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Background: FHIR (Fast Healthcare Interoperability Resources) has been proposed to enable health data interoperability. So far, its applicability has been demonstrated for selected research projects with limited data., Objective: This study aimed to design and implement a conceptual medical intelligence framework to leverage real-world care data for clinical decision-making., Methods: A Python package for the use of multimodal FHIR data (FHIRPACK [FHIR Python Analysis Conversion Kit]) was developed and pioneered in 5 real-world clinical use cases, that is, myocardial infarction, stroke, diabetes, sepsis, and prostate cancer. Patients were identified based on the ICD-10 (International Classification of Diseases, Tenth Revision) codes, and outcomes were derived from laboratory tests, prescriptions, procedures, and diagnostic reports. Results were provided as browser-based dashboards., Results: For 2022, a total of 1,302,988 patient encounters were analyzed. (1) Myocardial infarction: in 72.7% (261/359) of cases, medication regimens fulfilled guideline recommendations. (2) Stroke: out of 1277 patients, 165 received thrombolysis and 108 thrombectomy. (3) Diabetes: in 443,866 serum glucose and 16,180 glycated hemoglobin A 1c measurements from 35,494 unique patients, the prevalence of dysglycemic findings was 39% (13,887/35,494). Among those with dysglycemia, diagnosis was coded in 44.2% (6138/13,887) of the patients. (4) Sepsis: In 1803 patients, Staphylococcus epidermidis was the primarily isolated pathogen (773/2672, 28.9%) and piperacillin and tazobactam was the primarily prescribed antibiotic (593/1593, 37.2%). (5) PC: out of 54, three patients who received radical prostatectomy were identified as cases with prostate-specific antigen persistence or biochemical recurrence., Conclusions: Leveraging FHIR data through large-scale analytics can enhance health care quality and improve patient outcomes across 5 clinical specialties. We identified (1) patients with sepsis requiring less broad antibiotic therapy, (2) patients with myocardial infarction who could benefit from statin and antiplatelet therapy, (3) patients who had a stroke with longer than recommended times to intervention, (4) patients with hyperglycemia who could benefit from specialist referral, and (5) patients with PC with early increases in cancer markers., (©Alexander Brehmer, Christopher Martin Sauer, Jayson Salazar Rodríguez, Kelsey Herrmann, Moon Kim, Julius Keyl, Fin Hendrik Bahnsen, Benedikt Frank, Martin Köhrmann, Tienush Rassaf, Amir-Abbas Mahabadi, Boris Hadaschik, Christopher Darr, Ken Herrmann, Susanne Tan, Jan Buer, Thorsten Brenner, Hans Christian Reinhardt, Felix Nensa, Michael Gertz, Jan Egger, Jens Kleesiek. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.10.2024.)

Reports of Large Language Models (LLMs) passing board examinations have spurred medical enthusiasm for their clinical integration. Through a narrative review, we reflect upon the skill shifts necessary for clinicians to succeed in an LLM-enabled world, achieving benefits while minimizing risks. We suggest how medical education must evolve to prepare clinicians capable of navigating human-AI systems., (© 2024. The Author(s).)

Background: Hospitals use triage systems to prioritize the needs of patients within available resources. Misclassification of a patient can lead to either adverse outcomes in a patient who did not receive appropriate care in the case of undertriage or waste of hospital resources in the case of overtriage. Recent advances in machine learning algorithms allow for the quantification of variables important to under- and overtriage., Objective: The aim of this study was to identify clinical features most strongly associated with triage misclassification using a machine learning classification model to capture non-linear relationships., Methods: Multicenter retrospective cohort data from two big regional hospitals in Norway was extracted. The South African Triage system is used at Bergen University Hospital and the Rapid Emergency Triage and Treatment System is used at Trondheim University Hospital. Variables included triage score, age, gendersex, arrival time, subject area affiliation, reason for emergency department contact, discharge location, level of care, and time of death were retrieved. Random forest classification models were used to identify features with the strongest association with overtriage and undertriage in clinical practice in Bergen and Trondheim. We reported variable importance as SHAP-values (SHapley Additive exPlanations)., Results: We collected data on 205,488 patient records from Bergen University Hospital and 304,997 patient records from Trondheim University Hospital. Overall, overtriage was very uncommon at both hospitals (all <0.1%), with undertriage differing between both locationlocations with 0.8% at Bergen and 0.2% at Trondheim University Hospital. Demographics were similar for both hospitals, however the percentage given a high priority triage score (red or orange) was higher in Bergen (24%) compared to 9% in Trondheim. Clinical referral department was found to be the variable with the strongest association with undertriage (mean SHAP +0.62 and +0.37 for Bergen and Trondheim, respectively)., Conclusions: We identified subgroups of patients consistently undertriaged using two common triage systems. While the importance of clinical characteristics to triage misclassification varies by triage system and location, but we found consistent evidence between the two locations that clinical referral department is the most important variable associated with triage misclassification. Replication of this approach at other centers could help to further improve triage scoring systems and improve patient care worldwide.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 + cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5 + cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells., (© 2024. The Author(s).)

Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection of somatic mutations in single-cell transcriptomic and ATAC-seq (assay for transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or single-cell DNA sequencing data. SComatic distinguishes somatic mutations from polymorphisms, RNA-editing events and artefacts using filters and statistical tests parameterized on non-neoplastic samples. Using >2.6 million single cells from 688 single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) data sets spanning cancer and non-neoplastic samples, we show that SComatic detects mutations in single cells accurately, even in differentiated cells from polyclonal tissues that are not amenable to mutation detection using existing methods. Validated against matched genome sequencing and scRNA-seq data, SComatic achieves F1 scores between 0.6 and 0.7 across diverse data sets, in comparison to 0.2-0.4 for the second-best performing method. In summary, SComatic permits de novo mutational signature analysis, and the study of clonal heterogeneity and mutational burdens at single-cell resolution., (© 2023. The Author(s).)

The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome. Locus-specific proteomics identifies specialized DNA replication and repair proteins at centromeres, highlighting them as difficult-to-replicate regions. The translesion synthesis pathway, along with other factors, acts to sustain centromere replication and integrity. Prolonged stress causes centromeric alterations like ruptures and translocations, as observed in ovarian cancer models experiencing replication stress. This study provides unprecedented insights into centromere replication and integrity, proposing mechanistic insights into the origins of centromere alterations leading to abnormal cancerous karyotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis., (© 2024. The Author(s).)

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment., (© 2023. Springer Nature Limited.)

Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose "reprogramming" of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy., Competing Interests: Declaration of interests S.H. has been a consultant for Bristol Myers-Squibb (BMS), Novartis, Merck, Abbvie, and Roche, has received research funding from BMS and Novartis, and is an employee of and holds equity interest in Roche/Genentech. A.G. is a consultant for and has equity interest in Evox Therapeutics Ltd. and is inventor on several patent applications related to extracellular vesicles. B.G. is a scientific advisory board member of Innovex Therapeutics SL, PL BioScience, and Mursla Ltd, consultant for FUJIFILM Wako Chemicals, and a founding director of Exosla Ltd. G.H. is inventor on a patent covering synthetic RIG-I ligand, and co-founder of Rigontec GmbH. H.P. is a consultant for Gilead, Abbvie, Pfizer, Novartis, Servier, and BMS, and has received research funding from BMS., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers., (© 2023. The Author(s).)

Background: Atrial Fibrillation (AF) is the most common arrhythmia in the intensive care unit (ICU) and is associated with increased morbidity and mortality. Identification of patients at risk for AF is not routinely performed as AF prediction models are almost solely developed for the general population or for particular ICU populations. However, early AF risk identification could help to take targeted preemptive actions and possibly reduce morbidity and mortality. Predictive models need to be validated across hospitals with different standards of care and convey their predictions in a clinically useful manner. Therefore, we designed AF risk models for ICU patients using uncertainty quantification to provide a risk score and evaluated them on multiple ICU datasets., Methods: Three CatBoost models, utilizing feature windows comprising data 1.5-13.5, 6-18, or 12-24 hours before AF occurrence, were built using 2-repeat-10-fold cross-validation on AmsterdamUMCdb, the first freely available European ICU database. Furthermore, AF Patients were matched with no-AF patients for training. Transferability was validated using a direct and a recalibration evaluation on two independent external datasets, MIMIC-IV and GUH. The calibration of the predicted probability, used as an AF risk score, was measured using the Expected Calibration Error (ECE) and the presented Expected Signed Calibration Error (ESCE). Additionally, all models were evaluated across time during the ICU stay., Results: The model performance reached Areas Under the Curve (AUCs) of 0.81 at internal validation. Direct external validation showed partial generalizability with AUCs reaching 0.77. However, recalibration resulted in performances matching or exceeding that of the internal validation. All models furthermore showed calibration capabilities demonstrating adequate risk prediction competence., Conclusion: Ultimately, recalibrating models reduces the challenge of generalization to unseen datasets. Moreover, utilizing the patient-matching methodology together with the assessment of uncertainty calibration can serve as a step toward the development of clinical AF prediction models., Competing Interests: Declaration of Competing Interest Jarne Verhaeghe is funded by the Research Foundation Flanders (FWO, Ref. 1S59522N). Part of the research was funded by the FWO Junior Research project HEROI2C which investigates hybrid machine learning for improved infection management in critically ill patients (Ref. 1881020N). Olivier W. M. Thijssens received funding from Pacmed; he disclosed work for hire. Christopher M. Sauer is supported by the German Research Foundation funded UMEA Clinician Scientist Program (grant FU356/12-2). Jan De Waele is a senior clinical investigator funded by the Research Foundation Flanders (FWO, Ref. 1881020N)., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics., Competing Interests: MV, LM, CS, DS, DC, SB, BH, MS, JH, FC No competing interests declared, AP, FM, GM, JB GM, FM, AMP and JDB are founders and shareholders of Tailor Bio Ltd, (© 2023, Vias, Morrill Gavarró et al.)

Analysis of electronic health records (EHRs) is an increasingly common approach for studying real-world patient data. Use of routinely collected data offers several advantages compared with other study designs, including reduced administrative costs, the ability to update analysis as practice patterns evolve, and larger sample sizes. Methodologically, EHR analysis is subject to distinct challenges because data are not collected for research purposes. In this Viewpoint, we elaborate on the importance of in-depth knowledge of clinical workflows and describe six potential pitfalls to be avoided when working with EHR data, drawing on examples from the literature and our experience. We propose solutions for prevention or mitigation of factors associated with each of these six pitfalls-sample selection bias, imprecise variable definitions, limitations to deployment, variable measurement frequency, subjective treatment allocation, and model overfitting. Ultimately, we hope that this Viewpoint will guide researchers to further improve the methodological robustness of EHR analysis., Competing Interests: Declaration of interests SLH is an employee of Microsoft Research (UK) and a board member of the non-profit organisation Association for Health Learning and Inference. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine., (© 2022. The Author(s).)

Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: As data science and artificial intelligence continue to rapidly gain traction, the publication of freely available ICU datasets has become invaluable to propel data-driven clinical research. In this guide for clinicians and researchers, we aim to: 1) systematically search and identify all publicly available adult clinical ICU datasets, 2) compare their characteristics, data quality, and richness and critically appraise their strengths and weaknesses, and 3) provide researchers with suggestions, which datasets are appropriate for answering their clinical question., Data Sources: A systematic search was performed in Pubmed, ArXiv, MedRxiv, and BioRxiv., Study Selection: We selected all studies that reported on publicly available adult patient-level intensive care datasets., Data Extraction: A total of four publicly available, adult, critical care, patient-level databases were included (Amsterdam University Medical Center data base [AmsterdamUMCdb], eICU Collaborative Research Database eICU CRD], High time-resolution intensive care unit dataset [HiRID], and Medical Information Mart for Intensive Care-IV). Databases were compared using a priori defined categories, including demographics, patient characteristics, and data richness. The study protocol and search strategy were prospectively registered., Data Synthesis: Four ICU databases fulfilled all criteria for inclusion and were queried using SQL (PostgreSQL version 12; PostgreSQL Global Development Group) and analyzed using R (R Foundation for Statistical Computing, Vienna, Austria). The number of unique patient admissions varied between 23,106 (AmsterdamUMCdb) and 200,859 (eICU-CRD). Frequency of laboratory values and vital signs was highest in HiRID, for example, 5.2 (±3.4) lactate values per day and 29.7 (±10.2) systolic blood pressure values per hour. Treatment intensity varied with vasopressor and ventilatory support in 69.0% and 83.0% of patients in AmsterdamUMCdb versus 12.0% and 21.0% in eICU-CRD, respectively. ICU mortality ranged from 5.5% in eICU-CRD to 9.9% in AmsterdamUMCdb., Conclusions: We identified four publicly available adult clinical ICU datasets. Sample size, severity of illness, treatment intensity, and frequency of reported parameters differ markedly between the databases. This should guide clinicians and researchers which databases to best answer their clinical questions., Competing Interests: Dr. Dam received funding from AmsterdamUMC and the Netherlands Organization for Health Research and Development (project number 10430012010003). Dr. Celi received support for article research from the National Institutes of Health. Dr. Faltys received funding from the Swiss National Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

While serum lactate level is a predictor of poor clinical outcomes among critically ill patients with sepsis, many have normal serum lactate. A better understanding of this discordance may help differentiate sepsis phenotypes and offer clues to sepsis pathophysiology. Three intensive care unit datasets were utilized. Adult sepsis patients in the highest quartile of illness severity scores were identified. Logistic regression, random forests, and partial least square models were built for each data set. Features differentiating patients with normal/high serum lactate on day 1 were reported. To exclude that differences between the groups were due to potential confounding by pre-resuscitation hyperlactatemia, the analyses were repeated for day 2. Of 4861 patients included, 47% had normal lactate levels. Patients with normal serum lactate levels had lower 28-day mortality rates than those with high lactate levels (17% versus 40%) despite comparable physiologic phenotypes. While performance varied between datasets, logistic regression consistently performed best (area under the receiver operator curve 87-99%). The variables most strongly associated with normal serum lactate were serum bicarbonate, chloride, and pulmonary disease, while serum sodium, AST and liver disease were associated with high serum lactate. Future studies should confirm these findings and establish the underlying pathophysiological mechanisms, thus disentangling association and causation., (© 2021. The Author(s).)

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

Patients admitted to the intensive care unit frequently have anemia and impaired renal function, but often lack historical blood results to contextualize the acuteness of these findings. Using data available within two hours of ICU admission, we developed machine learning models that accurately (AUC 0.86-0.89) classify an individual patient's baseline hemoglobin and creatinine levels. Compared to assuming the baseline to be the same as the admission lab value, machine learning performed significantly better at classifying acute kidney injury regardless of initial creatinine value, and significantly better at predicting baseline hemoglobin value in patients with admission hemoglobin of <10 g/dl., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Purpose: Cancer patients are at increased risk of treatment- or disease-related admission to the intensive care unit. Over the past decades, both critical care and cancer care have improved substantially. Due to increased cancer-specific survival, we hypothesized that the number of cancer patients admitted to the intensive care unit (ICU) and survival have increased., Materials and Methods: MIMIC-III was used to study trends and outcomes of cancer patients admitted to the ICU between 2002 and 2011. Multiple logistic regression analysis was performed to adjust for confounders of mortality., Results: Among 41,468 patients analyzed, 1,083 were hemato-oncologic, 4,330 were oncologic and 66 patients had both a hematological and solid malignancy. Admission numbers more than doubled and the proportion of cancer patients in the ICU increased steadily from 2002 to 2011. In both the univariate and multivariate analyses, solid cancers and hematologic cancers were strongly associated with 28-day mortality. This association was even stronger for 1-year mortality, with odds ratios of 4.02 (95% confidence interval [CI], 3.69 to 4.38) and 2.25 (95% CI, 1.93 to 2.62), respectively. Over the 10-year study period, both 28-day and 1-year mortality decreased, with hematologic patients showing the strongest annual adjusted decrease in the odds of death. There was considerable heterogeneity among solid cancer types., Conclusion: Between 2002 and 2011, the number of cancer patients admitted to the ICU more than doubled, while clinical severity scores remained overall unchanged, suggesting improved treatment. Although cancer patients had higher mortality rates, both 28-day and 1-year mortality of hematologic patients decreased faster than that of non-cancer patients, while mortality rates of cancer patients strongly depended on cancer type.

Merkel cell carcinoma (MCC) is a highly aggressive non-melanoma skin cancer of the elderly which is associated with the Merkel cell polyomavirus (MCPyV). MCC reveals a trilinear differentiation characterized by neuroendocrine, epithelial and pre/pro B-cell lymphocytic gene expression disguising the cellular origin of MCC. Here we investigated the expression of the neuroendocrine key regulators RE1 silencing transcription factor (REST), neurogenic differentiation 1 (NeuroD1) and the Achaete-scute homolog 1 (ASCL1) in MCC. All MCCs were devoid of REST and were positive for NeuroD1 expression. Only one MCC tissue revealed focal ASCL1 expression. This was confirmed in MCPyV-positive MCC cell lines. Of interest, MCPyV-negative cell lines did express REST. The introduction of REST expression in REST-negative, MCPyV-positive MCC cells downregulated the neuroendocrine gene expression. The lack of the neuroendocrine master regulator ASCL1 in almost all tested MCCs points to an important role of the absence of the negative regulator REST towards the MCC neuroendocrine phenotype. This is underlined by the expression of the REST-regulated microRNAs miR-9/9* in REST-negative MCC cell lines. These data might provide the basis for the understanding of neuroendocrine gene expression profile which is expected to help to elucidate the cellular origin of MCC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening., Methods: A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria., Results: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97)., Conclusion: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control., Objective: To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure., Methods: On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone., Results: The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30-51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance., Conclusion: Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries., Competing Interests: The authors have declared that no competing interests exist.

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Merkel cell carcinoma (MCC) is a relatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre‑/pro-B cells. Here we review putative cells of MCC, including Merkel cells, (epi‑)dermal stem cells, and pro‑/pre-B cells. In the present work, the focus is on the concept of pre‑/pro-B cells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.

Recent studies have shown the benefits of extracorporeal membrane oxygenation (ECMO) in supporting adults with severe respiratory or cardiac failure refractory to conventional treatments. The purpose of this investigation was to analyze the usage of ECMO in adults to identify recent trends within the United States. The usage of ECMO, the survival rates, and the hospitalization costs from 2006 to 2011 were analyzed using the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project. The rate of ECMO cases per million adult discharges increased 433% from 11.4 (95% confidence interval, 6.1-16.8) in 2006 to 60.9 (95% confidence interval, 28.1-93.7) in 2011 (p for trend = 0.001). There was a trend toward improved survival rates, but this was not statistically significant (p for trend = 0.14). The costs per day have not changed significantly (p for trend = 0.07) nor have the total costs per patient (p for trend = 0.87). In conclusion, there was a huge increase in the usage of ECMO in adults from 2006 to 2011 with a trend toward improved survival rates and no increase in hospitalization costs.

Background: The number of alternatives to intra-aortic balloon counterpulsation in the treatment of anticipated and established acute circulatory failure is growing. Despite the clinical importance and significant cost of short-term mechanical circulatory support (MCS) devices, the state of their present use has not been analyzed on a national scale., Objectives: The purpose of this study was to characterize the demographics, treatment practices, survival rates, and cost of short-term MCS., Methods: In this serial cross-sectional study, we analyzed all adult patients receiving short-term MCS in the United States from 2004 to 2011 by using the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project., Results: From 2007 to 2011, use of percutaneous devices for short-term MCS increased by 1,511% compared with a 101% increase in nonpercutaneous devices. Mortality rates declined over this period (p for trend = 0.027) from 41.1% in 2004 to 2007 to 33.4% in 2008 to 2011. A similar trend was observed for the subset of patients with cardiogenic shock, decreasing from 51.6% to 43.1% (p for trend = 0.012). Hospital costs also declined over this period (p for trend = 0.011). Multivariable analysis revealed balloon pumps (odds ratio [OR]: 2.00; 95% confidence interval [CI]: 1.58 to 2.52), coagulopathy (OR: 2.35; 95% CI: 1.88 to 2.94), and cardiopulmonary resuscitation (OR: 3.50; 95% CI: 2.20 to 5.57) before short-term MCS were among the most significant predictors of mortality., Conclusions: Use of short-term MCS in the United States has increased rapidly, whereas rates of in-hospital mortality have decreased. These changes have taken place in the context of declining hospital costs associated with short-term MCS., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hematotrachelos, distension of the uterine cervix with accumulated blood, is an extremely rare condition resulting from a congenital anomaly or an acquired condition. We present a case in which an acquired hematotrachelos was the presenting sign of endometrial cancer., Case: An asymptomatic 66-year-old woman was found to have a bulging cervix during a well-woman visit. Further workup revealed a hematotrachelos and an underlying endometrial adenocarcinoma. She was treated with surgery and adjuvant radiotherapy., Conclusion: A hematotrachelos, although rare, can prevent vaginal bleeding, which is often the earliest symptom of a uterine malignancy. This case report illustrates the potential importance of the pelvic examination as part of the well-woman physical examination, because it led to the discovery of early-stage endometrial cancer.

Background: In-situ hybridisation studies demonstrate that Notch receptors and ligands are expressed in granulosa cells (GCs) and in the theca layer vasculature of growing follicles. Notch signaling involves cell-to-cell interaction mediated by transmembrane receptors and ligands. This signaling pathway may represent a novel intraovarian regulator of gonadotropin-dependent follicular development to the preovulatory stage. We hypothesized that blocking Notch pathways would disrupt follicular maturation in the mouse ovary., Methods: Hypophysectomized CD21 female mice were administered pregnant mare serum gonadotropin (PMSG) for 3 days to stimulate follicular development. In one experiment, a pan-notch inhibitor, compound E, was initiated 2 days prior to and throughout stimulation (n = 10), while in a second experiment, a humanized phage Dll4 blocking antibody, YW152F, was used (n = 5). After sacrifice, ovarian histology, serum estradiol levels and uterine weights were compared to controls. The ovarian morphology was evaluated with hematoxylin/eosin staining and immunohistochemistry was performed for Notch1, Notch2, Notch3, Notch4, Jagged1, Dll4, platelet endothelial cell adhesion molecule (PECAM) and alpha-smooth muscle actin (α-SMA) detection., Results: We localized specific Notch ligands and receptors in the following structures: Dll4 is specific to theca layer endothelial cells (ECs); Notch1/Notch4 and Jagged1 are expressed in theca layer ECs and vascular smooth muscle cells (VSMCs), whereas Notch3 is restricted to VSMCs; Notch2 is expressed mostly on GCs of small follicles. Administration of a pan-Notch inhibitor, compound E, inhibits follicular development to the preovulatory stage (8.5 preovulatory follicles in treatment vs. 3.4 preovulatory follicles in control, p < 0.01; average number per ovary) with significant secondary effects on ovarian and uterine weight and estradiol secretion in a setting of uninhibited vascular proliferation, but disorganized appearance of ECs and VSMCs. Inhibition of endothelial Notch1 function through the inactivation of its ligand Dll4 with the blocking antibody YW152F induces mild disorganisation of follicular vasculature, but has no significant effect on gonadotropin-dependent folliculogenesis., Conclusions: Our experiments suggest that the complete blockage of the Notch signaling pathway with compound E impairs folliculogenesis and induces disruption of gonadotropin stimulated angiogenesis. It seems the mechanism involves Notch1 and Notch3, specifically, causing the improper assembly of ECs and VSMCs in the theca layer, although the potential role of non-angiogenic Notch signaling, such as Jagged2 to Notch2 in GCs, remains to be elucidated.

Implantation of an embryo induces rapid proliferation and differentiation of uterine stromal cells, forming a new structure, the decidua. One salient feature of decidua formation is a marked increase in maternal angiogenesis. Vascular endothelial growth factor (VEGF)-dependent pathways are active in the ovary, uterus, and embryo, and inactivation of VEGF function in any of these structures might prevent normal pregnancy development. We hypothesized that decidual angiogenesis is regulated by VEGF acting through specific VEGF receptors (VEGFRs). To test this hypothesis, we developed a murine pregnancy model in which systemic administration of a receptor-blocking antibody would act specifically on uterine angiogenesis and not on ovarian or embryonic angiogenesis. In our model, ovarian function was replaced with exogenous progesterone, and blocking antibodies were administered prior to embryonic expression of VEGFRs. After administration of a single dose of the anti-VEGFR-2 antibody during the peri-implantation period, no embryos were detected on embryonic d 10.5. The pregnancy was disrupted because of a significant reduction in decidual angiogenesis, which under physiological conditions peaks on embryonic d 5.5 and 6.5. Inactivation of VEGFR-3 reduced angiogenesis in the primary decidual zone, whereas administration of VEGFR-1 blocking antibodies had no effect. Pregnancy was not disrupted after administration of anti-VEGFR-3 or anti-VEGFR-1 antibodies. Thus, the VEGF/VEGFR-2 pathway plays a key role in the maintenance of early pregnancy through its regulation of peri-implantation angiogenesis in the uterine decidua. This newly formed decidual vasculature serves as the first exchange apparatus for the developing embryo until the placenta becomes functionally active.

Measurement and feedback of vascular properties during microsurgery is generally not available. We carried out real-time in vivo measurement and analysis of microsurgical occlusion of 1-2-mm diameter arteries and veins in rodents. A pair of forceps mounted with strain gauges was designed for applying and directly measuring the force on tissue. Forces between 0 and 450 mN were applied, with the device having a resolution of 0.5 mN. We performed in vivo experiments on the rat femoral (n = 5) and abdominal (n = 8) blood vessels to measure the elastic restoration force of the tissue in response to radial compression at different levels of force. On average, the minimum occlusion force was 57 mN for the rat artery. During steady application of force, the perturbations in the blood vessel due to heartbeat are visible in the force data. These force oscillations ranged between 1 and 3 mN around the mean steady-state force applied. It was determined that the magnitude of the Fourier spectral peak corresponding to heartbeat frequency can be used as a measure of the patency of the blood vessel, and can provide feedback to microsurgeons to avoid damage to the vessel by application of excess force., (Copyright 2003 Wiley-Liss, Inc.)

We present the most extensive neuropsychological and language assessment yet reported of patients diagnosed with Floating-Harbor Syndrome (FHS), a rare genetic condition characterized by dysmorphid figures, short stature, and speech-onset delay. This is also the second reported occurrence of both a mother and daughter with FHS. Whereas the child demonstrated gross deficits in verbal expression, speech and language problems were largely ameliorated in the mother. Neuropsychological assessment also revealed a strikingly similar pattern of cognitive problems additional to language dysfunction, including difficulties with attention, mathematical, and visuospatial abilities. A mood disorder continued to be quite disabling for the mother.

Objective: To evaluate the impact of newborn screening for cystic fibrosis (CF) on the reproductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunoreactive trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and attitudes about reproduction in false-positive families., Methods: The Wisconsin CF Neonatal Screening Project investigated 650 340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to determine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowledge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 families. The same questionnaire was administered 1 year later to evaluate retention of information. It was completed by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families., Results: In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this information 1 year later. At the 1994 assessment, 52% of families had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval = 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups, >95% of families initially understood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or constantly. When asked whether the experience of screening affected feelings about having more children, an affirmative response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not understand that they were at increased risk of having a child with CF., Conclusions: We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the implications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting.

Objective: We sought to demonstrate that isolated episodes of vertigo can be the only manifestation of vertebrobasilar ischemia., Background: Isolated persistent vertigo is classically ascribed to labyrinthine disorders and is only rarely considered to reflect vertebrobasilar ischemia., Methods: We retrospectively analyzed all of the records of the Saint Louis University Stroke Registry between January 1, 1992 and September 1, 1993. We set out to identify those patients discharged with a diagnosis of transient ischemic attack (TIA) in the vertebrobasilar system. We reviewed their clinical records and the results of their diagnostic studies., Results: We screened 600 admissions and found 29 patients with vertebrobasilar circulation TIAs. Of these, five men and one woman had episodic vertigo for at least 4 weeks as their only presenting symptom. All six patients had one of two abnormal patterns on magnetic resonance angiography (MRA): focal basilar stenosis or widespread vertebrobasilar slow flow. In three patients, the MRA findings were confirmed by cerebral angiography. Five patients were treated with warfarin and one with aspirin. Two patients developed brainstem infarctions, one of them fatal., Conclusions: Isolated vertigo can be the only manifestation of vertebrobasilar ischemia. Its frequency may be underestimated in clinical practice. Noninvasive testing is helpful both for diagnosis and follow-up.

Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a demyelinating peripheral nerve disorder that is commonly associated with a submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p11.2p12 that contains the peripheral myelin gene PMP22. Clinical features of CMT1A include progressive distal muscle atrophy and weakness, foot and hand deformities, gait abnormalities, absent reflexes, and the completely penetrant electrophysiologic phenotype of symmetric reductions in motor nerve conduction velocities (NCVs). Molecular and fluorescense in situ hybridization (FISH) analyses were performed to determine the duplication status of the PMP22 gene in four patients with rare cytogenetic duplications of 17p. Neuropathologic features of CMT1A were seen in two of these four patients, in addition to the complex phenotype asociated with 17p partial trisomy. Our findings show that the CMT1A phenotype of reduced NCV is specifically associated with PMP22 gene duplications, thus providing further support for the PMP22 gene dosage mechanism for CMT1A.

Background and Purpose: Significant delays often occur during the treatment of patients with acute stroke. Some of those delays occur in the hospital. We attempted to shorten inhospital treatment intervals by creating a rapid-response system, similar to that available for cardiac arrest, that would allow the stroke team to be available within a few minutes to care for stroke victims., Methods: We connected all beepers (pocket pagers) of stroke team members to a common access number and instructed the emergency staff to activate that number immediately upon arrival of a stroke victim. We monitored the response time and treatment interval for patients who were treated after this system was activated (Code Stroke patients) during the first 3 months of its availability and compared the results to those of patients seen for similar reasons during the study period but without the use of Code Stroke (control patients)., Results: A total of 12 Code Stroke patients were available for analysis, representing 12% of all patients (n = 98) seen in the emergency department for ischemic stroke during the study period. The remaining 86 patients constituted the control group. The mean time to evaluation of a Code Stroke patient by a stroke team member was 4.8 minutes (range, 2 to 7 minutes), and the mean time to treatment institution was 30 minutes (range, 10 to 120 minutes). There were significant differences between the consultation intervals in the two groups (P < .05). There was only a trend of a difference between treatment institution intervals (P = .06)., Conclusions: It is possible to shorten inhospital treatment delays by instituting rapid-response systems within individual institutions.

The evaluation of victims of ischemic stroke has evolved over the last few years, primarily as a result of the introduction of innovative, sensitive, and informative diagnostic procedures. The role of the neurologist appears to have been redefined as one in which the identification of the presumptive cause and mechanism of the stroke is one of the primary responsibilities. We compared the etiologic stroke subtypes of patients entered into the Saint Louis University Stroke Registry for the period January to June, 1986 (Group A), with analogous data collected in patients entered from January to June, 1992 (Group B). Group A included 57 patients whose stroke subtype distribution was as follows: 19% due to athero-thromboembolism, 18% cardiogenic, 5% lacunar, and 4% due to other causes. In addition, 54% of patients had strokes of unknown etiology. Group B comprised 137 patients with the following etiologic distribution: 35% cardiogenic, 26% atherothrombolic, 3% lacunar, and 6% from other causes. Only 29% had strokes of unknown etiology. The apparent increase in the proportion of cardiogenic strokes may be related to wider utilization of transesophageal echocardiography. There was also a significant drop in the proportion of strokes of unknown etiology. Finally, in comparison with other stroke registries, our data suggest that many small strokes may also result from cardiogenic embolism. These apparent changes in the proportion of stroke subtypes should be considered when patients are being evaluated for risk stratification., (Copyright © 1994 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Numerous studies have demonstrated an association between acute cardiac events, cerebrovascular accidents, and cocaine use. The underlying mechanisms leading to these complications have not been well defined. Using various in vitro model systems, it has been reported that cocaine, up to or greater than an order of magnitude of the lethal dose, causes either inhibitory or proaggregatory effects on platelet function., Methods: To address these reported discrepancies, we examined the effect of cocaine and its carrier on the activation and aggregation of human platelets in vitro., Results: We found that cocaine inhibited platelet aggregation when platelets were challenged with ADP, collagen, or arachidonic acid. This inhibition was due to a direct effect on fibrinogen binding to the activated platelet. Cocaine also caused the dissociation of preformed platelet aggregates. At these same concentrations, cocaine did not inhibit agonist-mediated increases in cytosolic calcium or inhibit platelet shape change, suggesting that its effect on platelet aggregation was a selective process and not due to a total destruction of platelet function. Interestingly, the organization of the cytoskeleton of activated platelets, a secondary event critical to cell receptor clustering and clot retraction, was disrupted by cocaine treatment. In addition, alterations in platelet protein electrophoretic patterns were observed on preincubation of platelets with cocaine., Conclusions: We conclude that cocaine may have a direct inhibitory effect on the ability of platelets to participate in thrombus formation. The contribution of this effect as an underlying mechanism of sudden death in cocaine abusers is unknown.

Ischemic stroke temporally related to cocaine abuse has become increasingly common in young adults. Despite this relation, however, the pathogenesis of infarction in many of these patients remains obscure. I report the case of a 39-year-old man who developed occlusion of the frontopolar branches of the left middle cerebral artery 1 hour after intravenous cocaine use. Eleven days later he developed occlusion of the superior division of the right middle cerebral artery. In this case the mechanism of infarction was clearly cardiogenic embolization. Chest radiograph and echocardiogram revealed dilated cardiomyopathy with left ventricular thrombi. No cause other than cocaine abuse was found for his cardiomyopathy. This is the second reported case of cocaine-related cardiomyopathy presenting as embolic stroke and associated with intracavitary thrombus. Such an association may be more common than previously thought. Thorough cardiac evaluation in all patients with ischemic stroke related to cocaine abuse is appropriate.