % [ % ci ( . , . %)] for salivary gland, . % [ % ci ( . , . %)] for each one of kidney and cervix uteri and . % [ % ci ( , . %)] for each one of ovary and melanoma of the skin. cumulative incidence of sm was stratified based on race, gender and radiotherapy exposure, but there was no statistical difference in each of them. conclusion: race, gender, histological subtypes, and radioactive iodine may play an important role as prognostic factors for developing sm among pediatric thyroid cancer survivors. identification of underlying mechanisms that raise the risk of sm is important for both treatment and follow-up strategy. background: the ethical practice of informed consent requires it be both voluntary and understood by the research participant. in pediatric oncology, parents must undergo informed consent to enroll their child with cancer into clinical trials, but often it can be difficult to understand especially for parents with low english proficiency. previous research has shown that parents of children with cancer have difficulty understanding voluntariness, and that parental satisfaction with informed consent does not always correlate with adequate comprehension. objectives: to examine socio-demographic and contextual correlates of comprehension of informed consent, voluntariness, and satisfaction in parents who consented to participation of their child in a cancer clinical trial. we focused on characterizing differences between non-hispanics and hispanics, the fastest growing ethnic group in the u.s. design/method: parents/guardians (n = ) of children aged - years with newly diagnosed cancer, who had consented to participation of their child in a clinical trial for cancer treatment at rady children's hospital-san diego were s of s prospectively recruited. parents completed questionnaires assessing comprehension, voluntariness, satisfaction, health literacy, socio-demographics, and acculturation level, if hispanic. comprehension was surveyed at baseline and longitudinally at months. comprehension, voluntariness and satisfaction outcomes were analyzed by socio-demographics, health literacy, and acculturation level using logistic regression. results: of the participants surveyed, ( . %) were hispanic and ( . %) were non-hispanic. we found that higher health literacy was associated with greater objective comprehension (p< . ), voluntariness (p< . ), socioeconomic status (p< . ), and acculturation (p< . ). hispanics reported lower objective comprehension (p = . ), voluntariness (p = . ), health literacy (p< . ) and ses (p = . ) compared to non-hispanics. spanish-speakers reported lower voluntariness (p = . ), health literacy (p< . ), and acculturation (p< . ) compared to englishspeakers. at the -month follow-up, comprehension in hispanics significantly improved (p = . ) compared to their baseline comprehension. satisfaction was moderately high across all subgroups and was not significantly impacted by socio-demographics, health literacy, or acculturation. in this study, with equivalent numbers of hispanic and non-hispanic participants, we found that hispanic and spanish-speaking parents of children with newly diagnosed cancer had inadequate informed consent comprehension, voluntariness and health literacy despite high satisfaction. our study suggests that hispanics and individuals with limited english proficiency are not making truly informed decisions for their child with cancer. to ensure the ethical practice of research in pediatric oncology, the informed consent and decision-making process must be improved with culturally and linguistically interventions for these underserved populations. memorial sloan kettering cancer center, new york, new york, united states background: pediatric oncology patients undergo repeated bone marrow aspirations and biopsies (bma/bx). these potentially painful procedures can exacerbate anxiety and distress. standard practice at memorial sloan kettering (msk) department of pediatrics is to use propofol, which has amnestic but no analgesic properties. we sought to evaluate whether the addition of local anesthetic would improve patient experience with bma/bx. the purpose of reppair: reducing procedural pain and improving recovery of quality of life (qol) (nct ) is to evaluate the efficacy of local anesthesia with ropivacaine in reducing procedural pain and improving post-procedure qol in pediatric neuroblastoma patients undergoing bma/bx with general anesthesia. reppair is a prospective, randomized, crossover clinical trial that opened for enrollment october . eligible patients were - years old with neuroblastoma. participants were observed on trial for two sequential bm procedures; one procedure with intervention a: propofol alone (pa), and the other with intervention b: propofol plus ropivacaine (p+r). participants were randomized to intervention sequence ab or ba and were blinded to the order of interventions. participants and recovery room (rr) nurses, who were also blinded, followed a standardized postprocedure pain management algorithm. the primary endpoint was percentage of participants requiring opioid analgesia in the hours post-procedure. secondary endpoints included total opioid in hours, non-opioid analgesia use, pain scores, time to first opioid, and short-term qol. qol was assessed by a parent-proxy metric that evaluated pain interference with sleep, physical, emotional, and social recovery. as of january , patients were assessed for eligibility and patients were randomized ( have completed both procedures). for the primary endpoint, a slightly higher proportion of participants required opioid for pa than p+r ( % versus %, p = . ). pain scores in the rr were significantly higher for pa than p+r (median [ th, th percentile]: [ , ] versus [ , ], p = . ). there were no statistically significant differences in total opioid or non-opioid analgesia, -and -hour pain scores, median time to first opioid, or pain interference scores. there were no adverse events. conclusion: preliminary findings of the reppair trial suggest that local anesthesia does not reduce the need for opioid analgesia or improve short-term qol in pediatric patients undergoing bma/bx with general anesthesia. local anesthesia did improve pain scores in the immediate recovery period. final results of this study will help establish evidence-based guidelines and optimize the experience of pediatric patients with bone marrow procedures at our center. background: children with advanced cancer experience a range of symptoms throughout treatment or at end of life, some of which are poorly controlled. minimizing suffering, including effective symptom management, in children with advanced cancer is a central value for pediatric oncology clinicians. patient-reported outcomes have been used in symptomrelated research in pediatric oncology patients; however the majority of literature specific to symptoms during palliative care and end of life for children and adolescents with advanced cancer is based primarily upon medical record reviews and to a lesser extent, patient self-report. the purpose of this study was to prospectively describe symptom frequency, severity, and level of distress in children/adolescents with advanced cancer using patient selfreport and parent proxy. design/method: a prospective cohort design was used for this study. five pediatric oncology institutions from across the united states participated. children and adolescents were eligible to participate if they were - years of age, englishspeaking, and had a diagnosis of advanced cancer, defined as a -week history of progressive, recurrent, or non-responsive disease or a decision not to pursue curative-focused therapy. a modified version of the memorial symptom assessment scale (msas) was used to measure symptom frequency, severity, and level of distress and was administered to child/parent dyads electronically via smartphones every two weeks. information regarding disease status and cancer treatment was collected concurrently. data was analyzed using descriptive statistics and univariate logistic regression analysis. results: a total of children and adolescents and parents participated in the study. the median age of child participants was years, with half being male. the median age of parents was years. the child participants had a variety of primary diagnosis, including: leukemia/lymphoma (n = , %), solid tumor (n = , %), and brain tumor (n = , %). the most frequently reported symptoms by children with advanced cancer and parents were pain (n = / , . %), lack of energy (n = / , . %), and nausea (n = / , . %). presence of disease (p = < . ), recent disease progression (p = . ), and receiving cancer therapy (p = . ) were significant factors on the presence of pain. high intensity cancer therapy was a significant factor on pain frequency (p = . ) and level of distress (p = . ). it is feasible to collect data prospectively in children with advanced cancer regarding symptom frequency, severity, and level distress. clinicians' increased understanding of the symptom experience may promote communication with children and adolescents and timely intervention. more research is needed to understand symptom clusters in children with advanced cancer. vanderbilt children's hospital, nashville, tennessee, united states background: febrile neutropenia (fn) is a frequent occurrence in children undergoing chemotherapy. though guidelines recommend adding a second antibiotic to broad-spectrum antipseudomonal coverage in specific scenarios, augmenting empiric therapy with a second antibiotic is common practice. additional empiric antibiotic (aea) use increases the risk of antibiotic toxicity and future antimicrobial resistance. data clarifying the indications for aea are limited in pediatric patients. objectives: to identify risk factors for gram-positive (gp) and gram-negative (gn) bacteremia in patients presenting with fn to determine situations in which aea use is warranted. design/method: a retrospective chart review was conducted of pediatric severe fn with absolute neutrophil count < / l occurring at a single institution between and . potential a priori risk factors based on clinical reasons for antibiotic expansion were chills, hypotension, mucositis, skin or soft tissue infections (sstis), recent administration of highdose cytarabine (hdac), and a diagnosis of acute myeloid leukemia (aml). potential factors for gn bacteremia were chills, hypotension, mucositis, and abdominal pain. the association between each potential risk factor and gp or gn s of s bacteremia was identified. logistic regression was used for multi-variable analysis. the review yielded episodes. gp bacteremia was isolated in cases ( . %) and gn bacteremia in episodes ( . %). in multivariable analysis, hypotension (or . ( % ci . , . ), p = . ) and sstis (or . ( . , . ) , p = . ) were independently associated with increased risk of gp bacteremia, while mucositis (p = . ), recent administration of hdac (p = . ) and chills (p = . ) were not. ten patients with aml didn't receive hdac, thus the association between aml and gp bacteremia could not be reliably estimated. hypotension (or . ( . , . ), p< . ) and chills (or . ( . , . ), p< . ) were independently associated with a higher risk of gn bacteremia, while mucositis (p = . ) and abdominal pain (p = . ) were not. of the gn infections, ( %) were resistant to cefepime, the empiric agent of choice at our institution. patients with fn with sstis, hypotension, or recent hdac had increased risk of gp bacteremia indicating potential benefit of empiric vancomycin in these settings, while mucositis and chills were not associated with gp bacteremia. hypotension and chills were associated with gn bacteremia, potentially warranting empiric antibiotic expansion, while mucositis and abdominal pain were not. identifying specific indications for aea use in pediatric severe fn use may improve antimicrobial utilization, decrease unnecessary antibiotic use, and improve patient outcomes. background: for children/young adults with incurable high grade gliomas (hggs), like diffuse intrinsic pontine glioma (dipg) or glioblastoma multiforme (gbm), oncologists endeavor to align therapy with patient/family goals of care, but may be influenced by providers' preferences or limited resources. ethical challenges can arise around the perceived purpose, risks and benefits of therapy options, provider conflicts of interest, access to care, deciding decisional priority between patients and families, and conflicts around end-oflife care. objectives: evaluate factors that play into longitudinal decision making for children and young adults with hggs, their families and oncologists using a qualitative approach with ethnographic elements. design/method: eligible patients were aged - with dipg, gbm, or secondary hgg. patient exclusions included: non-english speaking, in state custody, death prior to diagnosis, seen by oncology once, or an oncologist declined participation. key decision making visits (e.g. mri reviews) were serially audio-recorded, along with subsequent : semistructured interviews with patients and/or parents about the decision making process. field notes from clinician meetings, chart notes, and oncologist questionnaires were obtained. discussions and interviews were transcribed and independently coded by three investigators. inter-rater reliability was assessed during code book development. discrepancies were discussed until consensus met. constant comparison analysis with maxqda software continued until thematic saturation. results: twenty-two of eligible patients were approached; agreed to participate. one withdrew upon transferring care. mean age was . years (sd . ); % male, % caucasian, % african american, % hispanic, and % asian. four encounters, ( . hours), were recorded on average per patient. parent/patient interview themes included: ) hope (for a cure, prolonged life, and quality of life), ) importance of physician recommendations, ) importance of support systems (family, community, social media), ) food (as cancer etiology, intervention) ) finances (personal, research funding), ) communication (with medical providers, family, community), ) death, and ) god (beliefs, prayer, existential questions). oncologists desired prolonged quality of life, while patients/families transitioned to that hope from hope for a cure. decisions made in the setting of hggs are multi-factorial, ultimately reflecting the competing values of decision makers. optimism about treatment efficacy is held in tension with poor prognosis, allowing for functional hope. acknowledging patients' and families' shifting hopes allows for changes in goals of care and shared decision making. future work is needed to ) develop preference tools for pediatric patients and families to inform medical providers and ) provide training in communication and shared decision making with oncologists. emory university, atlanta, georgia, united states background: bone marrow transplantation (bmt) is a potentially curative but underutilized treatment for scd. our previous work has shown that there is variation in physician philosophy and practice in considering bmt as a treatment option for patients with scd, and physicians may not discuss this with patients and families as a potential treatment option. in a randomized clinical trial to test the effectiveness of a decision aid for disease modifying therapies for sickle cell disease, adult patients with scd as well as caregivers of adult/pediatric patients were interviewed about how they seek or have sought information related to scd, made decisions about treatments for scd, and identified a treatment option they were interested in learning more about using the decision aid tool. we performed a secondary analysis of these baseline data to understand patient information needs and attitudes regarding bmt as a treatment option for scd. the goals of this analyses was to understand patient and caregivers' attitudes and perceived information needs regarding bmt as a treatment option for scd. we performed an analysis of baseline interviews from caregivers of patients with scd or adult patients from a randomized control trial for a decision aid tool for scd. of the interviews belonged to caregivers of patients with scd. in addition to reviewing interviews for discussion of bmt, we interrogated for mention of terms such as 'bone marrow transplant' or 'cure' or 'stem cell transplant'. interviews were coded using nvivo and analyzed for emerging themes. results: of the baseline interviews, interviews met selection criteria. thirteen of the interviews were with caregivers of pediatric patients, and the remainder were with adult patients, including young adult patients with scd. the majority of participants want to learn about bmt or curative options. in many participants, this was expressed despite knowledge that they were not a likely candidate for transplant. desired information about bmt included eligibility, benefits, risks, long-term effects, quality of life and financial aspects related to bmt. of the patients who discussed how they learnt about bmt, approximately half mentioned that their healthcare provider had not previously mentioned this to them. we then examined knowledge of bmt and attitudes with demographic and clinical variables. patients and caregivers of pediatric patients with scd want to learn about bmt as a treatment option. healthcare providers should consider discussing bmt with their patients with scd. natasha frederick, anna revette, alexis michaud, jennifer mack, sharon bober dana-farber cancer institute, boston, massachusetts, united states background: adolescents and young adults (ayas) consistently identify the need for improved patient-clinician communication on sexual and reproductive health (srh) issues. however, oncology clinicians do not routinely integrate srh conversations with ayas through disease treatment and survivorship. little is known about why these conversations do not take place. objectives: explore aya perceptions of and receptiveness to srh communication with oncology clinicians and to identify barriers and facilitators to these conversations. design/method: semi-structured interviews were held with aya cancer patients and survivors (ages - years, men, women). twelve participants were on active treatment and were within years of treatment completion. interviews were conducted in english by phone or in person. the interview transcript underwent pre-testing with ayas. all interviews were audio-recorded and transcribed verbatim. transcripts were analyzed and summarized by two trained qualitative researchers according to standard comprehensive thematic qualitative analysis methods. analyses were aided by nvivo software. results: ayas perceived existing srh communication between ayas and oncology providers as inadequate. all ayas reported a need for improved srh communication with oncology providers, and three key areas of need emerged: ) general education; ) addressing specific srh issues experienced during treatment and survivorship; and ) understanding the long-term impact of cancer and treatment on srh. ayas felt that current srh discussions are limited and too narrow in scope and scale. ayas reported that most srh conversations focus exclusively on fertility (n = ), usually taking place at the start of treatment. other additional yet limited communication reported was about sexual activity (n = ), contraception (n = ), sexual function (n = ). no ayas reported conversations about potential treatment complications related to sexuality other than infertility. key barriers to srh conversations include patient discomfort initiating conversation (n = ) and presence of family members (n = ), with additional reported barriers including perceived provider discomfort (n = ), lack of rapport with provider (n = ), and age/gender differences (n = ). ayas felt that s of s communication tools such as handouts, brochures, and websites would be helpful facilitators to direct communication from the oncology clinician, and wanted conversations to start before treatment initiation and to continue through treatment and survivorship conclusion: ayas identify a key role for pediatric oncology providers in srh care from diagnosis through survivorship, however multiple barriers interfere with discussions about srh on a regular basis. identified barriers suggest that future efforts should focus on provider education and training in srh and srh-related communication in order to optimize care provided to this unique patient population. background: peripherally inserted central venous catheters (picc) provide secure vascular access in pediatric patients for the delivery of necessary therapies. the ease of placement in the inpatient and outpatient settings has expanded their utilization. however, recent data analyses show a significant increase in venous thromboembolism (vte) risk with the use of picc lines. with its rising use, modifiable risk factors need to be understood for preventative measures. objectives: in this study we aim to understand patient and catheter specific characteristics in relation to the development of vte. design/method: with irb approval, a retrospective interrogation of the electronic medical record and a picc database, at rainbow babies and children's hospital, was completed. the study cohort contained patients < years of age who had a picc line placed between january of and december of . data collected included indication for line placement, line dwell time, location of insertion including blood vessel and extremity, number of attempts at line placement, lumen size and indwelling line length. in addition, we collected number of days to vte formation, associated symptoms and location of vte. chi-squared analyses and fischer's exact test were used where appropriate for statistical analysis. we analyzed ( neonatal) newly placed picc lines. fifty line-associated vte events were found, for an incidence of . %. all vte occurred with the placement of the first picc line. intravenous therapies were the most common reason for line placement. no statistical significance was found between various indications for placement. the most common symptom of vte manifestation was extremity swelling, follow by extremity pain. right extremity picc was found to have a higher incidence of vte. larger catheter lumen sizes (> french) had a higher incidence of vte. we found a mean time of . days to vte detection. we were unable to find any clinical, patient or line specific factors leading to increased vte formation after statistical analysis. special consideration should be given to the duration of picc line use as this may reduce the incidence and comorbities associated with vte. there is still much to be understood about catheter associated vte formation as our analyses indicates the need for prospective data collection on a larger scale in hopes to create guidelines related to catheter use in pediatrics. background: the decision to transfuse a patient is a complex one and is never based solely on a number; however, certain hemoglobin or platelet count thresholds have been proposed in aiding physicians make transfusion decisions. in our hospital, the thresholds for packed red blood cell (prbc) and platelet transfusion in pediatric oncology patients are hemoglobin levels below . g/dl and platelet counts below , /mm (< , for brain tumors), respectively. recently, these thresholds have been questioned and we were asked whether we could safely lower the thresholds to < . g/dl of hemoglobin and < , /mm platelet count objectives: to investigate platelet and hemoglobin transfusion thresholds for oncology patients at children hospital of michigan design/method: retrospective chart review over a -month period, examining platelet and hemoglobin pretransfusion levels for each prbc and platelet transfusion given to oncology patients results: over the course of months, eligible oncology patients (median age years) received transfusions ( prbc transfusions and platelet transfusions). the mean pretransfusion hemoglobin level was . ± . g/dl (range . - . ) (n = ) for total prbc transfusions and this was not different among disease categories (p = . ). patients who had anemia symptoms and signs (n = ) had a slightly lower hemoglobin level compared to those who did not (n = ): . ± . vs . ± . g/dl (p = . ). the mean pretransfusion platelet count was , ± , /mm (range , - , ) for total platelet transfusions (n = ); , ± , /mm in patients with brain tumors (n = ); , ± , in patients with leukemia (n = ); and , ± , in patients with solid tumors (n = ). the mean pretransfusion platelet count was significantly higher in transfusions for brain tumors compared to that in the other disease groups (p< . for both). the mean pretransfusion platelet count was not different among those patients who had bleeding/bruising symptoms ( , ± , , n = ) versus those who did not ( , ± , , n = ) (p = . ). the bleeding/bruising rate was slightly but insignificantly higher in those who had platelet counts < , vs those who had ≥ , ( . % vs . %, p = . ). since most patients develop symptoms of anemia at hemoglobin above g/dl and about / of patients develop bleeding/bruising symptoms at platelet counts above , /mm , our current policy so far reflects a safe threshold for transfusion, and further lowering of the thresholds should be investigated in prospective studies. background: renal impairment is an important complication of childhood cancer and its treatment. serum creatinine level is frequently used as a screening test to monitor renal function; however, patients can have significantly decreased glomerular filtration rate (gfr) with normal serum creatinine. to determine the prevalence of chronic kidney disease (ckd) among children with cancer diagnosis, based on calculated gfr. to compare the difference between using serum creatinine value alone versus gfr in detecting ckd. design/method: retrospective review of medical records of patients, age - years, diagnosed between / - / with solid tumors were analyzed. serum creatinine and calculated gfr using schwartz formula were recorded. ckd as classified by the foundation of kidney disease and outcome quality initiative was used: ckd stage : gfr ( to ml/min per . m ) ckd stage : gfr ( to ml/min per . m ) statistical analysis using spss software v. . chi-squared test for proportions within group, and pearson chi-squared and fisher exact tests for statistical differences between groups. p-value < . was considered to indicate significance results: out of the records reviewed, ( %) were males and ( %) females, with mean age of . ± . years. ( . %) patients received one or more of nephrotoxic chemotherapy drugs; cisplatinum, carboplatinum, or ifosphamide mainly in the non-wilms solid tumors group ( . %) compared to ( . %) in the wilms tumor (wt) group. based on calculated gfr (by schwartz formula) ckd stage /or was diagnosed in ( %) patients with overwhelming majority ( %) were in the mild stage ckd, only ( . %) of those patients had abnormally high serum creatinine levels (p = . ). . % of patients who received nephrotoxic chemotherapy developed ckd, compared to . % in those who did not receive it, (p = . ). despite that only / ( %) of wt group patients received nephrotoxic chemotherapy, yet this group had higher percentage of ckd ( . %) compared to non-wt group ( . %) p = . . significantly lower mean gfr . ± was noticed in the wt group compared to . ± in non-wt group (p = . ) conclusion: high prevalence of mild ckd was found among solid tumor patients. using serum creatinine alone as measure of renal function significantly under estimates renal impairment in those patients. early identification of ckd is easily achieved by using calculated gfr, which can helps providers and care givers to avoid potential nephrotoxic antibiotics, contrast media, nsaids and dehydration that may further deteriorate renal function the university of texas southwestern medical center, dallas, texas, united states background: children with down syndrome (ds) have increased risk of developing leukemia. pediatric patients with ds-associated acute lymphoblastic leukemia (ds-all) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (sct). anti-cd chimeric antigen receptor (car) t-cell therapy, tisagenlecleucel, demonstrated high rates of durable complete remission (cr) and a manageable safety profile in children with r/r b-cell acute lymphoblastic leukemia (b-all). objectives: characterize the efficacy and safety of tisagenlecleucel in pediatric/young adults with ds-all. design/method: pooled data from single-arm, multicenter, phase trials of tisagenlecleucel in pediatric/young-adult patients with r/r b-all (eliana, nct ; ensign, nct ) were analyzed. eight patients with ds-all were enrolled (data cutoff: eliana, november ; ensign, february ). seven were infused with tisagenlecleucel; patient died from all progression and intracranial hemorrhage before infusion. no manufacturing issues occurred during production. / infused patients were male, / had prior sct (age range, - years). / patients achieved cr or cr with incomplete blood count recovery (cri) by day (d) (cr+cri, %); died before d and was not evaluable. analysis of minimal residual disease was negative in bone marrow in responding patients. two patients had cd negative relapses at and months. ongoing remissions in patients without relapse ranged from to months. the safety profile (n = ) appears similar to that in patients without ds in the same trials (n = ). grade (g) / cytokine release syndrome occurred in % ( / ) of patients with ds and in % without ds. rates of other g / adverse events of special interest did not appear to favor a consistent trend between patients with/without ds (febrile neutropenia: % vs %; neurological events: % vs %; tumor lysis syndrome: % vs %). g / infections were not observed in patients with ds ( % vs %). one patient died after infusion due to intracranial parenchymal hemorrhage on d associated with ongoing coagulopathy. time and extent of tisagenlecleucel expansion and long-term persistence were similar between groups. conclusion: this is the first analysis of car t-cell therapy in pediatric patients with r/r b-all and ds. these data suggest that toxicities appear similar to those in patients with b-all without ds, remission rates in ds-all are high, and longterm outcomes with sustained persistence appear promising. further exploration of tisagenlecleucel as an alternative to sct in children with r/r ds-all is warranted. sponsored by novartis. background: hispanic adolescence and young adults are twice as likely to develop acute lymphoblastic leukemia (all) with high risk features as non-hispanic whites. they also have poor prognosis and % higher death rate. b-all with crlf overexpression caused by genetic alteration of the cytokine receptor, crlf is five times more common in this subgroup. approximately % of crlf b-all cases also have ikzf genetic alterations. ikaros is involved in transcriptional regulation of several important genes involved in leukemogenesis. overexpressed casein kinase ii (ck ) impairs functions of ikaros. objectives: understand the molecular mechanisms that regulate crlf expression in crlf b-all. here we present evidence that ikaros-mediated repression of crlf transcription in b-all in hispanic children is regulated by ck . design/method: primary b-all patient samples from hispanic children were used. ikaros retroviral transduction, ikaros shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: ikaros binding to promoter of crlf was confirmed using quantitative chip. functional experiments such as overexpression of ikaros in b-all primary cells results in transcriptional repression of crlf whereas ikaros silencing using shrna resulted in increased transcription. these results suggest that ikaros negatively regulates crlf expression. molecular inhibition of ck with shrna targeting the ck catalytic subunit, as well as pharmacological targeting of ck with cx resulted in transcriptional repression of crlf . ck inhibition was associated with increased ikaros dnabinding to the promoter of crlf . however, the ability of cx to repress crlf is lost or severely reduced, in cells with shrna silencing of ikaros, as compared to cells with intact ikaros. moreover, similar results were noted following treatment with cx in leukemia cells obtained from high risk b-all patients with deletion of one ikzf allele. ikaros binds poorly to promoters of crlf gene in these cells. treatment with cx restores ikaros dnabinding to the promoters of crlf , which is associated with its strong repression. serial qchip analysis of the epigenetic signature at the crlf promoter showed that increased ikaros binding to the crlf promoter, following ck inhibition, is associated with enrichment for the h k me histone modification, which is a marker of repressive chromatin. results demonstrate that crlf expression is epigenetically regulated by the ck -ikaros axis .cx show antileukemic effect via restoration of ikaros tumor suppressor function, resulting in crlf repression suggesting advantage of using ck inhibitors as potential therapeutic approach in crlf altered b-all. results: hypodiploid all (modal chromosome number < and/or di < . ) was identified in patients ( . % of all patients; . % of nci standard risk (sr) and . % of nci high risk (hr)), who were removed from frontline protocol therapy post-induction. overall -year efs and os were . %± . % and . %± . %. transplant status was retrospectively available for / ( %), of whom underwent hsct in cr . five-year efs with hsct was . %± . % vs. . %± . % without (p = . ). -year os with and without hsct was . %± . % vs. . %± . % (p = . ). when corrected for the median time to hsct ( days), there were no significant differences in -year efs or os rates with and without hsct: . %± . % and . %± . % vs. . %± . % and . %± . %. no nci risk group or mrd subset benefitted significantly from cr hsct. sr patients (n = ) had -year efs and os of . ± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. hr patients (n = ) had -year efs and os of . %± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. for those with end-induction mrd < . % (n = ), -year efs and os were . %± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. end-induction mrd-positive patients (n = ) fared poorly with both year efs and os of . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. multivariate regression analysis including nci risk group, mrd, and cr hsct, showed only mrd negativity was significantly associated with efs (hr . , p< . ) and os (hr . , p< . ). patients with hypodiploid all fare poorly, particularly those with end-induction mrd ≥ . %. while cr hsct is a standard treatment approach, it does not confer significant benefit. we were unable to assess bridging therapy prior to hsct, and comparator groups are small. taken together, however, new strategies are urgently needed for these patients. background: ras-pathway mutations are known to play a pivotal role in a significant proportion of myeloid malignancies, including upwards of % of pediatric aml cases. ras-pathway mutations in myeloid malignancy commonly co-occur with mutations of epigenetic regulators, suggesting cooperative leukemogenesis. among the epigenetic modifiers most frequently mutated in myeloid malignancy are regulators of dna methylation. this indicates that the alteration of dna methylation contributes to leukemogenesis. the ten-eleven translocation (tet ) is an epigenetic regulator that plays an important role in regulation of dna methylation through its action of hydroxylation of -methylcytosine, which ultimately leads to passive de-methylation of dna cytosines. in myeloid malignancy, loss of function tet mutation is one of the most frequently co-occurring lesions in ras mutated malignancy. how specifically the altered methylation patterns in ras-pathway driven diseases promotes leukemogenesis is unclear. objectives: we hypothesize in mice with a ras-pathway mutation, that when an epigenetic modifier co-occurs, such as loss of function of tet , this primes stem cells and/or early differentiating progenitors for transformation by preventing the repression of stem cell self-renewal genes, inhibiting differentiation, enhancing ras signaling and leading to leukemogenesis. we have generated a novel murine model with constitutive deletion of tet (tet -/-) combined with an inducible activating krasg d mutation (krasg d/wt). mice have been tracked for evidence of hematologic malignancies and compared to mice with corresponding single genetic lesions. cooperative leukemogenesis will be demonstrated by decreased latency to disease onset, impact on malignancy lineage, in addition to investigating mechanistically through which pathways leukemogenesis may be promoted. results: krasg d/wt/ tet -/-mice demonstrate statistically significant differences in peripheral white blood cell count, hemoglobin, and platelet levels as early as -weeks post ras-pathway activation. peripheral cell lineage analysis demonstrates early skewing toward myeloid differentiation and marked splenomegaly in mice harboring both genetic lesions compared to wild type or mice with single genetic lesions. phospho-flow cytometric analysis reveals increased perk and ps activation in krasg d/wt/ tet -/-sca- enriched bone marrow cells compared to either genetic lesion alone. our study utilizing a murine model to examine how in ras-pathway mutations the addition of a co-occurring epigenetic lesion demonstrates that these lesions appear to cooperate to promote early myeloid differentiation with attendant changes in signaling pathways. this exploration to elucidate the mechanics of ras-pathway mediated disease lay the foundation for identification of patients who may benefit from existing therapies, such as dmtis, or identify new signaling targets for therapeutic exploration. background: the humoral immunogenicity of car , a chimeric antigen receptor (car) with a murine scfv domain developed for treatment with tisagenlecleucel in relapsed/refractory (r/r) pediatric/young-adult acute lymphoblastic leukemia (all), was evaluated in studies. little is known about the presence/impact of preexisting/treatmentinduced anti-murine car (mcar ) antibodies in patients treated with car therapy. objectives: patients from eliana (nct ; n = ) and ensign (nct ; n = ) were evaluated before and after tisagenlecleucel infusion to determine the impact of anti-mcar antibodies on cellular kinetics, efficacy, and safety. design/method: anti-mcar antibodies were determined by flow cytometry and reported as median fluorescence intensity. assay validation included evaluation of the interferences of intravenous immunoglobulin (ivig) treatment with the anti-mcar antibody assay. impact of preexisting and treatment-induced immunogenicity on cellular kinetics, efficacy, and safety was determined. treatment-induced immunogenicity was defined by a positive increase in anti-mcar antibody levels over baseline and was assessed by calculating the fold-change between preexisting (ie, baseline) and postinfusion levels. results: % of patients displayed preexisting anti-mcar antibodies; a similar incidence was detected in healthy volunteer samples during method validation. % of patients developed treatment-induced anti-mcar antibodies. no relationship was identified between tisagenlecleucel expansion (auc - d) and preexisting/treatment-induced anti-mcar antibodies (r < . and r = . , respectively); similar results were seen for cmax. presence of treatment-induced anti-mcar antibodies did not appear to impact transgene persistence or response. kaplan-meier estimates showed that preexisting/treatment-induced anti-mcar antibodies did not appear to impact duration of response or event-free survival. strip plots showed consistent levels of preexisting/treatment-induced anti-mcar antibodies across patients with safety events, including cytokine release syndrome, neutropenia, thrombocytopenia, and neurological events. there was no apparent relationship between treatment-induced anti-mcar antibodies and b-cell recovery categories (≤ months, > and ≤ months, > months, and ongoing sustained aplasia). no association existed between time of b-cell recovery and presence of treatment-induced anti-mcar antibodies. b-cell aplasia requiring ivig occurred following tisagenlecleucel in the majority of patients. the tisagenlecleucel concentration-time profiles in patients with treatment-induced anti-mcar antibodies were categorized by time following ivig administration. time of ivig administration had no impact on in vivo transgene expansion and persistence. we report the first comprehensive assessment of the impact of anti-mcar antibodies on clinical endpoints with car therapy. pediatric/young-adult patients with r/r all had a high frequency of baseline anti-mcar antibodies, and preexisting/treatment-induced anti-mcar antibodies did not impact the cellular kinetics, safety, and efficacy of tisagenlecleucel. cell-mediated immunity studies are ongoing. sponsored by novartis. background: adoptive immunotherapy, using cd engager (cd -eng) t-cells, has shown success in preclinical studies, recognizing and killing acute myeloid leukemia (aml) blasts in vitro and in vivo. cd -eng t-cells secrete bispecific molecules that recognize cd (t-cells) and cd (aml blasts), and are able to direct transduced t-cells and recruit bystander t-cells to kill cd -positive blasts. however, cd -engs do not provide costimulation and have not shown the capability for sequential killing of targets in vitro. we are seeking to improve the expansion, persistence and sequential killing capabilities of cd -engs by genetically modifying these cells with an inducible costimulatory molecule, which can be activated by a chemical inducer of dimerization (cid). we generated a retroviral vector encoding cd -eng and the inducible costimulatory molecule myd .cd linked by a a sequence (cd -eng. a.imc). cd -eng and cd -eng.imc t-cells were generated by retroviral transduction, and their effector function was compared with and without cid. we used flow cytometric analysis to assess transduction efficiency, chromium release assays to evaluate cytolytic activity, and elisa to determine cytokine production. we successfully generated cd -eng.imc tcells and achieved a mean initial transduction efficiency of % that was maintained above % throughout our study period. cd -eng.imc t-cells +/-cid and cd -eng t-cells readily killed cd -positive aml blasts (molm and kg a) in cytotoxicity assays when compared to the cd -negative control (k ). in co-culture assays, cd -eng.imc t-cells secreted increased il- and ifn-gamma in the presence of cid and cd -positive targets (kg a and molm ) when compared to co-culture with cd -positive targets in the absence of cid. in addition, cd -eng.imc t-cells displayed enhanced sequential killing capabilities and ifn-gamma secretion when stimulated weekly with cid and tumor cells at a : ratio when compared to cd -eng t-cells. conclusion: cd -eng.imc t-cells are able to recognize and kill cd -positive aml blasts in an antigen dependent manner. cd -eng.imc t-cells have improved effector function in the presence of cid as judged by cytokine production and their ability to sequentially kill cd -positive target cells. thus, inducible myd and cd costimulation is a promising strategy to improve the effector function of cd -eng t-cells, and warrants further active exploration in preclinical studies. background: eliana (nct ; n = ) is a pivotal multicenter study testing the efficacy of tisagenlecleucel, anti-cd car-t, in children/young adults with r/r b-all. tocilizumab (toci) has been used for management of moderate/severe (grade / ) crs in ≈ % of patients treated with tisagenlecleucel at equivalent doses used in approved nononcological pediatric indications (< kg received mg/kg; ≥ kg received mg/kg [ mg max dose]).( ) crs onset, as graded by the penn grading scale, generally occurred at a median of days (range, - ) after infusion, requiring administration of - toci doses in some patients via a protocol-specific treatment algorithm. toci is a humanized monoclonal antibody that inhibits il- receptor (il- r) signaling. the pharmacokinetics (pk) and pharmacodynamics (pd) of toci in pediatric patients with b-all with carassociated crs have not previously been described. objectives: characterize toci pk/pd for crs management following tisagenlecleucel infusion and describe its impact on cellular kinetics. design/method: toci pk and levels of soluble il- r (sil- r) were determined from serum and quantified using validated assays. maximum toci concentration (cmax) was derived using noncompartmental methods. sil- r, proinflammatory cytokines, and crs resolution time were characterized to describe toci pd. summary statistics and graphical analyses of tisagenlecleucel exposure by number of doses were performed to describe the impact of toci on tisagenlecleucel kinetics in patients responding to tisagenlecleucel infusion. : / patients with crs received the first toci dose at a median of days (range, - ) after crs onset. seventeen patients received dose (range, . - mg/kg); received doses ( - mg/kg); received doses ( - mg/kg), per the crs treatment algorithm. first-dose mean cmax (sd) was ≈ ( . ) g/ml; second dose, ≈ ( ) g/ml. individual patient pd concentration-time profiles showed increased sil- r levels after the first toci dose which remained elevated following the second dose. following toci administration, median time to crs resolution (including fever resolution) was days (range, - ). crs onset coincided with tisagenlecleucel expansion, followed by a peak in serum cytokines, including il- . the geometric mean auc - day and cmax of tisagenlecleucel transgene (by pcr) were % and % higher in tisagenlecleucel-responding toci-treated patients. conclusion: crs symptoms resolved within a median of days after toci administration. toci levels achieved in patients with b-all were similar to reported pediatric nononcological indications (tocilizumab label) and resulted in concentration/time-dependent sil- r increases. transgene continued to expand and persist following toci administration. these data support treatment with toci for crs management. ( ) buechner, eha, . sponsored by novartis. background: in acute myeloid leukemia (aml), mesenchymal stem and stromal cells (mscs) in the bone marrow microenvironment contribute to extrinsically mediated chemo-resistance and are therefore important potential therapeutic targets. the study of patient-derived mscs is at a competitive disadvantage, however, because traditional means of isolating mscs from a bone marrow aspirate interferes with isolating the more highly prioritized leukemic cells. many opportunities to study mscs are therefore missed. objectives: to develop a novel method of isolating mscs using the otherwise discarded portion of a bone marrow aspirate, thereby de-coupling the isolation of primary mscs from the isolation of leukemia cells. design/method: aml patient bone marrow aspirates were obtained prospectively from the children's oncology group. healthy patient marrow was purchased. experimental mscs were isolated from the bottom-most layer (rbc-layer) produced by density-gradient separation of a bone marrow aspirate, which is typically discarded. control mscs were isolated from the buffy coat (mnc layer). non-adherent cells were removed after hours, and adherent cells were cultured at % co with mem-alpha containing % fbs. growth curves were obtained by seeding -well plates with , cells per well. cells were stained using oil red o to observe adipocyte differentiation. results: rbc-layer mscs grow successfully following overnight shipment of the aspirate. identical to mnc-layer mscs, rbc-layer mscs exhibit a fibroblastic morphology and are adherent to plastic. rbc-layer mscs persist in culture up to passages before senescence. they exhibit a slower growth curve relative to mnc-layer mscs, but their overall doubling time is similar at approximately hours. surprisingly, mscs from the rbc-layer exhibit adipocyte differentiation on stimulation, revealing their stem-cell like qualities. we present a method of isolating mscs from the discarded portion of a bone marrow aspirate that does not interfere with the isolation of leukemia cells from the same patient. this portion of the aspirate can be shipped, or can sit for at least hours, without sacrificing its mscs. rbclayer mscs are nearly identical to mscs obtained conventionally. perhaps most importantly, rbc-layer mscs retain a stem-cell like capacity, showing them to be a highly valuable cell population in aml research. future plans include investigating potential selective enrichment of stem-cell mscs in the rbc-layer, which could explain the unexpected difference in growth kinetics. aml researchers now have the opportunity to study this exciting component of the bone marrow microenvironment without sacrificing valuable leukemic cells in the process. background: neutropenia is one of the most frequent side effect of chemotherapy associated with an increase in the risk of infection, especially in the cases when the depth and duration of neutropenia are extended. some genes, as variations of darc, gsdma and cxcl are known to influence white blood cell and neutrophil counts. our previous study conducted in children with acute lymphoblastic leukemia (all), showed that polymorphisms in these genes might play a role in the onset of chemotherapy complications during consolidation and maintenance treatment. objectives: in order to support our previous finding, we have expanded the study to the induction period in a cohort of all children treated at the sainte-justine university health center between july and july . design/method: previous associated single nucleotide polymorphisms (snps) in darc, gsdma and cxcl genes were analyzed for an association with the complications occurring during induction including the duration of low neutrophil count (pnn) and low absolute phagocyte count (apc), proven infections and delay between induction and consolidation phases. results: significant effect was found for all studied polymorphims. minor alleles of darc rs , cxcl rs and gsdma rs were all associated with higher risk of complications during induction treatment, whereas that of darc rs (particularly gg genotype) had a protective effect. the gg genotype of rs was associated with a lower risk of post-induction delay (p = . or = . , %ci . - . ), less frequent febrile episodes (p = . ) and lower number of days with apc/pnn count reduction (p = . for apc< . and p = . for pnn< . ). in contrast, the minor t allele of another darc polymorphism (rs ), was associated with longer apc/pnn count reduction (p = . for apc< . and p = . for pnn < . ), as it was the tt genotype of gsdma rs (p = . for apc< . and p = . for pnn< . ). the patients with the gsdma rs had also a higher risk of documented febrile episodes (p = . or = . %ci - . ). the aa genotype of rs cxcl was associated with a higher risk of post-induction delay due to infection (p = . , or = . , % ci . - . ). conclusion: this complementary study confirmed our previous results, showing overall that variations in darc, gsdma and cxcl genes influence the onset of chemotherapy complications in pediatric all, regardless of treatment phases. these polymorphisms might be useful pharmacogenetics markers possibly guiding an adjustment of chemotherapy intensity. background: pediatric acute myeloid leukemia (aml) has a poor survival rate of about % and there is an urgent need for newer targeted therapies. car t-cell based therapies are effective against all but similar therapies against aml are still under development. recent clinical trials have highlighted the concerns about toxicity and therapy related deaths from car t-cells. antigen selection is the key factor determining the specificity, efficacy and toxicity of car t-cells. while contemporary adoptive t-cell therapies use monoclonal antibodies against tumor associated antigens we employed the naturally occurring flt ligand (fl) to target aml cells expressing flt receptors. flt receptor is expressed on multipotent and myelomonocytic progenitors as well as myeloid leukemia cells. to generate fl containing chimeric tlymphocytes designated flcar t-cells and to evaluate their efficacy against aml cells. design/method: flcar was constructed by fusing the coding sequences of the human fl, cd costimulatory domain, and cd -zeta chain (intracellular region) in series. it was then cloned into the phiv-egfp lentiviral vector for expression in cell lines and primary t cells obtained from healthy donors. the empty phiv-egfp vector was used as a negative control. flcar was expressed on both cd + and cd + t-lymphocytes, confirmed by western blot. cell cytoxicity was evaluated by co-culturing flcar t-cells and aml cells followed by flow cytometric analyses. cytokine production was assessed by analyzing expression of interleukin- using quantitative rt-pcr. results: flcar t-cells were generated from cd + jurkat and cd + tk- cell lines with up to % lentiviral transduction efficiency. the efficiency for primary t cells was lower ( - %). flcar was expressed as a ∼ kda protein in cells and was partially phosphorylated on tyrosine. the expression of flcar on lymphocytes lead to increased basal il- expression in the cells. this was further augmented (by > folds) upon co-incubating flcar t-cells with flt expressing target cells. jurkat cells, tk- cells and primary human t cells expressing flcar suppressed the growth of flt -expressing aml cell lines and primary aml cells in vitro. notably, flcar t-cells generated from healthy donors caused strong inhibition of aml cells even at a lower transduction efficiency. in vivo experiments using nsg-sgm mice xenografted with human aml cells are underway. our data demonstrate that flcar can be effectively expressed on t-lymphocytes and mediate potent cytotoxicity against flt -expressing aml cells in vitro. being a completely human derived chimeric protein, it represents a promising candidate for further therapeutic development. holly pacenta, kelly sullivan, ahwan pandey, kelly maloney, joaquin espinosa children's hospital colorado, denver, colorado, united states background: individuals with down syndrome (ds) have a -fold higher risk of developing acute lymphoblastic leukemia (all) than the typical population. there are several important differences between all in individuals with ds (ds-all) and all in individuals without ds (nds-all): first, patients with ds-all have a lower percentage of favorable cytogenetic features compared to nds-all. second, patients with ds-all are more likely to have activating mutations in jak , crlf overexpression, and ikzf deletions. despite these clear genotypic differences, this knowledge has not yet been exploited for therapeutic purposes in ds-all. when outcomes for ds-all are compared to nds-all with similar cytogenetic features, the survival rates are similar. however, individuals with ds-all have an increased risk of treatment-related mortality (trm). current therapy for ds-all is similar to that for nds-all, with the exception of small changes to decrease toxicities that are more prevalent in ds-all. it was recently identified that interferon signaling is constitutively activated in healthy individuals with t . we hypothesize that aberrant interferon signaling could play a role in the unique leukemias observed in ds patients. objectives: to identify differences in gene expression and intracellular signaling cascades that are unique to individuals with ds-all, relative to both nds-all and healthy individuals with ds that can be exploited for therapeutic use. design/method: bone marrow samples were obtained from ds-all patients and matched nds-all patients based on clinical characteristics and genetic features. rna sequencing of these samples was performed and a total of samples were used for the transcriptome analysis ( ds-all vs. nds-all). the differential expression data was generated by deseq and analyzed using ingenuity pathway analysis. the analysis revealed that the chromosome genes that have been implicated in leukemogenesis are not differentially expressed in the ds-all samples, relative to nds-all. an inflammatory signature was identified, which included interferon gamma as an upstream regulator with predicted activation in ds-all. this finding is consistent with prior observations from healthy individuals with ds. other examples of results with potentially actionable targets include the upregulation of several genes in the ras pathway and genes involved in histone methylation. the increased interferon signaling seen in healthy individuals with ds was also identified in ds-all. this may contribute to the development of mutations in inflammatory pathways such as jak and crlf in ds-all. targeting these common pathways with small molecule inhibitors may have a therapeutic benefit in ds-all. cincinnati children's hospital medical center, cincinnati, ohio, united states background: next-generation sequencing (ngs) guides precision medicine approaches in oncology using therapies targeting molecular alterations found within an individual cancer. increased availability of ngs coupled with a proliferation of targeted drugs in development heightens the need for reliable pre-clinical animal models. here we report a patientderived xenograft (pdx) system with integrated molecular profiling for pre-clinical testing of conventional cytotoxic and novel targeted agents. objectives: to utilize ngs from patients with pediatric leukemia to guide rational pre-clinical trials in pdx leukemia avatars, and to determine pdx mice tolerance of and response to cytotoxic and targeted therapies. pediatric acute lymphoblastic leukemia (all) samples were obtained in adherence to an irb-approved protocol and xenografted into nod/rag/interleukin- (il- )rg (nrg) mice. ngs was performed clinically using the foundationone® heme panel. a de novo all sample bearing mutations involving jak , crlf , ntrk , cdkn a/b, ptpn and wt was used for pre-clinical testing. thirty-seven nrg mice were transplanted with million patient cells/mouse via iv injection. standard -drug induction chemotherapy was administered consisting of vincristine, dexamethasone, pegaspargase, and daunorubicin [vxpd, n = mice], in comparison to vehicle control [n = ]. parallel pdx cohorts were treated with single agent targeted therapies based on ngs findings, including ruxolitinib [n = ], crizotinib [n = ] and loxo- [n = ]. the four-week treatment period began on day + from transplant after confirmation of engraftment. following completion of therapy, residual disease burden was analyzed by flow cytometry (hcd +, mcd -cells) in the bone marrow [bm] . to date, pdx models have been established using over thirty ngs-profiled pediatric all samples, including six samples bearing philadelphia (ph) chromosome or phlike mutations. pre-clinical testing was performed in a repre- conclusion: ngs reveals concomitant mutations in ph-like all that may represent additional targets for therapy, or predict tyrosine kinase inhibitor (tki) resistance. we show that all xenograft nrg mice can tolerate a -week multi-agent cytotoxic chemotherapy induction regimen, as well as rational targeted agents, and serve as a robust pre-clinical model for precision medicine trials. background: osteonecrosis is a well-characterized all therapeutic toxicity attributed to glucocorticoids, asparaginase, and methotrexate that disproportionately affects adolescents. in ccg- , alternate-week dexamethasone during double delayed intensification (di) reduced osteonecrosis vs continuous dexamethasone with single di in rapid early responders (rer) ≥ y. to compare efs and os between hr-all patients with vs without osteonecrosis. design/method: hr-all patients - y on aall ( - ) received cog augmented therapy with a × randomization to: ( ) induction dexamethasone ( mg/m d - ) vs prednisone ( mg/m d - ), and ( ) interim maintenance (im) high-dose methotrexate (hdm) vs escalating-dose methotrexate/pegaspargase (ema). rer received single, and slow early responders (ser) double, im/di. initially, all received monthly dexamethasone maintenance pulses, patients ≥ y received di alternate-week dexamethasone, and patients ≤ y received di continuous s of s dexamethasone. there were osteonecrosis-related amendments: after / all patients ≥ y received di alternateweek dexamethasone; after / all patients ≥ y were assigned to induction prednisone, and all patients received di alternate-week dexamethasone and maintenance prednisone pulses. results: osteonecrosis was confirmed in / patients. the y cumulative incidence (ci) was . % overall and increased with age: - y . %, - y . % (alternateweek dexamethasone . % vs continuous dexamethasone . %; p< . ), ≥ y . % (p< . ). among randomized rer patients ≥ y, ci differed by glucocorticoid (dexamethasone . % vs prednisone . %; p = . ) but not methotrexate assignment (hdm . % vs ema . %; p = . ). among randomized ser patients ≥ y, ci was . % with no difference by regimen. results were similar for patients ≥ y. in the entire study population, patients with osteonecrosis had superior y efs ( . % vs . %; p< . ) and os ( . % vs . %; p< . ) than those without osteonecrosis. y efs was significantly higher among randomized patients ≥ y with vs without osteonecrosis ( . % vs . %; p< . ); this finding was present in different age ranges (≥ y, ≥ y, ≥ y) and rer/ser subsets within each, especially in the ≥ y rer ( . % vs . %; p = . ) and ser ( . % vs . %; p< . ) cohorts. across groups, asparaginase allergy was significantly associated with reduced osteonecrosis risk (≥ y: hr . ; p = . ). patients who develop osteonecrosis have significantly increased efs and os, suggesting host differences that increase sensitivity to develop osteonecrosis and render all cells more chemo-responsive. pennsylvania state university, hershey, pennsylvania, united states background: cdc (cell division cycle protein ) belongs to rho family of small gtpases in ras-oncogene superfamily. pro-oncogenic role of overexpressed cdc in ras driven solid tumors are well known. however, role of cdc in leukemia is yet to be established. ikzf encodes ikaros protein which has important role in regulation of lymphoid development and tumor suppression in leukemia. casein kinase ii (ck ) oncogene is overexpressed in leukemia. ck impairs ikaros function which can be restored by using ck inhibitors. objectives: to investigate role of cdc in leukemia and regulation of cdc by ikaros and ck in b-cell acute lymphoblastic leukemia (b-all). shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: cdc is identified as one of the ikaros target genes by analysis of genome-wide dna binding of ikaros using chip-seq and qchip in b-all primary cells. expression of cdc was also noted to be higher in all patient samples compared to normal bone marrow. functional experiments showed that ikaros overexpression via retroviral transduction results in transcriptional repression of cdc . ikaros silencing using shrna resulted in increased expression of cdc . these data suggest that ikaros negatively regulates transcription and expression of cdc . ck directly phosphorylates ikaros and impairs its function as transcription factor. we noted that molecular inhibition of ck via sirna as well as treatment with specific ck inhibitor, cx also decreases expression of cdc . treatment with cx of primary b-all with ikaros haploinsufficiency restores ikaros binding to cdc promoter and represses cdc expression. however, this effect is evident only in presence of ikaros. treatment with cx in ikaros silenced (ikaros shrna) cells showed no change in expression of cdc . these results emphasizes the importance of ikaros in regulating cdc expression. furthermore, we analyzed the changes in epigenetic signature at the cdc promoter following treatment with cx . results show that loss of histone marker of open chromatin (h k ac) and increased histone marker for repressive chromatin (h k me ), at the cdc promoter. these data suggest that ikaros transcriptionally represses cdc via chromatin remodeling. a specific cdc inhibitor, ml showed cytotoxic effects on primary b-all cells. conclusion: cdc may have important role in hematologic malignancies. expression of cdc in b cell all is regulated by ikaros and ck . these results suggest that targeting cdc could be a potential therapeutic strategy in leukemia. caitlyn duffy, laura hall, justin godown, koyama tatsuki, scott borinstein monroe carell jr. children's hospital at vanderbilt, nashville, tennessee, united states background: systemic corticosteroids are widely used as treatment of acute lymphoblastic leukemia (all) and lymphoblastic lymphoma. there are anecdotal reports of bradycardia in pediatric patients receiving corticosteroids, but a more extensive analysis of this effect is needed. objectives: the aim of this study was to describe the incidence, severity, and timing of steroid-induced bradycardia and document any adverse events associated with bradycardia. design/method: we performed a retrospective review of all newly diagnosed patients at our center ( - ) with all/lymphoblastic lymphoma who received corticosteroids (dexamethasone - mg/m /dose or prednisone mg/m /dose) during induction chemotherapy. patients were excluded if they had a pre-existing cardiac abnormality or if they received prior corticosteroids. the average hour heart rate (hr) was assessed for the period prior to initiating steroid therapy and for the hour period surrounding the nadir following steroid administration. the degree and time of steroid induced bradycardia was assessed. adverse patient events and concomitant medication use was documented to identify other contributing factors to bradycardia. a total of children ( females, males, months- years) were included in the analysis with demonstrating a decrease in mean hr following steroid administration. median hr decrease was . beats per minute (quartiles . - ) from prior to initiating steroids to surrounding nadir. sixty one percent developed bradycardia less than or equal to the st percentile for their age range. nadir occurred doses (range - ) into treatment, which corresponded to hours ( - ) after initiation of therapy. of patients who experienced bradycardia, % were associated with dexamethasone rather than prednisone. hr nadir was not associated with other vital sign abnormalities. after completion of induction chemotherapy, % of patients had documented resolution of bradycardia with hr greater than the th percentile for age. it was observed that the children who continued to have relatively low hr were often younger ( months- years old). examination of nadir hr during subsequent hospitalizations in which steroids were not being administered (excluding hr during procedural sedation) did not demonstrate a significant incidence of bradycardia. concomitant opioid, beta-blocker, or other medication exposure did not contribute to the incidence of bradycardia. corticosteroid-induced bradycardia is extremely common in children, teenagers, and young adults with all receiving induction chemotherapy. bradycardia was not associated with clinical adverse events and resolved after completion of corticosteroid treatment. therefore, further cardiac assessment may not be warranted in the presence of bradycardia suspected to be secondary to steroid administration. baylor college of medicine, houston, texas, united states background: survival in newly diagnosed pediatric acute myeloid leukemia (aml) is approximately %; however survival falls dramatically if a patient relapses. currently, approximately one-third of patients with pediatric aml relapse on standard chemotherapy regimens. aml cells are exposed to proteotoxic stress at baseline due to their rapid and inefficient metabolism; proteotoxic stress increases after chemotherapy due to accumulation of reactive oxygen species resulting in misfolded proteins. this leads to activation of cell stress pathways, such as the unfolded protein response (upr) in the endoplasmic reticulum. because an activated upr can make cells more sensitive to proteotoxic stress, we hypothesize that upr activation correlates with response to chemotherapy. objectives: determine the status of upr in pediatric aml and its correlation with chemosensitivity; design/method: peripheral blood samples from pediatric patients with aml were collected at the start of induction chemotherapy, - hours (h) and h post initiation of systemic chemotherapy. tumor cells were sorted from peripheral blood mononuclear cells. expression of upr proteins was determined by chemiluminescence using an automated capillary electrophoresis system. clinical correlations were performed using an annotated database. we measured five upr proteins: grp (glucose regulated protein kda), phospho-eif , inositol-requiring enzyme (ire ) and activating transcription factor (atf ). patients with aml had - times higher expression of upr proteins (except atf ) at baseline than normal controls. grp -the key upr driver-had the highest level of protein expression in myeloid blasts. there was a wide variability in the level of baseline upr expression. eight out of samples expressed > fold increase in grp above those with the lowest grp levels. similarly, and patients respectively, had a > fold increase in peif and ire , compared to patients with low basal expression of these upr proteins. in our limited sample set, there was a trend towards lower overall survival (os) and event-free survival in patients with low baseline grp and ire . conclusion: upr has a variable expression at baseline in pediatric aml, with a trend towards lower os in patients with a low basal grp and low ire expression, suggesting less chemosensitivity in this subgroup. conversely, it is possible that blasts with an upregulated upr prior to chemotherapy manage proteotoxic stress less effectively, having faster apoptosis and hence a better response to chemotherapy in patients with a high basal upr. we are currently expanding our findings in a larger cohort of patients enrolled in the children's oncology group aaml protocol. background: children with newly diagnosed acute lymphoblastic leukemia (all) undergo chest x-ray (cxr) evaluation during initial diagnostic workup to ensure safe airway management. however, to our knowledge, no systematic assessment of cxr findings has been reported. objectives: to evaluate cxr findings at diagnosis of all and their associations with clinical characteristics. we reviewed the cxr findings at diagnosis of all in patients treated on the total xv and xvi protocols at st. jude children's research hospital. findings were evaluated for associations with clinical characteristics at presentation, and the clinical management of mediastinal masses was reviewed. mediastinal masses were seen in ( . %) of patients evaluated and were more common in older patients (mean age, . years) than in younger patients (mean age, . years) (p = . ), in males than in females (p = . ), and in patients with t-all than in those with b-all (p< . ). also associated with mediastinal masses were a higher white blood cell count (wbc) at diagnosis (mean, . × /l) (vs. a lower wbc; mean, . × /l) (p< . ), cns involvement (vs. no involvement) (p = . ), and standard/high-risk disease (vs. low-risk disease) (p< . ). other cxr findings included pulmonary opacity ( patients [ . %]), bronchial/perihilar thickening ( patients [ . %]), cardiomegaly ( patients [ . %]), and osteopenia/fracture/periosteal lesions ( patients [ . %]). pulmonary opacity was more common in younger patients (mean age, . years) than in older patients (mean age, . years) (p = . ) and in those with t-all (vs. b-all) (p = . ). bronchial/perihilar thickening, cardiomegaly, and osteopenia/fracture/periosteal lesions were also more common in younger patients than in older ones (p< . , p = . , and p< . , respectively) and in those with low-risk disease (versus standard/high-risk disease) (p< . , p = . , and p = . , respectively). of the patients with a mediastinal mass on cxr, underwent a confirmatory chest ct scan, and ( . %) were confirmed to have a mediastinal mass. notably, patients ( . %) had airway compression, and compression of venous structures was identified in of patients ( . %) who received iv contrast. the clinical course was evaluated for patients with mediastinal masses detected by cxr. fifty patients ( . %) required icu admission (mean stay, . days). general anesthesia was used for only patients ( . %), and patients ( . %) had a less invasive peripherally inserted central catheter. no deaths occurred in the acute phase. conclusion: cxr at the time of all diagnosis can detect various intrathoracic lesions and is helpful in planning initial diagnostic workup and management. background: mertk is a receptor tyrosine kinase that is aberrantly expressed in % of pediatric primary aml samples. mertk inhibition with the small molecule tyrosine kinase inhibitor (tki) mrx- decreases tumor burden and prolongs survival in aml xenografts. while treatment with mrx- reduces leukemia in the peripheral blood, it is less effective in the bone marrow, suggesting a role for the marrow microenvironment in therapeutic resistance. the jak/stat pathway has been implicated as a mediator of bone marrow derived resistance to tkis and inhibitors of this pathway are in clinical development for the treatment of aml. to determine the role of the bone marrow stromal niche in mediating resistance to mertk inhibition and to evaluate the efficacy of combined mertk and jak/stat inhibition. design/method: aml cell lines were cultured with or without the hs stromal cell line or hs conditioned medium, then treated with mrx- +/-the jak/stat inhibitor ruxolitinib, or control. induction of apoptosis and cell cycle arrest in aml cells was measured by flow cytometry. expression of h ax and total and phosphorylated stat were determined by immunoblot. results: co-culture with stromal cells significantly reduced aml cell death and g /m phase arrest in response to treatment with nm mrx- compared to no co-culture (cell death: . % versus . %, p< . ; g /m arrest: . % versus . %, p< . ). g /m arrest was accompanied by an increase in h ax expression which was similarly abrogated in co-culture. conditioned medium did not provide protection from mrx- induced apoptosis, g /m arrest, or h ax induction. mrx- inhibited stat phosphorylation but direct co-culture and conditioned medium potently increased basal stat phosphorylation which was not inhibited by mrx- . to determine whether the observed induction of stat phosphorylation was functionally relevant, cocultures were treated with both mrx- and ruxolitinib. while ruxolitinib potently inhibited the phosphorylation of stat in the presence of co-culture, combination treatment did not overcome stromal mediated protection from mrx- induced apoptosis. similarly, the addition of exogenous gm-csf induced stat phosphorylation but did not yield protection from mrx- functional effects in the absence of co-culture. together these data support a model whereby direct cell-cell contact with stromal cells in the bone marrow niche protects leukemia cells from mrx- induced apoptosis, cell cycle alterations, and dna damage. while co-culture potently induces phosphorylation of stat in leukemia cells, this is neither necessary nor sufficient for stromal-cell mediated protection from mertk inhibition and combined treatment with jak/stat inhibitors is unlikely to be therapeutically efficacious. background: mercaptopurine ( -mp) is an immunosuppressive thiopurine drug that is a key component of acute lymphoblastic leukemia (all) treatment. -mp is metabolized into -thioguanine ( -tgn), which is responsible for anti-leukemic effects, as well as -methylmercaptopurine nucleotides ( -mmpn/ -mmp), which are associated with hepatotoxicity. some patients preferentially metabolize -mp to -mmpn/ -mmp, increasing their risk for hepatotoxicity and potentially reducing anti-leukemic effects. hepatotoxicity can cause interruptions or delays in therapy that may jeopardize cure rates. allopurinol has been increasingly used in patients with inflammatory bowel disease (ibd) to shunt -mp metabolism toward -tgn and away from -mmpn to minimize hepatotoxicity and preserve therapeutic effects. objectives: this retrospective chart review expands upon our previously published case series of three patients with all in whom allopurinol was successfully used to redirect -mp metabolism. twelve additional patients have subsequently received allopurinol and -mp combination therapy at texas children's hospital. data from this larger patient sample, with longer follow up, is being analyzed to increase knowledge of the effectiveness and longitudinal effects of adding allopurinol to -mp to reduce risk of hepatotoxicity. design/method: data were abstracted from the electronic medical records of patients with all treated at texas children's hospital from to present, who had been found to have evidence of altered -mp metabolism and in whom allopurinol was added to -mp therapy due to concern for risk or recurrence of hepatotoxicity. metabolite levels, -mp dose, and alanine transaminase (alt) prior to initiation of allopurinol and approximately weeks later were compared. wilcoxon signed-rank test was applied for statistical analysis. : after the addition of allopurinol, patients experienced a significant decrease in mean levels of -mmpn (p = . ), correlating with a significant decrease in mean alt (p = . ). with the initiation of allopurinol, the mean -mp dose was decreased from to mg/m /day over an -week period. mean -tgn levels increased (p = . ). in follow up beyond weeks, no patients had further holds in -mp due to hepatotoxicity. addition of allopurinol appears to shift metabolism from -mmpn toward -tgn, with increases in mean -tgn levels despite a decrease in mean -mp dose. this may limit negative side effects, thus resulting in fewer gaps in therapy and possible improved outcomes. further analysis of -mp dose titration and effects on anc over time as well as effects on overall survival is ongoing. prospective background: alterations in epigenetic patterning are a fundamental feature in acute myeloid leukemia (aml). treatment with dna methyltransferase inhibitors (dnmti) yields responses in aml, but the molecular mechanisms underlying this effect are poorly understood. in prior work, we demonstrated induction of genes involved in the pirna rna (piwi) silencing pathway as a common gene feature of aml cell lines treated with decitabine. the piwi pathway is an rna silencing system, distinct from classical small rna transcriptional silencing, responsible for transposon-silencing in gametogenesis; emerging data suggest a role for this system in somatic cells. based on these data, we postulate that piwi induction plays a crucial role in aml recovery following demethylation and that disruption of this pathway would modulate response and/or recovery from decitabine treatment. to assess the effect contribution of the pirna pathway response following dnmti treatment in aml. design/method: to choose target genes in the pirna pathway for disruption, molm cells were first treated with escalating doses of decitabine. using quantitative rt-pcr, the dose-dependent expression of several pirna-associated genes were analyzed. two genes, mael and piwil , were selected for disruption experiments based on preliminary data suggesting decitabine dose-dependent responses. molm cells were transduced with shrna targeting these genes using a lentivirus delivery system with selection in puromycin. knockdown efficiency was assessed by rt-qpcr. to determine how gene disruption affected cell growth, knockdown cells were treated with decitabine nm. proliferation was assessed by celltiter glo assay following decitabine treatment. clonogenic potential was assessed by colony forming assays of transduced cells after treatment with decitabine at nm and nm. results: following decitabine exposure in molm , there was a markedly increased expression of mael and piwil compared to untreated cells ( : and : , respectively) . thus, these were the candidate genes chosen for disruption. of mael shrna constructs, two resulted in a % relative expression of mael compared to controls. of the piwil shrna constructs, the best knockdown showed % relative expression. there were no significant differences in proliferation or clonogenicity of stably selected mael or piwil knock-down molm cells following decitabine treatment. using gene knockdown procedures, mael and piwl do not appear to have a marked effect on growth and response to decitabine treatment in molm . however, these results may be limited by inefficient knockdown using shrna targeting methods. further work using a cas /crispr based inactivation of these genes is ongoing. children cancer hospital cairo, egypt background: hypodiploidy < chromosomes is very uncommon and have particularly poor outcomes in childhood acute lymphoblastic leukemia (all). it is subdivided into: near-haploid ( - chromosomes), lowhypodiploid ( - chromosomes) and high-hypodiploid ( - chromosomes). to determine if minimal residual disease (mrd) can identify a group of patients with better prognosis in the hypodploid population who can be treated with intensive chemotherapy alone. design/method: a retrospective study that included all patients under age of diagnosed as hypodiploid b-precursor all during the period between january -december and treated at children's cancer hospital egypt on sjcrh total study-xv for ir/hr all. sixteen patients had < chromosomes ( nearhaploid and low-hypodiploid), constituting % of all pediatric patients with b-precursor all during the study period. patients with near-haploid all had a median age of years (range - ), initial leukocyte count (wbc) median of . × /l (range . - . ), ( . %) were males and / ( . %) had hr-nci criteria. four patients ( . %) are alive in complete remission(cr) (range - months, median ), one died in induction and ( . %) had hematological relapse (range . - months, median ). patients with low-hypodiploid all had significantly older age (median years, range - ), median wbc . × /l (range . - . ), / ( . %) were males. one patient ( . %) is alive in cr, one died in induction, one failed to achieve cr post-induction and patients( %) had hematological relapse (range . - . months, median . ). mrd< . % by flow-cytometry on day- and end of induction was achieved in / ( . %) and / patients( %) with near-haploid, compared with / ( . %) and / patients( %) with low-hypodiploid; respectively (p = . , p = . ;respectively). allogeneic transplantation was performed during initial remission only in mrd negative patients (one relapsed and one is in cr) and in the patient with induction failure (relapsed post-transplant). five of the total six patients who had negative mrd on day- and end of induction are alive in cr ( / with chemotherapy alone). all patients with negative mrd at end of induction but with mrd levels≥ . % on day- (range . - . %) relapsed as well as all patients with detectable mrd at the end of induction. the difference in relapse was statistically significant in relation to negative-mrd on day- (p = . ), but not at end of induction(p = . ). conclusion: children with hypodiploid all and negative mrd on day- of induction are highly curable with intensive chemotherapy alone, while patients with negative mrd at the end of induction and detectable mrd on day- had dismal outcome. background: overall survival in pediatric acute myeloid leukemia (aml) has plateaued between - %, with death during induction chemotherapy seen in - % of patients. respiratory complications contribute to morbidity and mortality in pediatric aml induction, however the incidence, patterns, and predictors of respiratory adverse events (aes) during this period are unknown. to estimate the incidence of respiratory aes during induction therapy for de novo pediatric aml, to characterize and grade these respiratory aes, and to identify predictors of respiratory ae development. we conducted a retrospective longitudinal study from presentation to day in institutional de novo pediatric aml patients (≤ years) between march and december . outcomes included any nci ctcae grade - respiratory ae or death from another cause. demographic, disease, and treatment-related data were abstracted. the most specific, best-fitting ctcae category and grade for each ae was determined. descriptive statistics, survival analysis, multivariable logistic regression analysis, and time-toevent distributions were performed (sas v . , cary, nc) . among eligible patients, . % (n = ) experienced discrete respiratory aes. incidence of grade - aes was . % (n = ). a bimodal time-to-event distribution demonstrated peaks at treatment days and . induction death occurred in . % (n = ) including deaths from respiratory failure associated with disseminated fungal disease. in univariate analysis, those experiencing aes differed significantly in regards to older age at diagnosis (p< . ), higher initial wbc (p = . ), higher initial peripheral blast percentage (p = . ), coagulopathy at diagnosis (pt (p = . ), d-dimer (p = . )), fluid overload status (p< . ), occurrence of infection (p = . ), and occurrence of tumor lysis syndrome (tls) (p = . ). patients with hyperleukocytosis (p = . ), fluid overload (p< . ), and fab m morphology (p = . ) each had a significantly decreased probability of completing the follow up period without experiencing a respiratory ae. on multivariable analysis, fluid overload (aor . [ % ci: . - . ) and older age (aor . [ % ci: . - . ) were significantly associated with ae occurrence when gender, hyperleukocytosis, tls, and infection status were held constant. we describe a high incidence of respiratory aes during pediatric aml induction. fluid overload and older age at diagnosis are independently associated with ae development when controlling for other proposed risk factors. interventions focused on conservative fluid management and offset of fluid overload should be explored in newly diagnosed pediatric aml in an effort to reduce respiratory complications during induction. overall, all survival rates are outstanding and have continued to improve with risk-adapted therapy. the most striking improvement occurred in t-all where -year os rates now exceed % and parallel b-all. survival improvements, however, have not been observed uniformly across all subgroups. while the gap in outcome differences narrowed among blacks, outcomes for hispanics have remained static. further, no improvements in survival were observed in infants or ayas and new treatment approaches have been implemented for these populations. background: acute myeloid leukemia (aml) accounts for approximately % of new childhood leukemia cases. chest x-ray (cxr) is performed in all newly diagnosed aml cases to evaluate the safety of airway management for anesthesia during diagnostic procedures; however, cxr results in pediatric patients with aml have not been described. objectives: the primary objective was to evaluate cxr findings at diagnosis in patients with aml. the secondary objectives included assessing associations between cxr findings and clinical characteristics, with the overall goal of aiding in the evaluation of the use of cxrs as an initial diagnostic study in pediatric patients with aml. design/method: cxr findings and clinical characteristics were evaluated in patients with newly diagnosed aml who were enrolled in one of three protocols at st. jude children's research hospital (aml , aml , and aml ). the findings were categorized based on radiologic reports. further, the associations of these findings and clinical characteristics were evaluated. we evaluated cxr findings in a total of patients: from aml ; from aml ; and from aml . common cxr findings were pulmonary opacity (n = , . %), bronchial/perihilar thickening (n = , . %), splenomegaly (n = , . %), mediastinal mass and lymph nodes (n = , . %), pleural effusion/thickening (n = , . %), demineralization/fracture/periosteal lesions (n = , . %), scoliosis (n = , . %), and granulomatous disease (n = , . %). three cxr findings were associated with younger age at diagnosis: pulmonary opacity (median age, . years in patients with positive findings vs. . years in those with negative findings, p< . ), bronchial/perihilar thickening (median age, . years vs. . years, p< . ), and demineralization/fracture/periosteal lesions (median age; . years vs. . years, p = . ). two cxr findings were associated with older age at diagnosis: scoliosis (median age, . years vs. . years, p< . ) and granulomatous disease (median age, . years vs. . years, p = . ). higher white blood cell counts (wbcs) at diagnosis were associated with cxrs showing pulmonary opacity (median wbc; . × ^ /l vs. . × ^ /l, p = . ) or splenomegaly (median wbc; . × ^ /l vs. . × ^ /l, p = . ). french-american-british (fab) m /m subtypes were more frequently associated with pulmonary opacity compared with others (p< . ). we did not find significant differences between female and male patients. conclusion: cxr in patients with newly diagnosed aml showed a variety of thoracic, abdominal, and bony lesions that are important for the initial evaluation and management. pulmonary opacity was the most common finding and was frequently seen in patients who were younger or had higher wbcs at diagnosis or fab m /m . background: children diagnosed with acute lymphoblastic leukemia (all) require a central venous catheter (cvc) to administer chemotherapy safely. both external and internal cvcs carry risks of complications including thrombosis, infection, and possible replacement. internal catheters, such as a port, are generally used for the majority of patients for the duration of treatment since therapy lasts for several years. many institutions place a port at the time of diagnosis. other institutions prefer to start induction therapy via placement of a peripherally inserted central catheter (picc) and defer port placement until the completion of induction therapy due to concerns of increased risk of infectious complications with port placement. objectives: to compare rates of common cvc associated complications by type of cvc placed at start of induction therapy in children treated for newly diagnosed all at the jimmy everest center (jec) at the university of oklahoma health sciences center. design/method: a retrospective chart review analyzed data from newly diagnosed all patients treated at the jec between - . data was collected on complications including thrombosis, bacteremia, insertion site infection, cvc malfunction and need for removal. data collection began at the start of induction and was completed at the end of induction therapy. statistical analysis used a univariate and multivariate logistic regression model to compare complication rates between those who had a port versus those who had a picc placed at start of induction. results: data was collected on patients. fifty-six patients had a port placed at start of therapy while had a picc placed. fourteen percent of patients had a cvc associated complication. univariate analysis showed no statistically significant difference in rates of cvc associated complications between the groups (port %, picc . % p = . ). the rates of hospitalization for cvc associated complications were similar between both groups (port %, picc % p = . ). rates of cvc removal were also similar between both groups (port %, picc % p = . ). multivariate model that included baseline patient characteristics including type of all, patient body surface area, gender, ethnicity and age continued to demonstrate no significant difference in cvc associated complications between both groups. conclusion: this single institution study showed that there was no significant difference in cvc associated complications between port and picc line placement at the start of childhood all induction therapy. port placement can be considered as a safe option at the start of induction therapy. complete remission [cr] or cr with incomplete blood count recovery [cri]) within treatment cycles - . interim data are reported (nct ). results: seventeen patients were enrolled and received ≥ dose of lenalidomide; median age was years (range - ); patients were female. patients received median prior regimens (range - ). nine patients had previously undergone bone marrow transplantation (bmt). four patients had relapsed aml and were refractory to immediate prior treatment. median duration of study treatment was weeks (range - ); patients completed a median of treatment cycle (range - ). all patients were evaluable for primary outcome; achieved morphologic cri after cycles (no patients achieved cr). the responder was a -year-old male with history of r/r aml after first-and second-line treatment, bmt, and salvage chemotherapy. at baseline, he had a complex cytogenetic karyotype (monoallelic − q . , − q, − q . , − p ) with no identifiable molecular mutation; he was also positive for del( q) (− q , − q ). his post-treatment karyotype showed no abnormalities. sixteen patients experienced treatment failure; due to resistant disease, of indeterminate cause, and had treatment failure before a post-baseline assessment was performed. all patients experienced ≥ grade - treatment-emergent adverse event (teae). the most commonly reported were thrombocytopenia (n = ), anemia (n = ), febrile neutropenia (n = ), and hypokalemia (n = ). fifteen patients experienced ≥ teae related to lenalidomide. all patients discontinued treatment; remain in follow-up. the study is now closed to enrollment. ten patients died on study: during treatment, during follow-up. all deaths were attributed to aml or complications due to aml. conclusion: third-line lenalidomide monotherapy was associated with clinical response in of pediatric patients with r/r aml; however, treatment exposure was limited. safety data are consistent with the known profile of lenalidomide. lenalidomide was not an efficacious treatment for r/r pediatric aml. funding: celgene corporation, summit, nj, usa. cook children's medical center, fort worth, texas, united states background: it is well documented that pediatric patients with acute lymphoblastic leukemia (all) often experience significant weight gain during induction therapy and later struggle with obesity. however, some patients experience unintended weight loss during induction therapy; since this issue is not well reported, it often goes undertreated. although malnutrition is reported to be associated with decreased survival, increased risk of infection, and loss of lean body mass, there remains a scarcity of in-depth analysis of prevalence and risk factors that contribute to this problem. our study attempts to address this critical yet unmet need. objectives: our aim was to identify the clinical risk factors and outcomes associated with weight loss during induction therapy for pediatric all. design/method: this was a retrospective chart review of patients between and years of age diagnosed with all at cook children's medical center from / / to / / . for each patient, we collected height, weight, age, body mass index (bmi) z-scores at diagnosis and end of induction therapy, risk stratification, and whether consolidation was delayed. patients with a bmi > th percentile at diagnosis were categorized as being overweight or obese. using logistic regression analyses, we examined which variables predicted whether the patient had an increase or decrease in bmi z-score throughout induction. a critical alpha level of . indicated statistical significance. results: ninety-six patients met our inclusion criteria. of these, % experienced a decrease in bmi during induction therapy. compared to patients whose bmi increased during induction, patients with a decrease in bmi were more likely to be overweight or obese at diagnosis ( % vs. %; p< . ), to be ≥ years of age ( % vs. %; p< . ), to have a high-or very-high-risk stratification ( % vs. %; p< . ), and to experience a delay in the start of consolidation therapy ( % vs. %; p< . ). conclusion: this research highlights a risk not previously identified in the literature that may impact outcomes. patients treated on high-or very-high-risk protocols, who are overweight or obese at diagnosis, and who are ≥ years of age at diagnosis should be monitored closely for weight loss during induction therapy. patients who experience weight loss should receive prompt intervention. it is our hope that this information can be used for future prospective studies and to help develop evidence-based guidelines. background: p abnormalities have been observed in some patients with hematologic malignancies. loss of p function as a tumor suppressor gene in the chromosome plays an important role for development of leukemia. these patients usually have poor outcome due to the chemotherapy and are associated with poor prognosis. objectives: this study aimed to identify frequency of p abnormalities between iranian children and adult patients with aml (acute myeloid leukemia) malignancy. design/method: the p abnormalities were analyzed via bone marrow karyotyping and fish method in acute myeloid leukemia patients. in this study, p abnormalities were observed in ( %) patients out of diagnosed cases. a significant strong correlation between p abnormalities and other high risk factors (poor risk cytogenetic) were observed. from patients with aml malignancy ( p abnormalities), ( %) patients have complex karyotype, ( %) patients monosomal karyotype and ( %) patients have monosomal karyotype accompanied with a complex karyotype. overall, p abnormalities are independent risk factor in acute myeloid leukemia and evaluation of these abnormalities by fish or other complementary techniques prior to treatment, might help for better risk stratification of high risk aml patients. background: hepatotoxicity in treatment of acute lymphoblastic leukemia (all) is well studied and transiently affects most patients receiving antimetabolite therapy. rarely, patients develop liver injury severe or prolonged enough to undergo a liver biopsy. little is known about how these patients differ from patients that develop transient hepatotoxicity. we sought to describe disease and treatment characteristics for all patients that developed hepatotoxicity severe enough to undergo liver biopsy. we also looked for pre-dictive factors for liver biopsy, including signs of early hepatic injury from the initial treatment protocol. design/method: pathology reports of all patients from the liver biopsy database at children's healthcare of atlanta were collected. controls were matched : for age, all subtype, and treatment protocol. demographics, treatment protocols, and overall outcomes were collected through the electronic health record. hepatic lab results for transaminases, coagulation, and albumin were collected for induction, consolidation, interim maintenance, delayed intensification, and maintenance. results: sixteen patients diagnosed between - (median age at diagnosis years, range - ; % male; % pre-b all) were included in the case series. the median time from diagnosis to liver biopsy was . years (range - ). eight patients ( %) were in maintenance at the time of biopsy; none had active disease. eight ( %) were postbone marrow transplant. biopsy results included: steatosis ( ), acute inflammatory/infectious ( ), liver infiltration ( ), fibrosis ( ) and graft-vs-host disease (gvhd) ( ). six patients were deceased; -year all-cause mortality from diagnosis was %. thiopurine methyltransferase (tpmt) status was known in % cases and % controls. all cases had intermediate or wildtype status, which did not differ from controls (p > . ). patients requiring liver biopsy did not have evidence of acute hepatotoxicity (ast/alt > × normal values) during their initial treatment protocol. hepatotoxicity requiring liver biopsy is a rare outcome of all treatment. these patients had elevated rates of relapse, bmt, and -year all-cause mortality, suggestive of a more severe disease process. however, it is difficult to sort out the temporality of relapse, bmt, and hepatoxicity requiring biopsy in this limited sample. additionally, patients with bmt preceding liver biopsy have other confounding factors that makes them difficult to include in the analysis. finally, our limited descriptive data show no notable correlation between early hepatotoxicity and later indication for liver biopsy. future cohort or case-control studies with larger sample sizes are required to further explore early predictive factors for severe hepatotoxicity requiring liver biopsy. nathan gossai, joanna perkins, michael richards, yoav messinger, bruce bostrom background: the majority of chemotherapeutic agents used to treat hodgkin lymphoma are teratogenic. pregnancy screening prior to the start of chemotherapy is supported by clinical guidelines and baseline testing is a standard component in therapeutic trials. there is limited data available on the incidence of pregnancy screening prior to the start of hodgkin therapy but previous studies suggest that pregnancy screening, especially at pediatric institutions, is not consistently completed. objectives: the objective of this study is to evaluate the incidence of pregnancy screening and contraceptive counseling prior to the start of therapy in females diagnosed with hodgkin lymphoma. design/method: a retrospective chart review was performed for all female patients newly diagnosed with hodgkin lymphoma from to at the hospital for sick children in toronto, ontario. all patients who were intended to receive multi-agent chemotherapy were included, regardless of age. data collected included demographic and disease information, chemotherapy regimen and enrollment on clinical trial. all pregnancy testing within two weeks prior to the start of therapy was captured, as well as type of pregnancy test performed, documentation of menstrual status, contraceptive counseling and contraceptive provision. univariate and multivariate analyses were used to describe factors influencing the incidence of pregnancy testing. results: a total of female patients with newly diagnosed hodgkin lymphoma between the ages of and years were identified. sixty patients ( %) had pregnancy testing done prior to the start of therapy. testing modalities included serum and urine screens as well as quantitative beta-hcg measures. older age (p = . ), documentation of menstrual status at diagnosis (p = . ) and diagnosis between and (p = . ) were associated with higher incidence of screening. enrollment on a therapeutic trial was not associated with a higher incidence of screening (p = . ). contraceptive counseling was documented for patients ( %) and patients ( %) were prescribed contraceptive medications during therapy. pre-chemotherapy pregnancy testing was completed on % of females with newly diagnosed hodgkin lymphoma. improvement is required and interventions, including clarification of institutional standards, modification of chemotherapy order sets and staff education, are planned. (rao et al., cancer, ) . university of louisville, louisville, kentucky, united states background: granulocytic sarcomas (also known as chloromas or leukemia cutis) were first described by a. burns in . they are solid tumors comprised of immature granulocytic cells and represent extramedullary manifestations of underlying leukemia. chloromas are most commonly associated with acute myeloid leukemia. they may arise in other myeloproliferative disorders but are rarely seen in b or t cell acute lymphoblastic leukemia (all). objectives: although patients with all rarely have chloromas, it should remain on the differential for patients with unusual swelling or masses. design/method: we present a case series of two patients from our institution diagnosed with b cell all who had a chloroma as the presenting symptom. the first patient is a yo who presented to his primary provider with nasal congestion and a one-week history of bilateral eye swelling and was referred to an allergist when the symptoms did not resolve with anti-histamines. his review of systems was otherwise negative. he was referred urgently to ent two months later for a × cm mass palpated along the medial border of the left eye. an mri showed a left facial mass surrounding the zygoma and extending into the anterior inferior left orbit. biopsy revealed b cell acute lymphoblastic lymphoma, and bone marrow aspirate and biopsy confirmed the diagnosis as b cell all. the second patient is a yo who presented to his primary doctor for rapid growth of a scalp nodule that had been present for about months. he was referred to dermatology and treated for a supposed kerion from tinea capitis. the lesion continued to grow and became more irritated with this treatment. punch biopsy revealed a complicated phenotype of lymphoblastic lymphoma. however, after a lymph node biopsy and bone marrow aspirate and biopsy, the diagnosis was confirmed as b all. his only other positive point on review of systems was a questionably pathologic -pound weight loss and an area of matted cervical lymph nodes. for both of our patients, the chloromas completely disappeared during induction therapy. it is worth noting that both of these patients presented with the chloroma as the only symptom of the underlying leukemia. this led to initial misdiagnosis and delay in identifying their leukemia. therefore, while it is very rare for a patient with b all to present with a chloroma, our experience shows that all should be on the differential for patients presenting with unusual swelling or masses. background: hodgkin lymphoma (hl) is a lymphoproliferative neoplasm that commonly presents with history of adenopathy and a predictable pattern of disease involvement with or without systemic symptoms of fever and/or weight loss. in the hands of an experienced oncologist the diagnosis of hl is usually not a challenge. occasionally a diagnostic challenge is presented by a patient who has an atypical presentation which is suggestive of an alternative diagnosis. we describe a case series of patients diagnosed with hl whose initial clinical presentations lead to a diagnosis different form hl. honduras, nicaragua and the united states. results: six pediatric oncology centers from the american continent conducted a retrospective review of patients diagnosed with hl since . patients that had an initial presentation not suggestive of hl or who were initially diagnosed with a disease other that hl were included for a total of patients. argentina n = , guatemala n = , honduras n = , nicaragua n = , united states n = . five patients were female and male. patient's ages ranged from to years. most patients (n = ) were older than years. three patients ( %) presented with non-immune cytopenias without overt lymphadenopathy, of those one had active hemophagocytic syndrome. five patients ( %) were suspected to have localized solid tumors: ewing sarcoma n = , rhabdomyosarcoma n = , hepatocellular carcinoma n = , and soft tissue tumor of the cheek n = . two ( %) metastatic solid malignancy as they presented with disseminated pulmonary nodules. five ( %) with autoimmune disorders: hashimoto thyroiditis n = , autoimmune hemolytic anemia n = , nephrotic syndrome n = . ten ( %) with chronic infectious processes: brucella n = , tonsillar abscess n = , splenic abscess n = , and tuberculosis (tb) n = . patients with suspected tuberculosis were diagnosed outside of the united states. six of patients were ultimately diagnosed as having both tb and hl. seventeen patients had ann-arbor stage iii or iv, seven patient had stage ii with either b symptoms or bulky disease. patients were treated with various chemotherapy regimens according to the treating center: abvd, abve-pc oepa-copdac, avpc, beacopp. two patients had recurrent disease, one died of disease progression and one died from causes not related to hl conclusion: a small proportion of hl patients have atypical or unusual presentations. hl should be included in the differential diagnosis of solid tumors, autoimmune disorders, infections or cytopenias. the most common atypical presentation is an infectious process. background: acute lymphoblastic leukemia (all) represents the largest group of pediatric malignancies. the high cure rate of childhood all represents one of the most remarkable success stories in the war on cancer. in a lower middle income country (lmic) like the philippines, we reviewed the five year survival in a tertiary referral center. objectives: this retrospective cohort study aims to determine the survival of children - years old with all treated at a tertiary referral center for childhood cancer in the philippines from january to december . design/method: this is a retrospective cohort study that reviewed medical charts of newly diagnosed all ages to years old from january to december . a total of subjects were included in the study. the year overall survival (os) and event free survival (efs) were . % and . %, respectively. the year os for standard risk all was . % and for high risk patients was %. the year os for the patients on remission was . % and for those who relapsed was . %. univariate and multivariate by cox proportional hazards regression revealed wbc count at diagnosis, risk classification, immunophenotyping, and development of relapse showed significant prognostic impact for mortality. age and gender were reported with no prognostic significance. the -year os and efs were lower compared to developed countries but are comparable with other lmics. the prognostic factors for relapse and mortality were compatible with the literature. overall, the adopted treatment protocols for childhood all in this institution showed acceptable results. relapse has a significant prognostic impact for mortality. development of accessibility to care, increase awareness, early detection and resources at hand should be achieved. improvement in the follow up protocol to prevent delays in the treatment, patient education to prevent non-compliance and psychosocial support, to developed better supportive care, and expand facilities should be given emphasis to further improve survival and prevent relapse. objectives: here, we seek to further characterize this entity by describing the pathologic and clinical features of pediatric cases of burkitt-like lymphoma with q aberration. we collected pathologic and clinical data from the medical record on all pediatric high grade b-cell lymphoma (hgbcl) cases diagnosed at our institution over a -year period ( - ) . for those cases classified as neither burkitt lymphoma nor diffuse large b-cell lymphoma (dlbcl), fish for myc, bcl- and bcl- , as well as array comparative genomic hybridization (acgh), were performed. we identified cases of hgbcl, including cases of burkitt lymphoma presenting as purely leukemic phase. of the hgbcl cases, had burkitt lymphoma as defined by myc rearrangements, and had dlbcl. collectively, the majority of these patients had primary disease outside of the head/neck, and most patients presented with advanced stage (iii-iv) disease. of the remaining cases, q aberration was identified in cases using acgh. all cases histologically and immunophenotypically resembled burkitt lymphoma but lacked myc rearrangement, instead showing proximal gains in q -q and telomeric losses in q . qter. all cases involved primary disease in the cervical lymph node and/or tonsil. three of these cases were localized (stage ii), and the fourth case involved a few metabolically active but non-enlarged lymph nodes in the chest and abdomen (stage iii). all patients achieved complete remission with standard therapy for mature b-cell lymphoma, and were alive with no clinical evidence of disease at a median follow-up of months. although the number is small, our results suggest that the majority of non-burkitt, non-dlbcl cases of pediatric hgbcl carry q aberrations. in addition, patients with q aberrations appear to be more likely to present with lower stage disease, thus requiring less intensive therapy, and also tend to have primary disease in the head/neck. these findings further support the classification of burkitt-like lymphoma with q aberration as a distinct pathologic and clinical entity, and we propose that all pediatric non-burkitt, non-dlbcl cases of hgbcl regularly undergo further workup for possible q aberrations. marie claire milady auguste, joseph bernard st damien hospital, port-au-prince, port-au-prince, haiti background: hodgkin lymphoma (hl) and non-hodgkin lymphoma (nhl) account for % of cancers in the united states pediatric population ( , ). in central america and the caribbean, they are in second position among all types of pediatric cancers ( ). a previous study on pediatric cancers in haiti showed that the lymphomas were in fifth place after the leukemias, wilms tumor, retinoblastoma and the sarcomas ( ). the main objective of this study is to present the epidemiological profile of lymphomas managed at a haitian pediatric hospital. design/method: this is a retrospective study conducted on the cases of lymphoma diagnosed and managed at st damien hospital from january to december . key variables such as age, gender, stage at diagnosis, histopathological types and outcome were collected to present the characteristics of this retrospective cohort. of the cases of cancer diagnosed during the study period, ( . %) had the diagnosis of lymphoma. the sex ratio was . ( males for females) and the average age was . years [ - years]. there were cases of hl ( . %) and cases of nhl ( . %). . % of the patients were diagnosed at stages iii and iv. among the hl cases, ( . %) were nodular sclerosis lymphoma, ( . %) with mixed cellularity and ( . %) with lymphocytic predominance. for the nhl cases, ( . %) were burkitt's lymphoma and ( . %) lymphoblastic t-cell lymphoma. among the patients for who immunohistochemistry was found, the cases of hl were cd -positive and out of cases of nhl were cd -negative. only patient was hiv-positive, and patients had a confirmed exposure to epstein-barr virus. patients ( . %) were lost to follow-up, ( . %) were in remission, ( %) relapsed, ( . %) were still in treatment and ( %) were deceased. university of chicago, chicago, illinois, united states background: due to the adoption of risk-adapted therapy, pediatric and adolescent acute lymphoblastic leukemia (all) is associated with high cure rates. despite excellent outcomes in most children, patients with certain blast cytogenetic features do not fare as well. furthermore, african american, native american, and hispanic patients have worse outcomes than caucasian patients. while the outcome discrepancies are certainly multifactorial, and blast cytogenetics are related to age, it remains unclear whether ethnicity and blast cytogenetics correlate. the diverse patient population at the university of chicago provides an opportunity to evaluate for such a correlation. objectives: to describe cytogenetic findings in a racially and ethnically diverse population of patients of all age groups diagnosed with all at university of chicago from to and determine if there is a correlation between race/ethnicity and blast cytogenetics. results: a total of newly diagnosed patients with all between the ages of - from - were included in this study. of those, patients ( . %) had b-all, had t-all ( . %), one had early t-cell precursor all and one had mixed phenotype all (b/t). caucasians accounted for % of patients, african americans (aa) %, hispanics . %, asians . %, and % were of other races. age distribution had a bimodal pattern, with a peak in incidence at and another at years of age, consistent with published data. cytogenetic categories included: t( ; )(p ;q ), q rearrangements (kmt a), iamp , t( ; )(q ;p . ), t( ; ) (q ;q ), hypodiploidy, hyperdiploidy and double trisomy of chromosomes and . aa and hispanic patients with b-all presented more frequently between the ages of - years compared to caucasians (p = . and . , respectively). in aa patients, t( ; ) (q ;p . ) was overrepresented (p = . when compared to caucasians), and was mainly observed in patients between - years. caucasian patients were more likely than non-caucasians to have hyperdiploidy (p = . ), especially in patients aged - years. the rate of t( ; )(q ;p . ) was significantly higher in aa patients in our cohort, in particular in patients between the ages of - years. hyperdiploidy was more likely in caucasians aged - years. these findings may suggest that varying blast cytogenetics could contribute to outcome differences between races. ahmed elgammal, yasser elborai, mohamed fawzy, asmaa salama, eman d el-desouky, lobna shalaby national cancer institute, cairo, cairo, egypt background: hodgkin lymphoma (hl) in children is one of the malignancies that have a high chance of cure. stage iv hl remains a challenge for getting good clinical outcome as in other stages. many treatment protocols used to give combination chemotherapy while combined modality treatment is the mainstay in other treatment protocols. objectives: we aimed in to assess the outcome using consolidation radiotherapy to chemotherapy (combined modality treatment) versus combination chemotherapy alone in treatment of stage iv hl. design/method: we included patients with stage iv hl and whose data were retrieved from the medical records of the pediatric oncology department, national cancer institute, cairo university, egypt from till june and were followed till august . treatment was either to give cycles of abvd (adriamycin, bleomycin, vinblastine, dacarbazine) only or to give cycles of abvd followed by consolidation radiotherapy. the study included cases; were males and were females. mean age was . years ranging from to years. the histopathology subtype was nodular sclerosis in the majority of cases ( cases) followed by mixed cellularity ( cases) then only one case of lymphocyte rich. nine cases were initially bulky while cases were not. constitutional manifestations were present in cases while it was absent in cases. bone marrow was involved in only cases. radiotherapy was given after completion of chemotherapy to cases while cases received chemotherapy only. the -year overall survival for patients who received radiotherapy was superior to those who received chemotherapy alone; % versus . % respectively with statistical significance (p = . ). the -year progression free survival was also higher with radiotherapy than others; % versus . % (p = . ). patients with stage iv hl who received consolidation radiotherapy apparently had a better outcome than those who received chemotherapy only. this suggests that radiotherapy contributes significantly with chemotherapy to the cure rate for those patients. the feinstein institute for medical research, manhasset, new york, united states background: microrna (mirnas) are short non-coding rnas that play a decisive role in cancer biology, including leukemia. exosomes are microvesicles ( - nm) produced by most cells in biological fluids. exosomes represent the fingerprint of the parental tumor and are loaded with bioactive markers such as mirnas, which may regulate tumor growth. exosomal cargo can be transferred into target cells changing their biological properties. our study investigates a functional role for exosomal mir- a in pediatric acute lymphoid leukemia (p-all). objectives: / to demonstrate that p-all exosomes induce cell proliferation / to confirm that exosome-induced cell proliferation is disease-stage specific / to analyze exosomal mir- a expression profiles in p-all / to authenticate that inhibition of exosomal mir- a reduces leukemia proliferation design/method: exosomes were isolated by ultracentrifugation from healthy donors (hd) & p-all serum and conditioned medium (cm) of sup-b , jm , and cl- (control) human cell lines. cell lines were exposed to different sources of leukemia-derived exosomes in a paracrine or autocrine fashion for hrs in triplicates. proliferation was assessed by microscopic cell counting and confirmed by gene expression for proliferation, pro-survival and pro-apoptotic genes. mirna profiling was performed with the human cancer pathway finder microarray (qiagen). silencing of exosomal mir a was carried out by a mir- a inhibitor (qiagen), utilizing exo-fecttm exosome transfection reagent (sbi, system biosciences). further, exosomal mir- a silencing was confirmed by q-pcr. cellular uptake of texred-sirna (sbi, system biosciences) was confirmed by flow cytometry. transfer of exosomal mir a to the target cells was evaluated by q-pcr. we elucidated that cm-derived exosomes from sup-b and jm cell lines induce cell proliferation in sup-b , jm (autocrine and paracrine) and cl- cells (paracrine) (p< . ). serum p-all exosomes promote paracrine cell proliferation in all cell lines compared to hdderived exosomes (p< . ). heatmap analysis of mirna profiles of leukemia exosomes (all cell lines and p-all) identified mir- a significantly upregulated in leukemia exosomes compared to controls. mir- a was also upregulated in all cell lines after exposure to leukemia exosomes that induced proliferation. moreover, exosomal mir- a inhibition reduces leukemic proliferation in pediatric all. our data suggest that all exosomes induce cell proliferation of leukemic cell lines in both paracrine and autocrine fashion. exosomes regulate these phenomena in a highly orchestrated way, by transfer of functional exosomal mirnas such as mir- a. the results of this study suggest s of s that exosomal mir- a inhibition can act as a novel way for growth-suppression of pediatric leukemia. results: a total of disease sites were detected at pet/ct, while sites were detected at contrast-enhanced ct and bone marrow biopsy (bmb). pet/ct showed improved detection of nodal lesions (p < . ) (kappa value = . ), extranodal lesions (p < . ) (kappa value = . ) and bone marrow (p < . ) (kappa value = . ) compared to contrast enhanced ct and bmb. pet/ct had upstaged cases ( %) and down-staged cases ( . %) (p < . ) (kappa value = . ). among the upstaged cases, patients ( . %) were upstaged from stage ii to iii, based on residual in pet/ct not seen in contrast enhanced ct after abdominal mass excision. four patients ( . %) were upstaged from stage iii to iv based on bone marrow uptake in fdg-pet without positivity in bma or bmb.regarding response assessment, sensitivity was % for pet and % for contrastenhanced ct (p = . ). specificity was % for pet and % for ct (p< . ). positive predictive value for pet was %, while was % for ct scan (p< . ). negative predictive value for both pet and ct was % (p = . ). five patients had nd biopsy to confirm viability of the residual lesions, lesions were negative in pathological examination (all of them were metabolic negative in pet/ct; deauville score below ). one lesion was positive in pathological examination (was positive in pet/ct; deauville score of ). conclusion: pet/ct detected additional sites compared with contrast-enhanced ct and resulted in changing stage of disease. pet scan is significantly more specific than ct in the management of children with burkitt lymphoma. background: deep sequencing of the immunoglobulin heavy chain (igh) locus indicates that each b all is composed of innumerable subclones. in many cases, subclones exhibit differing phenotypic qualities. however, it remains unclear whether subclones demonstrate distinct tissue distribution within a patient. objectives: . to quantify the extent of clonal heterogeneity in diagnostic b all specimens; . to identify variability in clonal composition between bone marrow (bm) and peripheral blood (pb) disease sites. design/method: igh sequencing was performed on purified dna from pairs of matched bm and pb patient specimens. multiplex pcr was used to globally amplify the igh locus; next generation sequencing (ngs) was performed using illu-mina® miseq. index clones (defined as ≥ % of all sequence reads in a specimen) and their subclone progeny (defined by shared nucleotide bases immediately upstream of a common jh, or n_jx) were identified using igblast-determined vh and jh alignments (http://www.ncbi.nlm.nih.gov/igblast/) and an established in-house computational pipeline. results: up to index clones per specimen were discovered in of the samples. in the remaining ( bm/pb pairs), pair did not reveal a clonal igh and was eliminated from analysis; in the other, clone frequency did not reach the % index threshold, but predominant clonal precursors were inferred by the prevalence of their subclone progeny. subclone counts ranged from to , per index clone. a combined , subclones derived from pb index clones were observed; in contrast, bm index clones gave rise to only subclones. subclone heterogeneity was observed between all paired specimens. in bm/pb pairs, index clones existed in equivalent proportions between disease sites. in contrast, bm/pb pair demonstrated high-frequency index clones in the bm ( . % & . %) with limited representation of these clones in the pb ( . % & . %, respectively); in this case, the most prevalent clone in the pb ( . %) matched the least frequent index clone in the bm ( . %). similarly, another pair showed a predominant index clone in the pb ( . %) which was below index threshold ( . %) in the bm. in paired patient specimens, index clone predominance was discovered to be overtly distinct between bm and pb. among all pairs, the extent of subclone progeny derived from each index clone showed marked variability, with far higher subclone frequency in the pb than in the bm. our data indicate that b all clonal composition differs between disease sites. valley children's healthcare, madera, california, united states background: tuberculosis (tb) presenting with hodgkin lymphoma (hl) is rare. their coexistence could lead to delay in diagnosis of both tb and hodgkin lymphoma due to the similarities in signs and symptoms of presentation. most cases have been reported in the adult literature. we describe a case series of children that were suspected to have tb and were found to have coexisting tb and hl. results: a retrospective review of hl patients in guatemala and argentina over six years, uncovered patients with simultaneous diagnosis of tb and hl. eight patients were from guatemala (incidence of . %) and from argentina (incidence of . %). there were females and males. age ranged from - years (mean . years, media years). nine patients were suspected to have tb at presentation by the referring physician. two patients were found to have tb at the time of relapse through routine tissue culture. initial systemic symptoms included fever (n = ), weight loss (n = ), and night sweats (n = ). six patients had a second systemic symptom in addition to fever. time for referral to oncology center ranged from weeks to months. nine patients were diagnosed with tb and hl through a tissue cultures and with serum quantiferon. one patient was found to have hl without tb. two patients had no systemic symptoms and the diagnosis of tb came to light through routine tissue culture. five patients had stage iiib and ivb, two stage iia and one iib at diagnosis. hl treatment was given according to the insti-tutional standards depending on stage and risk with abvd, oepa/copdac +/-radiation therapy, and ice for relapse. five patients started anti tb treatment (isoniazid, rifampin, pyrazinamide +/-ethambutol for months followed by isoniazid and rifampin for - weeks) simultaneously with chemotherapy, and three others after completing cycles. the two relapsed patients started tb treatment after cycles of chemotherapy. seven patients are alive and have been followed for months - years. one patient died during therapy, another died for causes not related to tb or hl and one is currently receiving treatment. conclusion: tuberculosis can coexist with hl. in areas were the prevalence of tb is high, microbiology investigations of biopsy specimen should be strongly considered. therapy for tb can be given simultaneously with chemotherapy. coexistence of tb and hl does not appear to affect outcomes. the children's hospital affiliated to the capital institute of pediatrics, united states background: the pi k/akt signaling pathway plays a central role in cell growth, proliferation and survival in physiological conditions. this signal pathway is considered to be an innovative targeted therapy of cancer, and its abnormal activation has been proved to be related to t-cell acute lymphoblastic leukemia (t-all). despite improved treatment strategies, such as multi-drug combination, high-dose chemotherapy and all kinds of application and popularization of hematopoietic stem cell transplantation, children with drug resistance or relapse t-all are still rather worse and its overall outcome and prognosis are much poorer than the more common b-lineage all. objectives: to explore the relationship between the pi k/akt pathway and the pediatric t-all, so as to probe the exact molecular mechanisms of t-all and provide more directions for its treatment. design/method: cases of new or recurrent acute t lymphocyte leukemia children with clinical information were collected in the children's hospital affiliated to the capital institute of pediatrics from dec. to oct. , with age and gender matched healty children as control (all was informed consent). the expressions of key genes in pi k pathway were s of s analyzed by western blot rt-pcr analysis, the pi k enzyme activities were detected by elisa,and the ccrf -cem's proliferation and its apoptosis were tested by mtt and flow cytometry technology on t-all cell lines ccrf-cem in different treatment group. the results of t-all children in clinical showed that pi k protein and gene expression level were higher apparent than the control group (p< . ), and pi k enzyme activity increased as well (p< . ); pi k inhibitor ly made a significant inhibition of cell proliferation and promoted cell apoptosis. ly also enhanced the effectiveness of clinical commonly used chemotherapeutic drug dnr. in combination ly and dnr treatment group cell viability dramatically declined, apoptosis and the apoptosis relation protein casepase expression in t-all patients was obviously higher than the control and the single drug group; pi k/akt signaling pathway related proteins and gene expression level, pi k, akt, gsk transcription in ccrf-cem were significantly higher than the control (p< . ), while pten transcription was significantly lower than the control (p< . ). the abnormal activation of pi k/akt signaling pathway might play an important role in pediatric t-all patients, especially in the cell proliferation or apoptosis. the results might provide new train of thought and direction in targeted suppress this signal pathway or in combination with other chemotherapy drugs therapy in looking for the more effective and less cytotoxic treatment of pediatric t-all. cleveland clinic children's hospital, cleveland, ohio, united states background: non-hodgkin lymphomas (nhls) are a heterogeneous group of lymphoproliferative diseases which comprise % of all childhood malignancies. nhls can be divided in to b cell lymphomas and t cell/natural killer (nk) cell lymphomas depending on immunophenotype, molecular biology, and clinical response to treatment. although nk/t cell lymphomas occurring in childhood and adolescence comprise a small portion of all lymphomas, they present many diagnostic and therapeutic challenges. the role of angiogenesis in lymphoma pathogenesis is becoming more evident. high molecular weight kininogen (hk) is a central compo-nent of the kallikrein-kinin system. it has been previously reported that cleaved hk (hka) induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in matrigel plug and corneal angiogenesis models. however, the role of endogenous kininogen in regulation of angiogenesis is in tumor microenvironment is unknown. objectives: to elaborate the role of hk in lymphoma angiogenesis, we used a murine t-cell lymphoma model and compared angiogenesis and tumor growth between wild-type and kininogen deficient (mkng -/-) mice. we also evaluated the effect of hka on lymphoma cell proliferation. design/method: el- murine t-cell lymphoma cells ( × ^ ) were implanted into wild-type and mkng -/-mice. tumor size was measured using calipers and tumor volume was calculated using the formula volume = length × width^ × . . seventeen days after cell implantation, tumors were harvested and processed by immunoblotting and immunofluorescent staining. cell proliferation assays (mts) were performed to investigate any possible inhibitory effect of hka on el- cell growth, with human umbilical vein endothelial cells (huvec) were used as a positive control. results: el- lymphomas grew more rapidly and to larger sizes in mkng -/-mice compared to wild-type mice, with significant differences apparent by day after tumor implantation (p< . ). by day , the volume of tumors in mkng -/-mice was approximately . -fold larger than in wild-type mice (mean volume ± standard deviation; ± vs. ± mm , respectively, p< . ). mts assays showed that hka does not directly inhibit the proliferation of el- cells in vitro, though it does significantly impair the viability of ecs studied simultaneously. conclusion: these findings suggest that hk is an important endogenous regulator of angiogenesis and tumor growth in this t-cell lymphoma model, and suggests that hka specifically modulates endothelial proliferation in tumor microenvironment. further work is needed to understand the mechanisms underlying these findings and provide future anti-angiogenic approaches to increase the therapeutic options for patients with nhl. bruce bostrom, jack knudson, nathan gossai, joanna perkins, michael richards, jawhar rawwas, susan sencer, julie chu, nancy mcallister, yoav messinger children's minnesota, minneapolis, minnesota, united states background: osteonecrosis causes significant pain and morbidity in older patients treated for acute lymphoblastic leukemia. besides altering the schedule of dexamethasone in delayed intensification there is no other intervention known to reduce the incidence of symptomatic osteonecrosis. pamidronate has been shown to reduce bone pain from osteonecrosis but not to prevent joint collapse when advanced. objectives: to compare the incidence of symptomatic osteonecrosis in patients who received prophylactic pamidronate compared with concurrent controls. to describe any increase in side effects from the use of pamidronate. design/method: patients age to years at time of all diagnosis were given intravenous pamidronate monthly for one year at the discretion of the primary oncologist starting in the first year of therapy. concurrent controls were patients age to who did not receive pamidronate. all patients were treated according to the concurrent cog protocols and received intermittent dexamethasone during delayed intensification. patients with bcr-abl all were excluded as the use of imatinib may increase the risk of osteonecrosis. imaging was only done if osteonecrosis was suspect based on clinical symptoms. patients were censored at the time of relapse. data were analyzed as of / / . this retrospective study was approved by the children's minnesota irb. of the patients evaluated % were male and % female, % had b-cell and % t-cell. the median followup is . years with a range of . to years. pamidronate was given to patients with developing symptomatic osteonecrosis. there were concurrent controls with developing osteonecrosis. there was no significant difference in the leukemia lineage, gender distribution or body mass index (bmi) at diagnosis between groups. for all patients the median bmi was with a range of to . the age at diagnosis was significantly higher in the pamidronate group with a median of . years vs. . in the controls (p = . ). by kaplan-meier analyses the incidence of symptomatic osteonecrosis was significantly lower in the pamidronate group at % vs. % in controls. the log-rank p-value was . and the breslow p-value, which is more sensitive to early events, was . . there were no untoward side-effects from pamidronate. pamidronate infusions significantly reduced the incidence of symptomatic osteonecrosis in patients over the age of compared to concurrent controls who did not receive pamidronate. arahana awasthi, dina edani, janet ayello, christian klein, mitchell cairo new york medical college, valhalla, new york, united states background: mature b-nhl, including bl and pmbl express cd +/cd b+ and have an excellent prognosis, however, subset of patients relapse secondary to chemoimmunotherapy resistant disease and have a dismal prognosis (≤ % yr. efs, cairo et al. blood. ; gerrard/cairo et al., blood, , goldman/cairo et al. leukemia, . pv has been demonstrated to possess significant preclinical activity against indolent cd b+nhl (polson et al. can. res. ). we previously observed that obinutuzumab (anti-cd mab) significantly enhanced cell death and increased overall survival against bl (awasthi/cairo et al., bjh ) in xenografted nsg mice. however, additive/synergistic effects of pv with obinutuzumab against mature pmbl/bl are unknown. to determine the efficacy of the pv or obinutuzumab/rtx alone or in combination against pmbl and rituximab (rtx) sensitive/resistant bl cell lines. design/method: raji rh (provided by m. barth, md, roswell park cancer institute) and raji/ karpas p (atcc, usa) were cultured in rpmi. tumor cells were incubated with pv, and/or anti-cd b, mmae (generously supplied by genentech inc.) with obinutuzumab /rituximab ( ug/ml) for hr with nk cells at : e: t ratio and cytotoxicity was determined by delfia cytotoxicity assay. six to week old female nsg (nod.cg-prkdcscid il rgtm wjl/szj), were divided into groups: pbs, isotype control, pv, anticd b mab and mmae ( mg/kg). mice were xenografted with intravenous injections of luc+ bl and pmbl cells and tumor burden was monitored by ivis spectrum system. results: os of mice receiving pv alone was significantly increased compared to anticd b ab or isotype control in raji ( . vs. vs. . our preliminary data indicates that pv significantly increased survival in bl and pmbl nsg xenografts compared to anti-cd b ab alone. furthermore, pv in combination with obinutuzumab significantly enhances in-vitro cytotoxicity in bl and pmbl compared to obinutuzumab or pv alone. results: maximal grades (g) / , , and crs occurred in , , and patients, respectively. median lowest fibrinogen levels were . , . , and . g/l in patients with maximal g - , , and crs, respectively. %, %, and % of patients with maximal g - , , and crs had lowest reported fibrinogen levels of ≥ to < . g/l. eight patients (all with g crs) had very low fibrinogen levels (< g/l), which occurred before (n = ) or during (n = ) maximal crs grade or at time of improvement (n = ). no patients with maximal g - crs had < g/l fibrinogen levels. at the onset of < g/l fibrinogen levels, patient had concurrent g , and had g - increased international normalized ratio and activated partial thromboplastin. cryoprecipitate was the primary treatment in the us, and fibrinogen concentrate (fc) guidelines for tisagenlecleucel-associated coagulopathy were developed for other countries because administration of fresh frozen plasma can be problematic. fc was available at / sites for infused patients: / (g crs) and / (g - crs). cryoprecipitate was available at / sites for infused patients: / (g crs), / (g crs), and / (g - crs). risk of bleeding increases in pediatric patients with comorbid thrombocytopenia and anticoagulant treatments. / patients had g / decreased platelets within day of < g/l fibrinogen levels. fatal case of intraparenchymal cranial hemorrhage occurred during resolving crs with g hypofibrinogenemia, ongoing thrombocytopenia, and continuous veno-venous hemofiltration with citrate. hypofibrinogenemia was observed more frequently in patients with higher crs grades during/when crs was improving or resolving. fc and cryoprecipitate treatment guidelines were developed. frequent monitoring and fibrinogen replacement are needed in patients with g / crs. sponsored by novartis. its prolonged cns half-life, may allow a reduction in the number of intrathecal injections. objectives: to safely reduce the burden of therapy by reducing the number of it injections and reducing the total dose of doxorubicin with the addition of liposomal cytarabine and rituximab. design/method: patients ( - years) with cd + b-nhl with fab group b good risk (=stage i/ii and stage iii with ldh < xuln), fab group b intermediate risk (=stage iii ldh ≥ xuln and stage iv {bm blasts < %}) and fab group c high risk were eligible. patients received fab backbone therapy with the addition of six rituximab ( mg/m ) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. cumulative doxorubicin was reduced from to mg/m in gr patients. after systemic methotrexate clearance, patients received age based dosing of it liposomal cytarabine. it injections were reduced from nine to five. the primary outcome is safety and toxic deaths among evaluable patients with an estimated -year survival above %, monitored by an independent dsmb. results: to date, evaluable patients, fab group b and group c ( cns positive), median age years (range - ), males, burkitt/ dlbcl with gr, ir and hr have enrolled. there has been one grade anaphylactic reaction to rituximab and one grade facial nerve palsy. no other serious adverse events were attributable to protocol therapy. there has been death from progressive disease and relapse at a median follow up of months. efs and os are % and %, respectively. our initial results show excellent efs and os, consistent with published standard of care outcomes, with the addition of rituximab and intrathecal liposomal cytarabine despite the reductions in therapy. further enrollment is ongoing and continued long term outcomes are needed to confirm early results. future randomized studies are needed to examine both short term (mucositis, infections, hospitalization days) and long term (late cardiac toxicity) endpoints. . goldman etal, leukemia, . cairo etal, jco st. jude children's research hospital, memphis, tennessee, united states background: bereaved parents identify significant spiritual needs around time of death and throughout their bereavement journeys. spirituality has been identified as a primary means by which bereaved parents can find meaning in their losses, and this ability to find meaning is associated with lower maladaptive grief symptoms. the use of spiritual coping strategies has been associated with improved coping and mental health outcomes among bereaved parents. objectives: to better understand how bereaved parents' experiences with spirituality throughout bereavement effects objective measures of grief, depression, and meaning-making. design/method: thirty participants whose children died of progressive cancer or related complications one to three years prior to participation completed an in-depth semi-structured telephone interview about their experiences with grief. participants were prompted to describe the impact of their spirituality on their bereavement processes. additionally, participants completed surveys related to grief (prolonged grief disorder questionnaire, pg- ), depression (beck depression inventory, bdi), and meaning-making (integration of stressful life experiences scale, isles). results were analyzed using a mixed methods approach including semantic content analysis of qualitative content and kruskal-wallis h test and post-hoc analyses of quantitative data. results: correlation analyses demonstrated significant differences between participants with positive and negative spiritual experiences of bereavement. participants with negative experiences of bereavement had a statistically significant increase in scores on the pg- compared to those with positive spiritual experiences signifying greater symptoms of prolonged grief. participants with negative spiritual experiences with grief had significantly lower scores on the isles, suggesting a lesser degree of adaptive integration of their losses. there were no significant differences in depression scores between groups. conclusion: bereaved parents that have a negative spiritual experience of bereavement are at increased risk for prolonged grief symptoms and are less likely to find meaning in their children's deaths than bereaved parents that describe a positive spiritual experience of bereavement. providers should consider exploration of spiritual beliefs and provision of spiritual care for parents of children facing life-limiting illnesses during treatment and bereavement. background: langerhans cell histiocytosis (lch) is an inflammatory myeloid neoplasia characterized by frequent relapse, with treatment failure associated with higher risk of death and neurodegenerative disease (lch-nd). activating somatic mutations in mapk pathway genes have been identified in almost all cases, with braf-v e in approximately % of lesions. targeted therapies have been successful in treating other refractory cancers with braf v e mutations (such as melanoma). given the central role of mapk pathway activation in lch, mapk pathway inhibition may be an effective therapeutic strategy for children with lch. objectives: the purpose of this study was to report the efficacy and toxicity profile of a retrospective cohort of patients with lch treated with mapk pathway inhibitors. design/method: medical records from pediatric patients with lch (systemic and/or lch-associated neurodegeneration) who were treated with a mapk pathway inhibitor were retrospectively reviewed from five institutions. all patients had failed at least one prior systemic therapy and had a proven mapk pathway mutation. results: all patients in this series were less than years old (median = . years; range: - years) with a median of three prior treatments (range: - ). at the time of initial mapk inhibitor use, nine of the patients had lch-nd diagnosed clinically and/or by radiographic imaging; the remaining three patients had systemic disease. patients were treated for a median of months (range: - months) with various reasons for discontinuation. three patients received combination mapk inhibitor therapies and three patients received other concurrent lch-directed therapies. four of the twelve patients had a grade or toxicity reported and three of these patients required dose reduction in order to be able to successfully resume therapy. overall survival was % with median month follow-up (range: - months) with only one patient achieving transient complete response. the remaining ten patients had partial response or stable disease and four of these patients developed progressive disease while on therapy. conclusion: mapk pathway inhibitors may be a relatively safe salvage therapy for refractory systemic lch and lch-nd but the efficacy and durability of this strategy remains to be defined. combination with cytotoxic chemotherapies may be required in order to eradicate the disease-causing cell. future prospective trials of mapk pathway inhibitors for patients with refractory lch are needed in order to directly compare their efficacy and toxicity relative to other current salvage strategies. cincinnati children's hospital medical center, cincinnati, ohio, united states background: medication adherence during maintenance therapy has been shown to have a direct relationship with disease relapse in pediatric leukemia. previous research determined that patients who are ≤ % adherent to mercaptopurine ( mp) have a greater risk for relapse. the primary aim of the present study is to examine the relationship between metabolite profiles of mp with behavioral adherence rates obtained via electronic monitoring at , , and days. it is hypothesized that patients demonstrating low levels of thioguanine (tgn) and methylated mercaptopurine (mmp) will have lower behavioral adherence rates prior to the blood draw. design/method: in a multisite, prospective study of patients ages - years diagnosed with acute lymphoblastic leukemia (all) or lymphoblastic lymphoma (lbl), mp adherence was measured across months of maintenance therapy using behavioral adherence (electronic monitoring) and pharmacological (metabolites) measures of mp. mp is metabolized into mmp and tgn. cluster analysis was used to generate three mutually-exclusive profiles of mp adherence. behavioral adherence rates were calculated for , , and days prior to the blood draw. results: this study identified three metabolite profiles of mp across months. previous research indicated that low levels of both metabolites suggest nonadherence to medication. low levels of one metabolite with high levels of another metabolite indicate adherence to mp. in this study, . % of the low tgn-low mmp group had -day behavioral adherence rates ≥ % (mean = %); . % had adherence rates < % (mean = . %). in the high tgn-low mmp group, . % had a mean -day adherence of %; . % had adherence rates < % (mean = . %). the low tgn-high mmp group had % of patients with a mean -day adherence level of %; % had adherence rates < % (m = . %). at and -days, to % of patients in the low tgn-low mmp group had adherence rates < %. conclusion: these findings suggest that electronic monitoring and metabolite concentrations can be used to monitor mp medication adherence during maintenance therapy. it is notable that there is a sub-sample of pediatric patients who are identified as being nonadherent to mp based on electronic monitoring, however, metabolite levels indicate adherence to mp. similarly, a sub-sample of patients were identified as being adherent based on electronic monitoring, but metabolite profiles indicated sub-therapeutic levels of mp. our findings underscore the clinical significance of using both objective measures of medication adherence to inform clinical decision making. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hemophagocytic lymphohistiocytosis (hlh) is a life-threatening hyperinflammatory syndrome characterized by non-remitting fevers, rash, hepatosplenomegaly, cytopenias, liver dysfunction and coagulopathy, and can include central nervous system involvement. several genetic diseases cause hlh by impairing normal lymphocyte or macrophage function. the hlh panel at the cincinnati children's genetics laboratories includes genes associated with hlh and other lymphoproliferative diseases, including the genes that cause primary hlh (prf , unc d, stxbp , stx , rab a), x-linked lymphoproliferative diseases (sh d a, xiap), itk deficiency (itk), hermansky-pudlak syndrome types and (ap b and bloc s ), chediak-higashi syndrome (lyst), cd deficiency (cd ), xmen syndrome (magt ) and lysinuric protein intolerance (slc a ). deletion/duplication analysis is available as a reflex test for all genes, as copy number variations (cnvs) are not directly assessed by sequencing. objectives: the prevalence of cnvs among large groups of patients with hlh in north america is unknown. we assessed the frequency of cnvs in the genes on the hlh panel through a retrospective review of orders for deletion/duplication analysis performed after next-generation or sanger sequencing: orders for all genes on the panel, and orders of - genes from the panel. deletion/duplication analysis was performed on a custom × k microarray annotated against ncbi build (ucsc hg , march ). deletion/duplication analysis resulted in a confirmatory diagnosis in of cases ( . %). pathogenic or likely pathogenic cnvs were most common in the three x-linked genes: sh d a ( deletions), xiap ( deletions, duplication), and magt ( deletions). hemizygous deletions in xlinked genes in male patients were typically suspected after amplification failure during previous sequencing. of the autosomal recessive genes, pathogenic cnvs were observed once in each of three genes: rab a (heterozygous), lyst (heterozygous), and stxbp (homozygous). in the two heterozygous cases, a second change was not identified by sequencing, so deletion/duplication analysis did not offer a confirmatory diagnosis. in patients, deletion/duplication analysis was performed after a pathogenic or likely pathogenic variant was identified in an autosomal recessive gene during sequencing; however, in no case was a second mutation uncovered by cnv analysis. we recommend that deletion/duplication analysis be routinely performed in all male patients with hlh who lack a genetic diagnosis after sequencing of hlh-associated genes, especially if any regions failed to amplify. deletion/duplication analysis may be performed in female patients after sequencing if a genetic form of hlh is highly suspected, but the yield is expected to be low. cleveland clinic children's hospital, cleveland, ohio, united states background: the development of post-transplant neoplasia, typically from lymphoproliferative disease (ptld), is a severe complication in transplant recipients and affects approximately % of pediatric solid organ recipients. rates of lymphoma in adult heart transplantation patients are comparatively low, at less two percent at ten years. there are few published reports of the long-term outcomes of neoplasia after pediatric heart transplantation. we aimed to identify the subsequent malignancies that occurred in pediatric heart transplantation patients in a large single institution, and describe their treatment and subsequent clinical course. we performed a retrospective chart review of all pediatric heart transplant recipients followed at the cleveland clinic children's hospital from january to october . we excluded patients who died within days of heart transplantation. we reviewed in depth the history and clinical course of subjects who developed neoplasms. results: between and , patients underwent heart transplantation and survived at least days post transplantation. nine patients ( . %) developed a subsequent malignancy. in this case series, the median age at heart transplant was years old and the median time to develop neoplasia was . months. primary neoplasia included monomorphic ptld ( ), polymorphic ptld ( ), burkitt lymphoma ( ), hodgkin's lymphoma ( ), plasmacytoma-like lymphoma ( ) and epstein-barr virus-associated smooth muscle tumor (ebv-smt) ( ). one patient with hodgkin lymphoma subsequently developed monomorphic ptld, one patient with polymorphic ptld subsequently developed ebv-smt and later, an undifferentiated gastric cancer. one patient with monomorphic ptld developed an ebv-smt. evidence of epstein-barr virus was present in six of nine patients at diagnosis of first malignancy. four of nine patients received reduction in immunosuppression as a primary intervention for the initial malignancy, with two complete responses (cr), one partial response, and one with progressive disease. five patients were treated with chemotherapy, with four cr and one with progressive disease. three patients died of malignancy (recurrent ebv-smt, undifferentiated gastric cancer, and monomorphic ptld post-hodgkin disease) and two patients died of other transplant related complications. conclusion: secondary malignancies represent a significant disease burden to survivors of cardiac transplantation. as expected, much of the malignancy burden is driven by ebv. despite aggressive histology, many malignancies can be successfully cured in this setting with a multidisciplinary approach. stanford university school of medicine, palo alto, california, united states background: current treatment of langerhans cell histiocytosis (lch) is based on extent of organ system involvement and if high risk systems are affected. gastrointestinal (gi) involvement is diagnosed in about % of lch patients, and classically presents in children under years of age with malabsorption, failure to thrive, bloody diarrhea and anemia. although the gi system is considered standard risk, a mortality rate over % occurring within years of diagnosis has been reported. this study was performed due to this discrepancy and the limited number of published cases. objectives: to review the clinical course and outcomes of patients diagnosed with gi lch. design/method: a retrospective chart review of patients with histologically confirmed gi lch diagnosed in the last years identified from the bass center histiocytosis clinical database was performed. two other pediatric hematology/oncology centers (ucsf benioff children's hospital oakland and san francisco) were queried for additional cases. results: four patients with biopsy proven gi lch [ subjects ( . %) from database records and l from center queries] were identified. failure to thrive, hypoalbuminemia, bloody diarrhea and rash were the most common presenting symptoms. lch of the skin was found in all patients. risk organ systems were involved in patients. of note, subjects were of african racial background. the median age at diagnosis was . months ( . months to years), mean albumin . g/dl ( . - . g/dl), mean esr of mm/hr ( - mm/hr). all patients initially received combination therapy per lchiii protocol (vinblastine, prednisone, and mercaptopurine). two patients had recurrent disease and received second line therapy (cytarabine, cda, and local radiation therapy). all patients are alive without active disease at last follow-up ( to months after completion of therapy). a systematic approach to evaluate gi involvement should be performed in children diagnosed with lch. from our experience, combination chemotherapy for patients with lch involving the gi tract is an effective intervention for active disease. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bhatia indicated that rates of mp adherence ≥ % have better clinical outcomes. those with adherence rates ≤ % have an increased risk for disease relapse. the present study investigated patterns of mp medication adherence using group-based trajectory modeling in a large sample of pediatric patients. to describe patterns of behavioral adherence during the maintenance phase of therapy for a cohort of pediatric patients ages - years who were diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma (n = ). previous research has documented the relationship between optimal levels of medication adherence with positive health outcomes. it was hypothesized that three groups would be identified: optimal adherence, deteriorating adherence, and chronic nonadherence. it was hypothesized that patients in the optimal adherence group would have adherence rates ≥ %. those with poor adherence would have adherence rates ≤ %. design/method: the present study was a longitudinal, multisite study investigating adherence to -mercaptopurine in a pediatric cohort of patients using electronic monitoring devices. daily adherence rates (electronic monitoring of mp) were examined across -months. health outcomes were measured at quarterly intervals through medical chart reviews. results: unconditional growth curve modeling indicated that the mean percentage of behavioral adherence was . % at baseline and declined to . % at -months. three trajectories of mp behavioral adherence were identified: ) optimal adherence ( % of patients): averaging % behavioral adherence across months; ) moderate adherence ( %): relatively stable nonadherence with rates of % across months; and, ) chronically nonadherent ( %): adherence decreased from % to %. with respect to patterns of medication adherence and relationship to clinically-relevant health outcomes, there were no significant differences in health outcomes between patients in the adherent versus nonadherent trajectories, including mean absolute neutrophil counts (anc), risk for infection as measured by anc, healthcare utilization, or risk for disease relapse. although longitudinal patterns of mp behavioral adherence were not related to health outcomes, it is notable that only % of the current sample had adherence rates ≥ %. in fact, % of the current sample demonstrated adherence rates ≤ %. our findings are important for development of future adherence promotion studies in pediatric cancer. our findings underscore the relative significance of tailoring adherence promotion interventions to subgroups of patients, including those with problematic patterns of adherence. patients who demonstrate adequate levels of adherence could still benefit from less intensive, preventative interventions to sustain and improve adherence. sophie gatineau-sailliant, pascale grimard, marie-claude miron, guy grimard, anne-sophie carret, jean-marie leclerc chu sainte-justine, montreal, quebec, canada background: vertebral involvement in langerhans cell histiocytosis (lch) is still a subject of interest, due to its low frequency and the absence of management's guidelines. objectives: to provide additional information on presentation, treatment and morbidity of pediatric lch vertebral lesions, we report cases of children with vertebral lesion of biopsy-proven lch, between january st and december st , at sainte-justine university health center (montreal, quebec, canada). we conducted a retrospective study by reviewing charts and imaging of vertebral lch in a population of children (median age of . years at lch diagnosis), followed for a median duration of months. symptoms at presentation, treatment modalities and morbidities were collected. results: vertebral lesions were present at lch diagnosis in of cases. they were usually diagnosed secondary to back pain in of cases and were asymptomatic in only one case. despite an epidural extension in of cases, no child developed neurological symptoms. lesions frequently involved vertebral body ( of cases) and were rarely unstable ( of cases). out of vertebral lesions, most of them had a dorsal localization ( of lesions) and of patients had lch in multiple vertebrae. at diagnosis, median vertebral height loss was . % compared to % at last imaging control. most used imaging modalities were pet-scan and plain x-rays. treatments were diverse and consisted in chemotherapy in all children but three and bisphosphonates in only cases. radiation therapy was not used in any patient. six out patients did benefit of an orthosis. a lch recurrence was observed in patients and involved vertebrae in cases. one patient with treatment-resistant lch disease had relapses, and required multiple lines of treatment. all children were alive and disease-free at their last follow-up, patients having radiological vertebral sequelae and only had clinical sequelae. our study is consistent with the epidemiological data described in larger cohorts of children with vertebral lesions of lch and the favorable prognosis associated with such lesions. nevertheless, aggressive treatment and long term follow-up seemed to be essential as recurrences are s of s not rare and spontaneous bone regeneration often incomplete. plain x-rays appears to be a good follow-up tool for vertebral lesions as it allows reliable measures, less exposure to radiation at lower cost. national cancer institue, giza, giza, egypt background: acute lymphoblastic leukemia (all) is the most common type of childhood cancer and also the most complicated in the treatment, so it requires many interventions for both treatment and to alleviate suffer form side effects. pancreatitis is one of the toxicities, which is more common in all as it appears in about % of the patients. it occurs in many drug combinations which induce pre-pancreatitis and even direct destruction of pancreatic tissues. pancreatitis can be induced by many drugs used in the treatment such as chemotherapeutic agents or supportive treatment. lasparaginase is the backbone drug of the treatment of all in which to doses are required to achieve complete remission status in the induction phase of treatment and to doses in the maintenance phase.it is an enzyme that destructs the l-asparagine amino acid into aspartic acid and ammonia thus deplete the asparagine from the extracellular matrix . many drugs are investigated for their effect on treatment of induced pancreatitis such as interleukin- , nsaid as antiinflammatory, glycerin tri nitrates as improvement of microcirculation, tnf-alpha antibody, paf inhibitor as specific anti-inflammatory and low molecular weight heparin .none of the drugs was investigated for their ability to prevent the occurrence of pancreatitis. objectives: this study was designed to evaluate the protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis design/method: acute pancreatitis was induced in rats by intra-muscular injection of l-asparaginase ( i.u/kg) given daily for five days. enoxaparin was given subcutaneous ( i.u/kg) and diclofenac was given intra-peritoneal ( mg/kg) daily for five days. then, markers of pancreatic injury, lipids, immune cell infiltration and oxidative stress were analyzed with histo-pathological examination of the pancreatic tissue results: during acute pancreatitis, oxidative stress markers were significantly changed as indicated by reduced tis-sue glutathione and increased malondialdehyde levels. this was accompanied with significant increase in immune cells infiltration as indicated by high levels of myeloperoxidase and pro-inflammatory cytokine tnf-alpha. triglyceride only showed increase level. treatment with enoxaparin and/or diclofenac restored levels of biochemical markers including serum alpha-amylase, reduced glutathione, malondialdehyde, pro-inflammatory cytokine tnf-alpha, myeloperoxidase and triglyceride. histological injuries of pancreatic tissues as vacuolation and necrosis of epithelial lining pancreatic acini, inflammatory cells infiltration and focal pancreatic hemorrhage were also reduced by treatment with enoxaparin and/or diclofenac. the present study emphasizes the potential protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis background: rosai dorfman disease (rdd), or sinus histiocytosis with massive lymphadenopathy (shml), is a rare condition of immune dysregulation of unknown etiology arising from the massive accumulation of non-langerhans type histiocytic cells inside lymph nodes. the disease classically presents as bulky, painless lymphadenopathy often associated with infection showing distension of lymph node sinuses by abundant histiocytic cells (cd a(-), s- (+)/cd (+)). in some cases, the disease can be self-limiting, but in cases with a prolonged chronic course of exacerbations and remissions, those with extranodal involvement, or disease that threatens vitals structures, treatment may be necessary. there is no treatment consensus. to describe a case of life-threatening, unresectable, recurrent rdd successfully treated with langerhans cell histiocytosis (lch) -inspired therapy. design/method: we compared this case to the current literature on chemotherapeutic treatments for rdd. we searched pubmed, ovid, and google scholar for similar cases. we believe this to be the first reported case of using lch therapy to successfully treat rdd. an -year-old male presented to an outside hospital with two years of massive neck swelling causing torticollis. biopsy confirmed rdd. he was intermittently treated with courses of antibiotics with partial response. surgical removal of the affected lymph nodes was unsuccessful due to proximity to the spinal cord. two years later, the patient presented to our institution. he was initially treated with prednisone with a fast tapering dose, but after a second relapse the decision was made to try chemotherapy following the lch- protocol of weekly vinblastine ( mg/m ), -mp ( mg/m ), and high dose steroid bursts. he experienced two additional relapses off therapy at ages and years old, including cmv(+) associated septic shock and cytokine storm requiring rapid response, picu admission, and ionotropic support. this last episode was treated with a more prolonged induction and maintenance therapy. an extended and slowly tapered maintenance therapy regimen of . years of daily -mp, monthly vinblastine and steroids with a slowly tapered dose during his fourth remission has resulted in -months of continuous complete remission-the longest stretch of his life. no similar cases were found. literature search demonstrated no consensus regarding the most effective treatment of rdd, with no previous cases being successfully treated following lch chemotherapy protocols. we hypothesize that the multi-agent relatively mild lch- therapy mitigates the immune dysregulation of rdd. this case suggests that lch- therapy can be used to treat cases of rdd that is not amendable to surgery or observation. nicklaus children's hospital, miami, florida, united states background: central venous catheters (cvc) are necessary in the management of patients with malignancies, especially children. patients with acute leukemia (al) have higher rates of central line associated complications such as bloodstream infections compared with other malignancies. objectives: to examine the choice of placement of cvc and the differences in outcome between peripherally inserted central catheters (picc) and ports in patients with leukemia during induction. design/method: retrospective chart review of patients with newly diagnosed leukemia at nicklaus children's hospital between and . results: ninety four patients with a new diagnosis of leukemia undergoing induction chemotherapy were identified. the average age was . years. overall, ( . %) patients had a port placed and ( . %) had a picc placed. the decision for picc or port was subjective and physician based. the main outcome measures were local inflammation/infection, bacteremia, thrombophlebitis, blocked catheter and premature removal. the most common complication was bacteremia ( . %). in a multiple logistic regression analysis for predicting whether patients had at least one complication, results showed that having at least one complication is . times the odds in patients with aml compared to patients with all (p = . ). when comparing picc vs. ports, patients with picc had more frequent episodes of blocked catheters ( . %) and premature removal ( . %) compared to the patients with ports ( . % and . %) (p = . and p = . respectively) during induction. local inflammation, bacteremia and thrombophlebitis were not statistically different (p = . , p = . and p = . respectively). the most common place for port placement was the right subclavian vein ( %). there was no significant association between port location and having at least one complication (p = . ). acute lymphocytic leukemia subgroup analysis: fourteen patients ( %) in the picc group had at least one complication and ( %) in the port group but that was not statistically significant (p = . ). our series showed a higher incidence of blocked catheters and premature removals with picc compared to ports in patients with leukemia during induction. the choice of placement of picc vs port was subjective and physician based. patients with all, despite receiving steroids and asparaginase during induction, did not show a statistically significant increase risk in thrombosis or infection but larger numbers may be needed in future studies. university of california, san francisco, san francisco, california, united states background: hemophagocytic lymphohistiocytosis (hlh) is classically a disorder of young children meeting systemic hyperinflammation criteria. presentation in late adolescence is uncommon. furthermore, though cns signs occur in - % of cases, initial isolated neurologic presentation is rare, frequently resembling encephalitis or demyelinating disorders. these cns signs can be isolated or precede systemic disease, delaying hlh diagnosis. hlh declaring in adolescence with predominant psychiatric features has not been well documented. objectives: to describe a case of cns hlh presenting with neuropsychiatric features in absence of classic hlh criteria. design/method: retrospective review of clinical, radiologic, histologic, immunophenotypic, and molecular features of a patient with cns hlh. a -year-old female presented with acute-onset headaches following nine months of progressive anxiety, short-term memory loss, emotional lability, perceptual disturbances, and hypomania. brain mri demonstrated numerous enhancing t hyperintense supratentorial and infratentorial white matter lesions in the left thalamus and caudate head. brain biopsy showed histiocyte-rich inflammation and associated demyelination. extensive evaluation including universal microbial pcr failed to reveal underlying infection or malignancy. past medical history was notable for presumptive pulmonary sarcoidosis diagnosed months prior with progressive respiratory failure with associated granulomatous pulmonary nodules which responded to systemic immunosuppression. at presentation of her neuropsychiatric symptoms, she had normal sil- r, ferritin, fibrinogen, and triglycerides. there was no pancytopenia, coagulopathy, bone marrow hemophagocytosis, fevers, or splenomegaly. given the possibility of partial immune suppression of systemic symptoms and the prominent neurologic symptoms, hlh screening labs were sent and notable for decreased natural killer and cytotoxic t lymphocyte function, normal granzyme expression and cd a mobilization, and absent perforin expression. genetic testing confirmed compound heterozygous mutations in prf (c. g>a, c. a>c) and familial hlh type . she was treated with low-dose dexamethasone and intrathecal chemotherapy per hlh- . due to lack of evidence of systemic inflammation, vp- and high-dose steroids were held. within one week of initiating therapy, she had decreased anxiety and improved cognition, with sustained, incremental neuropsychiatric improvement with additional intrathecal treatments. she tolerated dexamethasone tapering without symptom flare. mri also demonstrated parenchymal lesion improvement. for definitive treatment, she underwent unrelated allogeneic hematopoietic cell transplantation and remains at neurologic baseline as of eight months post-transplant with ongoing imaging improvement. conclusion: this case of familial hlh with compound heterozygous perforin mutations in an adolescent with isolated neuropsychiatric symptoms illustrates that cns hlh may be an underrecognized phenomenon in absence of systemic signs. standard hlh therapy may effectively reverse these symptoms with associated radiologic responses. rush university children's hospital, chicago, illinois, united states background: posterior reversible encephalopathy syndrome (pres), a recognized complication of pediatric leukemia treatment has been reported in up to % patients in various series. hypertension, chemotherapy and cortical spreading depression have been implicated in the pathophysiology. due to the combinations used, it is difficult to identify the offending drug, several have been implicated. since delay of chemotherapeutic treatment in children with high risk leukemia is unfavorable, it is important to recognize the characteristic radiologic findings, manage appropriately and reintroduce the treatment as soon as possible. pharmacoethnicity is now recognized as an important factor for variation in neurotoxicity in children with all. ethnic differences in reported pres events in pediatric patients with all has not been well described in literature. to describe the factors associated with pres in a cohort of high risk pediatric all patients at a single institution. design/method: a total of children with an average age of years ( - years) diagnosed with all between - were retrospectively reviewed for the occurrence of pres. various demographic factors, therapy received, clinical features, radiology related findings and management were reviewed. a search for all published articles on pres in leukemia was conducted using pubmed databases. results: five ( %) children (average age . years) developed pres during days - of induction. % of the patients that developed and % of those that did not develop pres were hispanic. all the patients that developed pres and % of those that did not were diagnosed with high risk all. all patients received vincristine, % received daunomycin and intrathecal methotrexate and % received asparaginase in the week prior to the event. mri findings confirmed pres in all patients with no evidence of methotrexate related leukoencephalopathy or leukemia. at the time of pres all patients were in remission based on mrd and spinal fluid cytology. two-thirds of the patients had seizures and hypertension at the time of the event with no prior history of either. all patients had complete recovery of normal mental status after resolution of pres. a higher incidence of pres than previously reported was noted in our series. hispanic ethnicity, high-risk all and exposure to vincristine, daunomycin and intrathecal methotrexate in induction were associated with pres in our cohort. a new association that emerged was that of hispanic ethnicity with pres .larger studies to understand the importance of pharmacoethnicity in pres may help in individualization of chemotherapy based on ethnic differences. children's hospital of illinois, peoria, illinois, united states background: hyper ige syndrome is a primary immunodeficiency characterized by susceptibility to skin and lung infections as well as increased propensity for malignancy. hemophagocytic lymphohistiocytosis (hlh) is a syndrome characterized by overwhelming activation of t lymphocytes and macrophages occurring as either primary hlh caused by genetic abnormalities or secondary hlh associated with infectious, malignant, metabolic, or immunodeficiency causes. we describe the first case to our knowledge of hlh in a patient with hyper ige syndrome. to describe a case of hlh in a pediatric patient with hyper ige syndrome. results: a -year old caucasian male with known autosomal dominant hyper ige syndrome (stat mutation) was transferred to the pediatric intensive care unit secondary to concern for septic shock. the patient had persistent slow bleeding from oral lesions and central catheter sites despite the addition of aminocaproic acid and recombinant factor viia. he also required numerous blood product transfusions sec-ondary to anemia and thrombocytopenia. clinical suspicion was high for hlh and the patient met criteria for diagnosis of hlh with the following: ferritin > , ng/ml, triglycerides mg/dl, decreased nk cell function with the sample only containing % nk cells, elevated soluble il- receptor at u/ml, splenomegaly, and fever. infectious workup was remarkable for a positive ebv qpcr with , copies/ml suggestive of ebv driven secondary hlh. familial hlh testing was unable to be completed. therapy was initiated based upon the hlh- study. the addition of ruxolitinib and anakinra were considered but the patient declined rapidly prior to treatment. ct of the head was concerning for a stroke with signs of edema and increased intracranial pressure likely leading to the development of symptoms consistent with brain stem herniation. the decision was then made to withdraw care. conclusion: to our knowledge, this is the first report of hlh in a patient with hyper ige syndrome. diagnosing hlh requires a high index of suspicion in critically ill patients, and prompt initiation of therapy is essential. this challenging case of hlh in a patient with hyper ige syndrome highlights the diagnostic challenge, variable presentation, and need for effective therapy in this vulnerable patient population. background: adolescents and young adults (ayas) with cancer are at risk for psycho-social as well as physical symptom burden during cancer therapy. the purpose of this study is to explore psychological and physical symptoms endorsed by aya while receiving therapy for cancer design/method: surveys were given in both inpatient and outpatient settings during cancer therapy. symptom screening in pediatrics tool (sspedi) and memorial symptom assessment scale (msas). symptoms severity was rated by teens on a point likert scale. spss , used for statistical analysis. results: : a total of aya on cancer therapy (age range - . years) % female, % male, . % acute leukemia, . % solid tumors, and . % diagnosis was not reported. % of aya on cancer therapy reported at least or more symptoms, % reported > symptoms cluster. of the physical symptoms that were reported as most distressing to the teens, mouth sores and headaches were the top causes. of the physical symptoms that were most frequently endorsed; fatigue was on the top ( %), followed by change in appetite %, vomiting %, and pain %., the least was bowel habit changes. aya rated sadness as the most frequent psychological symptom %, followed by feeling angry %, and scared %. statistically significant difference was noticed based on gender difference with more females reported symptoms (p = . ), while type of cancer (acute leukemia versus solid tumors) was not statistically different. conclusion: aya with cancer reported multiple physical and psychological symptoms with significant distress. females seem to report more symptoms compared to males. screening aya for cancer therapy related symptoms is feasible during routine visits and adds important information about the aya well-being. background: sinus histiocytosis with massive lymphadenopathy (shml), also known as rosai-dorfman disease, is a rare histiocytic proliferative disorder of unknown etiology. many treatment modalities have been employed; however, no uniform guidelines exist. objectives: literature review of treatment options for shml. design/method: chart review was performed on pediatric patients diagnosed with shml at the children's hospital at montefiore between and after irb approval. inclusion criteria included children between the ages of and years with shml. exclusion criteria included children with cutaneous shml. four cases of shml seen at montefiore are described. a comprehensive review of the literature identified additional cases published between and . manuscripts that did not include the treatment modality or outcome were excluded. results: many of the patients with shml responded to observation alone. of patients, patients were observed, with ( %) having resolution of disease, five having stable disease, and five being lost to follow-up. one patient received subsequent systemic therapy. surgical management was con-ducted upfront in patients. of those, ( %) had resolution of disease, one had stable disease, and one had recurrence with no further therapy noted. of the remaining nine patients, % were successfully treated with systemic therapy, consisting of either steroids ( ) or steroids and chemotherapy ( ). systemic therapy was used as first-line therapy in patients. steroids alone or in conjunction with chemotherapy resulted in resolution of disease in / and / patients ( / , %), respectively, with four patients having stable and three with progressive disease. chemotherapy without steroids resulted in resolution of or stable disease in / patients. radiation was ineffective. conclusion: shml is a rare disease with no published guidelines for treatment. from the results of the cases and a detailed review of the literature, it can be suggested that observation may be considered as first line management in patients providing there are no significant symptoms. for patients who are symptomatic or have significant progression, surgery may be considered. in patients with recurrence or refractory disease, steroids and/or chemotherapy may be used. the presence of nodal or extra-nodal disease did not seem to have a significant impact on the course of treatment. given the rarity of the disease, it is difficult to conduct a randomized control trial. further work, involving collaboration between centers and cooperation with the international rare histiocytic disorders registry would be helpful. boston children's hospital, boston, massechusettes, united states background: increasing census and intensified work compression on the inpatient oncology service at our institution was identified as leading to resident dissatisfaction, impaired resident learning and decreased perceived quality of patient care. objectives: to evaluate the impact of a redesign of a pediatric inpatient hematologic malignancy (ihm) service on resident perceptions of the educational value of the rotation and safety of patient care. design/method: during the - academic year, we initiated a bundled intervention on the ihm service. modifications included ) decreased patient volume: the ihm service was divided into two teams, utilizing an extra attending -a teaching service consisting of residents and fellows and a team comprised of nurse practitioners. ) intentional patient team assignment: patients were deliberately assigned to a care team based on educational opportunities and provider skill sets. ) intentional attending faculty selection: attending faculty with deeper clinical and teaching experience were selected to supervise on the teaching team. ) increased weekend staffing. after completing the service, junior residents completed an electronic survey to evaluate their perceptions of the educational value of the rotation, as well as their ability to deliver safe care while on the rotation. fisher's exact tests were used to compare responses from residents in who experienced the redesign to residents in , whose experience results: survey completion rates were % ( / ) in and % ( / ) in . intervention residents were significantly more likely than comparison group residents to choose the answers "very good" or "excellent" to describe both the overall quality of the rotation ( % intervention vs. % comparison, p< . ) and the educational experience on rounds ( % intervention vs. % comparison, p< . ). intervention residents also reported caring for fewer average primary patients daily on weekdays as compared to comparison residents ( . vs . patients, p< . , % ci - . to - . ). furthermore, intervention residents were more likely than comparison residents to "agree" or "strongly agree" that they could provide safe patient care on weekend days ( % intervention vs. % comparison, p< . ) and on nights ( % intervention vs. % comparison, p< . ) while on the oncology service. a redesign initiative of an oncology service with the development of a new teaching service led to improved resident perceptions of the educational value of the rotation and ability to provide safe care to patients. this approach could be useful to other services and institutions to promote similar outcomes in resident education and patient care. background: alk-positive histiocytosis is a rare histiocytic proliferative disorder that has been reported in three infants presenting primarily with hepatosplenomegaly, anemia, and thrombocytopenia. given the rarity of this disease, there are no standard treatment algorithms for this diagnosis and the disease course and outcomes remain largely unknown. the published series describes treatment ranging from monitoring alone to multi-drug chemotherapy regimens. there was ulti-mately resolution of presenting symptoms in all three cases despite varying treatment strategies. objectives: to report a newly diagnosed case of alkpositive histiocytosis that was treated with a novel approach using cytarabine monotherapy. results: a full term male infant presented at birth with difficulty feeding and hyperbilirubinemia. over the first few weeks of his life, he subsequently developed thrombocytopenia, transaminitis, and profound hypoalbuminemia. by six weeks of life, he was experiencing significant abdominal ascites requiring repeat paracenteses, massive hepatosplenomegaly, respiratory distress secondary to abdominal distension, anemia, and coagulopathy. he underwent numerous diagnostic tests, including a liver biopsy followed by a bone marrow biopsy that showed alk-positive histiocytic infiltrates in both sites. treatment was initiated with cytarabine mg/kg/day x days, repeating every weeks. throughout his course of five cycles of treatment, he experienced intermittent fevers and mild nausea with no other adverse events. by the end of five cycles, his hepatosplenomegaly resolved, his blood counts normalized, he demonstrated weight gain on oral feeds, and his liver enzymes normalized. he is currently months post completion of therapy and remains well with a normal physical exam and laboratory values. conclusion: treatment of alk-positive histiocytosis with lose dose cytarabine resulted in complete resolution of our patient's symptoms with minimal treatment related adverse effects, and few long-term treatment related risks. given the rarity of the diagnosis, the reporting of effective novel treatment options is important for future patient care. background: adult patients with melanoma or lung cancer harboring braf v e have benefitted from the development and subsequent approval of specific braf inhibitors. as such, delineating the subset of similarly targetable pediatric oncology patients may spur development and rational use of these inhibitors in children. importantly, other point mutations and fusions of braf may also be targetable in s of s children analogous to recent emerging data in adult cancer patients. objectives: to define the genomic landscape of known and novel braf alterations and raf fusions in pediatric malignancies and report index cases with clinical response to braf or mek inhibitors. design/method: dna was extracted from microns of ffpe sections of , tumors from pediatric (< years of age) oncology patients, and cgp was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of x for up to cancer-related genes plus introns from genes frequently rearranged in cancer. genomic alterations (ga) included base substitutions, indels, copy number alterations and fusions/rearrangements. a total of ( . %) braf-altered pediatric malignancies were identified. ( . %) harbored a single kinaseactivating braf short variant, indel, or fusion. an alteration resulting in reduced braf kinase activity was identified in ( . %) tumors while ( . %) tumors harbored multiple braf alterations, of which contained at least a single activating short variant. the remaining tumors ( . %) contained functionally uncharacterized variants. kinaseactivating braf alterations were identified in diverse tumor spectra comprised of brain tumors ( . %; subtypes), carcinomas ( . %; subtypes, with melanoma constituting % of cases), hematological malignancies ( . %; subtypes), sarcomas ( . %; subtypes), and extracranial embryonal tumors ( . %; subtypes). seventy-two ( . % of braf-altered cases) braf fusions were identified, ( . %) of which were kiaa -braf; involved the novel fusion partners: stard nl and khdrbs . seven ( . %) raf fusionpositive cases, predominantly brain tumors ( ), were identified; involved the novel fusion partners: tmf and sox . index cases of response to therapy of intracranial tumors will be presented. we describe a population of pediatric patients with targetable braf alterations predominantly enriched in primary intracranial tumors, but spanning diverse solid tumor types and hematologic malignancies. we additionally report a cohort of raf fusion-positive patients. an index case and multiple previous reports suggest raf or mek inhibitors may benefit pediatric patients with either intracranial or extracranial disease, and development of such drugs in pediatric indications is strongly warranted. background: diffuse midline gliomas (dmg) with h k m mutation, including diffuse intrinsic pontine glioma (dipg), are the leading cause of brain tumor-related deaths in children. there are no effective therapeutic strategies and the median survival remains dismal. genomic studies have identified a recurrent mutation in the majority of dmgs involving a lysine to methionine substitution (k m) in histones . and . , resulting in changes in the epigenetic landscape that dysregulate gene expression and promote gliomagenesis. panobinostat, a multiple histone deacetylase (hdac) inhibitor, was found to be one of the most effective agents against dipg patient-derived cell cultures and xenograft models in previous studies and is presently in clinical trial for dipg. hdac inhibition with panobinostat may also exhibit activity against h k m+ diffuse midline gliomas of the thalamus and spinal cord. to evaluate the effect of panobinostat as a single agent against patient-derived thalamic and spinal cord h k m+ diffuse midline glioma cell cultures and in an orthotopic xenograft murine model of h k m+ spinal cord glioma. design/method: patient-derived thalamic and spinal cord h k m+ diffuse midline glioma cell cultures were treated with single agent panobinostat at a range of concentrations. cell viability was evaluated using the celltiter-glo assay. panobinostat was systemically administered to orthotopic xenograft murine models of luciferase-expressing spinal cord h k m+ diffuse midline glioma. response to panobinostat was evaluated with ivis in vivo imaging. results: hdac inhibition with panobinostat significantly decreases cell proliferation with an ic of nm and nm in the spinal cord and thalamic glioma patient-derived cell cultures respectively. panobinostat slowed tumor growth in murine models of spinal cord glioma by . -fold in the brain (p = . , n = ) and -fold in the spinal cord (p = . , n = ) when compared to vehicle controls after week of administration. panobinostat is in clinical trials for dipg. this study suggests that hdac inhibition with panobinostat may also be beneficial for patients with thalamic and spinal cord diffuse midline glioma h k m mutants. background: brain tumors are the most common solid tumor of childhood and the leading cause of childhood cancer deaths. while medulloblastoma is the most common malignant brain tumor of childhood with a -year survival - %, children with high-grade gliomas (hggs) such as glioblastoma multiforme (gbm) fare much worse with a -year survival of - %. implicated in this poor outcome is the presence of treatment resistant brain tumor stem-like cells. gbm stem-like cells (gscs) have been implicated in tumor growth, treatment resistance and patient relapse, making them a key therapeutic priority. antipsychotic drugs (apds) have been used for decades in various psychiatric clinical settings and are associated with a lower incidence of cancer, including malignant brain tumors. currently, atypical apds are being evaluated for their potential to alleviate cancer and treatment induced side effects. furthermore these drugs may have direct anti-tumor effects, potentially via inhibition of dopamine d receptors (drd ). objectives: determine the anti-cancer effects of atypical apds on gbm stem-like cells design/method: the anti-cancer effects of apds (quetiapine and risperidone) were evaluated on gbm stem-like cell lines developed in our laboratory (glio and ) and the group medulloblastoma cell line hdmbo . cell proliferation/viability was determined using trypan blue exclusion and mts assays. the effect of apds on cancer stem cell self-renewal was determined by neurosphere assay. receptor expression and apds effect on cell cycle proteins were examined by western blot analysis. results: western blot analysis of gscs and hdmbo demonstrated robust drd expression indicating a viable therapeutic target. both apds induced dose dependent cell death of all cell lines tested. treatment with only um of either apd for days significantly reduced cell proliferation by % (hdmbo ) and - % (gscs). consistent with these findings, we observed an increase in cell cycle inhibitors p and p . furthermore at day both apds induced a robust increase in gsc death, approximately % compared to only % in non-treated controls. lastly, um apds significantly reduced gsc neurosphere formation compared to untreated controls by up to % suggesting inhibition of gbm stem cell self-renewal. our data indicates that clinically relevant concentrations (low micromolar) of these apds induce anticancer effects in both gscs, which are enriched with tumor initiation/propagation properties, and in the group (myc amplified) medulloblastoma cell line. these apds represent strong candidates as potential adjuvant therapies for the treatment of these brain tumors. background: while the poor prognosis for high risk neuroblastoma (hrnb) underscores the need for new treatment strategies, the elucidation of specific biologic subsets of neuroblastoma suggests a way to improve disease management. the identification of agents that target specific molecular pathways associated with the development or progression of diseases holds promise. dfmo, an inhibitor of odc, has been shown to decrease lin and mycn and target cancer stem cells in preclinical studies. currently % of patients undergoing immunotherapy relapse. dfmo is in studies to prevent relapse after immunotherapy and may be helpful during immunotherapy as well. the hypotheses for this study were that: ) the incorporation of a targeted therapy, selected based upon upfront tumor genomic interrogation, into standard induction chemotherapy for hrnb is safe, feasible and may increase the pr/cr/vgpr response rate at the end of induction therapy; and ) the addition of dfmo as maintenance during immunotherapy is safe and feasible and may decrease the relapse rate for hrnb. a multicenter feasibility pilot trial in subjects with newly diagnosed hrnb within the beat childhood cancer consortium. at diagnosis, patients' tumors underwent dna exome and rna sequencing which were analyzed within a molecular tumor board to identify the single best drug of targeted agents to be added to cycles - of induction chemotherapy. after consolidation with asct and radiation, the patients received dfmo along with standard dinutuximab and retinoic acid and dfmo for years after immunotherapy. patients were evaluated for additional toxicities with the addition of targeted agents and dfmo in addition to induction response. results: the pilot study of eligible patients has shown this process to be feasible. all patients have completed induction portions of the study. the combination of targeted agent with chemotherapy was shown to be safe without any unexpected toxicities. delays between induction cycles were < weeks and related to surgery, infection, or thrombocytopenia. the induction response demonstrated % cr/vgpr/pr rate, which suggests improvement over historical %. in addition, patients were eligible for the combination of dfmo with dinutuximab and retinoic acid was well tolerated and safe without additional toxicities due to dfmo. the pilot study of patients has shown the process of genomic sequencing and addition of a targeted agent to upfront chemotherapy and addition of dfmo to dinutuximab and retinoic acid maintenance therapy in newly diagnosed hrnb patients and is feasible and safe without any unexpected toxicities. background: identifying sub-populations of medulloblastoma tumors with stem cell-like properties holds promise for reducing disease recurrence, but there is no known unifying marker of medulloblastoma cancer stem cells. the granulocyte stimulating factor receptor (gcsf-r or cd ) is well understood in the context of hematopoiesis, but its role in solid tumor pathogenesis is less clear. neuroblastoma and melanoma subpopulations expressing gcsf-r have cancer stem cell properties of chemoresistance and increased tumorigenicity, and are enriched in tumors after chemotherapy. gcsf-r activation leads to signaling through the jak-stat pathway, suggesting a potential therapeutic target. we hypothesized that a subpopulation of medulloblastoma cells would express the gcsf-r and that this subpopulation would demonstrate chemoresistance and response to inhibitors of the jak/stat pathway. objectives: our objective was to identify a subpopulation of medulloblastoma cells expressing the gcsf-r and determine their relative growth rates, tumorigenicity, and responses to chemotherapy and jak/stat inhibition. design/method: medulloblastoma cell lines were sorted via flow cytometry for gcsf-r surface expression. subpopulations of gcsf-r-positive and -negative medulloblastoma cells were then monitored for growth by continuous live cell imaging. responses to chemotherapy were measured in subpopulations of gcsf-r-positive and -negative medulloblastoma cells using continuous live cell imaging to measure percent cell confluence and cell viability assays. ic values were calculated for each cell line and each agent. parental medulloblastoma cell lines and isolated gcsf-r-positive and -negative subpopulations were also treated with the jak / inhibitor ruxolitinib and growth rates, viability, and ic values were calculated. results: gcsf-r surface expression was identified on . - . % of medulloblastoma cell lines. isolated gcsf-r positive cells demonstrate a slower growth rate compared to gcsf-rnegative or parental unsorted medulloblastoma cells. gcsf-r positive cells are more resistant in vitro to vincristine, etoposide, and carboplatin, when compared to the gcsf-r negative population and an unsorted population of the same cell line. ruxolitinib is cytotoxic to medulloblastoma cells in vitro, with higher ic values noted in gcsf-r positive cells compared to unsorted and gcsf-r negative cells. we show that a subpopulation of gcsf-r positive cells are present in multiple medulloblastoma cell lines via flow cytometry, and that isolated gcsf-r-positive cells have a slower growth rate than gcsf-r-negative or unsorted populations. we also show that ruxolitinib has in vitro activity against medulloblastoma cell lines. we propose that jak inhibition may represent an adjunct therapy targeting overall tumor burden and specifically targeting the gcsf-r-positive subpopulation of medulloblastoma cells that may drive tumor recurrence. we investigated the efficacy of intensified adjuvant chemotherapy in osteosarcoma patients. design/method: we retrospectively analyzed the medical records of children with osteosarcoma treated at asan medical center between and . all patients received a -drug induction consisting of cycles of cisplatin and doxorubicin along with cycles of methotrexate (map), and proceeded to surgical resection. adjuvant ct was map or map with the additional ifosfamide and etoposide (mapie), and mapie was mainly considered for poor responders (tumor necrosis below %) or patients with metastases. results: among patients, patients had metastases at diagnosis. surgery was conducted in patients who responded to induction ct, and showed over % tumor necrosis. among patients who proceeded to adjuvant ct, and patients received to map and mapie protocols. with a median follow-up of months, the -year overall survival (os) and event-free survival (efs) rates of all patients were % and . %. of those patients, patients recurred, and of them died of disease progression. relapsed patients received salvage ct and/or surgery, and were rescued after autologous stem cell transplantation (sct). three patients developed treatment-related acute myeloid leukemia, and they are alive after allogeneic sct. according to the response to neoadjuvant ct, the os rates of good responders (n = ) and poor responders (n = ) were % and . % (p = . ), and efs rates were . % and . % (p = . ). of the poor responders, patients received map as adjuvant ct, and the other received mapie. the os rates of map and mapie group were . % and . % (p = . ), and efs rates were . % and . % (p = . ), respectively. when patients were classified into three groups: . localized disease & necrosis ≥ % (n = ), . localized disease & necrosis < % (n = ), . metastatic disease (n = ), survival rates were in the order of group > > (os = %: . %: . %, efs = . %: . %: %). in each group, intensified adjuvant ct by mapie did not improve survival outcomes. conclusion: initial metastatic disease and poor histological response to neoadjuvant ct were major risk factors for poor survival in osteosarcoma patients. we found that adding ifosfamide and etoposide to map did not improve survival outcomes of patients with adverse risk factors. more effective adjuvant therapy for these patients is needed. background: circulating cell-free dna (cfdna) that shed from tumors into circulation have been used for noninvasive molecular profiling in adult cancers but little is known about its utility in pediatric cancers. pediatric patients with metastatic and refractory solid tumors are known to have poor survival rates, and a key challenge in their management is obtaining biopsy samples especially at times when disease is widely spread or the patient is physically unfit for sampling. the development of a noninvasive profiling strategy is critical for optimizing molecularly guided therapy and assessing response to treatment. in this study, we want to determine the utility of cfdna to noninvasively analyze the molecular profiles of pediatric solid tumors such as neuroblastoma (nb), osteosarcoma (os), and wilms tumor (wt). design/method: tumor, plasma, and matched controls were collected from patients with nb, wt, and os, at diagnosis or time of disease progression. cfdna was extracted from the plasma and analyzed through multiple methodologies including a targeted next generation sequencing panels and shallow whole genome sequencing (swgs). results: fifteen nb patients, os patients, and wt patients had tumor molecular profiles known from different targeted next-generation sequencing platforms. in the cfdna of / nb patients, somatic mutations and copy number alterations previously reported in the tumors were detected, including recurrent nb drivers such as mycn amplification, alk, and atrx mutations. mutations not detected in the original tumor were also found in / nb patients including nras, mll , arid b, some of which are potentially actionable. in os, mutations known from the tumor were found in the cfdna of of patients, including atrx and notch mutations, as well as copy number alterations such as cdk amplification, which has targetable therapeutics available. of the two wt patients analyzed, cfdna revealed the same mutations as tumor in one patient, however in a cohort of patients where tumor was not available, cfdna revealed recurrent driver mutations such as amer , dicer . it is feasible to noninvasively identify somatic mutations and copy number alterations in cfdna of patients with pediatric solid tumors. establishing a platform using cfdna to identify molecular profiles of these tumors can serve as a powerful tool for guiding treatment and monitoring response to treatment. background: despite multi-modality therapy, the prognosis for patients with metastatic osteosarcoma remains poor necessitating development of novel targeted therapies. immunotherapy can be exploited to target osteosarcoma with exquisite specificity but remains limited by insufficient tumor specific targets. objectives: to overcome the dearth in tumor specific antigens, we have explored the use of tumor derived mrna (representing a tumor specific transcriptome) for development of personalized nanoparticle vaccines. design/method: rna-nanoparticles (rna-nps) can be amplified from limited amounts of biopsied tissue for induction of tumor specific t cells against osteosarcoma. since local vaccination strategies are mired by poor overall immunogenicity, we assessed the feasibility, immunogenicity and antitumor activity of intravenously administered rna-nps (tumor mrna complexed to dotap nanoliposomes) in pre-clinical murine and canine tumor models. we identified a clinically translatable np formulation for the delivery of rna to antigen presenting cells (apcs) that induces in vivo gene expression and preserves rna stability over time. tumor derived rna-nps induced antigen specific t cell immunity and mediated anti-tumor efficacy in several pre-clinical solid tumor models (i.e. b f , kr b). when administered intravenously, rna-nps increased expression of co-stimulatory molecules (i.e. cd , cd , cd , ccr ) and pd-l on cd c+ cells throughout reticuloendothelial organs (i.e. spleen, liver, bone marrow) and within the tumor microenvironment; this phenotype was strictly dependent on type i interferon. targeted inhibition of type i interferon signaling (via infar mabs) abrogated anti-tumor efficacy mediated by rna-nps. we enhanced the immunogenicity of this platform by simply combining mrnas encoding for immunomodulatory molecules (i.e. hcv-pamps, gm-csf) or by combining rna-nps with immune checkpoint inhibitors. addition of checkpoint inhibitors (pd-l mabs) to rna-nps increased tumor infiltrating lymphocytes, and intratumoral mhc class i/ii expression, and mediated synergistic anti-tumor activity in settings where pd- or pd-l inhibition alone did not confer therapeutic benefit. we then explored the feasibility of rna-nps in a large animal osteosarcoma model. in ongoing studies for canines with osteosarcomas, we have shown that sufficient amounts of rna can be extracted, amplified, and manufactured into personalized rna-np vaccines. conclusion: rna-nps reprogram systemic immunity and mediate anti-tumor activity providing near immediate immune induction without the complexity of cellular immunotherapy. the immune correlate of preclinical response to rna-nps is hallmarked by interferon dependent pd-l expression on activated apcs (cd c+ mhcii+ cd + cells). based on these findings, we are exploring the preclinical safety, efficacy and immunologic effects of rna-nps targeting canine osteosarcoma before first in-human evaluation. background: ewing sarcoma is an aggressive bone tumor affecting mainly adolescent and young adults. treatments are based on compressed schedule chemotherapy combined with local control (surgery and/or radiation). prognosis is poorer for patients with metastatic disease, older age and central primaries. survival when disease recurs within two years of diagnosis is < %. the ews-fli fusion gene t( ; ) (q ; q ) has been well characterized as a dominant ews driver-gene. the most common variation is ews exon with fli exon ( % of fusion positive patients). we designed a novel pbi-shrna tm ews/fli type lpx which has demonstrated, safety and efficacy in animal model (rao et all). the pbi-shrna strategy silences target gene expression by concurrently inducing translational repression and p-body sequestration as well as post-transcriptional mrna cleavage. to determine the safety and maximum tolerated dose of intravenous administration of pbi-shrna tm ews/fli type lipoplex in patients advanced ews. design/method: phase i study × escalation cohort. testing pbi-shrna tm ews/fli type lpx (starting iv dose of . mg/kg) on patients (≥ age ) with advanced ewing's sarcoma, all with a type translocation. intravenous infusion was given twice a week for weeks with the following escalation schema: % → % → % → % → %. required kps > % and adequate organ function. cytokines induction pre and post-infusion was analyzed (il- , il- , tnf-alpha, il ra). first cohort of patients has been enrolled (ages between - years). three relapsed patients had > lines of therapy and patient had refractory disease, patients received a complete cycle of pbi-shrna tm ews/fli type lpx with twice a week infusions. a total of doses were given. the most prominent related toxicity has been hematological, patient developed transient g neutropenia, another patient developed g anemia that required prbc transfusion, and of note this patient had significant bone and bone marrow involvement. one patient only received two lpx infusions; she developed a fatal rsv pneumonia. other reported grade toxicity includes fatigue and headache. evaluable patients (n ) had stable disease between and months before progression. one patient had sustained response for month before progression, two patients are still alive. our preliminary experience supports the safety and potential efficacy of pbi-shrna tm ews/fli type lpx as novel treatment for advanced ews with limited toxicity. il- increase correlates with higher bi-shrnai ews/fli lpx infusion rate and clinical symptoms. further clinical testing is indicated. background: as more children with cns malignancies (bt) are surviving, the late effects of the therapies they receive are better described. studies show that radiation therapy is particularly harmful to neurocognitive functioning, specifically processing speed, working memory, and attention span. these deficits have negative effects on quality of life, especially in academic and professional settings. a large proportion of s of s adult survivors of bt are unable to reach adult milestones such as living on their own, holding a steady job, and getting married. proton beam radiation therapy (pbrt), is touted for the potential to have fewer and less severe side effects than traditional photon radiation therapy (xrt). because of the properties of protons, the amount of damaging energy released in non-target healthy tissue is reduced when compared to xrt. although a study comparing iq testing between pbrt and xrt found no difference between the two therapies, no studies have compared the specific neurocognitive domains. it would be valuable to evaluate full neurocognitive testing scores (nct) since the specific domains, particularly processing speed (psi), appear to be most vulnerable to radiation therapy. objectives: our primary aim was to assess differences in psi for patients with bt who underwent pbrt versus xrt. a secondary aim was to assess differences in iq (fsiq) and working memory (wmi). we retrospectively evaluated all patients treated for bt at the jimmy everest cancer center within the past years who received rt and had nct post radiation. we examined the full nct results for both subsets of participants to evaluate differences in the specific domains of processing speed, working memory, and iq by measuring percentiles scored in these domains. objectives: we report our experience on imaging children with mm treated uniformly on an institutional melanoma trial. we retrospectively reviewed the clinical and imaging findings of patients with ajcc stage iic-iv cutaneous mm treated on our institutional mel protocol. brain mri/ct, pet/ct, ct chest, abdomen, and pelvis (ctcap) were performed at diagnosis in all patients. on treatment, stratum a patients (peg-interferon; ajcc iic, iiia, iiib) (n = ) had the same imaging repeated every months; stratum b (peg-interferon and temozolomide; unresectable measurable disease metastatic, or recurrent) (n = ) had pet scans every months and brain imaging every months; those in stratum b (peg-interferon and temozolomide; unresectable non-measurable, metastatic, or recurrent) (n = ) had the same imaging performed every months. off therapy all patients continued same imaging every months for years. results: there were patients ( female; median age years). eleven had spitzoid and conventional melanoma. primary sites included head/neck (n = ), trunk (n = ), and extremities (n = ). patients with spitzoid melanoma had imaging studies ( pet, ctcap, ct chest, ct brain, and mri brain) with a median of , , , and studies/patient respectively. median cost per patient was $ , . thirteen studies ( . %) showed suspicious lesions with additional scans and diagnostic biopsies of which one only was positive stratum a with tert promoter mutation and died from disease). for conventional mm, studies ( pet, ctcap, ct chest, ct brain, and mri brain) were performed with a median of , . , , , studies/patient respectively. median cost per patient was $ , . twenty ( %) showed suspicious lesions with additional scans and diagnostic biopsies; four were positive (two at diagnosis); both died of disease; the other two recurred locoregionally and were detected clinically; both are alive and disease free; one patient had diffuse metastases and died shortly after enrollment. after a median follow up of . years (range . - . ) patients are alive and disease free. children with spitzoid melanoma should have minimal imaging at diagnosis and follow-up given the low risk of recurrence and low yield and high cost of aggressive imaging protocols. patients with conventional mm should be imaged according to the adult guidelines. nationwide children's hospital, columbus, ohio, united states background: the role of infections in the long term outcome of patients with bone tumors is controversial. two retrospective studies have shown increased survival in osteosarcoma patients who had a post-operative wound infection, while another showed no changes in overall survival. to determine the relationship between wound infections and/or bloodstream infection (bsi) on survival in pediatric and young adult patients with osteosarcoma and ewing sarcoma treated at a tertiary children's hospital. design/method: a retrospective chart review was performed for patients with diagnosis of osteosarcoma or ewing sarcoma from - . patients received standard chemotherapy regimens for their disease type and stage. local control included surgical resection and/or radiation therapy. presence of infection was determined by bsi or wound cultures while receiving treatment for primary tumor. the median age of patients was (range - years) at diagnosis. % had a diagnosis of osteosarcoma and % had ewing sarcoma. of these, % of patients developed an infection during treatment; % had bsi, % had wound infections, and % had both. patients with bsi had a year os of . %, compared to % in those without bsi (p = . ). those with both bsi and wound infections had the poorest overall survival of %, compared to . % for patients without any infection. patients with wound infections alone had a year os of . %, compared to % of patients without a wound infection. our analysis revealed decreased os in patients with bsi; however, this could be due to other confounding factors in the presence of bsi. those with bsi or bsi and wound infections had the poorest survival. wound infections without bsi were associated with a slight increase in survival; however, this study was limited by the number of patients that had local wound infections. with the use of newer surgical techniques, availability of antimicrobials and routine use of prophylactic antibiotics, the incidence of infections while undergoing treatment is low. however, the importance of this clinical observation indicates a likely enhanced immune system associated with infection, supporting the role of immunotherapy for treatment of these aggressive tumors. background: hypoalbuminemia is a well-recognized effect of cancer and other chronic illnesses and is often regarded as a marker of malnutrition. in adults, hypoalbuminemia has been associated with adverse outcomes in patients with cancers of the lung, pelvis, head and neck, gastrointestinal tract, and bone marrow, as well as in some pediatric patients with ewing sarcoma and hodgkin lymphoma. hypoalbuminemia has not been well studied in children with cancer. to determine the incidence of hypoalbuminemia (using age-specific references) in children with cancer receiving chemotherapy at baseline (prior to starting chemotherapy) and to determine whether hypoalbuminemia is associated with inferior -year overall survival. design/method: we performed a single institution, irbapproved, retrospective review of pediatric oncology patients diagnosed between and . five-year survival was estimated using the kaplan-meier method; groups were compared using cox regression. we identified pediatric patients with a first diagnosis of cancer, brain tumor, or other condition possibly requiring chemotherapy. of these patients, were excluded for reasons including not receiving chemotherapy and missing data, leaving patients who had a serum albumin level within days prior to starting chemotherapy. the mean age was . years (sd . years); % were male; % were non-hispanic. the most common diagnosis was acute lymphoblastic leukemia ( of ; %). one hundred thirty nine of ( %) had hypoalbuminemia prior to starting chemotherapy. there was no statistically significant difference in -year overall survival between those with and without hypoalbuminemia ( % vs. %, respectively; hazard ratio . , % c.i. . - . ). conclusion: hypoalbuminemia at baseline in pediatric oncology patients requiring chemotherapy is common (one in five), and was not associated with inferior -year overall survival in this cohort. leptomeningeal metastases at diagnosis. standard treatment for completely resected, non-anaplastic supratentorial ependymomas is close observation. treatment for anaplastic or incompletely resected non-anaplastic ependymomas is maximal safe surgical resection followed by focal radiation. however, up to % of localized ependymomas recur. the role of chemotherapy in treating ependymomas is under investigation. extraneural metastases of anaplastic ependymomas have rarely been reported and the outcome is dismal. objectives: to report extraneural cervical node metastases of a non-anaplastic ependymoma and successful treatment with surgical resection, radiation, and systemic chemotherapy. design/method: retrospective review of patient medical records, including radiographic imaging and tumor tissue pathology, and comprehensive literature review. results: a previously healthy -year-old girl underwent gross total resection (gtr) of an isolated right parietal lobe ependymoma (who grade ii). at age years, magnetic resonance imaging (mri) revealed an isolated localized recurrence. she underwent gtr followed by observation. at age years, she again experienced isolated localized recurrence and underwent gtr followed by . gy focal conformal photon radiation. at each recurrence, pathology revealed a non-anaplastic ependymoma, and cerebral spinal fluid (csf) cytopathology and spine mri were negative. at age years, she developed an enlarged right posterior cervical chain lymph node. subsequent mri revealed a large rim-enhancing, t hyperintense lymph node and multiple abnormally enhancing regional nodes consistent with metastases. biopsy revealed a non-anaplastic ependymoma. mri of the brain and spine, computed tomography of the chest, abdomen, and pelvis, and csf and marrow evaluations were unremarkable. chemotherapy according to acns was initiated. mri after course demonstrated significant node size reduction. she underwent right neck node dissection. only one right level ii lymph node showed metastases. she was treated with . gy irradiation to the neck and additional courses of chemotherapy. she remains in remission months and months after diagnosis of metastatic disease and end of therapy, respectively. literature review reveals rare reports of extraneural metastatic disease of anaplastic ependymomas to bone, lung, or liver, and only involving lymph nodes, all associated with a poor outcome despite multimodal therapy. to our knowledge, this is the first report of extraneural metastases of a non-anaplastic ependymoma. extraneural metastases should be considered in children previously treated for non-anaplastic ependymomas who experience systemic symptoms, even in absence of cns relapse. multimodal treatment offers potential long-term disease control with acceptable toxicity. arun gurunathan, joel sorger, andrew trout, joseph pressey, rajaram nagarajan, brian turpin cincinnati children's hospital medical center, cincinnati, ohio, united states background: pigmented villonodular synovitis (pvns) is a benign neoplasm of the synovium. standard treatment is surgery, but post-operative recurrence rate is as high as %. radiation therapy can be used for local control, but is associated with late effects. while pvns is rarely fatal, aggressive disease and/or extensive surgery can result in substantial functional impairment. colony stimulating factor- (csf ) overexpression, often due to chromosomal translocation involving csf , drives pvns through recruitment of synovial-like mononuclear cells expressing the csf -receptor. tyrosine kinase inhibitors such as imatinib are active against the csf -receptor, and have shown benefit in the post-surgical relapse setting. however, questions remain regarding the broader application of imatinib and regarding optimal response assessment. to present three patients with pvns, each with different clinical scenarios, who demonstrate clinical response to imatinib monitored by changes in metabolic activity (maximum suv) on pet/ct. results: three patients with pvns demonstrate pet/ct response to imatinib, guiding management of their challenging clinical scenarios. patient is a year-old female with left hip pvns and high grade articular cartilage loss, with decrease in metabolic activity (suvmax . to . in months) on neoadjuvant imatinib, enabling total hip replacement surgery planning. patient is a year-old female with left knee pvns with recurrences after synovectomies, spared subsequent surgical control attempts after clinical improvement correlating with pet/ct response to imatinib (suvmax . to . in months). patient is a year-old male with right knee pvns that recurred after total knee replacement, now with clinical improvement correlating with pet/ct response to imatinib (suvmax . to . in months). all patients would have been characterized as stable disease by response evaluation criteria in solid tumors (recist). in each of these patients, imatinib has been tolerated well, with no therapy interruptions and absent or easily managed side effects (one patient takes dronabinol for decreased appetite, one patient takes prn immodium for diarrhea). all patients are currently still taking imatinib, with therapy length ranging from five to eleven months. in our series of three patients with pvns, imatinib shows promise for disease management in neoadjuvant and adjuvant settings with a tolerable side effect profile. imatinib should be considered in the treatment of pvns to spare surgical and radiotherapy related morbidity, and treatment effect can be monitored by pet/ct. background: metastatic rhabdomyosarcoma (rms) carries a poor prognosis with three-year event free survival rates ranging between %- % (depending on oberlin risk factors) due to the lack of significantly effective breakthroughs in the recent past. there is an urgent and unmet need for new treatment strategies against this disease. metastatic rms cell lines exhibit increased expression of the erm family membrane-cytoskeleton linker protein ezrin. knockdown of ezrin expression using sirnas decreases the metastatic potential of these cells, whereas forced expression of ezrin results in increased degree of metastasis. the activity of ezrin is controlled by its phosphorylation at the threonine (thr ) residue at the c-terminus of the protein, suggesting that alteration of ezrin phosphorylation may control rms growth and metastasis. our goal was to determine if pharmacological inhibition of thr phosphorylation in ezrin affects the growth, survival and metastasis in rms in vitro as well as in vivo. design/method: rms cell lines representative of the alveolar and embryonal histological subtypes were used. rms cells were treated with a small molecule inhibitor of ezrin, nsc , which specifically dephosphorylates ezrin at the thr residue. baseline expression of ezrin and perm levels as well as the effect of nsc on perm levels in the rms cell lines was determined by western blotting of cell lysates. viability of cells was assessed by trypan blue exclusion, and morphology visualized by bright field microscopy. the extent of apoptosis was detected by imaging caspase / activation using fluorescent microscopy. motility of rms cells was examined by performing a wound-healing assay. subcutaneous and orthotopic xenografts were established in nsg mice using rd cells (embryonal rms). mice harbor-ing xenografts were treated with intraperitoneal injections of nsc or dmso. results: ezrin is constitutively phosphorylated at the thr residue in a majority of the rms cell lines examined. nsc dephosphorylates ezrin at the thr residue in these cell lines. treatment with nsc inhibits growth, induces apoptosis and inhibits the migration of rms cell lines in vitro. further, treatment of nsg mice bearing subcutaneous or orthotopic embryonal rhabdomyosarcoma xenografts with nsc significantly impedes tumor progression without any obvious adverse effects. our findings suggest that dephosphorylation of ezrin at the threonine residue may have the potential to be a novel therapeutic strategy for rms patients. all india institute of medical sciences, new delhi, new delhi, delhi, india background: the role of laparoscopy in the management of pediatric intra-abdominal solid tumors is yet to be established. the safety of laparoscopic management of pediatric intra-abdominal tumors is still questionable. we study the results of the initial case series of pediatric intraabdominal tumors managed laparoscopically at our institute from july onwards. design/method: total children ( -males, females) who presented to us with pediatric intra-abdominal tumors were included. the tumors included wilms tumor (n = ), neuroblastoma(n = ), adrenal cortical tumor(n = ), ovarian teratoma(n = ).children were between months - years and received neo-adjuvant chemotherapy. a -port laparoscopic nephrectomy and lymph node sampling for wilms tumor and adrenalectomy for adrenal tumors was performed. the tumors were removed in-toto with no rupture (except in one). specimens were retrieved through a lumbar incision (n = ) or an inguinal incision(n = ). all the children are under regular follow up. two children with wilms tumor had recurrence. the neuroblastoma child underwent open surgery for recurrence later. conclusion: laparoscopy/laparoscopic assisted removal of pediatric intra abdominal tumor is a feasible and safe option. it has the advantage of less postoperative pain, shorter hospital stay and a better cosmetic result. proper patient selection, port placement and laparoscopic experience are contributory. background: targeting of proteins and cell surface antigens specific to cancer cells with monoclonal antibodies has proven to be an effective form of treatment in many forms of cancer. gd is a cell surface disialoganglioside that is expressed on the cell surface of some normal tissues including nerve cells, melanocytes, and mesenchymal stromal cells and is overexpressed in some pediatric cancers like neuroblastoma and osteosarcoma. dinutuiximab is a chimeric monoclonal antibody that is fda approved for the treatment of patients with high risk neuroblastoma and under investigation for the treatment of relapsed osteosarcoma. little is known about the patterns of gd expression in other pediatric malignancies. objectives: we sought to describe the patterns of gd expression in the following pediatric sarcomas: synovial sarcoma, rhabdomyosarcoma and ewing sarcoma. design/method: synovial sarcoma (n = ), rhabdomyosarcoma (n = ) and ewing's sarcomas (n = ) formalin fixed, paraffin embedded cores were obtained from the seattle children's research institute tissue microarray (tma) biorepository. tma blocks consisting of melanoma cores stained with and without gd antibody were used as positive and negative controls, respectively. slides were incubated with anti-ganglioside gd antibody clone q (ab from abcam) diluted : in % normal goat serum and % bsa in tbs overnight at ˚c. the negative control of human melanoma section was incubated in % normal goat serum and % bsa in tbs without primary antibody. the expression of gd was indicated by characteristic brown diaminobenzidine staining. the intensity and location of tissue staining were assessed and compared to positive and negative controls. staining was considered positive (+++) if the intensity of the staining was consistent with that of the positive control with - % of cells staining positive. classification of intermediate gd expression (++) was assigned to slides in which - % of cells stained positive. slides were classified as sporadic staining (+) if - % of cells stained positive. tissue was considered (-) if there was complete absence of staining, similar to the negative control. objectives: to evaluate the clinical presentation, management and treatment outcomes of children with malignant germ cell tumor at our institute design/method: a prospective study was conducted from june to dec in the department of pediatric surgery in a tertiary care institute in a developing country. all patients were evaluated for local disease and metastatic disease by imaging and tumor markers. risk stratified chemotherapy was used with low risk tumor receiving no chemotherapy, intermediate risk: courses of peb chemotherapy and high risk: courses of peb + courses of pe. upfront resection of the primary or the residual disease after neoadjuvant chemotherapy if feasible was performed. follow up was done with monthly tumor markers for months and imaging studies every - months for initial years. five year overall survival and disease free survival was calculated. results: during the study we treated children who formed the study group. of these ( %) were gonadal ( ; % testicular and ; % ovarian) and the remaining ( %) were extragonadal with sacrococcygeal (sct) being the most common site ( %). one hundred and thirteen children ( %) presented to us primarily while the remaining had received treatment elsewhere. stage or stage disease at presentation was present in ( %) children. recurrence was noted in ( %) patients. respectively. patients with testicular mgct and children with age - years and males had significantly poor rfs rates. conclusion: patients with mgct should be staged correctly and adjuvant chemotherapy is advisable to all patients except stage i endermal sinus tumor of testis. awareness regarding the same is still lacking in our country. meticulous follow up is needed as more than % of will recur. cure rates are dismal in children with recurrent mgct especially those who are not chemotherapy naïve. nemours children's specialty care, jacksonville, florida, united states background: radiotherapy for pediatric head and neck tumors often results in mucositis, limiting oral intake and compromising patients' nutritional status. this may be reduced through the improved conformality offered by proton therapy. despite widespread use of enteral tube feeding through a percutaneous gastrostomy (peg) or nasogastric tube (ngt), there is little data available regarding overall incidence of ngt/peg placement and perspectives of pediatric patients and caregivers. objectives: to (a) estimate the need for ngt/peg support and (b) characterize patient and caregiver perceptions surrounding enteral feeding in children with head and neck tumors undergoing proton therapy. design/method: dependent on development stage, patient (n = ) or parents (n = ) filled out a series of customized surveys according to a prospective irb approved study. seventythree percent of patients also received concurrent chemotherapy. questions addressed their current feeding route and perception, for example, "what aspect(s) of tube feedings are beneficial to you?" and "what aspect(s) of tube feeding worry or scare you?" fifty-five surveys were distributed before and after radiation, and with any change in feeding route. results: at the start of proton therapy, patient had a ngt and patients had peg. of these, patients ( %) had a ngt/peg in place exclusively for the administration of medication; only patient ( %) needed a ngt/peg for nutrition. in those patients without ngt/peg, % would "consider" enteral feeds. in patients without ngt/peg, the most commonly cited benefit was "maximizing my nutrition" ( %) and the most common negative aspect was "fear" of tube placement ( % of patients). all sub-populations ( % of patients) cited change in appearance as a negative aspect. in patients without ngt/peg at the start of proton therapy, % of patients/caregivers felt enteral feeding to be "unnecessary," and % of these patients would not "consider" ngt/peg even if their "physician advised it." over the course of proton therapy, the patients/caregivers who deemed enteral feeding "unnecessary" decreased from % to %. at completion of treatment, patients ( %) were using a ngt/peg tube for nutritional support but only one ( %) patient relied exclusively on their enteral feeds. two patients (without ngt/peg) ( %) required parenteral support. our data does not support prophylactic placement of ngt/peg in of children with head and neck tumors undergoing proton therapy. ongoing research is needed to identify which patients will need ngt or peg to supplement their diet. in this cohort, anticipatory counseling should focus on pain, cosmesis, and utility. children's national medical center, washington, district of columbia, united states background: ovarian sex cord-stromal tumors (osct) are rare neoplasms that typically present with signs/symptoms of an adnexal mass and signs of hormonal production approximately % of ovarian sex cord-stromal tumors in children are sertoli-leydig cell tumors (slct) with median age of presentation years overall. to our knowledge the youngest reported case in the literature describes a -month old female in china with a slct that was treated with oophorectomy alone. some studies have found an association in families between pleuopulmonary blastoma and osct with a germline mutation leading to dicer syndrome, which has been associated with a younger age at diagnosis. , objectives: to describe an unusual case presentation of slct in an infant results: -month old, twin female, ex- week premature infant presented to the emergency department on multiple occasions for abdominal distention and feeding intolerance initially thought to be related to previous omphalocele repair and umbilical hernia. an ultrasound demonstrated an × cm mass arising from the right ovary with large volume ascites. she required admission to the intensive care unit due to s of s respiratory distress from her significant ascites. serum tumor marker including hcg, afp and ldh were negative. patient underwent right oophorectomy with tumor capsule noted to be open at time of surgery. further imaging post operatively demonstrated no other sites of disease. the patient was classified as figo stage ic due to the presence of her significant abdominal ascites that was presumed to be malignant pre-operative tumor rupture. the pathological diagnosis was challenging and eventually resulted as a mixed germ cell sex cord stromal tumor with pattern of sertoli cell tumor with neuroendocrine differentiation. based on the staging of figo ic with pre-operative rupture, the decision was made to treat with a standard platinum based regimen as there is a higher incidence of relapse in stage ic patients when compared to ia treated with observation alone. our patient tolerated four cycles of chemotherapy well and end of therapy scans showed no evidence of disease. interestingly, her dicer mutation genetics performed by ion torrent tm next generation sequencing was negative in germline and tumor studies. to our knowledge, our patient is the youngest described with slct. she will continue to be followed with serial imaging alone as she had no evidence of elevated tumor markers at diagnosis. , due to young age and unusual diagnosis, she was referred to cancer genetics team. background: approximately % of patients with wilms tumor (wt) have metastatic disease at diagnosis and often have a grave prognosis. limited cell lines are available for the study of metastatic wt and long-term passaged cell lines do not always recapitulate the human condition. focal adhesion kinase (fak) is a non-receptor tyrosine kinase that controls cellular pathways involved in the tumorigenesis of pediatric renal tumors. using a novel patient-derived xenograft (pdx) model from a patient's primary wt (coa ) and matched isogenic metastatic wt (coa ), we previously demonstrated that fak is expressed and its inhibition led to decreased tumorigenicity of both the primary and metastatic pdxs. kinomic profiling is an innovative, high-throughput method used to investigate kinase signaling to identify potential therapeutic targets. to date, the kinomic profile of primary and metastatic wt has not been examined. objectives: investigate baseline kinomic differences between primary and metastatic wt and evaluate kinases upstream and downstream of fak as potential targetable therapies. design/method: cells from coa and coa were treated with pf- , (pf), a small molecule fak inhibitor. protein from cell lysates of treated and untreated coa and coa were combined with kinase buffer, atp, and fluorescently labeled antibodies and loaded into a phosphotyrosine kinase or serine-threonine kinase pam-chip® per the uab kinome core protocol. phosphopeptide substrate analysis with the pamstation® kinomics workstation (pamgene® international), pamchip® protocol using evolve software, and bionavigator v. . were used to analyze kinases upstream and downstream of fak. the primary wt had increased epha , ror sgk and decreased pdgfrb relative to the paired metastatic wt at baseline. treatment with pf increased ron, pdgfrb, p s kb, mak, camk g, vacamkl, camk d, ck a and pskh in the primary wt. treatment with pf decreased tnk , lmr , cck , epha , pdk , sgk , lkb and increased pskh in the paired metastatic wt. primary wt displayed a different kinomic profile compared to metastatic wt in a matched isogenic pdx model. these data reveal that alternative therapies to specifically target metastases are needed. furthermore, fak inhibition resulted in diverse kinomic alterations between primary and metastatic wt. inhibitors targeting many of these pathways, such as pdgfrb inhibitors, are currently available and potentially could be combined with fak inhibitors in the treatment of wt. the results of the current study indicate that kinases upstream and downstream of fak in primary and metastatic wt warrant further investigation. background: use of high-dose methotrexate (hd-mtx, g/m^ ) is a mainstay of standard therapy for pediatric osteosarcoma (os) in north america. in pediatric os, there is a narrow therapeutic window for hd-mtx, with decreased tumor response rate with mtx concentrations < m and decreased survival due to severe toxicity with concentrations > m. risk factors for hd-mtx toxicity have been defined in adults, including body mass index (bmi) and male gender, but such studies have not been conducted in children. we sought to examine the relationship between mtx levels and toxicities during hd-mtx infusion for pedi-atric os, thereby identifying risk factors for increased toxicity and providing a framework for therapeutic drug monitoring. design/method: this retrospective chart review included patients treated at texas children's hospital with hd-mtx as first-line therapy for os from - . data abstracted from electronic records included patient characteristics, bmi and body surface area (bsa), baseline and post-treatment laboratory values, mtx levels and hours after dose given ( h, h), hour mtx cleared (mtx < . um), grade / mucositis, myleosuppression, persistent lft elevation (ctace v . ), and % tumor necrosis. correlation between h mtx level and other covariates was summarized using descriptive statistics. we reviewed hd-mtx infusions corresponding to patients. bmi was found to significantly impact h mtx level (p< . ). female gender was also significantly associated with higher h mtx level (p< . ). percent necrosis (available in patients) was associated with h mtx levels at near-statistical significance (p = . ). h mtx level was not found to contribute to toxicities or associate significantly with mtx clearance. analysis in a larger cohort is ongoing. we have identified at least one patient factor (bmi) that significantly impacts h mtx levels and is of potential use for future modeling, as current models incorporate bsa only. our findings concord with studies in adult os in that bmi significantly impacts h mtx level but diverge in that female gender is associated with higher h levels. importantly, these data support targeting h mtx levels to ensure that minimum concentration for adequate tumor necrosis is reached. these results do not suggest that monitoring h levels would prevent toxicities, thus necessitating further characterization of any intrinsic patient factors that associate with toxicity. overall, our definition of the clinical factors that associate with h mtx levels contributes to a framework for therapeutic drug monitoring in pediatric os. children 's mercy hospital kansas city, kansas city, missouri, united states background: post consolidation immunotherapy with dinutuximab, aldesleukin (il- ), granulocyte macrophage colony stimulating factor (gmcsf) and isotretinoin is standard of care for children with high risk neuroblastoma. dinutuximab is combined in alternating cycles with s of s gmcsf or il , followed by a th cycle with isotretinoin alone. il- is administered as a hour continuous infusion on days - at miu/m /day followed by a higher infusion dose, . miu/m /day, in combination with dinutuximab on days - of cycles and . the miu/m /day dose may be administered inpatient or in the ambulatory setting. objectives: to retrospectively compare the incidence of inpatient and outpatient side effects and complications associated with low dose ( miu) il to provide the tolerability data necessary to evaluate these venues for future administration options. design/method: this study was a descriptive, singlecentered definitive study utilizing a retrospective convenience sample population of children with high risk neuroblastoma who received low dose il either as an inpatient or an outpatient without exclusion from may to june . subjects were identified by a tumor registry query post irb approval. electronic and paper medical records were reviewed for the dates and location of the infusions, the home health company used if applicable and all documentation regarding clinical status, side effects and toxicity. demographics was limited to age and gender. results: infusion venue was chosen by provider preference. twenty-six infusions, inpatient and outpatient via separate home health companies were all administered in entirety and without interruption. there were males and females ranging from - years of age. two children received a single outpatient infusion due to intolerance of il when combined with dinutuximab and received therapy in both settings. fever, inpatient and outpatient was the only common side effect. no source of infection was ever identified. there was one incidence of diarrhea and one patient with pruritus in both the outpatient and inpatient settings respectively. no planned outpatient infusions required subsequent admission however the outpatient fever did necessitate an er evaluation. conclusion: low dose il can successfully be administered outpatient. the medication has minimal side effects with fever occurring in %, none of which were associated with infection. no outpatient infusion required a subsequent admission. no patients who received cycle infusions outpatient opted to receive the next cycle inpatient. baylor college of medicine, houston, texas, united states background: metastatic ewing sarcoma (es) has an extremely poor overall survival, necessitating investigations into molecular mechanisms to identify novel targets and develop new therapies. we previously performed an in vivo study, using our mouse model, designed to provide insights into transcriptomic and proteomic signatures for metastatic es to identify potential therapeutic targets. comparing profiles of primary tumors to corresponding metastatic lesions, we identified aberrant expression of integrin ß (itgb ) and downstream activation of integrin-linked kinase (ilk) in metastatic lesions compared to primary tumors, implicating this pathway as a key regulator in the ability of es to establish and enhance metastasis. our hypothesis is that upregulation of itgb and its downstream signaling events play a key role in es metastasis and are viable therapeutic targets. objectives: to investigate the role of itgb and its downstream signaling pathways in driving the establishment and enhancement of metastasis in es and to investigate this pathway as a potential therapeutic target. to investigate the role of itgb and ilk in es metastasis, we used sirna to knock down itgb and ilk expression in established es cell lines and then performed functional assays in vitro, including cell proliferation and invasion/migration assays. we also tested inhibition of this itgb signaling pathway using available small molecule inhibitors targeting itgb , ilk and the downstream target ap- , using cilengitide, compound and sr , respectively. we are currently using these small molecule inhibitors as treatment in vivo and assessing rates of metastatic tumor formation. we generated stable itgb and ilk overexpression and knockdown cell lines, which we are using for similar in vitro and in vivo investigations. knockdown of itgb and ilk in our sirna cell lines resulted in decreased cell proliferation and decreased invasion and migration compared to controls. we also found significantly decreased cell proliferation using each of the small molecule inhibitors in vitro. our preliminary studies using compound in vivo established a safety profile and dose escalation is underway to assess the effectiveness of inhibiting es metastasis. these results support our hypothesis that itgb and its downstream signaling events play a key role in the ability of es to establish metastatic foci and may serve as a potential therapeutic target. we continue to investigate this pathway in vitro. we are also using our small molecule inhibitors and itgb and ilk overexpression and knockdown approaches to study these effects on metastatic tumor development in vivo using our mouse model. background: neuroblastoma (nbl) is characterized by phenotypic heterogeneity. outcome is excellent for patients with low-(lr) and intermediate-risk (ir) disease, whereas only % of high-risk (hr) patients will survive. -hydroxymethylcytosine ( hmc) is an epigenetic marker of active gene transcription, and hmc profiles are prognostic in many types of adult cancers. we hypothesized that hmc profiles will serve as robust biomarkers in children with nbl tumors, refining current risk stratification. objectives: analyze genome-wide hmc in nbl tumors and correlate hmc deposition with chromosomal copy number and gene expression. design/method: hmc was quantified by nano-hmc-seal-seq from the dna extracted from hr, ir and lr nbl tumors. read counts and clinical data were analyzed with deseq to identify genes with differential hmc patterns between risk groups. chromosomal copy number was assessed by chromosomal microarray analysis (cma) in a subset of samples ( lr and hr). expression of genes located on chromosome p was evaluated using publically available microarrays (e-mtab- ) of hr nbl tumors with known p loh status. results: globally, lr tumors had more hmc peaks ( , ) than ir ( , , p = . ) tumors, or hr tumors ( , , p = . ). , genes had different patterns of hmc deposition in hr versus lr tumors. ( %) of these genes mapped to chromosome p and had decreased hmc in hr versus lr tumors (padj < . ). in the cma analysis p deletion was detected in of the tumors tested. in the tumors with p loss, genes that map to p showed decreased hmc deposition compared to the hr tumors without p loss (p< . ). further, compared to the tumors without p loss, the expression of of the p genes was decreased (p< × - ), including chd , camta , and arid a, known and proposed tumor suppressor genes in nbl. conclusion: different patterns of hmc accumulation are associated with neuroblastoma risk classification. nano-hmc-seal-seq is sensitive to copy number variations and has the potential to identify these changes in patient tumors. our results suggest that hmc deposition contributes to the silencing of tumor suppressor genes in p and may also regulate the transcription of other genes that drive tumor phenotype. background: metastatic osteosarcoma has a -year survival rate of - %. pulmonary metastases remain a major treatment challenge in osteosarcoma. current treatment with conventional chemotherapy shows inadequate activity towards metastases and has toxic systemic side effects. chloroquine is a widely used anti-malarial drug and has been shown to have promising anti-cancer and anti-metastatic activity. polymeric drugs have been shown to have multiple advantages over their small molecular parent drugs, including enhancing the therapeutic efficacy, an improved pharmacokinetics profile and decreased systemic toxicity. we hypothesized that by developing chloroquine into a polymeric drug and combining it with conventional chemotherapy it will improve the treatment of metastatic osteosarcoma. objectives: to identify the optimal combination of polymeric chloroquine (pcq) with conventional chemotherapy active in osteosarcoma as a new means of treating metastatic disease in a murine osteosarcoma model. we synthesized and developed pcq and evaluated its anti-invasive activity using an osteosarcoma cell migration and invasion assay. we evaluated the efficacy of cell killing using combination drug therapies with pcq and a panel of conventional chemotherapy agents (doxorubicin, docetaxel, cisplatin and paclitaxel) using celltiter blue cell viability assay. to develop the murine osteosarcoma model, we intravenously injected luciferase-expressing human osteosarcoma cells b into nsg mice. we administered the drug combination that showed the strongest in vitro synergy to the mice and evaluated their anti-cancer and anti-metastatic effects in vivo. tumor growth and suppression were evaluated using whole body bioluminescence imaging. results: we successfully synthesized pcq that contains . % chloroquine with a molecular weight of . kd. pcq was also found to decrease the toxicity of the parent chloroquine. pcq showed strong inhibition of osteosarcoma cell migration with % inhibition compared to % by chloroquine. we screened the combination drug therapies and found the combination of pcq and doxorubicin to show the strongest synergism. the pcq/doxorubicin combination is currently being evaluated in the murine model. combination drug therapy using pcq and doxorubicin showed synergistic cell killing and inhibition of cell migration in vitro. the combination represents a promising treatment strategy for pulmonary metastatic osteosarcoma. emory university/children's healthcare of atlanta, atlanta, georgia, united states background: survival for relapsed high-risk neuroblastoma (rnb) is < %, underscoring the critical need for novel therapies. rnbs have increased ras/raf/mapk mutations and increased yes-associated protein (yap) transcriptional activity. yap is a transcriptional co-activator that binds with tea-domain (tead) transcription factors to regulate cellular proliferation, self-renewal, and survival. we found that shrna inhibition of yap decreases nb cell proliferation and sensitizes ras-mutated nbs to mek inhibitors, supporting yap as a tractable therapeutic target. verteporfin (vp), a photodynamic drug used for macular degeneration, is the only drug found to inhibit yap expression or yap:tead binding to kill tumor-derived cells. peptide is a mer yap peptidomimetic that also disrupts yap:tead interactions. we sought to determine whether these compounds are potent in nb via yap direct effects. design/method: yap expressing (nlf, sk-n-as) or yap null (ngp, lan , sk-n-as-shyap) human-derived nbs were incubated with vp, with and without direct light exposure, or with peptide . celltiter-glo and immunoblots were used to assess for cell death and yap-downstream protein expression, respectively. results: without direct light exposure, vp inhibits yap expression at nm dosing, yet no nb cell death was observed at equal or higher concentrations. egfr and erk / were inhibited along with yap, confirming yap/ras pathway coregulation. when vp was exposed to direct incandescent light for minutes, > % nb cell death occurred in all nbs tested, even those lacking yap. peptide caused no cell death or yap inhibition up to um. neuroblastomas are resistant to vp at doses sufficient to inhibit yap expression. in macular degeneration, light-activated vp produces reactive oxygen species, which we hypothesize is the off target mechanism killing nbs independent of yap. given the off target effects and the need for light activation, vp is not an ideal preclinical or clinical yap inhibitor. accordingly, peptide has poor cell permeability and low tead affinity, leading to its lack of efficacy. given the relevance of yap in rnb and other cancers, we are chemically optimizing a yap peptidomimetic with enhanced permeability, nuclear localization, and tead affinity to create a bonafide yap inhibitor for preclinical and clinical application. kayeleigh higgerson, aaron sugalski, rajiv rajani, josefine heim-hall, jaclyn hung, anne-marie langevin ut health san antonio, san antonio, texas, united states background: osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. most study cohorts have to % hispanic patients that encompass many different hispanic backgrounds. the university of texas health science center at san antonio (uthscsa) sarcoma team serves a latino population that is predominantly mexican american, thus providing a unique opportunity for evaluation this population. this study expands on previous data collected from january to december from the same institution, providing increased insight into outcomes of mexican american children, adolescents, and young adults with osteosarcoma. objectives: to further understanding of osteosarcoma in latino children, adolescents and young adults. design/method: a retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below years of age diagnosed and treated by the uthscsa sarcoma team between january and june was performed. results: in our original cohort from january to december , we observed a significantly decreased -year eventfree survival (efs) in patients diagnosed before age (preadolescent) relative to patients diagnosed between ages and ( % vs. %, p< . ). patients had a -year overall survival (os) and event-free survival of % and % respectively. in our expanded cohort from january to june we evaluated sixty-six patients with a median age of (range, to y) with localized high-grade osteosarcoma of the extremity. the expanded cohort was % mexican american, with a median follow-up of months (range, to ). the analysis of our expanded cohort is ongoing and we postulate that the findings will hold true, as we increase the cohort size and length of follow-up. conclusion: analysis of our previous cohort, predominantly of mexican american ethnicity, showed that preadolescent patients had an increased rate of relapse when compared with previous large studies. we also showed a trend towards decreased efs for the entire cohort. we hypothesize that we will further validate these findings with this expanded cohort and this will support further investigation into potential causes of poor outcome in this vulnerable latino population. background: neuroblastoma in infants has the potential to regress or mature spontaneously. growing literature showed that some cases subjected to initial observation didn't show inferior outcome compared to actively treated similar categories. objectives: we investigated whether early active treatment can be safely avoided/deferred in selected favorable cases at the children's cancer hospital-egypt (cche). design/method: patients enrolled on the watch and see strategy (w&s) at cche had small primary tumor; inss stage - , uncomplicated stage s or stage infants (< days). tissue biopsy was not mandatory for infants below months of age with localized adrenal mass (stage - ). on progression, immediate intervention took place according to stage and risk of disease after biological characterization. results: thirty four nbl patients were enrolled on w&s strategy; m/f: . / . eighteen patients had stage s disease, patients had stage - and were stage . primary adrenal site was reported in patients ( . %), patients ( . %) had small mass measuring ≤ cm in its largest diameter. the -year os & efs were . ± . % and . ± %, respectively, with months median follow-up (range: - months). spontaneous total/near total resolution of mass occurred in / patients ( %). median time to eliciting regression was . months (range: . - . months), and . months (range: - months) till complete resolution. only / patients ( . %) witnessed progression ( local, distant and combined local and distant progression); median time to progression was months (range: - months) with / deaths after starting chemotherapy. watch and see strategy is a safe approach in localized and uncomplicated stage s neuroblastoma. progressive cases could be rescued. baylor college of medicine, houston, texas, united states background: ga- dotatate binds to somatostatin receptor expressed in neuroendocrine tumors (nets). it was approved by fda in for use with pet/ct scan for localization of somatostatin receptor positive nets in adult and pediatric patients. pediatric approval was based mainly on extrapolation of data from adults. objectives: to describe the use of ga- dotatate pet/ct scan in children with neuroendocrine tumors and compare with other imaging modalities. design/method: patients with nets enrolled in texas children's rare tumor registry between february and october were reviewed and those patients who underwent ga- scan were included. results: four patients with nets underwent ga- scans without any adverse reactions. first patient was a -yearold female with small bowel net with multiple liver metastases. mri abdomen and fdg pet at diagnosis showed s of s multiple liver metastases but could not identify the primary lesion. ga- scan was able to accurately identify the enlarged lymph nodes in the small bowel and was better than fdg pet in delineating the liver metastases. second patient was a -year-old female with recurrent small bowel net with liver, lung and paraspinal metastases. the lesions were initially detected by ct scan. octreotide scan failed to show any uptake in the identified lesions while ga- was taken up by the liver lesions, lung lesions > cm in size and the paraspinal lesion. third patient is an year-old male with pancreatic net with peripancreatic lymphadenopathy, multiple liver metastases and cardiophrenic lymph node involvement. the primary lesion in the pancreas could not be identified by ct scan, ct angiogram, mibg scan, or octreotide scan. in addition, there was uncertainty about involvement of the enlarged cardiophrenic lymph node. in addition to clearly identifying the primary lesion, ga- scan was able to detect multiple peripancreatic lymph nodes not detected by other scans and revealed uptake in the cardiophrenic lymph node confirming its involvement by the tumor. fourth patient is a -year-old female with malignant abdominal paraganglioma with solitary lung metastasis. both mibg scan and ga- scan were able to identify the primary lesion. ga- scan was performed after the lung metastasis was removed and thus its ability to detect it could not be confirmed. background: neuroblastoma is the most common extracranial solid tumor of childhood, with overall survival for high-risk patients (hrnbl) near %. the outcomes of hrnbl have improved with high dose chemotherapy followed by autologous stem cell rescue (abmt). data about factors influencing the rate of hematopoietic recovery following abmt in hrnbl is lacking in the literature. our objective was to identify factors influencing the rate of hematopoietic recovery following abmt in hrnbl. design/method: this was a retrospective chart review of patients with hrnbl treated at texas children's hospital from to . neutrophil engraftment was considered the first of three consecutive days with post-transplant neutrophil count greater than cells/ul. red blood cell and platelet engraftment were considered at a hemoglobin greater than g/dl and platelets greater than , /ul three days after the last transfusion. race and conditioning regimen were analyzed using one-way anova; amount of infused cells was analyzed using pearson correlation coefficients; chemotherapy delay and bone marrow (bm) involvement after cycle of induction chemotherapy were analyzed using independent sample t-tests. the study included males and females with a median age at diagnosis of . years. thirtyeight patients were caucasian, african-american, hispanic, asian, and did not have race documented. the mean dose of infused cd + cells was . × ^ cells/kg. forty-five patients received conditioning therapy with carboplatin/etoposide/melphalan (cem), received busulfan/melphalan (bu/mel), and received thiotepa/cyclophosphamide (thiotepa/cpm). the conditioning regimen administered was significant (p = . ) for time to engraftment of neutrophils, with bu/mel at . days, cem at . days, and thiotepa/cpm at days. a delay of chemotherapy during induction (n = ) was significant (p = . ) for time to platelet engraftment of greater than , /ul and trended towards significance (p = . ) for time to neutrophil engraftment. bm involvement at diagnosis and after cycle of induction was not significant for time to engraftment. dose of stem cells infused was the only variable significant for hemoglobin engraftment. background: osteosarcoma (os) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. approximately % to % of patients have metastatic disease at initial presentation, and % of those patients have isolated pulmonary metastases. although overall survival in patients with os has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with metastatic disease. recent studies suggest that tumor-associated vascular cell adhesion molecule (tvcam- or cd ) plays a critical role in the metastatic progression of various tumors. indirect evidence from these studies suggest that vcam- / integrin signaling promotes tumor survival and metastatic progression by changing the tumor niche and associated immune response. to determine if interfering vcam- / signaling between pulmonary metastatic osteosarcoma (pos) and macrophages (macs) by down-regulating vcam- , depleting macs or blocking vcam- / signaling will reduce pos and improve overall disease-free survival. design/method: we used a pair of spontaneous, high-grade murine os cell lines from balb/c mouse (h- d), k and k m (derived from in vivo k metastasis). we used lentiviral shrnas to knockdown vcam- mrna and protein expression in k m (vcam- kd). we introduced luciferase into k , k m and various k m shrna cell lines to follow lung metastasis by bioluminescence (bli). we depleted macs by intranasal administration of liposomal clodronate formulation. we tested the ability of k and k m supernatants to polarize m macs into m or m phenotype in vitro. we also administered anti- monoclonal antibody (anti- mab) intranasally to assess the outcome of functional blockade of vcam- / signaling. results: k m over-expressed vcam- compared to k . mac depletion in k m -bearing animals exhibited reduced pos. weekly administration of anti- mab resulted in % tumor-free rescue among mice with established k m pos. interestingly, supernatant from k m but not k preferentially induced m -like macs, suggesting a novel integrin-mediated mechanism of m differentiation. validation data with additional os cell lines will be presented. despite aggressive multimodal therapy, overall outcome for patients with pos remains dismal at - %. for this reason, novel and directed therapy approaches are desperately needed. molecular targeted approaches for therapy are challenging, due to the complex genetic heterogeneity of os. immune-modifying therapy is a promising new alternative approach for pos. university of chicago, chicago, illinois, united states background: only half of all patients diagnosed with high-risk neuroblastoma achieve long-term survival. imetaiodobenzylguanidine (mibg) scans are routinely used to evaluate disease at diagnosis and following treatment, and the extent of disease is quantified using the curie scoring system. a previous study by yanik et al., has shown that for high-risk patients with mycn non-ampliified tumors, scores less than versus greater than following cycles chemotherapy are associated of superior survival, whereas scores less than versus greater than were prognostic in patients with mycn-amplified tumors. however, the prognostic significance of specific sites of metastatic disease at diagnosis is not known. to determine if site of metastatic disease determined by i-metaiodobenzylguanidine (mibg) imaging in high-risk patients at the time of diagnosis was associated with outcome design/method: we performed a retrospective chart review of high-risk neuroblastoma patients treated at comer children's hospital and lurie children's hospital in chicago between and with positive mibg scans at the time of diagnosis. we collected imaging data as well as other clinical data including bone marrow status. sites of disease were defined as curie regions with any positive value. kaplan-meier analysis was performed to evaluate the association with disease sites and survival. pearson correlation coefficients were calculated to compare bone marrow disease to sites of positivity on mibg scan. the cohort consisted of high-risk patients. had skull disease, and had pelvic disease. the presence of mibg positive disease in the skull and in the pelvis trended toward worse efs. efs at years for patients with disease in the skull at diagnosis was ± % and for patients without skull disease was ± % (p = . ). efs at years for patients with and without pelvic disease was ± % and ± % (p = . ). consistent with prior data, we found that the presence of bone marrow disease was associated with worse survival with year efs of ± % and ± % with and without marrow disease at diagnosis (p = . ). there is the highest correlation between pelvic disease on mibg scan and bone marrow disease with pearson coefficient . . pelvic disease noted on mibg scan likely reflects underlying bone marrow disease. in patients with high-risk neuroblastoma, skull disease and pelvic disease on mibg scan at diagnosis may predict worse event free survival. background: osteosarcoma is one of the deadliest cancers in the pediatric population with little progress in morbidity and recurrence rates since the 's. oncolytic herpes simplex- virus (ohsv) is an attenuated virus that has shown encouraging results against certain solid tumors. programmed cell death protein (pd)- -mediated t cell suppression via engagement of its ligand, pd-l , is also of particular interest due to recent successes in selected cancers, especially those with high genetic mutational loads. most pediatric cancers do not have a wide variety of mutations; however, osteosarcoma has a chaotic genome, prone to genetic mutations. it has been shown through numerous other studies that pd- inhibition alone is not sufficient to result in statistically significant tumor growth delays in osteosarcoma models and patients. we hypothesize the addition of ohsv therapy as an immunologic stimulus to pd- inhibition is efficacious for osteosarcoma. ( ) to determine whether ohsv therapy enhances response to pd- inhibition in immunocompetent murine models of osteosarcoma and ( ) to quantify and characterize the anti-tumor t-cells infiltration after treatment with ohsv and pd- inhibition individually and in combination. we utilized an immunocompetent transplantable murine model using a cell line derived from a spontaneous metastatic osteosarcoma (k m , balb/c background). we transplanted established tumor wedges subcutaneously and monitored tumor volume by caliper measurement. once tumors reached - mm , we administered intratumoral injections of hsv ( × plaque-forming units) every other day for a total of injections. we then gave intraperitoneal injections of ug anti-pd- or control antibody twice weekly, up to weeks, starting from the last dose of virus treatment. we monitored tumor growth via calipers twice weekly until tumors reached mm or cm diameter. we quantified and characterized innate and adaptive immune cell infiltrates in tumors using flow analysis. we found significantly prolonged survival with our combination therapy group compared to all other groups. we found that anti-pd- by itself had little impact on t cell recruitment while the combination group had higher influx of cd + cells with a reduced amount of t-regulatory cells (cd +foxp +cd +). we also found an increase in cd + effector memory cells. osteosarcoma is a deadly cancer with therapeutics remaining unchanged for the last years. here, we describe prolonged murine survival after treatment with combination of pd- inhibition and ohsv injection. the combination treatment changed the microenvironment to be more inflammatory. our data support further preclinical and clinical studies. background: neuroblastoma is the second most common cause of cancer related death in children. treatment for high-risk neuroblastoma has improved significantly over the past twenty years, however cure rates remain below %. immunotherapy has emerged as an effective therapy for neuroblastoma, however new modalities and targets are needed to improve outcomes. objectives: our lab has developed a chimeric antigen receptor (car) that targets b -h (cd ), an immune checkpoint molecule overexpressed on many cancers, including neuroblastoma. we hypothesized that b -h would be a good target for car based immunotherapy for neuroblastoma. design/method: neuroblastoma tissue microarrays of primary patient samples were screened for b -h expression by immunohistochemistry and cell lines were screened using flow cytometry. b -h car t cells were tested in vitro by measuring tumor cell killing and cytokine production after coculture with tumor cell lines and in vivo in an orthotopic model of neuroblastoma. results: b -h expression was detected by ihc on % of the screened neuroblastoma patient samples. b -h was expressed at high levels ( + or +) in more than half of these samples ( %). almost all cell lines screened were homogeneously positive for b -h by flow cytometry. retrovirally transduced b -h . - bb. car t cells were cocultured with three b -h positive neuroblastoma cell lines (sk-n-be , kcnr, and chla ) and robust tumor cell killing was demonstrated using an incucyte assay. supernatant from the co-cultures was harvested after hours and both interferon gamma and il- production were detected by elisa.in an orthotopic subrenal capsule xenograft model of neuroblastoma, mice treated with b -h car t cells show significant reductions in tumor growth and prolonged survival compared to those treated with untransduced control t cells. however, the treatment is not always curative.b -h car t cells express high levels of exhaustion markers (pd , tim , and lag ) when compared to cd car controls. in order to overcome inhibition from exhaustion, b -h car t cells were co-cultured with neuroblastoma cell lines and pd- blocking antibody. nivolumab significantly increased the production of il- and interferon-gamma by b -h car t cells. further studies are underway to determine if b -h car t cell activity is enhanced in vivo by treating animals with pd- blockade along with car t cells. conclusion: b -h is expressed on a majority of neuroblastoma samples and appears to be a promising candidate for car t cell therapy. b -h car t cells demonstrate activity against neuroblastoma xenografts that may be enhanced by the addition of pd inhibitors. helen devos children's hospital, michigan state university, grand rapids, michigan, united states background: osteosarcoma is the most common bone tumor in children. it is often metastatic at diagnosis and in this scenario less than % of children survive. polyamines, small molecules found in all cells, are involved in many cell processes including cell cycle regulation, immune modulation, cell signaling and apoptosis. they are also involved in tumor development, invasion and metastasis. in neuroblastoma, inhibition of the polyamine biosynthesis pathway with odc inhibitor alpha-difluoromethylornithine (dfmo) results in decreased cell proliferation and differentiation. these finding have led to multiple phase i and phase ii multicenter clinical trials in pediatric neuroblastoma patients. dfmo is an attractive drug as it is oral, well-tolerated, can be given for prolonged periods and is already used in pediatric patients. the polyamine pathway has not been evaluated in osteosarcoma. objectives: evaluate effect of inhibition of polyamine biosynthesis with dfmo on osteosarcoma proliferation and cell differentiation. design/method: up to three osteosarcoma cell lines were used: mg- , u- os and saos- . cells were exposed to mm dfmo for days with replacement of media and dfmo on day . intracellular polyamine levels were measured by high performance liquid chromatography (hplc). cell numbers were obtained with a hemocytometer using trypan blue. flow cytometry cell cycle distribution (facs) and propidium iodide were used to evaluate for cell cycle arrest. the protein expression of several osteosarcoma differentiation markers was measured by sds-page and western blot using differentiation specific antibodies. a bioluminescent cell viability assay was used to measure cell recovery over several days after dfmo was removed and replaced with standard media. results: dfmo exposure resulted in significantly decreased cell proliferation in all cell lines. after treatment, intracellular spermidine levels were nearly eliminated in all cells. cell cycle arrest at g was observed in u- os. cell differentiation was most pronounced in mg- and u- os cells as determined by increased osteopontin levels. remarkably, cell proliferation continued to be suppressed for several days after removal of dfmo. conclusion: based on our findings dfmo is a promising new adjunct to the current osteosarcoma therapy for high risk patients. it is a well-tolerated oral drug that is currently in phase ii clinical trials in pediatric neuroblastoma patients as a maintenance therapy. the same type of regimen may also improve outcomes in metastatic or recurrent osteosarcoma patients for whom there have been essentially no medical advances in the last years. background: recent studies demonstrate that lower levels of the ews-fli fusion oncoprotein are associated with enhanced metastatic capability in ewing sarcoma. the nf-kb transcription factor is a critical mediator of cxcr and cxcr -driven metastasis in multiple cancers, and increased cxcr and cxcr expression have each been associated with increased metastasis and poor prognosis in ewing sarcoma. we thus sought to investigate the impact of ews-fli on cxcr /cxcr -dependent nf-kb signaling in ewing sarcoma. objectives: the goals of this study are ) to determine the impact of cxcr /cxcr signaling on metastasis-associated nf-kb target gene expression in ewing sarcoma and then ) to investigate how the ews-fli fusion oncoprotein modulates this response . design/method: we utilized multiple ewing sarcoma cells lines including a , chla , chla , tc and tc . cxcr /cxcr cell surface expression was determined by flow cytometry. ews-fli level was modulated using sirna and expression levels were confirmed by western blot and rt-pcr. p dna binding was measured via elisa. nf-kb target gene expression was assessed via rt-pcr. results: consistent with ihc analysis of primary and metastatic patient tumor samples, the paired primary and metastatic ewing sarcoma cell lines chla and chla showed dramatic differences in cxcr and cxcr expression, with the metastatic chla line demonstrating much higher expression of both receptors. other cell lines (nonpaired) showed variable cxcr /cxcr expression. genetic knock-out of cxcr lead to significant decrease in expression of both cxcl /sdf- and il- , two nf-kb transcriptional targets known to play a key role in tumor metastasis. knock-out of cxcr did not alter endogenous ews-fli mrna levels. conversely, lowering the level of ews-fli using sirna lead to enhanced nf-kb signaling, indicated by an increase in p dna binding. consistent with this observation, treating ewing cell lines with ews-fli sirna also resulted in significantly increased nf-kb target gene expression compared to control cells and target gene expression was then further enhanced upon cxcr /cxcr receptor stimulation with the receptor ligand cxcl /sdf- . our findings indicate that the ews-fli oncoprotein negatively modulates cxcr /cxcr -dependent nf-kb signaling. this suggests that ews-fli low, cxcr /cxcr high cells, which are associated with enhanced metastasis and poor prognosis, would be anticipated to exhibit enhanced expression of key nf-kb target genes. importantly, the nf-kb pathway is a druggable target that could potentially serve as an "achilles heel" in this subset of high risk tumors. current work is evaluating nf-kb inhibition as an approach to treating metastatic and refractory ewing sarcoma. background: acute graft versus host disease (agvhd) is a major cause of morbidity and mortality following allogeneic bone marrow transplant (bmt) in pediatric patients. gastrointestinal (gi) agvhd is the most serious manifestation. recently, decreased paneth cell (pc) in a predominantly adult cohort was shown to correlate with agvhd clinical grading and response to treatment. we aim to demonstrate the relationship between pc counts and gi agvhd stage and response to therapy. design/method: charts of patients who underwent endoscopy following bmt between - were reviewed. for repeated biopsies during the course of agvhd, only the first was included for analysis. one pathologist retrospectively reviewed the biopsies and counted pcs in high powered fields; the average pc count was analyzed. twenty-six percent of biopsies were reviewed by a second blinded pathologist. statistical associations between pc counts and day (d ) response, agvhd stage, and other study covariates of interest were gauged using general linear regression. agreement in pathologist pc counts was quantified by intraclass correlation (icc). the research was approved by the children's healthcare of atlanta irb. results: seventy-eight biopsies were included in the analysis. mean age at transplant was . years ± . (range: months - years). most patients underwent transplant for hematologic malignancies ( , %). the majority of transplants used a matched unrelated donor graft -including cords ( , %) and myeloablative conditioning regimens ( , %) - % received total body irradiation. of these, % were diagnosed clinically with gi agvhd (stage , %; stage , %; stage , %; stage , %). icc showed good agreement ( . ) between the pathologists. mean pc was . for patients with no gut agvhd, . for stage , . for stage , . for stage and . for stage (p = . ). on multivariate analysis pc was strongly associated with gi agvhd stage (p< . ) after controlling for age, preparative regimen intensity, and diagnosis (malignant vs. non-malignant). mean pc counts were significantly lower in patients with no response to steroid therapy at d (complete response (mean . ) vs. persistent disease ( . ) vs. partial response ( . ) (p = . )). patients diagnosed with gi agvhd with pc counts less than had a higher risk of mortality (hr . , % ci: . , . ; p = . ). lower pc count correlated with stage gi agvhd, refractory disease at d , and mortality. incorporating pc count in pathology review during gi agvhd work-up may help in agvhd risk stratification. background: there have been increasing discussions pressuring health care teams and institutions for potentially bearing the cost of clostridium difficile infections (cdi) as a health care-associated infection in the recent years. the pediatric oncology patient population, though small, accounts for significant portion of all cdi with - -fold increased risk. hematopoietic stem cell transplant (hsct) recipients constitute a unique subset with distinct risk factors, such as severe immune deficiency state and graft versus host disease (gvhd). although there is ample data on cdi in adult hsct recipients, reports on pediatric experience are limited. objectives: to evaluate the incidence and patterns of cdi among pediatric hematology, oncology and hsct inpatients at our institution. a retrospective review of all clostridium difficile (cd) stool tests performed using toxin enzyme immunoassay and later, polymerase chain reaction targeting toxin genes between and in a large, urban academic children's hospital was performed. the data were analyzed for hematology, oncology, hsct inpatient population and all the other cases separately and statistical comparisons were performed. results: a total of samples were submitted to the microbiology laboratory for cd testing during the study period. while hematology patients constituted . %, oncology . %, hsct . % and others . % of the cases on whom cd testing was done; per patient average test number was . , . , . , and . , respectively. of all the cd tests per-formed, . % were positive. test positivity was higher in hsct ( . %) and oncology ( . %) cases tested compared with hematology ( . %) and other cases ( . %) with statistical significance (p< . ). overall recurrence rate was . %; hsct patients had the highest recurrence with a rate of % followed by oncology ( . %), hematology ( . %) and other ( . %) cases, again reaching statistical significance (p< . ). again, hsct patients had the highest average number of recurrences at . ( - ) followed by oncology . ( - ), general . ( - ) and hematology . ( - ) groups. there was no seasonal variability in the incidence of cdi among populations analyzed. prolonged hospital stay/antibiotic use and persistent diarrhea due to gvhd are the likely reasons for higher rate of cd testing in hsct as a result of increased monitoring and thus might have even caused underrepresentation of positive cd test frequency. higher incidence and frequencies of recurrence underscores the inevitable nature of cdi in hsct population as a consequence of the current therapies and may lead to future radical treatment approaches like fecal implantation. background: viral infections remain a challenge to treat post hct in children, and significantly contribute to morbidity and mortality. virus specific t cells (vsts) have shown tremendous clinical efficacy in treating viral infections post-hct, with minimal toxicity and long term efficacy. we have used donor-derived vsts in individual patients, however not all donors are agreeable to the process, and numerous patients may benefit from vsts who do not have an identified donor/have other disease indications objectives: we sought to actively build a third-party vst bank, for "off the shelf" use in eligible patients. design/method: vsts targeting cmv, adenovirus and ebv were manufactured using one of techniques. initially ebv transformed b cells were genetically modified with an ad f pp vector and used as antigen presenting cells (apc) to stimulate and expand ebv, ad and cmvpp specific t cells. more recently, vsts were expanded using s of s apc pulsed with commercially available peptide pools (pep-mixes) to expand ebv/cmv/ad specific t cells. products were entered into the "bank" via two mechanisms: a) left over products from our "donor-derived" protocol when patients no longer required vsts or were not at risk of developing viral infections, or b) by targeting regular blood donors based on their hla typing to ensure an appropriate mix of high frequency hla types for optimal patient matching and antigen presentation based on current knowledge of antigen presentation. results: a total of products are currently in the thirdparty vst bank ready for use. twenty seven of these are from our donor derived protocol, and three from targeted donors. all vst products met safety and in vitro efficacy testing. thirteen vst infusions have been given to patients. eleven infusions have been given for cmv and two for adenovirus. five out of seven patients responded to thirdparty vst infusions, with a median of vst infusions per patient (range - ). the median hla matching was out of per patient (range to ) no patients experienced adverse reactions, gvhd or other toxicity related to the vst infusion. a third-party vst bank is feasible and produces clinically appropriate vsts for use in patients with viral infections. hla typing and matching of vst products is essential to reduce toxicity and promote appropriate antigen presentation and expansion of vsts in vivo. further work is underway to further characterize the vsts using epitope mapping to better define the hla restriction and immunogenicity of each vst product. akron children's hospital, akron, ohio, united states background: acute graft-versus-host disease (agvhd) is a well-known complication of hematopoietic stem cell transplant (hsct) and a major cause of post-transplant related morbidity and mortality. first line therapy of agvhd involves corticosteroids and calcineurin inhibition. in patients with severe refractory gvhd, mortality can reach up to %. currently, there is no standard of care for the treatment of steroid refractory agvhd. many centers have looked at the use of antibody mediated control of agvhd to competitively inhibit the inflammatory cascade. basiliximab, a chimeric monoclonal antibody against the t-cell il- receptor, has been used in adults with steroid refractory agvhd. patients receiving this medication have demonstrated complete and partial responses to therapy with minimal toxicities. objectives: report the successful use of basiliximab in the treatment of agvhd in a -year-old following matched unrelated (mud) hsct. design/method: a -year-old male underwent mud transplant for high risk aml with monosomy . conditioning regimen included busulfan, fludarabine and equine atg. his clinical course was complicated by fever, mucositis and agvhd (stage skin; stage gi-biopsy proven). gvhd prophylaxis included tacrolimus and methotrexate, however with progressive skin rash, diarrhea, and early satiety, gvhd treatment with corticosteroids was initiated. as the patient continued to have worsening symptoms, basiliximab therapy was started. the patient received doses ( mg) iv basiliximab on two consecutive days and then received weekly therapy for a total of doses leading to initial improvement. the patient further developed acute on chronic gvhd on day + , and subsequently received a second course of basiliximab. after initial administration of basiliximab, the patient had near complete resolution of symptoms. however, with a small wean in his tacrolimus dose, the patient experienced another skin gvhd flare prompting the second basiliximab course. the patient was subsequently weaned off all immunosuppression by day + . the only acute complication the patient experienced while receiving basiliximab was right toe paronychia and asymptomatic low ebv titer. the patient is currently off all immunosuppression at the time of report without evidence of cgvhd. conclusion: this single case report, in a young pediatric patient, demonstrates the use of basiliximab may be a safe and efficacious treatment for pediatric patients with agvhd. university of california, san diego, la jolla, california, united states background: clinical outcomes after allogeneic hematopoietic stem cell transplantation (hsct) depend on restoration of t lymphocyte populations. association between recovery of cd +foxp + regulatory t cells (tregs) and protection from chronic graft versus host disease (cgvhd) has been described in adult hsct. in adults, t cell recovery is driven by expansion of donor t cells and treg reconstitution is hypothesized to result from peripheral conversion. restoration of t cells in pediatric patients has a larger contribution from thymopoiesis, however, the relationship between thymopoiesis and treg recovery is undefined. objectives: we hypothesized that effective thymopoiesis is important for restoration of treg populations and protection from cgvhd in pediatric hsct patients. design/method: we performed longitudinal flow cytometry of peripheral blood t cells from pediatric hsct patients and age-matched healthy donors. laboratory data were correlated with clinical outcomes to evaluate impact. recovery of tregs occurred in / ( . %) patients by post-transplant day . day treg frequency in patients that developed cgvhd ( . ± . % of cd + t cells) was reduced compared to cgvhd-free patients ( . ± . %). failure to restore tregs to > . % of cd + cells by day was associated with increased risk of cgvhd in the first year post-hsct (rr = . , p = . ). a majority ( . ± . %) of tregs from patients recovering the peripheral treg compartment expressed helios, a marker of thymic-derived tregs; only . ± . % of tregs expressed helios in patients failing to restore adequate tregs. this prompted examining the relationship between defects in thymopoiesis and inability to restore tregs. we evaluated thymic function by flow cytometry quantification of cd ra+cd +ptk + recent thymic emigrant (rte) cd + cells (confirmed by qpcr for trec content). most ( / , . %) hsct patients had detectable rtes by day post-hsct. thymic production of rtes was persistently absent in patients that developed cgvhd (< / ^ cd + cells in / patients), compared to cgvhd-free patients ( / patients > rte/ ^ cd + cells by day , average . ± . / ^ cd + cells). post-hsct thymic activity as measured by rte enumeration correlated with treg restoration; / ( %) rte+ patients restored tregs, compared to / ( %) of rte-patients. conclusion: failure to restore tregs after allogeneic hsct results in increased risk for cgvhd. in pediatric patients thymic generation of new t cells is an important contributor to restoration of the treg compartment. this data supports further investigation into mechanisms impairing post-hsct thymopoiesis and suggests peripheral blood tregs may be a prognostic biomarker for cgvhd. background: haploidentical stem cell transplantation (haplo sct) is riddled with unique challenges. objectives: we present our experience in the use of haplo sct with post-transplant cyclophosphamide (ptcy) and the adaptations required for each disorder for optimal outcome. design/method: we performed a retrospective study at the pediatric blood and marrow transplant unit, apollo cancer institutes, chennai, india. children up to years of age, diagnosed to have benign disorders and underwent haplo sct with ptcy from to july were included. results: ptcy was used in i.e. % haplo transplants for children with benign disorders. the underlying conditions included fanconi anemia , severe aplastic anemia , mds , jmml , hemoglobinopathy , prca , xld and primary immunedeficiency disorders (pid) . source of stem cells was peripheral blood in %, bone marrow in %. conditioning included fludarabine with treosulphan or cyclophosphamide for pids and aplastic anemia respectively. neutrophil engraftment by day+ - with a durable graft was noted in % transplants with graft versus host disease in %, cmv reactivation in %. mortality rate was % with infants less than months of age developing severe fatal cytokine release syndrome. the median follow up is year with years being the longest. no significant late effects have been noted with chronic skin gvhd in children. survival rate was superior among children with pids with survival of % in this group. haplo sct with ptcy is a feasible and costeffective option for cure in children with life-threatening benign disorders with no compatible family or matched unrelated donor. careful patient selection, reducing cyclophosphamide related free radical toxicity with the use of n acetylcysteine, limiting t cell numbers by capping cd at × /kg, post-transplant viral monitoring protocols are required to reduce morbidity and mortality. we have been working on universal access to care for children from s of s all socioeconomic background and incorporating innovations to reduce the cost of hsct without compromising outcomes. haploidentical hsct using tcr / depletion costs usd as compared to ptcy priced at usd. children with severe aplastic anemia and pids can be transplanted using reduced intensity conditioning and ptcy. in hemoglobinopathies, pretransplant immunosuppression is required to prevent graft rejection. graft versus host disease remains the main cause of mortality in children with fanconi anemia. mortality in infants less than months after ptcy has been high, tcr / depletion would be superior in this cohort. cincinnati children's hospital medical center, cincinnati, ohio, united states background: fanconi anemia (fa) is a congenital bone marrow failure syndrome with hsct the only curative option for associated bone marrow failure. patients with fa undergoing hsct may experience increased toxicity related to either their underlying disease, or the effects of medications, resulting in the inability to tolerate prophylactic medications or sideeffects from anti-microbial therapy. objectives: we postulated that increased cd cell dose would be associated with a rapid immune reconstitution and therefore early withdrawal of anti-infective prophylactic medications. design/method: patients with fa transplanted at cchmc from an unrelated donor had peripheral blood stem cell grafts collected and cd selection performed. where possible, patients had serial measurements of their immune system performed at varying intervals post hsct. we defined immune reconstitution as normalization of lymphocyte subsets-cd , cd , cd and cd cells, as well as a normal response to mitogen stimulation including phytohemagglutinin, concanavalin a and pokeweed. the first measurement of either normal cell number or mitogen response was recorded for each patient. results: a total of patients underwent hsct for fa at cchmc between and . patient demographics included a median age of years at hsct, the vast majority of patients having a fully matched or one anti-gen mismatched donor, and the majority of patients transplanted for bone marrow failure. there was a statistically significantly decreased time post-transplant to immune cell recovery in patients receiving > × /kg cd cells (median . ) compared to those receiving < × /kg cd cells (median . ). the median time to normalization of cd count was days (cd count > /kg) versus days (cd count < /kg), cd count days (cd count > /kg) versus days (cd count < /kg), cd count days (cd count > /kg) versus days (cd count < /kg) and cd count days (cd count > /kg) versus days (cd count < /kg). time to normalization of mitogen response was decreased posttransplant in those patients receiving increased cd cell dose at time of transplant, though this was not significant, reflecting low number of patients with evaluable responses. no patients in either group experienced gvhd or graft failure. patients with fa who are transplanted with higher cd cell doses have quicker immune reconstitution than those who receive lower cell doses. along with benefit to patients including less risk of infection and early termination of immune-prophylaxis medications, this supports the use of high dose cd selected grafts in this vulnerable population. background: parvovirus b (pvb ) infection after transplantation was first reported in . since then, numerous cases of pvb infections after hematopoietic stem cell transplantation (hsct) and solid organ transplantation (sot) have been reported. most report anemia as the predominant clinical manifestation. however, pvb has been associated with pancytopenia, hepatitis, myocarditis, and allograft rejection. we present a patient with acute lymphoblastic leukemia who developed bone pain and pancytopenia following hsct in the setting of pvb infection. to describe an unusual presentation of pvb in a patient with acute lymphoblastic leukemia following hsct. design/method: a search of the english-language medical literature was performed using pubmed and medline databases. a review of the patient's medical history was performed. a year old male with relapsed b-cell all and history of "fifth disease" in infancy presented four months after hsct with focal left arm pain and difficulties fully extending the arm. bone mri showed enhancement of the medullary space centered within incomplete transverse cortical fracture interpreted as pathologic fracture due to neoplastic involvement of the ulna with no history of inciting injury. subsequently, peripheral blood counts decreased from low normal values to wbc . k/microl, anc /microl, plt k/microl, and hemoglobin . g/dl. the patient's chimerism remained % donor. a bone marrow biopsy and aspirate were performed to assess for recurrent leukemia given persistence of bone pain and developing pancytopenia. marrow findings included morphologic cytopathic effects with erythroid precursors and strong parvovirus staining with no signs of red cell aplasia or recurrent b-cell disease by morphology or flow cytometry. pvb was detected in blood by pcr and immunoglobulins with resolution of cytopenia and bone pain. this case highlights an unusual constellation of symptoms following hsct in a child with all. unexplained bone pain and medullary infiltrates with pancytopenia suggestive of recurrent leukemia were likely triggered by pvb infection. the question remains if he had reactivation of pvb , a primary infection by a new strain, or the virus was aquired through stem cells. bone biopsy could not be justified in light of clinical improvement. so far, bone lesions have only been described with congenital pvb infection. pvb appears to be uncommon after hsct, with a review of literature yielding pediatric cases. however, it may be underestimated due to lack of routine screening. our patient's presentation supports that evaluating for pvb may be warranted in hsct patients presenting with symptoms suggestive of relapsed leukemia. background: cardiac injury may occur during hematopoietic stem cell transplant (hsct) in pediatric patients and can be asymptomatic for many years. recommendations for screening are available for patients who received anthracyclines or chest irradiation, but no guidelines exist for unexposed longterm survivors. we sought to define the prevalence of echocardiographic abnormalities in long-term survivors of pediatric hsct and determine the need for screening in asymptomatic patients. design/method: we analyzed echocardiograms performed on long-term survivors (≥ five years) who underwent hsct at cincinnati children's hospital between and . we analyzed echocardiograms for left ventricular ejection fraction (ef), end-diastolic dimension (lvedd), septal thickness, posterior wall thickness, and global longitudinal strain (gls). we normalized linear measurements for age and patient body surface area. we included for further analysis patients who had echocardiogram obtained for routine surveillance. results: a total of patients underwent hsct and were alive more than years after transplant in , with having an echocardiogram obtained ≥ five years postinfusion. those with an echocardiogram were transplanted more recently (median vs. ). however, no difference between screened and unscreened individuals was noted for age at transplant, sex, transplant indication, anthracycline exposure, chest irradiation, or cyclophosphamide based preparative regimen. indications for echocardiograms included: cardiac symptoms ( . %), congenital cardiac anomalies ( . %), hypertension ( . %), known cardiac or pulmonary disease ( . %), routine post-hsct surveillance ( . %), and unknown ( . %). the mean time post-hsct was . years. among routine surveillance echocardiograms, the mean ef z-score was - . . mean lvedd zscore was - . , mean septal thickness z-score - . , mean posterior wall thickness z-score - . , and mean gls - . %. for patients that had echocardiogram performed for routine surveillance, / patients ( . %) had ef measured, and / ( . %) had ef z-scores ≤ - . (abnormally low). patients exposed to anthracyclines had a mean z-score ef of - . vs. unexposed patients - . (p = . ). among individuals who received neither anthracyclines nor tbi only / ( . %) was found to have an abnormal ef, . % (z-score - . ) or gls (- . %). only one patient who had a normal ejection fraction (z-score - . , ef . %) had an abnormal gls, - . % (normal ≤ - . ). long-term survivors of pediatric hsct who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless indicated by clinical symptoms. patients exposed to anthracyclines or tbi require close echocardiographic s of s screening and clinical monitoring for the development of cardiac complications. duke children's hospital, durham, north carolina, united states background: children undergoing pediatric blood and marrow transplants (pbmt) experience significant symptom distress. mobile health (mhealth) technologies can be leveraged to collect and monitor patient generated health data, and subsequently enhance our understanding of pbmt symptom clusters, patterns, and trajectories. better understanding of symptom complexity can foster development of precision health strategies to improve patient outcomes. however, limited research exists in integrating mhealth technology into pbmt management. we aimed to explore the feasibility, acceptability, and usability of using a pbmt specific mobile application to collect and monitor symptoms and wearable technology (apple watch) to measure objective data such as heart rate (hr) and activity. design/method: an exploratory mixed method design began in october to monitor pbmt symptoms for patients using real-time data from: ) a self-developed mhealth application (app) to collect subjective symptom data; and ) apple watch to collect physiologic measures such as heart rate and number of daily steps. data is collected pre-transplant through days. acceptability will be assessed through satisfaction surveys at study completion. we have enrolled patients to date who are all currently using the app and watch. patients' average frequency of daily charting in the app %. the wearable average daily recorded measurements are for hr and for step count. most common symptoms recorded within the app include fatigue and pain. we have noted trends in data including a decrease in activity following transplant and gvhd and an increase following engraftment. patients have stated "the app is helpful to keep track of how my pain is doing day to day" and "i try to take more steps each day than the day before". patients often remove the watch for charging, then forget to put it back on, but consistently put it on upon reminder. finally, parents often were required to make app entries with patients too sick to record. we continue to enroll patients with enthusiasm from both patients and parents to use mhealth during pbmt. preliminary findings suggest feasibility of using the mhealth devices is strongly correlated to the patient's post-transplant stage and is facilitated by caregiver participation with device management (charging devices, reminders to wear watch and record in app). patients reported satisfaction and ease of use with devices, but found it difficult to keep up with charging and charting. these findings indicate using mobile devices may be useful methods to collect patient generated health data. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bacterial bloodstream infections (bsi) are a common complication following hematopoietic stem cell transplantation (hsct) in both pediatric and adult populations, and are associated with poor outcomes. there is limited data describing the outcomes and characteristics of patients who develop three or more bsi after hsct. objectives: to describe the characteristics and outcomes of pediatric patients who develop three or more blood stream infections in the first-year post hsct. design/method: we performed a retrospective chart review of consecutive patients who underwent hsct at our institution from through to compile this case series. data were collected through the first year post-hsct including: patient demographics, underlying disease and therapy characteristics; and transplant complications such as thrombotic microangiopathy (tma), graft versus host disease (gvhd) and overall survival. bsis were classified according to current center of disease control guidelines. results: of patients, ( %) developed or more bsi in the first-year post transplant (total bsi cases = including all patients). of the cases, the majority underwent allogeneic hsct (n = / ; %). most cases were from unrelated donor (n = / , %). more than half of patients had grade - gvhd (n = / , %). sixteen ( %) had tma. of these cases, tma preceded the first bsi in n = / ( %). the majority of bsis were classified as central line-associated bloodstream infections (clabsis, n = / , %), followed by mucosal barrier injury laboratory-confirmed bloodstream infections (n = / , %) and secondary bsi (n = / , %). the majority of isolated organisms ( %) were associated with mucosal barrier injury pathogens. one-year overall survival in the cohort was % (n = / ). pediatric patients undergoing hsct who develop or more bsis in the first-year post transplant demonstrated an increased rate of tma compared to the overall institutional incidence of roughly %. tma diagnosis preceded the first bsi in over half of patients, suggesting that tma may predispose to recurrent bsi. improved strategies for early detection and treatment of tma as well as prevention of clabsis may help reduce the number of bsis ultimately leading to decreased morbidity and mortality in this patient population. background: in neutropenic pediatric patients, infection remains a significant cause of morbidity and mortality. while granulocyte transfusions have been utilized for decades to treat infections, including in the pediatric population, the efficacy of this intervention remains poorly described. previous guidelines have primarily utilized information from adult populations. furthermore, recruitment of donors typically involves friends or relatives of the patient with periodic involvement of community donors. the use of a readily available local donor population to improve availability has yet to be well described. as the immunocompromised population is particularly susceptible to worsening infection and clinical deterioration, the ability to rapidly harvest and deliver granulocytes warrants further investigation. to investigate the efficacy, safety, and outcomes of severely immunocompromised patients receiving granulocyte transfusions from a local altruistic granulocyte program in a pediatric tertiary care center. design/method: a retrospective review was performed to evaluate the context for receiving a transfusion as well as primary outcomes including infection clearance, survival to discharge, and overall mortality. the indiana blood bank assisted with timing the interval from initial order placement to onset of first granulocyte infusion. results: among the patient population reviewed, patients received separate granulocyte regimens. ages ranged from - years with a mean neutrophil count of at time of first transfusion. indications for transfusions included bacteremia (n = ), fungal pneumonia (n = ), and fungemia (n = ). primary outcomes included clearing infection ( %) and surviving to discharge ( %). the median time from initial order placement to infusion was hours, although there was no significant difference between responders who cleared the infection and non-responders who did not. however, additional investigation found that ward patients had a % chance of surviving to discharge while patients in the icu at time of initial transfusion had a % chance of survival to discharge. the readily available granulocyte transfusion program allows patients to quickly receive therapy in neutropenic settings. this is beneficial for patients as transfusion prior to clinical decompensation correlates with increased likelihood of infection clearance, and subsequently improved mortality. further investigation is needed, likely as a prospective study, to better explore circumstances that are beneficial for granulocyte transfusions. background: donor lymphocyte infusions (dli) are composed of immune cells to treat relapse after hematopoietic cell transplantation (hct). to date, data regarding its efficacy is limited in pediatric populations. furthermore, while outcomes related to cd content have been characterized, to our knowledge, the relationship between outcomes and other cellular content in dli has never been reported. objectives: determine whether the primary hematological malignancy, presence/absence of graft-versus-host disease s of s (gvhd), and unique phenotypic content of each dli impact overall survival (os) in pediatric patients with hematological malignancies. design/method: irb-approved, retrospective study investigating all consecutive dlis given to patients at the children's hospital of wisconsin. analyses were conducted using mann-whitney, fisher's exact, and chi-square. from from - patients ≤ years old with hematologic malignancies [myeloid (aml/ mds/cml/jmml),n = ; lymphoid (all),n = ] underwent dlis ( %% ≥ dlis). the median time between hct and dli was . (range, . - . ) years. there were significant differences between the lymphoid and myeloid groups, respectively, in regard to median age at hct ( . vs . yrs, p = . ) and at first dli ( vs years, p = . ). ultimately, there were no statistically significant differences in gvhd or os in products with either higher or lower cd , cd , cd , cd , or cd cellular content. however, the median cd /kg content was more than double in the patients who developed gvhd as compared to patients who exhibited no gvhd after dli ( . × vs . × , p = . ). patients receiving one dli had a -year os of ± % vs those receiving + dli of ± % (p = . ). with a median follow-up of . (range, . - . ) years, the year estimated os of patients in the lymphoid group was higher at ± % vs ± % in the myeloid group, although not significant (p = . ). our results indicate a survival benefit when using dli in a subset of patients who relapse after hct. unlike adult studies demonstrating little effect of dli in lymphoid diseases, many children with all achieved durable remission. while our analysis did not demonstrate that dli cellular content had a statistically significant effect on gvhd or os, it is possible that differences could be found if a larger population and more targeted cell doses were studied. more data will be needed to further define these relationships and identify patients who stand to benefit most. cincinnati children's hospital medical center, cincinnati, ohio, united states background: many arabic speaking muslim parents of children requiring bone marrow transplantation (bmt) receive medical care in the united states. providers may not understand the impact of islamic parents' religious beliefs and practices on their health care experience. objectives: to explore how islamic parents used religion in decision making and to understand the impact of their religious beliefs and practices on their overall health care experience. design/method: we used grounded theory, an inductive method gathering data from interviews and analyzing text, to identify core themes. ten caregivers of bmt children from middle eastern countries were interviewed by an arabicspeaking provider; interviews were coded by an interdisciplinary team. we identified key themes: . patience is a core belief in islam. patience results from the acceptance of allah's will. behaviors showing patience include praying rather than questioning and crying. . al qur'an provides comfort, healing, and protection. families listen to recitations of al qur'an in the patient's room because they feel that this practice not only comforts them but promotes healing as well. for some, certain portions of the qur'an were especially meaningful such as surat al-baqara, which explains that while we may think something is bad for us, allah will know it is good for us. . religious care in the medical center helped families feel respected. religious care in the medical center included interactions with chaplains, who were understood to be "religion experts," and provision of space for prayer and religious resources. . seeking religious consultation. religious consultation from imams or religious scholars (muftis or sheikhs) provides interpretations of the qur'an applied to the family's specific situation helps families make difficult decisions and follow allah's plan. . muslim beliefs guided decision making; muslim practices brought comfort, strength, and peace. drawn from the parents' understanding of islam. parents who addressed this topic said they would only do what islam allowed. they did indicate that most aspects of healthcare were understood to be allowed within islam. additionally, muslim practices of prayer, reading/listening to qur'an, and giving alms all provided comfort, strength and peace. we identified several recurring themes through our interviews that allowed us to understand how families use their muslim faith to deal with their children's illnesses and how it influences their decision making. we believe this better understanding will allow for more informed conversations about patients' health care and decision making, and shows respect for religious beliefs and practices. nemours/dupont hospital for children, wilmington, delaware, united states background: virtually all children will be infected with human herpesvirus (hhv- ) by the age of two. hhv- reactivation after stem cell transplantation causes multiorgan toxicities, including encephalitis, with inflammation and destruction of the temporal lobes and hippocampi, memory loss, and seizures. catatonia is characterized by posturing, immobility, mutism, and autonomic instability, and it's associated with various psychiatric and medical conditions. we describe a patient with hhv- encephalitis and unusual neurologic sequelae, including cognitive and neurobehavioral dysfunction and catatonia, which may impact our understanding of the pathophysiology of hhv- reactivation encephalitis. objectives: describe a case of hhv encephalitis with practice implications for stem cell transplantation. results: our patient was diagnosed with acute myeloid leukemia at age . within years, he relapsed and received two stem cell transplants. on the th day after his second transplant, he developed hyponatremia and refractory seizures. brain mri showed edema in the medial right temporal lobe with linear ischemic change. eeg showed diffuse encephalopathy. cerebrospinal fluid (csf) demonstrated white blood cells, red blood cells, and hhv- by pcr. his prophylactic antiviral was switched to foscarnet and ganciclovir. repeat mri showed abnormal signals in bilateral medial temporal lobes and the right insula. three months later he developed episodes of diaphoresis, hypothermia, agitation, mutism, and unusual posturing, recurring almost daily, recognized as catatonia. mri showed improvement of the abnormalities in the bilateral medial temporal lobes and hippocampi. eegs showed diffuse slowing. after months of antiviral therapy, csf was negative for hhv- . over the ensuing years, he had numerous episodes of diaphoresis, hypertension, hypothermia, pruritis, confusion, agitation, cogwheel rigidity, and bizarre posturing. dopamine blocking agents did not help. clonazepam helped reduce their frequency, and hot showers helped break acute episodes. further mris showed generalized cortical volume loss. he suffered from depression and severely impaired sleep and cognitive function. we describe a novel, debilitating outcome of hhv encephalitis which may provide diagnostic considerations as we continue to improve our understanding of the breadth of possible neurologic sequelae in transplant patients. hhv- is understood to infect and destroy the temporal lobes and hippocampi, but our patient's autonomic dysfunction indicate involvement of the hypothalamus and basal ganglia. antidopaminergic agents may worsen catatonia, and they were not effective for our patient. treatment of catatonia includes benzodiazepines; electroconvulsive therapy was not attempted in this case but may also be useful. background: epstein-barr virus (ebv)-related posttransplant lymphoproliferative disorder (ptld) is a lifethreatening complication in patients following hematopoietic stem cell transplantation, with a frequency estimated at . % and a cumulative incidence of mortality estimated as high as %. studies of ebv have hypothesized that the tonsils are critical for propagating this infection, as tonsillar epithelial cells have been shown to be the site of primary viral infection and continued viral shedding; however, to date no studies have been performed assessing the role of tonsillectomy in patients with ebv ptld. objectives: identify patients with localized ebv ptld treated with tonsillectomy to identify prognostic factors that may be able to help guide future treatment decisions. design/method: patients treated at memorial sloan kettering cancer center who had received hematopoietic stem cell transplantation and had billing codes for both ebv and tonsillectomy were eligible for inclusion in this study. a retrospective chart review was performed, assessing patient demographics, transplant characteristics, laboratory values, tonsillar pathology, and clinical course. any patient who did not have unilateral or bilateral tonsillectomy performed or who had non-localized disease (defined as disease involvement outside of the oropharynx and neck) was subsequently immunodeficiency; % (n = / ) fanconi anemia (fa); % (n = / ) hemoglobinopathy; % (n = / ) non-fa marrow failure and % (n = / ) a metabolic disorder. seventy one percent (n = / ) had normal amh for age pre-transplant, % (n = / ) had low amh for age pre-transplant; of these, % (n = / ) had an oncologic diagnosis; % (n = / ) had fa; % (n = / ) had previously treated hlh; % (n = / ) had non-fa marrow failure; one had a metabolic disorder and one a hemoglobinopathy. of the patients with post-transplant amh measurement % (n = / ) had low levels. of the patients with previously normal pre-transplant amh % (n = / ) underwent myeloablative conditioning (mac) regimen with a % (n = / ) having low amh levels post-transplant compared to %(n = / ) who underwent reduced intensity conditioning (ric) regimen with % (n = / ) having low amh levels post-transplant (p . ). fifteen percent (n = / ) had low levels pre-transplant and underwent mac regimen with % (n = / ) remaining low; % of these patients (n = / ) had fa. nine percent (n = / ) had low levels and underwent a ric regimen with % (n = / ) of amh levels remaining low; % (n = / ) of these patients had hlh treated prior to transplant. conclusion: amh levels can be used for detection of premature ovarian failure and fertility counseling. there is a higher risk of premature ovarian failure with mac regimens and prior chemotherapy vs ric regimens. follow up of this cohort will provide more information to understand the effects of hsct in ovarian function and the usefulness of amh as a predictor of fertility potential. background: there are no proven strategies to prevent blood stream infections (bsi) secondary to oral mucosal barrier injury after hematopoietic stem cell transplant (hsct). additionally, we recently reported progressive gingivitis and dental plaque accumulation in hsct recipients despite our current oral standard of care (three times daily oral rinse). xylitol is a non-fermentable sugar alcohol that reduces dental caries, plaque accumulation, and oral disease progression by inhibiting bacterial growth. we hypothesized that the addition of xylitol to standard oral care will decrease dental plaque accumulation, gingivitis and bacteremia from oral flora. objectives: identify a clinically effective strategy to improve oral health and prevent bsi secondary to bacterial translocation through the oral mucosa in patients undergoing hsct. we are conducting a prospective randomized control study to test our hypothesis. those in the intervention arm receive our current standard of care (three times daily oral rinse) in addition to daily xylitol wipes; controls receive oral standard of care alone. oral exams are performed at baseline and weekly for the first days post hsct. metagenomic shotgun sequencing (mss) of gingival samples is performed at all time points to evaluate microbiome diversity and pathogenic bacterial load. finally, we performed whole genome sequencing of pathogenic bacterial isolates causing bacteremia to assess for genetic relatedness to corresponding strains present within the patient's oral microbiome preceding the infection. : preliminary interim analysis of patients demonstrates improved oral health in patients receiving xylitol (n = ) over those receiving standard of care (n = ), measured by the oral hygiene index (p = . ) and gingivitis index (p = . ). in the nine patients having complete oral mss analysis, xylitol appeared to be associated with decreased streptococcus mitis/oralis domination in the oral microbiome. finally, patients receiving xylitol had no incidence of streptococcus mitis/oralis bacteremia through the first days compared to three patients ( %) in standard of care arm. interestingly, streptococcus mitis/oralis comprised % of the oral microbiome in one child who subsequently developed a streptococcus mitis/oralis bsi. we expect to complete this study in the next months (n = ). the addition of xylitol to oral standard care appears to decrease dental plaque and gingivitis in patients undergoing hsct. xylitol may also impede streptococcus mitis/oralis dominance in the oral microbiome with potential reduction in blood stream infections. (range: - days). twenty-one mdli ( %) were administered because of lymphopenia, fourteen of them ( %) in patients with concomitant viral/opportunistic infections. mixed chimerism/graft failure was the motive of % of the mdli (n = ) and six ( %) were administered to accelerate immune reconstitution. all infusions were well tolerated without appearance or worsening of gvhd. an increase in t-cell counts was observed following six mdli ( . %), although it was a transitory response ( - weeks) in five cases. viral/opportunistic infections were controlled in five cases ( . %), requiring a median of mdli to achieve this response. none of the mdli administered in cases of mixed chimerism/graft failure were effective in reverting this situation. our preliminary data suggests that mdli, is a safe adoptive immunotherapy strategy even with high dose of t-cells without infusion side effects or gvhd complications. some efficacy has been observed in patients with lymphopenia and opportunistic infections, with no positive results in patients with mixed chimerism/graft failure, up to date. however, to determine the real efficacy of this strategy, prospective studies are required. jun zhao, kristen beebe, lucia mirea, alexandra walsh, shane lipskind, alexander, ngwube phoenix children's hospital, phoenix, arizona, united states background: male adolescents undergoing myeloablative hematopoietic stem cell transplantation (hsct) develop infertility with impaired spermatogenesis with reported rates ranging from % to %. in nonmalignant diseases, myeloablative regimens have been replaced with reduced intensity conditioning (ric) with the hopes of better survival rate, less organ toxicity and improved quality of life. despite the increased use of ric regimens for hsct, the effects of ric on fertility remain unknown. objectives: to assess fertility following ric hsct in young adult males. we assessed gonadal function and semen characteristics in adolescent males (> years) who received a single ric hsct at phoenix children's hospital for nonmalignant diseases during - . male patients who were a minimum of year from ric hsct and had postpubertal development at tanner stage iii or above were eligible for this study. gonadal status was assessed by measuring fsh, lh, testosterone, and inhibin b levels, and semen anal-yses assessed fertility indicators (semen volume, sperm concentration, motility, viability, forward progression, morphology, and total count). results: hormone levels and semen analysis have been obtained for patients thus far. the median time between transplant and semen analysis was years. post hsct, ( %) patients showed abnormally elevated lh levels, but fsh, testosterone (total and free), and inhibin b levels were within normal range for all patients. sperm morphology and viability testing were not able to be performed due to low concentrations and volumes. as a result, the total motile sperm count, the most useful estimate for fertile potential, is essentially for all patients. conclusion: recruitment is ongoing, but so far our limited results suggest that ric hsct may have detrimental longterm effects on male fertility. a multi-institutional trial may be appropriate due to small patient numbers at each institution. we are currently exploring options to expand to other centers. further consideration is warranted regarding decisions made by providers, ways to improve anticipatory counseling provided to patients and their families prior to transplant, and how to augment the preventive care of these patients in longterm follow-up. currently all male patients being considered for ric transplant should be counseled to sperm bank prior to transplant. background: a previous systematic literature review identified all published studies of defibrotide treatment for patients of all ages with vod/sos. to assess day+ survival for defibrotidetreated pediatric patients (≤ or ≤ years, per study) all patients exhibited infectious complications with at least viral infection. four patients also had bacterial infections. of note, no patient developed evidence of fungal infections. conclusion: early institution of ecp in patients with high risk acute gvhd (grade - ) was very effective at treating agvhd, allowed for an aggressive steroid taper and contributed to excellent overall survival rates ( %). infectious complications were primarily viral and bacterial, with no fungal infections in this very high risk population. background: vod/sos is a life-threatening complication of hsct conditioning. vod/sos with multi-organ dysfunction (mod) may be associated with > % mortality. defibrotide is approved to treat hepatic vod/sos with renal/pulmonary dysfunction post-hsct in the us and severe hepatic vod/sos post-hsct patients aged > month in the eu. there are few published data on survival of neuroblastoma patients with vod/sos post-hsct. objectives: to report day+ survival and safety post hoc for patients with neuroblastoma and vod/sos post-hsct in the defibrotide t-ind trial. design/method: vod/sos was diagnosed by baltimore or modified seattle criteria or biopsy, with/without mod, after hsct or chemotherapy. defibrotide treatment ( mg/kg/day) was recommended for ≥ days. this post hoc analysis is based on adult and pediatric patients receiving ≥ dose of defibrotide, including with mod. results: among patients with neuroblastoma, developed vod/sos after hsct. for these post-hsct patients, . % were male and . % were female, median age was years (range - years): . % aged - months, . % - years, . % - years, and patient > years. day+ survival data were available for / of these neuroblastoma patients ( with mod and without mod); had autologous and had allogeneic transplants. kaplan-meier estimated day+ survival for the neuroblastoma group was . % ( % confidence interval [ci] , . %- . %). for the mod and no mod subgroups, kaplan-meier estimated day+ survival was . % ( % ci, . %- . %) and . % ( % ci, . %- . %), respectively. in the overall t-ind hsct population aged ≤ years (n = ) and pediatric autologous hsct subgroup (n = ), kaplan-meier estimated day+ survival was . % and . %, respectively. treatment emergent adverse events (teaes) occurred in . % (n = / ), with serious teaes in . % ( / ; most common: multi-organ failure, . % [ / ]). teaes lead to treatment discontinuation in . % (n = ; most common: pulmonary hemorrhage, n = ); death occurred in . % (n = ; > %: multi-organ failure, . %; vod/sos, . %). treatment-related adverse events, as assessed by investigators, occurred in . % (n = ; most common: pulmonary hemorrhage, . %). this post hoc analysis found kaplan-meier estimated day+ survival of . % in patients with neuroblastoma and vod/sos post-hsct, which was consistent with outcomes in pediatric patients after autologous hsct. the safety profile of defibrotide in neuroblastoma patients was consistent with the overall hsct population in this study and other defibrotide studies in pediatric patients. cincinnati children's hospital medical center, cincinnati, ohio, united states background: blood stream infections occur in nearly % of patients undergoing hematopoietic stem cell transplant (hsct) and fever is often the first symptom. timely administration of antibiotics is associated with improved outcomes, thus, early recognition of fever is paramount. current standard of care (soc) includes episodic monitoring of temperature in hospitalized patients, which may delay fever detection. therefore, continuous real-time body temperature measurement may detect fever prior to the current soc. temptraq is a food and drug administration cleared class ii medical device and consists of a soft, comfortable, disposable patch that results: of patients, were started on a pca in the days post hct. % were male with median age of y. % had all, and % aml. matched related donors were used in % and % received tbi. pca was initiated median d+ . oral mucositis alone was the most common indication ( %). a majority of patients were started on hydromorphone ( %); % started on morphine and % started on fentanyl. % started on continuous infusion. pca was used for a median of days (range - days). median pain score was highest d+ of pca use, however, there was inconsistency in charting of numerical pain scores. on d+ , patients had insufficient data to determine efficacy of pain control; of the remaining patients, % had good pain control while % had moderate and % had poor pain control using our devised scale. the most common toxicity observed was respiratory depression (∼ %), however, etiology was often multifactorial and not due to opiates alone. analysis is ongoing to assess variables predicting pca use as well as efficacy of pain control and correlation between current reporting scales and patient perception. conclusion: pca use is common in pediatric hct yet pain control remains inadequate. there's a need for better evaluation of pca management, especially uniform assessment of pain, thereby improving quality of life post hct. children's national health system, washington, district of columbia, united states background: actinomycosis is a rare invasive anaerobic gram-positive bacterial disease caused by actinomyces spp. that may colonize the oropathynx, gastrointestinal tract and urogenitial tract and can lead to abscesses. respiratory tract actinomycosis is characterized by pulmonary cavities, nodules, consolidations and pleural effusions. although actinomyces are nearly always sensitive to penicillin they are frequently resistant to cephalosporins and variable sensitives to fluoroquinolones. although rare in children, immunosuppressed patients are at increased risk for actinomycosis. to describe a case of next-generation sequencing identification of actinomycosis. a -year-old male with a history of very high risk b-cell acute lymphoblastic leukemia who was months status post a / matched unrelated donor bone marrow transplant complicated by prolonged fevers, persistent weight loss, and splenic lesions, treated with posaconazole and levofloxacin developed fever and cough in the setting of neutropenia. blood cultures demonstrated staphylococcus epidermidis. ct showed micronodules and effusion not consistent with s. epi, prompting bronchoscopy. all bacterial cultures were negative. patient was prescribed a three-week course of vancomycin with rapid improvement. design/method: s next generation sequencing (ngs) from bronchoalveolar levage sample was performed at the university of washington laboratory results: ngs assay from bronchoalveolar lavage showed major abundance of actinomyces most closely related to meyeri or oodontolyticus. demonstrated actinomyces. the patient was started on a six month course of amoxicillin with continued clinical improvement. in retrospect, the splenic nodules that were presumed fungal disease were likely actinomycosis, partially treated with levofloxacin. this case highlights the potential utility of ngs in the diagnosis of rare diseases in immunocompromised patients. actinomycosis was only demonstrated through ngs and led to a change in treatment regimen and durable clinical improvement. because actinomyces often mimics malignancy, tuberculosis or nocardiosis, the use of this novel test both targeted appropriate therapy and reduced the exposure to unnecessary medications to treat the differential diagnosis. finally, we highlight that actinomyces should be considered in patients who present with unexplained fevers, weight loss, and night sweats. haneen shalabi, cynthia delbrook, maryalice stetler-stevenson, constance yuan, bonnie yates, terry j. fry, nirali n. shah center for cancer research, national cancer institute, national institute of health, bethesda, maryland, united states background: car-t therapy, while effective, may not be durable for all, and antigen negative escape is a growing problem. hct, in relapsed/refractory all, can be curative, particularly for those in an mrd negative remission. we demonstrated that cd directed car-t therapy effectively rendered patients into mrd negative remissions (by flow cytometry) and the leukemia free survival post-hct was high . in pastorek, jesssica bruce, michael a. pulsipher, chloe anthias, peter bader, andre willasch, jennifer sees, jennifer hoag, wendy pelletier, brent logan, pintip chitphakdithai, lori wiener university of pittsburgh, pittsburgh, pennsylvania, united states background: more than , pediatric hscts are performed in north american and europe each year. the ethics of exposing a healthy child to donation procedures which have some risks and no direct medical benefits continue to be a topic of debate. pediatric donors may experience psychological distress and poorer quality-of-life during and after donation compared to healthy controls. although there are fact/jacie requirements related to the management of pediatric donors, it is unclear what standardized practices exist for psychosocial assessment/management of this group. objectives: to describe transplant center practices for psychosocial evaluation/ management of pediatric donors (< years) and to examine differences in practices by location (cibmtr/ebmt) and number of harvests (volume). design/method: data were collected via a single crosssectional survey distributed electronically to cibmtr and ebmt centers between / / and / / . : / ( %) of cibmtr and / ( %) of ebmt centers completed the survey. most centers had written eligibility guidelines for pediatric donors ( %). most also had a process for ensuring that donors were freely assenting to donate ( %), managed by a transplant physician ( %). a single physician often jointly managed donor/recipient care ( %). half of centers had a pediatric donor advocate ( %), who was most often a physician ( %) or social worker ( %). cost was the largest barrier to having a donor advocate ( %). most centers performed psychosocial screening of donors ( %) but rarely declined donors based on psychosocial concerns ( %). less than half of centers provided post-donation psychosocial follow-up ( %). comparisons by center location indicated that ebmt centers were more likely to have a physician doing joint donor/recipient care ( % vs. %; p = . ), less likely to have a psychosocial assessment policy ( % vs. %; p = . ), less likely to have a donor advocate ( % vs. %; p = . ), but marginally more likely to do post-donation psychosocial follow-up ( % vs. %; p = . ). large volume centers were more likely to have a psychosocial assessment policy than their medium/smaller counterparts ( % vs. %, %; p = . ) â€"there were no other differences on key psychosocial management variables by volume. although most centers have written guidelines for pediatric donor eligibility and mechanisms for ensuring assent, substantial numbers of donors do not undergo psychosocial assessment, are jointly managed with the recipient by a single physician without an assigned donor advocate, and do not receive psychosocial follow-up. the field would benefit from guideline development for the psychosocial management of pediatric donors. background: germline mutations in samd and samd l genes cause mirage (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) and ataxia-pancytopenia syndromes, respectively, and are associated with chromosome deletions, mds and bone marrow failure (bmf). there are limited data on outcomes of hct in these patients. to describe outcomes of allogeneic hct in patients with hematologic disorders associated with samd /samd l mutations. results: seven patients underwent allogeneic hct for primary mds (n = ), congenital amegakaryocytic thrombocytopenia (camt)(n = ), and dyskeratosis congenita (n = ). retrospective exome sequencing revealed gain-of-function mutations in samd (n = ) or samd l (n = ) genes. constitutional mosaic monosomy was present in cases. two samd patients had features of mirage syndrome. unusual findings of panhypopituitarism, laryngeal cleft, and glomerulosclerosis were noted in one case. in another case with a samd mutation hypospadias & bifid scrotum were the only findings. the remaining patients had no phenotypic abnormalities. median age at hct was y (range: . - . ). patients received transplants from bone marrow (matched unrelated (n = ) & hla identical sibling (n = )), or unrelated cord blood (ucb) (n = ). five mds patients received myeloablative s of s conditioning (busulfan-based (n = ) or tbi-based (n = )); patients (mds (n = ); camt (n = )) received reducedintensity conditioning (ric) (fludarabine, cyclophosphamide, with ratg or alemtuzumab). syndrome-related comorbidities (diarrhea, infections, malnutrition, electrolyte imbalance, lung disease and hypoxia) were present in both patients with mirage syndrome. one patient with a familial samd l mutation, mds and morbid obesity failed to engraft following ric double ucbt. she died one year later from refractory aml. all other patients achieved neutrophil and platelet engraftment, at a median (range) of ( - ) and ( - ) days, respectively. posttransplant complications included severe hypertension (n = ), pericardial effusions (n = ), veno-occlusive disease of liver (n = ), and recurrent aspiration pneumonias (n = ). one patient developed grade iii agvhd which resolved with treatment. one patient developed mild skin cgvhd and suffers from chronic lung disease. all surviving patients had resolution of hematological disorder and sustained peripheral blood donor chimerism ( - %). overall survival was % with a median follow-up of years (range: . - . y). patients with hematological disorders associated with germline samd /samd l mutations tolerated transplant conditioning without unusual, or unexpectedly severe toxicities. allogeneic hct led to successful resolution of mds or bmf, with excellent overall survival. more data is needed to refine transplant approaches in samd /samd l patients with significant comorbidities, and develop guidelines for their long-term follow-up. shyamli singla, tiffany simms-waldrip, andrew y. koh, victor m. aquino background: steroid-refractory acute graft versus host disease (agvhd) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (hsct). basiliximab (anti-il -r monoclonal antibody) as a single agent or in combination infliximab (anti-tnf-monoclonal antibody) has demonstrated efficacy in adult cohorts with steroid-refractory agvhd, but has not been well studied in the pediatric population. we adopted the use of basiliximab and infliximab as our institutional standard of care for steroid-refractory agvhd in pediatric hsct patients. to determine the response and survival of hsct children who received basiliximab and infliximab for the treatment of steroid-refractory agvhd. design/method: we retrospectively reviewed children who received basiliximab and infliximab for steroid-refractory agvhd refractory between september and december . complete response (cr) was defined as resolution of all clinical signs of agvhd. partial response (pr) was defined as at least one grade reduction in one target organ (e.g. skin, gut or liver) without increased grade in another target organ. no response was defined as either no improvement or progressive worsening of agvhd in at least one organ. baseline demographics, transplant details, laboratory findings, and treatment outcomes were also evaluated. results: of the evaluable hsct patients, children (median age yrs, range mo- yrs) with steroid-refractory agvhd received combination monoclonal antibody (mab) therapy. the median time from the start of steroid therapy to initiation of mab was days. the overall glucksberg grade of agvhd at the time of initiating mab therapy was grade i (n = , . %) ii (n = ; %), iii (n = ; %) or iv (n = ; %). the overall response rate was %, with ( %) patients achieving cr, ( . %) patients achieving pr, and ( . %) patients with no response at days following the start of mab therapy. the median overall survival was , , and days for patients who exhibited cr, pr, and no response, respectively. the overall survival at year following start of mab therapy was %. background: the role of high dose chemotherapy (hdc) and autologous stem cell rescue (ascr) in patients with high risk (advanced metastatic or relapsed) soft tissue sarcomas is controversial. despite multimodal chemotherapy, radiotherapy, and local control measure advancements, prognosis of patients with advanced metastatic or unresectable and relapsed sarcomas remains poor, with less than % years disease free survival. objectives: to determine if consolidation with myeloablative hdc and ascr improves relapse free (rfs) and overall survival (os) outcomes in a high risk patient subgroup. we performed retrospective review of all high risk soft tissue sarcoma patients who underwent hdc and ascr at the children's hospital at montefiore, bronx, ny between october and january . the protocol was approved by albert einstein college of medicine institutional review board. results: patients ( primary metastatic high risk disease, relapsed or recurrent disease) received hdc with ascr. primary diagnoses were rhabdomyosarcoma (rms) (n = , alveolar histology), primary site nasopharynx (n = ) and lower extremity (n = ). ewing's sarcoma (ews) (n = ), axial site (pelvic) in patients ( %). median age years (range - years), ( %) were male. all patients were in complete metabolic remission before transplant. median pre transplant comorbidity index was (range - ). patients ( rms and ews) received conditioning with carboplatin, etoposide and melphalan. remaining patients with ews received conditioning with busulfan, melphalan and topotecan. all patients received peripheral blood mobilized hematopoietic stem cell transplantation. stem cell mobilization achieved with high dose filgrastim in all patients except one who required addition of plerixafor. median cd +/kg s of s recipient body weight cell dose infused was . × ^ (range . - . × ^ ). median times to neutrophil and platelet (> , / l) engraftment were (range - ) and ( - ) days respectively. patients ( %) developed bk viuria (one with grade iii hemorrhagic cystitis); ( %) developed cmv viremia; and one patient ( %) had asymptomatic ebv viremia. there was no graft failure, sinusoidal obstruction syndrome or transplant related mortality. median follow up post-transplant was days (range - days). year probability of os and rfs were % and % respectively. hdc with ascr is a promising therapeutic strategy to consolidate remission and improve survival in select high risk soft tissue sarcoma patient subgroups. prospective clinical trials will inform the impact of disease status prior to hdc and ascr on outcome, optimal conditioning and long term relapse free and overall survival. background: absence of minimal residual disease is paramount for cure of pediatric acute lymphoblastic leukemia (all). the testis may harbor occult leukemia and this disease may result in treatment failure. objectives: the purpose of this study was to assess the longterm outcomes of boys with or without testicular leukemia pre-hematopoietic stem cell transplantation (hsct). design/method: retrospective analysis of boys with high-risk de novo ( with hypodiploidy all) or recurrent/refractory all was conducted. flow cytometry of bone marrow mononuclear cells was used to determine remission status. testicular evaluations were performed by physical examination and wedge biopsy pre-hsct. the median age at time of transplant was . years. all patients were in remission by flow cytometry of bone marrow mononuclear cells at the time of transplant and none had evidence of clinically apparent testicular disease. testicular leukemia was detected in patient and he underwent bilateral orchiectomy. he developed acute graft versus host disease (gvhd) of the duodenum and sigmoid colon which resolved, and the leukemia remains in second complete remission and he is free of hsct-related morbidity . months post-hsct. of the patients without testicular leukemia died a median of . months (range, . to . ) post-hsct ( with adenovirus infection and each with thrombotic microangiopathy and aspergillus pneumonia); experienced infection (staphylococcus species, corynebacterium, enterococcus, klebsiella, citrobacter, e. coli, epstein barr virus, adenovirus, bk virus, human herpesvirus- , candida albicans, fusarium, aspergillus, yeast, and other fungus); experienced gvhd ( of the gi tract, of the skin, of the liver, of the eyes, of the mouth, and of the lungs); and developed a second neoplasia (right lower leg leiomyosarcoma). one patient developed bone marrow minimal residual disease ( . % phenotypically abnormal cells detected months after / matched sibling hsct). reinduction therapy comprised weekly doses of rituxan, courses of blinatumomab and donor lymphocyte infusions with il- . two subsequent bone marrow evaluations were minimal residual disease negative. thirteen months post-hsct residual disease recurred ( . %) and he will receive inotumumab. overall median survival post-transplant of the boys is . months (range, . to . ) and of the surviving boys is . months (range, to . ). conclusion: testicular biopsy can detect occult leukemia pre-hsct. testicular leukemia pre-hsct does not appear to increase the risk of subsequent relapse or other hsct-related adverse events compared to those without it. yaya chu, nang kham su, sarah alter, emily k. jeng, peter r. rhode, mathew barth, dean a. lee, hing c. wong, mitchell s. cairo new york medical college, valhalla, new york, united states background: rituximab has been widely used in frontline treatment of b-nhl including burkitt lymphoma (bl), however, some patients retreated with rituximab relapse, which limit patient treatment options. novel therapies are desperately needed for relapsed/refractory b-nhl patients. several strategies for overcoming rituximab-resistance are currently being evaluated, including engineering immune cells with chimeric antigen receptors (car), as well as second-generation anti-cd antibodies. nature killer (nk) cells play important roles in the rejection of tumors. however, nk therapy is limited by small numbers of active nk cells in unmodified peripheral blood, lack of tumor targeting specificity, and multiple mechanisms of tumor escape of nk cell immunosurveillance. our group has successfully expanded functional and active peripheral blood nk cells (expbnk). b t m was generated by fusing alt- , an il- superagonist, to four single-chains of rituximab. b t m displayed tri-specific binding activity through its recognition of the cd molecule on tumor cells, activated nk cells to enhance adcc, and induced apoptosis of b-lymphoma cells. objectives: to examine if b t m significantly enhances the cytotoxicity of expbnk against rituximab-sensitive and -resistant bl cells. design/method: expbnks were expanded with lethally irradiated k -mbil - bbl and isolated using miltenyi nk cell isolation kit. alt- and b t m were generously provided by altor bioscience. nk receptors expression and cytotoxicity were examined as we previous described. ifng and granzyme b levels were examined by elisa assays. equal doses of rituximab, alt- , rituximab+alt- , obinutuzumab (obinu) were used for comparison. igg was used as controls. anti-cd car expbnk cells were generated as we previously described by mrna electroporation. rituximab-sensitive raji andresistant bl cells raji- r and raji- rh, were used as target cells. results: b t m significantly enhanced expbnk cytotoxicity against rituximab-sensitive raji cells, rituximab-resistant raji- r cells and resistant raji- rh cells compared to the controls igg, rituximab, alt- , rituximab+alt- , obinu (p< . , e:t = : ). furthermore, we confirmed the enhanced cytotoxicity by measuring ifn-g and granzyme b production. b t m significantly enhanced ifn-g and granzyme b production from expbnk against raji, raji- r and raji- rh compared to igg (p< . ), rituximab (p< . ), alt- (p< . ), rituximab+alt- (p< . ), and obinutuzumab (p< . ). when compared to anti-cd car expbnk cells, b t m + expbnk had the similar cytotoxicity against raji, raji- r and raji- rh as anti-cd car expbnk cells did (p> . ). conclusion: b t m significantly enhanced expbnk activating receptor expression and in vitro cytotoxicity against rituximab-sensitive and -resistant bl cells. the in vivo functions of b t m with expbnk against rituximab-sensitive and -resistant bl cells using humanized nsg models are under investigation. background: cardiac dysfunction, including left ventricular systolic dysfunction (lvsd), is a known complication in stem cell transplant (sct) survivors. while detection of lvsd by echocardiography is important in this population, there has been minimal research to determine if subclinical cardiac dysfunction exists in sct patients. cardiopulmonary exercise testing (cpet) is a valuable tool to assess cardiac function, and to determine how the heart responds to the stress of exercise. no studies have been performed to determine if sct patients with normal lvsd on standard echocardiography may have abnormal cpet. to determine the feasibility of cpet, as well as additional echocardiographic parameters, to detect dysfunction in sct patients with a normal ejection fraction on echocardiogram. design/method: we performed a cross-sectional analysis of sct survivors who were at least years post sct, years of age or older and with an ejection fraction > % (low end of normal range) on echocardiogram. we assessed the exercise capacity of all patients with cpet, and sub-clinical cardiac dysfunction through tissue doppler and strain analysis from the echocardiogram. results: seven patients ( male) have qualified and completed this study so far with an average age of . ± . years. the median time from transplant is . ± . years. all seven patients had a normal ejection fraction, however four patients had abnormalities on their cpet. these abnormalities included abnormal predicted peak oxygen consumption (vo ) ( %± . , normal > %) (the best predictor of functional capacity), predicted oxygen pulse ( %± . , normal > %) (measure of cardiac stroke volume) and ventilatory efficiency (ve/vco slope) ( ± . , normal < ). submaximal exercise data, used when patients are unable to complete a maximal effort test, demonstrated low-normal predicted vo at anaerobic threshold ( . %± . %, normal > % of was . days while patients who received autologous infusions had a mean number of days to engraftment of . . engraftment after hsct needs to be prompt to minimize duration of neutropenia and maximize survival rates . our data demonstrates that the infusion of hematopoietic stem cell products with a syringe or iv pump is an effective method of delivery for stem cell products and does not delay the time to engraftment. the median days to neutrophil engraftment was . days. this is comparable to data from the nmdp, which reports engraftment occurs within - days. the main limitation to this study was its small sample size due to the number of transplants done at our center. however, it does provide evidence to support that infusion of stem cell products via pump mechanism is a safe alternative to the infusion by gravity method in the process of the hematopoietic stem cell administration. johns hopkins all children 's hospital, st. petersburg, florida, united states background: leukemic relapse remains the most common cause of treatment failure after allogeneic hematopoietic cell transplant (allohct) for myeloid malignancies. most children who relapse post-allohct will die of their disease, making interventions to minimize this risk a high priority. objectives: to evaluate the safety and efficacy of posttransplant azacitidine for relapse prevention in children undergoing allohct for myeloid malignancy. design/method: we retrospectively reviewed the charts of children undergoing allohct for myeloid malignancies between february and november at johns hopkins all children's hospital. results: during the study period, children (ages to years, median ) underwent allohct for myeloid malignancies: de novo acute myeloid leukemia (aml), ; mixed phenotype acute leukemia, ; treatment-related aml, ; juvenile myelomonocytic leukemia with aml transformation, ; and myelodysplasia/aml, . thirteen were in first complete remission, were in cr or greater. most patients ( / ) received fludarabine/melphalan/thiotepa conditioning; received hla-identical related or unrelated donors, and received haploidentical bone marrow grafts with post-transplant cyclophosphamide. three patients never received planned azacitidine ( early relapse; early trm), leaving evaluable patients. azacitidine ( mg/m /dose for days, in -day cycles for up to cycles) was started at a median of days post-transplant (range - ). two-thirds ( / ) of patients received eight or more cycles. of five patients who stopped therapy early, only one was due to toxicity; other reasons included severe gvhd ( ), parental preference ( ), and relapse ( ). cycle delays occurred in patients, with a median cycles delayed per patient, mostly for mild myelosuppression with early cycles. no patient required blood product transfusion during therapy, but g-csf was used in three patients to maintain anc> / l. dose-modifications were made in patients (renal tubular acidosis, acute kidney injury, and myelosuppression). there were relapses ( %), two of which occurred in patients in cr , for a relapse incidence of % in patients in cr , with a median follow-up of months (range . to ). no patients who received azacitidine died of transplant-related mortality. conclusion: administration of azacitidine in children undergoing allohct for myeloid malignancies is safe and feasible, with most patients successfully receiving all planned cycles. toxicity was acceptable and there was no trm or secondary graft failure. despite the limitations of a small cohort, relapse incidence-particularly in patients transplanted in cr suggests a potential benefit in disease control that warrants investigation in follow-up studies. background: despite significant improvements in the success rate of hematopoietic cell transplantation (hct), graft failure remains an important complication in patients transplanted for severe aplastic anemia (saa). second allogeneic hct can salvage patients, but -year overall survival (os) rates have been reported as low as % . objectives: identify patients who developed dropping donor chimerism, graft rejection, and/or graft failure after first hct for saa, necessitating additional hcts or cellular boosts (defined as stem cell products infused without preceding chemotherapy), and evaluate treatment-related complications and os. with vod/sos with and without multi-organ dysfunction (mod) pubmed and embase databases were searched for "defibrotide and retrospective chart reviews; excluded publication types were: case reports (< cases); meta-analyses; reviews; animal, modeling, pharmacokinetic, chromatography, and adult-only studies; guidelines; articles; and letters. resulting reports were screened for exclusion criteria. full-text articles were then reviewed for eligibility. study characteristics of selected publications were summarized, and publications were categorized by patients' mod status. when necessary, additional data tables were requested. a random effects model was used for pooling data for efficacy. interstudy heterogeneity was assessed with cochran's q-test. percentage of total variation across studies due to heterogeneity (i ) was evaluated we quantified ∼ proteins in each sample. reproducibility for one donor at different time points children 's minnesota, minneapolis, minnesota, united states background: pediatric and young adult hodgkin lymphoma (hl) has five-year survival rates > %. chemotherapy required to achieve this rate is associated with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. as effective salvage therapy exists, outcomes may be improved by de-intensifying initial therapy to lessen toxicity.objectives: we piloted a regimen in low and intermediate risk hl patients using agents without known association to significant late effects. this retrospective chart review was approved by children's minnesota irb.design/method: the bvg(p) regimen incorporated bortezomib ( . mg/m day , , , ); vinorelbine ( mg/m day , ); gemcitabine ( mg/m day , ) every days and prednisone ( mg/m /dose bid x days). we treated newly diagnosed patients, ages - years, with non-bulk stage iia (n = ) or iib (n = ) hl. two patients received bvg and received bvgp with the addition of prednisone.results: newly diagnosed patients were all pet negative after the first or second cycle and remained pet negative at end of therapy, cycles. nausea was well controlled with -ht antagonists and scopolamine. pegfilgrastim was not necessary due to the high absolute neutrophil count nadir [median . and minimum . × /l]. there were no episodes of febrile neutropenia, infection or transfusion need. no patients experienced alopecia. one patient developed sensory neuropathy after the eighth dose of bortezomib that was controlled with gabapentin and a switch to subcutaneous bortezomib administration. of the five newly diagnosed patients, four remain in remission at , , , days; relapsed at previous disease sites at days and subsequently achieved remission with bvgp with the addition of brentuximab. this series provides early evidence to stimulate expansion of this pilot experience and subsequent multiinstitutional study leading to a randomized trial of bvgp and current chemotherapy for low and intermediate hl. st jude affiliate clinic at st francis hospital, tulsa, oklahoma, united states background: symptoms suggestive of morning hypoglycemia has been noticed in children receiving all chemotherapy. only few small studies looked at this therapy related complication. factors increase risk of hypoglycemia in all patients include accelerated starvation, steroid induced adrenal suppression, mercaptopurine therapy and prolonged fasting for procedures.objectives: to study the prevalence and risk factors for hypoglycemia during all therapy design/method: medical records of of children (up to years old) treated for all between - ( patients) were studied for evidence of morning hypoglycemia defined as blood sugar (bs) < mg/dl. statistical mean differences between the subgroups were analyzed with spss using a nonparametric mann-whitney u test.results: fifty two percent ( %) of patients developed hypoglycemia during all treatment, with an average of . episodes/patient. % were males and % females. almost / ( %) of patients with hypoglycemia were in maintenance phase of therapy. % of hypoglycemic episodes occurred in % of patients. majority of hypoglycemic episodes ( . %) occurred on the day of procedure when patients were fasting overnight. . % of hypoglycemic episodes occurred in children ≤ years, with . % in ≤ years. patients who developed hypoglycemia were significantly younger (mean age at time of diagnosis of all was . ± . at the hypoglycemia group versus the non-hypoglycemia ( . ± . ) p< . . no statistically significant difference was found regarding sex, or tpmt genotype. % of hypoglycemic children-all < years of age-presented with life threatening hypoglycemia symptoms including seizure and loss of consciousness. this study showed high prevalence of hypoglycemia during childhood all therapy. younger age, especially ≤ years, is associated with higher risk of hypoglycemia as well as life-threatening episodes. to decrease fasting hypoglycemia during therapy for childhood all, we recommend that children under the age of years receive bed time snack high in proteins and complex carbohydrates, and to get them up early the day of procedure to take clear sugary drink. hospital for sick children, toronto, ontario, canada ann & robert h. lurie children's hospital of chicago, chicago, illinois, united states background: childhood brain tumors are the most common solid malignancy and the leading cause of cancer-related mortality in children. the most aggressive type of pediatric central nervous system (cns) tumors is diffuse intrinsic pontine glioma (dipg). despite decades of clinical trials, there has been no substantial improvement with respect to therapeutic outcomes with most children eventually succumbing to the disease. research on adult high-grade gliomas has shown a targetable pathway through the inflammationinduced expression of indoleamine , dioxygenase (ido ) and its recognized ability to suppress the anti-tumor immune response. a limited understanding into the role of ido in pediatric central nervous system tumors serves as the foundation of this research project. furthermore, the integration of nanotechnology is a fundamental step for the investigation and targeting of ido . spherical nucleic acids (snas) composed of nanoparticles have been shown to transverse cellular membranes, exhibit stability in physiological environments, escape from degradation, and create precise targeting in brain tumors.objectives: the purpose of our project is to delineate the role of ido in pediatric dipg, and develop small inhibitory (si)rna oligonucleotides and snas aimed at therapeutically inhibiting the gene expression of immunosuppressive ido . our specific aims are to: ( ) confirm the gene expression ido in different human dipg cell lines; ( ) generate and characterize sirna oligonucleotides targeting human ido in vitro; and ( ) generate and characterize gold nanoparticles for targeted inhibition of ido .design/method: unique patient-derived dipg cell lines were grown in culture, stimulated with increasing concentrations of the proinflammatory cytokine, ifn , and analyzed for mrna levels. sirna specific to ido was transfected into cells. sna generation is in progress.results: ido is expressed in multiple human pediatric dipg cell lines. sirna targeting ido among exons and results in a significant decrease in overall ido expression by dipg cells. sna generation for targeting ido with improved penetration & stability is ongoing, with preliminary results demonstrating a robust ability to inhibit ido expression. the grim prognosis of children with dipg, the lack of effective therapies, and the expression of ido by human dipg cells emphasize the importance of developing the treatment capability to inhibit ido gene expression, as a excluded from this study. the remaining patients were analyzed using descriptive statistics.results: a total of patients meeting inclusion criteria were identified. of these, patients ( . %) received tonsillectomy alone, ( . %) underwent tonsillectomy and decreased immunosuppression, ( . %) received tonsillectomy and rituximab, and another ( . %) received tonsillectomy with additional therapy (including ebv-specific cytotoxic tlymphocytes, donor leukocyte infusion, and chemotherapy). of the patients who received tonsillectomy with or without a decrease in immunosuppression, all were diagnosed with high-grade lymphoma and achieved clinical remission following tonsillectomy with no evidence of relapse to date. on further analysis looking at ptld risk factors, all patients were under years of age, all received t-cell depleted grafts, and none had significant graft-versus-host disease (gvhd) at the time of ptld diagnosis. we have identified a population of patients with localized ebv ptld that achieved clinical remission with no evidence of recurrence following tonsillectomy, suggesting that tonsillectomy alone may be an adequate treatment for localized ebv ptld in a specific subgroup of patients. further analysis is needed to identify characteristics of this subgroup to determine which patients would be most likely to respond to this treatment. university of rochester, rochester, new york, united states background: malignant central nervous system (cns) tumors in young children have a poor prognosis and pose a significant therapeutic challenge. consolidation therapy with carboplatin and thiotepa was piloted in ccg- , cog acns , and cog acns with the goals of intensifying therapy and omitting or delaying radiation.objectives: to document outcomes for patients undergoing carboplatin/thiotepa consolidation with autologous stem cell rescue (ascr) and to demonstrate the feasibility and toxicity of this regimen.design/method: patients up to years old (median age: months) with malignant cns tumors treated at the university of rochester from - with at least one cycle of carboplatin ( mg/kg/day x days) and thiotepa ( mg/kg x days) followed by peripheral blood ascr were included in retrospective analysis. data were recorded on time to engraftment (defined by absolute neutrophil count (anc) recovery to > . × ^ /l), length of hospitalization, toxicity with each consolidation cycle, progression free survival (pfs) and overall survival (os). stem cell harvest data were also collected.results: eleven patients with malignant cns tumors ( atypical teratoid/rhabdoid tumor, primitive neuroectodermal tumor, glioblastoma multiforme, and pineoblastoma) received a total of cycles of carboplatin/thiotepa. of these, underwent stem cell harvest at our institution, with complications limited to procedure-related hypotension for patient with known autonomic instability, and catheter-associated deep vein thrombosis (dvt) for patient. four patients were in complete remission (cr) /status-post gross total resection, was in cr , and had residual tumor at the time of consolidation. nine patients received planned consolidation cycles, patient (of ) planned cycles, and patient of an anticipated cycles thus far. average time to engraftment for these cycles was . (+/- . ) days, with a mean hospital length of stay of (+/- . ) days. fever occurred in of cycles ( %); infectious toxicity included documented bacterial infection in cases (enterococcus faecalis bacteremia in , klebsiella pneumoniae in ). there were no regimenrelated deaths. with a mean follow-up of months, survivors have not yet completed all therapies, and patients have relapsed ( have died of disease). of the survivors, have been disease-free for > months. background: autologous hematopoietic stem cell transplantation (auto-hsct) has resulted in improved survival for patients with high-risk neuroblastoma. treatment intensification is however associated with greater complications. data on early infectious complications in low-and-middle income countries are limited.objectives: to review the early infectious complications following auto-hsct in patients with high-risk neuroblastoma.design/method: a retrospective chart review of pediatric patients with high-risk neuroblastoma who underwent auto-hsct at the american university of beirut medical center between and was conducted. infectious complications during the first days post-transplant were reviewed.results: forty-three patients ( males and females) with a median age at diagnosis of . years [range: . - . ] years underwent auto-hsct during the above-mentioned period. conditioning regimen consisted of melphalan, etoposide and carboplatin. all patients received antiviral and antifungal prophylaxis. median time for neutrophil engraftment was days [range: - ]. bacteremia and clostridium difficile infections occurred in ( %) and ( %) patients respectively. seven ( %) patients developed enterocolitis diagnosed by imaging, were adenovirus induced. cmv viremia was diagnosed in ( %) patients, of whom required treatment. varicella zoster reactivation, parvovirus viremia, toxoplasmosis encephalitis, bk virus cystitis ( patients) and central nervous system ebv related post-transplant lymphoproliferative disorder were diagnosed in different patients. there was no invasive fungal infection. sixteen ( %) patients have died, of whom died in the early post-transplant period, due to disease progression and ( . %) due to infectious complications. among the patients who died due to infection, developed toxoplasmosis encephalitis, developed severe enterocolitis, of which were adenovirus related. the mean igg level within one week post-transplant was lower in patients with clinically significant viral infection compared to others ( vs . mg/dl, p: . ). the mean igg level at the time of clinically significant bacterial infection was lower in infected patients compared to others ( . vs . mg/dl, p: . ). neither absolute lymphocyte count nor absolute neutrophil count at day post-transplant affected the incidence of clinically significant infections. our results show that the rate of infections during the early post auto-hsct period is higher than what has been described in developed countries and has a significant impact on mortality. prevention, early detection and improvement in the treatment is required to improve outcome. university of miami, miami, florida, united states background: allogeneic hematopoietic stem cell transplantation (allo-hsct) is a curative treatment for many malignant and non-malignant (bone marrow failure, immunodeficiency, or metabolic diseases) in pediatrics. despite advances in medicine, graft-versus-host-disease (gvhd) remains a significant cause of non-relapsed morbidity and mortality, specifically in those with malignant diseases.objectives: to highlight the complexity to acute gvhd management and seldom-described treatment approach. a year male with a history of high risk acute myeloid leukemia (aml) due to failed induction therapy. he received a matched ( / ) unrelated donor hsctmarrow product-conditioned with busulfan, fludarabine, and anti-thymoglobulin (atg). his post-transplant course was complicated by hhv- viremia, pres (prompting a change from prograf to cyclosporine), mucositis, and grade iii acute gvhd (skin s , gut s , liver s ) around post transplant day , which later morphed to ocular involvement by d+ . he was started on mg/kg steroids with good response but flared up with each attempt to taper steroid dose. a course of rituximab and later atg were tried without success in weaning off steroids. switching cyclosporine to sirolimus did not provide any additional benefit either. extracorporeal photopheresis (ecp) was started times a week. he initially responded well, yet was not able to wean off steroids. in addition, he developed a flare when ecp session was reduced to days per week. ecp was therefore increased to days per week, which appeared to stabilize skin lesions. a trial of weekly methotrexate was attempted to wean off steroids and photopheresis, which provided no response. finally, a trial of bortezomib on days , , , and of a day cycle as published in a case series of multiple myeloma patients who developed post hsct gvhd. skin lesions improved remarkably however dose had to be reduced due to related pancytopenia. given the response to therapy, he was continued on a weekly dose of bortezomib, receiving a total doses, which has permitted the slow taper of prednisone that has since been discontinued without a major flare. he however is currently maintained on ecp times per week, which is now been slowly withdrawn.conclusion: management of acute gvhd in pediatric patients after hsct can be challenging with no definite options for those who fail steroids or become steroid dependent after initial response. in these situations, bortezomib could be a valid therapeutic option. background: neuroblastoma (nbl) is the second most common solid tumor in children and despite recent treatment advances, overall survival for high risk nbl remains < %. the addition of immunotherapy has improved survival and includes anti-gd antibody therapy. the success of antibody therapy in neuroblastoma is primarily due to natural killer (nk) cell mediated antibody dependent cellular cytotoxicity. we previously demonstrated that nk cells from patients with high risk nbl can be successfully isolated and expanded to large numbers and exhibit potent anti-tumor effects against nbl ( ). thus, infusions of autologous expanded nk cells in high risk nbl in combination with anti-gd antibody are being studied in clinical trials. toll-like receptors (tlr) present on the surface of leukocytes are responsible for pathogen recognition, and activation of these receptors stimulate the production of cytokines that critically link innate and adaptive immune responses. the tlr agonist, poly(ic) is a synthetic analog of dsrna that has previously been shown to directly stimulate cytokine production and improve cytotoxicity in primary nk cells through activation of genes regulated by interferon-response elements (ire) ( ). we hypothesized that ex vivo activation of tlr pathways in nk cells during our normal -day expansion using k feeder cells expressing membrane bound il- would enhance their function.design/method: nk cells were isolated from peripheral blood mononuclear cells and expanded with our previously described expansion protocol in media containing il- and ug/ml poly(ic) ( ). at the end of the -day expansion, nk cells expanded with poly(ic) were compared to controls using a calcein cytotoxicity assay to measure cytotoxicity against high risk neuroblastoma and cytometric bead array to measure cytokine production. : surprisingly, the addition of poly(ic) during nk cell expansion did not improve proliferation, cytokine production or cytotoxicity compared to our standard expansion method. rnaseq demonstrated that our standard expansion method results in a modest decrease in tlr expression at the transcriptional level, but significant upregulation of several ireregulated genes. we conclude that either our standard approach interferes with tlr signaling or saturates the innate immune response pathway such that co-stimulation with poly ic does not produce an additive effect. we are performing expression analysis on nk cells receiving poly(ic) during expansion to further explore this hypothesis. background: gonadal dysfunction leading to infertility is a complication after hematopoietic stem cell transplant (hsct). anti-müllerian hormone (amh) is a marker of ovarian reserve; it is not controlled by gonadotropins and has minimal inter-cycle variations, therefore, it can be used as a marker of ovarian reserve and aid in fertility counseling.objectives: assess ovarian reserve in hsct patients utilizing amh levels. background: tgf beta is an immune suppressive cytokine frequently elevated in the tumor microenvironment causing tumor immune evasion. acute tgf beta treatment potently inhibits nk cell cytotoxicity, cytokine secretion, and proliferation. however, tumor infiltrating nk cells receive chronic inhibitory tgf beta signals in conjunction with activating signals from tumor cells. objectives: to this end, we hypothesized that long-term tgf beta-cultured nk cells would induce functional and phenotypical changes on nk cells that differ from short-term tgf beta treatment.design/method: to explore this, primary human nk cells were cultured with the leukemia cell line, k , alone or with exogenous tgf beta for weeks. : surprisingly, nk cells cultured in tgf beta proliferated faster, and upon challenge with a variety of cell line targets they secreted much greater quantities of ifnÎ ( -to -fold increase against / cell lines) and tnf ( -to -fold increase against / cell lines). further, the high cytokine secretion induced in these nk cells was no longer inhibited by adding additional tgf beta. degranulation was also increased ( / cell lines), however cytotoxicity was not enhanced in a -hour cytotoxicity assay. after resting in il- , the cytokine hypersecretion of tgf betacultured nk cells was maintained for several weeks suggesting this functional change might involve cellular reprogramming. we investigated the mechanism behind these functional changes and profiled genes involved in tgf beta signaling. we found significant reduction of smad transcription which corresponded to a striking decrease in smad chromatin accessibility. we also found significantly increased smad and decreased tgfbr expression. phenotypic analysis revealed that tgf beta also induced remodeling of the nk receptor repertoire with decreased nkp , cd , and klrg and upregulation of trail. the functional consequences of these tgf beta-induced changes on in vitro and in vivo nk cell function are currently under investigation. background: the use of t-cell depleted grafts in haploidentical stem cell transplantation (hsct) has been associated with a delay in early t-cell recovery which increases the risk of viral infections, relapse or graft rejection. conventional donor lymphocyte infusion (dli) after hsct transplantation is effective but conditioned because of a high prevalence of gvhd. the infusion of selected lymphocyte subpopulations with low aloreactivity is emerging as an effective strategy to rectify this issue. the depletion of cd ra+ naive lymphocytes, preserving cd ro+ memory t-cells, could provide a safe source of functional lymphocytes with anti-infection, antileukemic and anti-rejection properties, and lower rates of adverse effects. our objective is to present data of patients that have received cd ro+ memory t-cells dli (mdli) and assess its safety and outcome. we present data of mdli performed after hsct in cases of mixed chimerism, persistent lymphopenia, viral/opportunistic infections or as a strategy to accelerate immune reconstitution.results: fifteen patients with diagnosis of all (n = ), aml (n = ), mds (n = ), saa (n = ), sideroblastic anemia (n = ) and cgd (n = ), received mdli after hsct. a total of forty-three mdli were infused. the median dose of cd ro+ memory t-cells infused was . × /kg (range: . × - . × /kg), with a median dose of cd ra+ naive t-cells of . × /kg (range: - . × /kg). the mdli were infused at a median of seventy-seven days after hsct (range: - days), with a median interval between mdli of thirty-four days results: eight published studies reported survival outcomes for pediatric vod/sos patients (n = ), across all defibrotide doses. estimated day+ survival ( % confidence interval) was % ( %- %). for vod/sos with mod, studies were identified (n = ) with pooled estimated day+ survival of % ( %- %). only one openlabel expanded-access study, the treatment-ind, reported outcomes separately for pediatric vod/sos patients without mod (n = patients aged ≤ years). the day+ kaplan-meier estimated survival for those patients was % ( %- %). safety results were not pooled due to differences in reporting methodology; however, study results were consistent with the safety profile of the phase historicallycontrolled trial in vod/sos patients with mod ( % pediatric), in which / defibrotide-treated patients and all controls experienced ≥ ae. hypotension was the most frequent ae ( %, defibrotide; %, controls); common hemorrhagic aes (ie, pulmonary alveolar and gastrointestinal hemorrhage) occurred in % of defibrotide-treated patients and % of controls. in this pooled analysis of studies with defibrotide-treated pediatric patients with vod/sos, estimated day + survival was % (without mod, %; with mod, %). safety results in individual studies were generally consistent with the known safety profile of defibrotide. taken together, these results show a largely consistent defibrotide treatment effect in pediatric patients treated with defibrotide for vod/sos, with or without mod. results: six patients met inclusion/exclusion criteria. all patients were started on ecp while concurrently receiving . to mg/kg steroid therapy for agvhd plus a calcineurin inhibitor. patients had initiation of ecp within a maximum of weeks from initial diagnosis of agvhd (range - days). patients had grade - agvhd ( / patients with grade ) with skin, liver, and gi gvhd represented. patients received ei-ecp - times per week for the first weeks and then had ei-ecp frequency tapered based on initial response.after weeks of therapy patient had a decrease in overall gvhd grade by grade. all patients were able to have steroids tapered, with doses decreased by an average of % ( % - % decrease).at weeks of therapy, one patient with grade agvhd died of mof associated with infections. three patients had complete resolution of agvhd and patients decreased by grade. steroid doses were decreased by an average of % ( % - % decrease). continuously measures axillary temperature and wirelessly transmits real time-time data. the primary aim of the study was to evaluate the feasibility, safety and tolerability of continuous temperature monitoring in hsct patients using temptraq. we are performing a prospective observational study of pediatric patients ( - years of age) undergoing hsct at cincinnati children's hospital in cincinnati, ohio. enrolled patients wore a temptraq patch for days. a - rating scale survey was completed by the parent/guardian at the end of the study to determine tolerability, ease of use, satisfaction and desire for future use in the inpatient and outpatient setting. temperature data from the temptraq patch was compared to the standard episodic temperature monitoring to determine detection of febrile episodes. seven of ten patients have completed screening. we anticipate completion of the study in early february. the temptraq patch was well tolerated by study subjects (mean tolerability rating of . / ). one patient developed skin breakdown at the site of the temptraq patch attributed to recent thiotepa. the patch was easy to apply with an easy of application rating of . / . parents were overall satisfied (rating . / ) and would like to use the temptraq patches in future hospitalizations (rating . / ) and at home (rating . / ). temptraq patch identified fever (≥ . • f) in patients. the fever was never detected by episodic monitoring (soc) in patients and significantly delayed in the other patients (> hours). temptraq was well tolerated in pediatric hsct patients. timely fever detection was improved in temptraq over the current soc. background: serotherapy is commonly used in patients undergoing hematopoietic stem cell transplant (hsct) to reduce the incidences of engraftment failure and graft versus host disease. however, one well-known side effect is fever. as children undergoing hsct have compromised immune defenses, fever may also be an early indicator of bloodstream infection, which would warrant prompt use of broad-spectrum antibiotics. in a subset of patients with serotherapy-associated fever, antibiotics, which may induce antibiotic resistance and increase costs, may be unnecessary. we aimed to determine the incidence and characteristics of serotherapy-related fever, as well as the likelihood of concomitant bacteremia, in our institutional experience. a -year retrospective chart review was conducted of pediatric patients who received serotherapy as part of hsct conditioning at the university of minnesota. one-hundred sixty eight consecutive hsct patients who received serotherapy -either atg (n = ) or alentuzumab (n = ) -were identified. the median age at hsct was -years (range, . - years). a total of patients ( %) developed fever while on serotherapy (atg = , alentuzumab = ). one-hundred sixteen patients presented fever following the first infusion, and the median onset of fever was hours after commencing infusion (range, . - hours). fever resolved at a median hours (range, - hours). one hundred and fourteen patients ( %) underwent blood cultures. only seven patient were not started on ( %) empiric antibiotics, while % (n = ) were on antibiotic treatment prior to serotherapy for previously known or suspected infections. nine patients ( % of febrile patients, % of all patients) had positive blood cultures (atg = ; alentuzumab = ). no infection-associated deaths were observed.conclusion: while fever is common during serotherapy conditioning in children undergoing sct, episodes of concomitant bloodstream infection are rare. ongoing analysis identified potential risk factors for bacteremia as recent history of infection, first episode of fever following second or subsequent infusions, and previous central line placement. further analysis is being conducted to identify subgroups of patients for whom close monitoring alone may be safe. background: hsct is potentially curative for caya with high-risk leukemias; however, most lack an hla-matched aspho abstracts related donor. the risk of gvhd is increased with unrelated (urd) or partially matched related (pmrd) donors. selective t-cell depletion based on the elimination of t cells carrying and chains of the t-cell receptor may greatly reduce the gvhd risks, while allowing the maintenance of mature donor-derived alloreactive nk cells and / (+) t cells, which may augment the anti-leukemia effect.objectives: this is a prospective study of caya with acute leukemia who underwent hsct with mmrd or urds and tcr / /cd depletion. outcomes included engraftment, toxicities, viral reactivation, and relapse.design/method: this study included caya with acute leukemia transplanted between october and may . all received a myeloablative preparative regimen with targeted busulfan (n = ) or tbi ( cgy/ fractions) (n = ), with thiotepa ( mg/kg) and cyclophosphamide ( mg/kg). atg ( mg/kg x ) was given to those receiving haploidentical grafts and to the first who received urd grafts. immune suppression was not given post-hsct. the stem cell source was mobilized peripheral blood stem cells (pscs), which then underwent tcr / /cd depletion utilizing the clinimacs device under gmp conditions in the chop cellular immunotherapy lab.results: median age was (range . - . ). diagnoses included all ( -b-cell, -t-cell) and aml ( ; -secondary aml). urd were used for ; were / allele matched and were / matched. haploidentical donors were used for . median cd (+) dose - . × , / (+) cd (+) cells - . × , and b cells - . × . all patients achieved an anc at a median of d+ ( - ), and % had platelet engraftment at median d+ ( - ). nine patients ( %) developed acute gvhd (all skin, grades i-iv). five developed chronic gvhd (skin, gut, lung): limited in , extensive in . viral reactivations included: adenovirus ( , %), bk virus ( , %), cmv ( , %), and hhv ( , %). nine ( %) patients relapsed at a median of days (range - ) post-hsct, including aml patients ( . %) and all patients ( . %). transplant-related mortality was %; causes included sepsis ( ) and ards ( ). os was %; efs was % (gvhd-free efs %, lfs %). hsct with tcr / /cd depletion demonstrates excellent engraftment kinetics with limited gvhd without immune suppression. elimination of post-hsct immunosuppression may offer an excellent platform to augment anti-leukemic immune therapy or to enhance immune reconstitution. background: hematopoietic cell transplantation (hct) is the only curative treatment available for patients with sickle cell disease (scd). low bone mineral density (bmd) has been described in scd, but little is known about the impact of curative hct on this outcome. to determine the prevalence of low bmd and variables associated with low bmd in scd patients after hct. we conducted a retrospective chart review of scd patients who underwent hct at children's healthcare of atlanta (choa) between / and / and survived ≥ year post-hct. transplant characteristics, post-hct dual-energy x-ray absorptiometry (dexa) scan results, vitamin d levels, graft-versus-host-disease (gvhd) status, and fsh levels were reviewed. for patients - years of age, height corrected z-scores were calculated using a nihvalidated calculator, with t-scores used for older patients. bmd was categorized as low if between - and - sd below the mean and clinically significantly low if >- sd, in accordance with the children's oncology group long-term follow-up guidelines. vitamin d levels < ng/mol were considered deficient, and fsh levels > miu/ml suggestive of premature ovarian failure. fisher's exact test was used to compare variables in those with normal versus abnormal dexa scan results, with p< . considered significant.results: hct was performed on patients with scd, with surviving ≥ year post-hct. dexa scans were obtained in patients ( % female), with mean time from hct to dexa scan being years ( . - . years) and mean age at time of dexa . years ( . - . years). patients with and without dexa scans did not differ by sex, donor source, age at transplant, or vitamin d status. low bmd was noted in patients ( . %), with these patients more likely to be > years (pubertal; . versus . %, p = . ). acute gvhd was more common in patients with low bmd ( . versus . %), but not statistically significant (p = . ). clinically significant low bmd was noted in patients ( . % of those with dexa scans). these patients were older ( . years at testing), were more likely to be male ( . %), and all had acute and chronic gvhd, while none had evidence of gonadal failure.conclusion: clinically significant low bmd is uncommon after hsct for scd. patients at risk for low bmd include older patients and likely those with gvhd. this preliminary data suggests routine dexas may not be indicated for all patients who undergo hct for scd, but further data is needed. background: causes of renal dysfunction after hematopoietic cell transplantation (hct) include damage from radiation, nephrotoxic medications, graft vs. host disease (gvhd), hepatorenal syndrome, viral infections, or transplant associated microangiopathy. we sought to investigate the incidence of, and risk factors for, acute kidney injury in pediatric hct patients and associated risk with mortality.design/method: data from patients who underwent hct between and at a single institution were sequentially retrospectively captured on irb approved protocol. acute kidney injury (aki) was defined at multiple time points post-hct using the standardized criteria: kidney disease: improving global outcomes (kdigo). interval differences between values were analyzed using wilcoxon rank sum testing and categorical variables were analyzed using chi-square analysis.results: ninety-eight patients were included in the study: allogeneic (n = ) and autologous (n = ), mean age . years, of whom % were african american, % asian, % caucasian, % latino, and % mixed race. forty-seven percent of patients developed aki within the first years of hct. increased risk for aki was associated with a lower pre-transplant creatinine level (p = . ), abnormal pretransplant bun (p = . ) and an unrelated donor (p = . ) while preparative regimen intensity, race, or primary disease were not. twenty-six percent of patients developed aki within days of hct. of those with aki, % were exposed to either cidofovir, aminoglycosides, and/or ambisome for at least days versus % without aki and % were exposed to vancomycin compared to % without aki. evaluating outcomes at year after hct, of those with stage aki: % had reduced gfr and % died, while % had reduced gfr and % had died for patients with aki stage or . the absence of aki by day was associated with % reduced gfr and % death at -year after hct. overall, those with aki at any time in the first year post-hct had a . fold increased risk of death compared to those without. for patients who required renal replacement therapy (rrt, n = ), the risk of death was . fold greater compared to those who did not. in the % of patients who survived rrt, both recovered renal function within years.conclusion: acute kidney injury is common after pediatric hct, and may be associated with low creatinine, abnormal bun, unrelated donor pre-hct, and renal toxic medications. early-onset aki post hct is associated with an increased risk of mortality. these data should be validated in a larger prospective study but may offer opportunities to intervene and enhance outcomes. background: myeloablative hematopoietic stem cell transplant (hct) for pediatric malignant disease is associated with significant morbidity with % patients experiencing mucositis. patient controlled analgesia (pca) utilizing opioids is an effective strategy for pain management. we sought to describe and analyze pca use in d+ days post myeloablative hct for malignancies at lurie children's hospital of chicago from - .design/method: utilizing retrospective chart review, pca details were collected: indication, initiation day, pca duration, team managing pca (anesthesia or palliative), medication and dose in morphine equivalents, and pca toxicities. efficacy of pca was evaluated on pca day + , + , + , + using demands %, maximum pain score (rflacc, faces, vas) and subjective patient, parent and/or pain team perception of pain control. we devised a scale based on the above to designate pain control as good, moderate or poor. variables being analyzed include recipient age, sex, donor type, source, diagnosis, tbi use, gvhd/trm. this analysis, we analyze the depth of remission, car-t persistence, and post-transplant gvhd on our phase i anti-cd car-t protocol (nct ) to better understand the role of car-t in the peri-hct setting.design/method: children and young adults with relapsed/refractory cd + all treated on our phase i anti-cd car-t protocol were analyzed. mrd was assessed by flow cytometry (fc) in all, with pcr-based mrd analysis using igh or tcr testing assessed in select patients. hcts were performed at each patient's local institution based on standard of care and included varying conditioning regimens, donor types, stem cell source, and gvhd prophylaxis.results: on our cd car trial, patients were treated, the majority of patients (n = ) having relapsed following a prior hct. / patients ( %) attained a cr, of whom were mrd negative by fc. concurrent pcr based mrd analysis available in patients demonstrated that all patients achieved pcr based negativity. in , this was simultaneous with the month mrd negative fc, and in , pcr negativity was achieved over time (fc remained negative). patients proceeded to hct at a median time of days (range: - days) post-car-t, which was a first hct in . these two patients remain in an mrd negative cr, year post-car-t. no patients developed acute or chronic gvhd. car persistence was seen in patients who had detectable car-t cells on the pre-hct marrow suggesting the possibility of ongoing anti-leukemia surveillance prior to initiation of the conditioning regimen.conclusion: by inducing pcr negativity, car-t therapy may have a synergistic role with hct to improve leukemia free survival, prior to emergence of antigen negative leukemia, without an increased risk of gvhd. while the sample size is small, car-t therapy may offer an effective bridge to hct, particularly for those who are pcr negative, and those who have not had a previous transplant. given the underlying risk of hct related trm, pre-hct car may potentially allow for hct conditioning de-intensification as it may not be needed to eradicate residual disease. lee dw, ash abstract , background: post-transplant lymphoproliferative disease (ptld) is a complication after solid organ transplantation (sot) that is frequently due to epstein -barr virus (ebv) as a decrease in ebv-specific t cell immunity due to immune suppression allows for uncontrolled proliferation of ebv-infected b cells. outcomes for ptld are suboptimal with relapse rates approaching %. however, ebv-infected b cells in ptld express the ebv antigens lmp and lmp that can be targeted with immune therapy.objectives: we hypothesize that third party "off the shelf" lmp-specific t cell products may improve outcomes and decrease associated co-morbidities for patients with ptld by not only target the lymphoproliferating ebv-infected b cells but also restoring ebv-specific immunity.design/method: lmp-specific t cells (lmp-tcs) are manufactured from eligible donors with a broad range of hla types in our gmp facility to be used in a children's oncology group (cog) trial (anhl ) for patients with ptld after sot. lmp-tc products are manufactured from healthy donors using autologous monocytes and lymphoblastoid cell lines (lcl) transduced with an adenoviral vector expressing Δlmp and lmp as antigen presenting cells. lmp-tc products undergo comprehensive characterization by ifn-elispot assay to determine lmpspecific epitopes, class i and/or ii response, and hla restriction to guide selection of lmp-tc product for each patient.results: thus far, lmp-tc products have been manufactured. lmp-tcs were active against lmp (mean: sfu/ × ^ cells; range: - ), lmp ( ; - ), and lcl ( ; - ) as determined by ifn-elispot assay. at the time of cryopreservation, the lmp-tc products comprised a mean of % cd + t-cells, % cd + t-cells, and % nk cells. no b cells or monocytes were detected in the final products. thus far, we have identified novel lmp epitopes (lmp specific: n = ; lmp specific: n = ). approximately % of the lmp-tc products have lmp-specific activity through multiple hla alleles, and % have a mixed class i and class ii response. conclusion: thus, lmp-specific t cell products can be expanded from healthy donors to creat a third party bank, and identifying epitopes and hla alleles with lmp activity will facilitate selecting the most appropriate product for patients. while lmp-specific t cells have previously demonstrated safety and efficacy in phase i studies, anhl is the first trial using cellular therapy within a cooperative group setting. children's cancer hospital at the university of texas md anderson cancer center, houston, texas, united states background: in , the united states food and drug administration (fda) approved the first chimeric antigen receptor t cell (car-t) therapy; tisagenlecleucel. this cd -directed genetically modified autologous t cell immunotherapy has shown response rates of almost % among children and young adults with b-cell precursor acute lymphoblastic leukemia (all) that are refractory or in second or later relapse. cytokine release syndrome (crs) and car-t cell related encephalopathy syndrome (cres) are well described toxicities associated with car-t therapy. crs is a systemic inflammatory response and is typically characterized by fever, hypoxia, tachycardia, hypotension and multi-organ toxicity. cres may occur concurrently or following crs, or without any associated crs symptoms and is characterized by encephalopathy, delirium, seizures and rarely cerebral edema. almost half of patients who receive tisagenlecleucel may require pediatric intensive care unit (picu) support. crs and cres are generally reversible but may be associated with fatal outcomes. pediatric specific management guidelines, comprehensive training of multidisciplinary staff, effective communication and phased infrastructure ensure that adequate resources are available to facilitate early diagnosis and appropriate management of pediatric patients with crs and cres and allow for optimal patient outcomes and accreditation by the foundation for accreditation of cellular therapy (fact).objectives: develop a comprehensive program to ensure safe administration of immune effector cell (iec) therapy to pediatric patients.design/method: an inter-disciplinary pediatric cartox (car t cell therapy associated toxicity) committee consisting of cell therapy and picu physicians, neurologists, fellows, nursing leadership, advanced practice practitioners, pharmacists, registered nurses and social workers was created to monitor patient toxicity and establish specific clinical guidelines and diagnostic and treatments algorithms for pediatric patients receiving iec therapy. educational modules were developed as (i) live in-services and (ii) an online module with a competency based assessment. electronic medical record (emr) order sets and documentation and warning systems were also developed by the committee. the pediatric cartox committee developed a diagnostic and treatment algorithm for patients receiving iec therapy. emr orders and flowsheets were developed to support adherence to the algorithm. inter-disciplinary staff training and competency assessments were closely tracked. almost % of identified staff have completed training and achieved competency including, pediatric cell therapy staff, emergency center, picu, outpatient clinic/triage, neurology and sub-specialty staff and nocturnalists.conclusion: an inter-disciplinary approach can assist in institutional readiness for an iec program, promote quality assurance and perhaps fact iec accreditation. future directions include a program for ongoing staff competency assessments. predicted peak vo ) and abnormal oxygen uptake efficiency slope at the anaerobic threshold ( . ± . . , normal ± ). additionally, on echocardiogram three patients had evidence of diastolic dysfunction as evidenced by an elevated e/a ratio ( . ± . ) on tissue doppler. three patients demonstrated depressed longitudinal peak systolic strain (- . ± . ), indicating dysfunction not captured by ejection fraction. in this feasibility study, sct patients without evidence of lvsd on standard measures by resting echocardiogram can demonstrate abnormal exercise capacity. additionally, they can demonstrate systolic and diastolic dysfunction by measures not always included in standard echocardiography. these data suggest the need for a more thorough screening of survivors, and will be further validated as additional patients are recruited for this study. background: in hematopoietic transplantation, the t lymphocytes of the inoculum play a determining role in promoting hematopoiesis, transferring immunity to pathogens and acting as mediators of the graft-versus-leukemia effect (gvl). however, they are also responsible for graft-versus-host disease (gvhd), the main cause of post-transplant morbidity and mortality. the depletion of cd ra lymphocytes, by eliminating naive t lymphocytes from the inoculum, aims to conserve the gvl without producing gvhd.design/method: since april , patients ( boys and girls), with a median age of years, have undergone an allogeneic hematopoietic transplant from an hla donor identical with cd ra/cd depletion. the indication for transplant was: acute lymphoblastic leukemia ( ), acute myeloblastic leukemia ( ), myelodysplasia ( ) and medullary aplasia ( ). the donor was familiar in cases and unrelated in . the conditioning regimen was with fludarabine, busulfan and thiotepa. the median of cd + cells infused was . × / kg. on the day , + and + a programmed infusion of × / kg lymphocytes cd ra-was performed.results: all the patients grafted with a median leukocyte (> . × / l) and platelet (> × / l) engraftment time of and days, respectively. only one patient has developed acute gvhd grade i and no patient has developed chronic gvhd. immune reconstitution was early and rapid in all t cell subsets no patient has relapsed so far and only patient with myelodysplasia has developed an aml. she has received a nd transplant and has died of relapse. there was no case of toxic mortality. the event-free survival (sle) was ± % with a median follow-up of months. at present, patients are alive, out of immunosuppressive treatment and doing well. allogeneic transplantation with cd lymphocytes ra depletion resulted on very encouraging results, with a very low incidence of acute and chronic gvhd, but preserving the gvl effect by infusing cd ra-donor lymphocytes. miami children's health system, miami, florida, united states background: hematopoietic stem cell transplantation (hsct) using autologous or allogeneic progenitor cells is a potentially curative treatment for patients with high-risk malignancies and nonmalignant conditions. the american society for blood and marrow transplantation developed a task force to establish consensus guidelines for defining patient care in hsct and advocated for further studies to delineate safe procedural steps as an increasing amount of hsct are being offered to patients. there is limited evidence to support engraftment in recipients who receive their infusions via iv or syringe pump. we present novel data from patients who achieved neutrophil engraftment following hsct by a pump mechanism.objectives: to provide evidence supporting the use of pump (intravenous or syringe) infusion method in hematopoietic stem cell transplantations.design/method: a retrospective review was completed for patients who underwent hsct between and . inclusion criteria included patients who had received hematopoietic stem cell transplants between and and who were ages months to years old. the main outcome measure was days to neutrophil engraftment (defined as the first of three consecutive days with an anc > × /l).results: among patients who received infusion of hematopoietic stem cell products via pump mechanism, patients ( . %) received autologous products and ( . %) received stem cells from allogeneic donors. neutrophil engraftment (anc > × /l) occurred in a median of . days after stem cell infusion. the mean number of days to engraftment for patients who received allogeneic infusions s of s design/method: a retrospective chart review was performed at the children's hospital of wisconsin. statistical analyses included kaplan-meier estimate for os, mann-whitney test for comparing outcomes between subjects, and descriptive analyses.results: from - , patients with a median age of . ( . - . ) years at st hct were identified. patients were conditioned with cy/atg (n = ), cy/flu/atg (n = ), or cy/flu/atg/tbi (n = ) and received marrow (n = ) or cord blood (n = ) with median cd /kg dose of . ( . - . ) × . two patients developed grade i acute graftversus-host disease (gvhd); none developed chronic gvhd. due to dropping chimerism, graft rejection, or graft failure, nd hct (n = ) or boost (n = ) was offered. the median cd chimerism prior to hct/boost was ( - )%. median time between st hct and nd hct or boost was days ( days- . years). in patients receiving nd hct, used the same donor, of which used the same stem cell source (marrow) and switched to peripheral blood stem cells (pbsc). in patients who switched donors, used pbsc and used cord blood. most patients receiving nd hct underwent a uniform conditioning regimen of cy /flu /equine atg/ gy tli (n = ) or cy /flu /rabbit atg/ gy tbi (n = ); one received cy/atg. acute and chronic gvhd (limited seen in %) developed in % and % of patients, respectively. four patients required additional boosts and additional hct. after final intervention, cd and whole-blood chimerism at last follow-up was between - % (n = ) and - % (n = ), respectively. with a median follow-up of . ( . - . ) years, of patients are alive with an estimated -year os of . ± . %, having performance status ≥ % (n = ) or % (n = ). one patient developed chronic extensive gvhd and died of fungal infection . years after nd hct. our single-center experience demonstrates excellent ability to salvage patients who develop graft failure after initial hct. transplant-related complications such as gvhd and infections remain significant concerns.