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Introduction: Rapid response teams (RRTs) have been shown to reduce cardiopulmonary arrests outside the intensive care unit (ICU). Yet the utility of RRTs remains in question, as most large studies have failed to demonstrate a significant reduction in hospital-wide mortality after RRT implementation.Methods: A cohort design with historical controls was used to determine the effect on hospital-wide mortality of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely promoted as a key trigger for activation. All nonprisoner patients admitted to a tertiary referral public teaching hospital from 2003 through 2008 were included. In total, 77, 021 admissions before RRT implementation (2003 through 2005) and 79, 013 admissions after RRT implementation (2006 through 2008) were evaluated. The a priori primary outcome was unadjusted hospital-wide mortality. A Poisson regression model was then used to adjust for hospital-wide mortality trends over time. Secondary outcomes defined a priori were unadjusted out-of-ICU mortality and out-of-ICU cardiopulmonary-arrest codes.Results: In total, 855 inpatient RRTs (10.8 per 1, 000 hospital-wide discharges) were activated during the 3-year postintervention period. Forty-seven percent of RRTs were activated for reasons of clinical judgment. Hospital-wide mortality decreased from 15.50 to 13.74 deaths per 1, 000 discharges after RRT implementation (relative risk, 0.887; 95% confidence interval (CI), 0.817 to 0.963; P = 0.004). After adjusting for inpatient mortality trends over time, the reduction in hospital-wide mortality remained statistically significant (relative risk, 0.825; 95% CI, 0.694 to 0.981; P = 0.029). Out-of-ICU mortality decreased from 7.08 to 4.61 deaths per 1, 000 discharges (relative risk, 0.651; 95% CI, 0.570 to 0.743; P < 0.001). Out-of-ICU cardiopulmonary-arrest codes decreased from 3.28 to 1.62 codes per 1, 000 discharges (relative risk, 0.493; 95% CI, 0.399 to 0.610; P < 0.001).Conclusions: Implementation of an RRT in which clinical judgment, in addition to vital-signs criteria, was widely cited as a rationale for activation, was associated with a significant reduction in hospital-wide mortality, out-of-ICU mortality, and out-of-ICU cardiopulmonary-arrest codes. The frequent use of clinical judgment as a criterion for RRT activation was associated with high RRT utilization. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the X chromosome gene PIGA lead to phosphatidylinositol glycan class A congenital disorder of glycosylation (PIGA-CDG), an ultra-rare CDG typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA c.395C>G (p.Ser132Cys), an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great uncle also carry the same PIGA variant, but neither presents with symptoms associated with PIGA-CDG. We hypothesized that genetic modifiers might contribute to this reduced penetrance. Using whole-genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in the carriers and possible protective variants found in the carriers and not in the probands. Candidate genetic modifier variants included heterozygous, damaging variants in three genes involved directly in glycosylphosphatidylinositol (GPI)-anchor biosynthesis and additional variants in other glycosylation pathways or encoding GPI-anchored proteins. Using a Drosophila eye-based model, we tested modifiers identified through genome sequencing. Loss of CNTN2, a predicted protective modifier that encodes a GPI-anchored protein responsible for neuron/glial interactions, rescues loss of PIGA in the eye-based model, as we predict in the family. Further testing found that the loss of CNTN2 also rescues PIGA-CDG-specific phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. Using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in families may lead to therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2025 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: Health research that significantly impacts global clinical practice and policy is often published in high-impact factor (IF) medical journals. These outlets play a pivotal role in the worldwide dissemination of novel medical knowledge. However, researchers identifying as women and those affiliated with institutions in low- and middle-income countries (LMICs) have been largely under-represented in high-IF journals across multiple fields of medicine. To evaluate disparities in gender and geographical representation among authors who have published in any of five top general medical journals, we conducted scientometric analyses using a large-scale dataset extracted from the New England Journal of Medicine , Journal of the American Medical Association , The BMJ , The Lancet and Nature Medicine ., Methods: Author metadata from all articles published in the selected journals between 2007 and 2022 were collected using the DimensionsAI platform. The Genderize.io Application Programming Interface was then used to infer each author's likely gender based on their extracted first name. The World Bank country classification was used to map countries associated with researcher affiliations to the LMIC or the high-income country (HIC) category. We characterised the overall gender and country income category representation across the five medical journals. In addition, we computed article-level diversity metrics and contrasted their distributions across the journals., Results: We studied 151 536 authors across 49 764 articles published in five top medical journals, over a period spanning 15 years. On average, approximately one-third (33.1%) of the authors of a given paper were inferred to be women; this result was consistent across the journals we studied. Further, 86.6% of the teams were exclusively composed of HIC authors; in contrast, only 3.9% were exclusively composed of LMIC authors. The probability of serving as the first or last author was significantly higher if the author was inferred to be a man (18.1% vs 16.8%, p<0.01) or was affiliated with an institution in a HIC (16.9% vs 15.5%, p<0.01). Our primary finding reveals that having a diverse team promotes further diversity, within the same dimension (ie, gender or geography) and across dimensions. Notably, papers with at least one woman among the authors were more likely to also involve at least two LMIC authors (11.7% vs 10.4% in baseline, p<0.001; based on inferred gender); conversely, papers with at least one LMIC author were more likely to also involve at least two women (49.4% vs 37.6%, p<0.001; based on inferred gender)., Conclusion: We provide a scientometric framework to assess authorship diversity. Our research suggests that the inclusiveness of high-impact medical journals is limited in terms of both gender and geography. We advocate for medical journals to adopt policies and practices that promote greater diversity and collaborative research. In addition, our findings offer a first step towards understanding the composition of teams conducting medical research globally and an opportunity for individual authors to reflect on their own collaborative research practices and possibilities to cultivate more diverse partnerships in their work., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

To identify genes required for brain growth, we took an RNAi knockdown reverse genetic approach in Drosophila . One potential candidate isolated from this effort is the anti-lipogenic gene adipose ( adp ). Adp has an established role in the negative regulation of lipogenesis in the fat body of the fly and adipose tissue in mammals. While fat is key to proper development in general, adp has not been investigated during brain development. Here, we found that RNAi knockdown of adp in neuronal stem cells and neurons results in reduced brain lobe volume and sought to replicate this with a mutant fly. We generated a novel adp mutant that acts as a loss-of-function mutant based on buoyancy assay results. We found that despite a change in fat content in the body overall and a decrease in the number of larger (>5 µm) brain lipid droplets, there was no change in the brain lobe volume of mutant larvae. Overall, our work describes a novel adp mutant that can functionally replace the long-standing adp 60 mutant and shows that the adp gene has no obvious involvement in brain growth.

Seizures affect a large proportion of the global population and occur due to abnormal neuronal activity in the brain. Unfortunately, widespread genetic and phenotypic heterogeneity contribute to insufficient treatment options. It is critical to identify the genetic underpinnings of how seizures occur to better understand seizure disorders and improve therapeutic development. We used the Drosophila model to identify that IGF-II mRNA Binding Protein (Imp) is linked to the onset of this phenotype. Specific reduction of Imp in neurons causes seizures after mechanical stimulation. Importantly, gross motor behavior is unaffected, showing Imp loss does not affect general neuronal activity. Developmental loss of Imp is sufficient to cause seizures in adults, thus Imp-modulated neuron development affects mature neuronal function. Since Imp is an RNA-binding protein, we sought to identify the mRNA target that Imp regulates in neurons to ensure proper neuronal activity after mechanical stress. We find that Imp protein binds Syndecan ( Sdc ) mRNA, and reduction of Sdc also causes mechanically-induced seizures. Expression of Sdc in Imp deficient neurons rescues seizure defects, showing that Sdc is sufficient to restore normal behavior after mechanical stress. We suggest that Imp protein binds Sdc mRNA in neurons, and this functional interaction is important for normal neuronal biology and animal behavior in a mechanically-induced seizure model. Since Imp and Sdc are conserved, our work highlights a neuronal specific pathway that might contribute to seizure disorder when mutated in humans.

Background: With an increasing demand for critical care expertise and limitations in intensivist availability, innovative staffing models, such as the utilization of advanced practice providers (APPs), have emerged., Objectives: The purpose of the study was to compare patient outcomes between APP and housestaff teams in the cardiac intensive care unit (CICU)., Methods: This retrospective study, spanning March 2022 to July 2023, compares patient characteristics and outcomes between two CICU teams embedded in the same CICU at a large urban academic hospital: one staffed by housestaff and the other by APPs (80% physician assistants, 20% nurse practitioners) who each had approximately 1 to 2 years of experience in the CICU. The primary outcome was CICU mortality. Multivariable Cox regression analyses and Kaplan-Meier curves were used to assess the primary outcome., Results: A total of 1,620 admissions were analyzed: 1,013 patients on the housestaff service and 607 patients on the APP service. There were no significant differences in patient demographics, admitting diagnoses, use of vasoactive medications, inotropes, or mechanical circulatory support. There was no difference in CICU mortality (8.4% vs 8.2%, adjusted hazard ratio 0.73; 95% CI: 0.51-1.05; P  = 0.10), in-hospital mortality (13.5% vs 13.8%, aHR 0.82; 95% CI: 0.62-1.08; P  = 0.17), or in-hospital length of stay between the housestaff and APP teams. Patients managed by the housestaff team had a lower CICU length of stay (2 days IQR: 1-4 days] vs 3 days [IQR: 1-5 days], P  = 0.047). Fellowship rotation scores (based on surveys completed by the cardiology fellows) of the CICU also improved after the implementation of the APP-based team (3.87 ± 0.14 before vs 4.61 ± 0.06 after, P  < 0.0001)., Conclusions: Our moderately sized study demonstrated no difference in CICU or in-hospital mortality between patients managed by a housestaff team versus those managed by an APP team., Competing Interests: Dr Bangalore serves on the advisory board of Abbott Vascular, Boston Scientific, Biotronik, Amgen, Pfizer, Merck, REATA, Inari, and Truvic. Dr Alviar serves as a consultant at Zoll Inc, Abbott, and Abiomed and receives research grants from Baxter Medical. Dr Katz has received research support (modest) from Abbott Corporation, Speaker Honoraria of Zoll Inc, and the member of the Data Safety & Monitoring Board of Abiomed Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Background & Objectives: Cardiopulmonary resuscitation (CPR) is the key for surviving cardiac arrest. Recent recommendations propose that CPR can - and should -be taught to schoolchildren. This e-learning-based study analyzes whether face-to-face CPR training can be partly substituted with e-learning by measuring CPR knowledge and self-efficacy in trainees., Methods: In this cluster randomized-controlled prospective, students attending grades 5 to 7 of a German secondary school volunteered to participate and were randomly assigned to one of two groups with different methods for CPR training each: a traditional instructor-led group (control) where students received face-to-face teaching by a BLS instructor (45 min), and an e-learning group (intervention) where schoolchildren were able to accomplish their theoretical CPR training using an e-learning module (15 min). CPR knowledge and self-efficacy were measured and compared before (t0) and after (t1) the training using questionnaires. Face-to-face CPR training (45 min) on manikins proceeded in both groups hereafter. The formal hypothesis was that e-learning would result in better CPR knowledge., Results: Overall, 375 students participated; 33 of which had to be excluded. 342 participants were included in statistical analysis (instructor-led group n  = 109; e-learning group n  = 233). The study was terminated early due to the Covid19 pandemic, and did not reach the required number of participants. Lacking statistical power, an analysis of the existing datasets failed to show superiority of e-learning vs. conventional training for CPR knowledge ( p  = 0.306). Both groups improved CPR knowledge ( p  < 0.001) and self-efficacy ( p  < 0.001) after CPR training and showed an equal, high level of satisfaction with their perceived training method (face-to-face: 4.1[4.0-4.2] vs. e-learning: 4.0[3.9-4.1]; p  = 0.153; maximum 5 points)., Conclusions: This study failed to demonstrate superiority for e-learning but was terminated early and hence underpowered. Further research is necessary to prove the efficiency of e-learning tools for CPR., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wolfgang A. Wetsch, Nikolas Link, Niels Rahe-Meyer and Rico Dumcke have no conflicts of interest to declare regarding this manuscript. Jan Stock is Head of the L2R GmbH and Projekt Manager at the Hans Peter Esser GmbH. Bernd W. Böttiger is treasurer of the European Resuscitation Council (ERC), Founder of the ERC Research NET, Chairman of the German Resuscitation Council (GRC), Member of the „Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR), Member of the Executive Committee of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), Founder of the “Deutsche Stiftung Wiederbelebung”, Federal Medical Advisor of the German Red Cross (DRK), Member of the Advisory Board of the “Deutsche Herzstiftung”, Co-Editor of “Resuscitation”, Editor of the Journal “Notfall + Rettungsmedizin”, Co-Editor of the Brazilian Journal of Anesthesiology. He received fees for lectures from the following companies: Forum für medizinische Fortbildung (FomF), Baxalta Deutschland GmbH, ZOLL Medical Deutschland GmbH, C.R. Bard GmbH, GS Elektromedizinische Geräte G. Stemple GmbH, Novartis Pharma GmbH, Philips GmbH Market DACH, Bioscience Valuation BSV GmbH, Becton Dickinson GmbH, Fundacja Polski Instytut Evidence Based Medicine. Sabine Wingen is executive personal assistant of the executive board of the German Resuscitation Council (GRC)., (© 2024 The Author(s).)

Loss of function mutations in the X-linked PIGA gene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA S132C , an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carry PIGA S132C , but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using a Drosophila eye-based model of PIGA-CDG. We found that loss of CNTN2 , a predicted protective modifier, rescues loss of PIGA in Drosophila eye-based model, like what we predict in the family. Further testing found that loss of CNTN2 also rescues patient-relevant phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. By using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. Although adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of disease caused by this virus, which includes microcephaly. In this study, we generated a toolkit to ectopically express ZIKV proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We used this toolkit to identify phenotypes and potential host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins caused scorable phenotypes, such as overall lethality, gross morphological defects, reduced brain size and neuronal function defects. We further used this system to identify strain-dependent phenotypes that may have contributed to the increased pathogenesis associated with the outbreak of ZIKV in the Americas in 2015. Our work demonstrates the use of Drosophila as an efficient in vivo model to rapidly decipher how pathogens cause disease and lays the groundwork for further molecular study of ZIKV pathogenesis in flies., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. While adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of symptoms caused by this virus including microcephaly. In this study, we generated a toolkit to ectopically express Zika viral proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We use this toolkit to identify phenotypes and host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins cause scorable phenotypes, such as overall lethality, gross morphological defects, reduced brain size, and neuronal function defects. We further use this system to identify strain-dependent phenotypes that may contribute to the increased pathogenesis associated with the more recent outbreak of ZIKV in the Americas. Our work demonstrates Drosophila's use as an efficient in vivo model to rapidly decipher how pathogens cause disease and lays the groundwork for further molecular study of ZIKV pathogenesis in flies.

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus., Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster., Results: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra-axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper- and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial-loss-of-function variants, whereas the c.1421-1G>C splicing variant demonstrated a strong loss-of-function effect., Interpretation: Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2-related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The increasing availability of electronic health record (EHR) systems has created enormous potential for translational research. However, it is difficult to know all the relevant codes related to a phenotype due to the large number of codes available. Traditional data mining approaches often require the use of patient-level data, which hinders the ability to share data across institutions. In this project, we demonstrate that multi-center large-scale code embeddings can be used to efficiently identify relevant features related to a disease of interest. We constructed large-scale code embeddings for a wide range of codified concepts from EHRs from two large medical centers. We developed knowledge extraction via sparse embedding regression (KESER) for feature selection and integrative network analysis. We evaluated the quality of the code embeddings and assessed the performance of KESER in feature selection for eight diseases. Besides, we developed an integrated clinical knowledge map combining embedding data from both institutions. The features selected by KESER were comprehensive compared to lists of codified data generated by domain experts. Features identified via KESER resulted in comparable performance to those built upon features selected manually or with patient-level data. The knowledge map created using an integrative analysis identified disease-disease and disease-drug pairs more accurately compared to those identified using single institution data. Analysis of code embeddings via KESER can effectively reveal clinical knowledge and infer relatedness among codified concepts. KESER bypasses the need for patient-level data in individual analyses providing a significant advance in enabling multi-center studies using EHR data., (© 2021. The Author(s).)

The fruit fly, Drosophila melanogaster , has been used to understand fundamental principles of genetics and biology for over a century. Drosophila is now also considered an essential tool to study mechanisms underlying numerous human genetic diseases. In this review, we will discuss how flies can be used to deepen our knowledge of infectious disease mechanisms in vivo. Flies make effective and applicable models for studying host-pathogen interactions thanks to their highly conserved innate immune systems and cellular processes commonly hijacked by pathogens. Drosophila researchers also possess the most powerful, rapid, and versatile tools for genetic manipulation in multicellular organisms. This allows for robust experiments in which specific pathogenic proteins can be expressed either one at a time or in conjunction with each other to dissect the molecular functions of each virulent factor in a cell-type-specific manner. Well documented phenotypes allow large genetic and pharmacological screens to be performed with relative ease using huge collections of mutant and transgenic strains that are publicly available. These factors combine to make Drosophila a powerful tool for dissecting out host-pathogen interactions as well as a tool to better understand how we can treat infectious diseases that pose risks to public health, including COVID-19, caused by SARS-CoV-2.

Objective: Reducing risk of coronavirus disease 2019 (COVID-19) infection among healthcare personnel requires a robust occupational health response involving multiple disciplines. We describe a flexible informatics solution to enable such coordination, and we make it available as open-source software., Materials and Methods: We developed a stand-alone application that integrates data from several sources, including electronic health record data and data captured outside the electronic health record., Results: The application facilitates workflows from different hospital departments, including Occupational Health and Infection Control, and has been used extensively. As of June 2020, 4629 employees and 7768 patients and have been added for tracking by the application, and the application has been accessed over 46 000 times., Discussion: Data captured by the application provides both a historical and real-time view into the operational impact of COVID-19 within the hospital, enabling aggregate and patient-level reporting to support identification of new cases, contact tracing, outbreak investigations, and employee workforce management., Conclusions: We have developed an open-source application that facilitates communication and workflow across multiple disciplines to manage hospital employees impacted by the COVID-19 pandemic., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2020. This work is written by US Government employees and is in the public domain in the US.)

Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila , can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: It is important to monitor the scope of clinical research of all types, to involve participants of all ages and subgroups in studies that are appropriate to their condition, and to ensure equal access and broad validity of the findings., Objective: We conducted a review of clinical research performed at New York University with the following objectives: (1) to determine the utility of institutional administrative data to characterize clinical research activity; (2) to assess the inclusion of special populations; and (3) to determine if the type, initiation, and completion of the study differed by age., Methods: Data for all studies that were institutional review board-approved between January 1, 2014, and November 2, 2016, were obtained from the research navigator system, which was launched in November 2013. One module provided details about the study protocol, and another module provided the characteristics of individual participants. Research studies were classified as observational or interventional. Descriptive statistics were used to assess the characteristics of clinical studies across the lifespan, by type, and over time., Results: A total of 22%-24% of studies included children (minimum age <18 years) and 4%-5% focused exclusively on pediatrics. Similarly, 64%-72% of studies included older patients (maximum age >65 years) but only 5%-12% focused exclusively on geriatrics. Approximately 85% of the studies included both male and female participants. Of the remaining studies, those open only to girls or women were approximately 3 times as common as those confined to boys or men. A total of 56%-58% of projects focused on nonvulnerable patients. Among the special populations studied, children (12%-15%) were the most common. Noninterventional trial types included research on human data sets (24%), observational research (22%), survey research (16%), and biospecimen research (8%). The percentage of projects designed to test an intervention in a vulnerable population increased from 17% in 2014 to 21% in 2015., Conclusions: Pediatric participants were the special population that was most often studied based on the number of registered projects that included children and adolescents. However, they were much less likely to be successfully enrolled in research studies compared with adults older than 65 years. Only 20% of the studies were interventional, and 20%-35% of participants in this category were from vulnerable populations. More studies are exclusively devoted to women's health issues compared with men's health issues., (©Aisha Langford, Scott Sherman, Rachel Thornton, Kira Nightingale, Simona Kwon, Deborah Chavis-Keeling, Nathan Link, Bruce Cronstein, Judith Hochman, Howard Trachtman. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 24.08.2020.)

To explore demographics, comorbidities, transfers, and mortality in critically ill patients with confirmed severe acute respiratory syndrome coronavirus 2., Design: Retrospective cohort study., Setting: Data were collected from a large tertiary care public hospital ICU that is part of the largest public healthcare network in the United States., Patients: One-hundred thirty-seven adult (≥ 18 yr old) ICU patients admitted between March 10, 2020, and April 7, 2020, with follow-up collected through May 18, 2020., Interventions: None., Measurements: Demographic, clinical, laboratory, treatment, and outcome data extracted from electronic medical records., Main Results: The majority of patients were male (99/137; 72.3%) and older than 50 years old (108/137; 78.9%). The most reported ethnicity and race were Hispanic (61/137; 44.5%) and Black (23/137; 16.7%). One-hundred six of 137 patients had at least one comorbidity (77.4%). One-hundred twenty-one of 137 (78.1%) required mechanical ventilation of whom 30 (24.8%) moved to tracheostomy and 46 of 137 (33.6%) required new onset renal replacement therapy. Eighty-two of 137 patients (59.9%) died after a median of 8 days (interquartile range 5-15 d) in the ICU. Male sex had a trend toward a higher hazard of death (hazard ratio, 2.1 [1.1-4.0]) in the multivariable Cox model., Conclusions: We report a mortality rate of 59.9% in a predominantly Hispanic and Black patient population. A significant association between comorbidities and mortality was not found in multivariable regression, and further research is needed to study factors that impact mortality in critical coronavirus disease 2019 patients. We also describe how a public hospital developed innovative approaches to safely manage a large volume of interhospital transfers and admitted patients., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Studies are needed to evaluate medication-related problems (MRPs) to assess the effect of a pharmacist on managing medications postdischarge. Objective: To assess the ability of pharmacist-led medication review and reconciliation to reduce the number of MRPs found in transitional care medicine (TCM) visits, leading to medication optimization. Methods: This study involved a retrospective chart review of standard TCM procedure at a family/internal medicine clinic and a prospective, team-based TCM visit in the same clinic. Inclusion criteria included patients discharged from any hospital within our institution and seen in the clinic. The primary outcome was the difference in the proportion of MRPs found between the prospective and retrospective groups. Secondary outcomes included the number and specific type of MRPs found, classified by the Pharmaceutical Care Network Europe tool, and further subdivided by patient aware or unaware of MRP, only in the prospective group, as well as 30-day readmission rate. Results: Patients in the prospective group (n = 50) had an average age of 67.9 years versus 65.5 years in the retrospective group (n = 50). Four times as many patients in the prospective group were found to have MRPs than the retrospective group. The most common MRP was due to a patient-related factor, meaning the cause is related to a patient's behavior. Patients were unaware of the MRP in a majority of these cases. Thirty-day readmission rate did not differ between the groups. Conclusion: Team-based TCM visits that included a pharmacist-led medication reconciliation uncovered more MRPs than patients who did not have a pharmacist perform a medication reconciliation., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Electronic health records linked with biorepositories are a powerful platform for translational studies. A major bottleneck exists in the ability to phenotype patients accurately and efficiently. The objective of this study was to develop an automated high-throughput phenotyping method integrating International Classification of Diseases (ICD) codes and narrative data extracted using natural language processing (NLP)., Materials and Methods: We developed a mapping method for automatically identifying relevant ICD and NLP concepts for a specific phenotype leveraging the Unified Medical Language System. Along with health care utilization, aggregated ICD and NLP counts were jointly analyzed by fitting an ensemble of latent mixture models. The multimodal automated phenotyping (MAP) algorithm yields a predicted probability of phenotype for each patient and a threshold for classifying participants with phenotype yes/no. The algorithm was validated using labeled data for 16 phenotypes from a biorepository and further tested in an independent cohort phenome-wide association studies (PheWAS) for 2 single nucleotide polymorphisms with known associations., Results: The MAP algorithm achieved higher or similar AUC and F-scores compared to the ICD code across all 16 phenotypes. The features assembled via the automated approach had comparable accuracy to those assembled via manual curation (AUCMAP 0.943, AUCmanual 0.941). The PheWAS results suggest that the MAP approach detected previously validated associations with higher power when compared to the standard PheWAS method based on ICD codes., Conclusion: The MAP approach increased the accuracy of phenotype definition while maintaining scalability, thereby facilitating use in studies requiring large-scale phenotyping, such as PheWAS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

During 2014-2016, the largest outbreak of Ebola virus disease (EVD) in history occurred in West Africa. The New York City Department of Health and Mental Hygiene (DOHMH) worked with health care providers to prepare for persons under investigation (PUIs) for EVD in New York City. From July 1, 2014, through December 29, 2015, we classified as a PUI a person with EVD-compatible signs or symptoms and an epidemiologic risk factor within 21 days before illness onset. Of 112 persons who met PUI criteria, 74 (66%) sought medical care and 49 (44%) were hospitalized. The remaining 38 (34%) were isolated at home with daily contact by DOHMH staff members. Thirty-two (29%) PUIs received a diagnosis of malaria. Of 10 PUIs tested, 1 received a diagnosis of EVD. Home isolation minimized unnecessary hospitalization. This case study highlights the importance of developing competency among clinical and public health staff managing persons suspected to be infected with a high-consequence pathogen.

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RE rpr ) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RE rpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation-seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Knowing which proteins and RNAs directly interact is essential for understanding cellular mechanisms. Unfortunately, discovering such interactions is costly and often unreliable. To overcome these limitations, we developed rec-YnH, a new yeast two and three-hybrid-based screening pipeline capable of detecting interactions within protein libraries or between protein libraries and RNA fragment pools. rec-YnH combines batch cloning and transformation with intracellular homologous recombination to generate bait-prey fusion libraries. By developing interaction selection in liquid-gels and using an ORF sequence-based readout of interactions via next-generation sequencing, we eliminate laborious plating and barcoding steps required by existing methods. We use rec-Y2H to simultaneously map interactions of protein domains and reveal novel putative interactors of PAR proteins. We further employ rec-Y2H to predict the architecture of published coprecipitated complexes. Finally, we use rec-Y3H to map interactions between multiple RNA-binding proteins and RNAs-the first time interactions between protein and RNA pools are simultaneously detected.

Objective: The aim of this study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) in low-grade serous ovarian carcinoma (LGSOC)., Methods: We retrospectively identified patients with LGSOC who were treated with PLD. Response to therapy was evaluated by RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival were calculated. In addition, PFS on PLD was compared with the patient's most recent PFS on previous therapy., Results: Twenty-four patients were treated with PLD. Three patients were not evaluable, leaving 21 patients evaluable for response. Pegylated liposomal doxorubicin was dosed at 40 mg/M every 28 days except in 7 patients (5 received PLD dosed at 30 mg/M in combination with carboplatin and 2 received PLD dosed at 20 mg/M, one of which was in combination with etoposide). Four of the patients who received PLD in combination subsequently received PLD alone for 4+, 12, 21, and 29 cycles, respectively. Three patients (14.3%) had a complete response and remained progression free at 8, 31, and 34 months, respectively. Two of these patients received PLD alone. The third complete response patient initially received PLD in combination with carboplatin and then went on to receive PLD alone during which a complete radiologic response was achieved. No difference in response or PFS by platinum sensitivity was noted (Ps = 0.73 and 0.62, respectively). Fourteen patients had stable disease for a median of 18 months. Among the 14 patients with stable disease, the PFS on PLD exceeded the previous PFS in 11 patients (78.6%) from 1.3 to 20.6 folds, with a median of 3.5 folds. The 2 of the 3 lowest increases in PFSs were seen in patients whose therapy was terminated despite stable disease., Conclusions: Pegylated liposomal doxorubicin is relatively active in LGSOC. The treatment of stable disease resulted in increase in PFS in 78.6% of patients by a mean of 350%.

Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development.

Cofactors such as NAD, AMP, and Coenzyme A (CoA) are essential for a diverse set of reactions and pathways in the cell. Specific carrier proteins are required to distribute these cofactors to different cell compartments, including peroxisomes. We previously identified a peroxisomal transport protein in Arabidopsis (Arabidopsis thaliana) called the peroxisomal NAD carrier (PXN). When assayed in vitro, this carrier exhibits versatile transport functions, e.g. catalyzing the import of NAD or CoA, the exchange of NAD/NADH, and the export of CoA. These observations raise the question about the physiological function of PXN in plants. Here, we used Saccharomyces cerevisiae to address this question. First, we confirmed that PXN, when expressed in yeast, is active and targeted to yeast peroxisomes. Secondl, detailed uptake analyses revealed that the CoA transport function of PXN can be excluded under physiological conditions due to its low affinity for this substrate. Third, we expressed PXN in diverse mutant yeast strains and investigated the suppression of the mutant phenotypes. These studies provided strong evidences that PXN was not able to function as a CoA transporter or a redox shuttle by mediating a NAD/NADH exchange, but instead catalyzed the import of NAD into peroxisomes against AMP in intact yeast cells., (© 2016 American Society of Plant Biologists. All Rights Reserved.)

Because weak interagency coordination between community correctional agencies (e.g., probation and parole) and community-based treatment providers has been identified as a major barrier to the use of evidence-based practices (EBPs) for treating druginvolved offenders, this study sought to examine how key organizational (e.g., leadership, support, staffing) and individual (e.g., burnout, satisfaction) factors influence interagency relationships between these agencies. At each of 20 sites, probation/parole officials ( n = 366) and community treatment providers ( n = 204) were surveyed about characteristics of their agencies, themselves, and interorganizational relationships with each other. Key organizational and individual correlates of interagency relationships were examined using hierarchical linear models (HLM) analyses, supplemented by interview data. The strongest correlates included Adaptability, Efficacy, and Burnout. Implications for policy and practice are discussed.

Elimination of cells and tissues by apoptosis is a highly conserved and tightly regulated process. In Drosophila, the entire wing epithelium is completely removed shortly after eclosion. The cells that make up this epithelium are collectively eliminated through a highly synchronized form of apoptotic cell death, involving canonical apoptosome genes. Here we present evidence that collective cell death does not require cell-cell contact and show that transcription of the IAP antagonist, head involution defective, is acutely induced in wing epithelial cells prior to this process. hid mRNAs accumulate to levels that exceed a component of the ribosome and likewise, Hid protein becomes highly abundant in these same cells. hid function is required for collective cell death, since loss of function mutants shows persisting wing epithelial cells and, furthermore, silencing of the hormone bursicon in the CNS produced collective cell death defective phenotypes manifested in the wing epithelium. Taken together, our observations suggest that acute induction of Hid primes wing epithelial cells for collective cell death and that Bursicon is a strong candidate to trigger this process, possibly by activating the abundant pool of Hid protein already present., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Apoptotic programmed cell death (PCD) is a fundamental aspect of developmental maturation. However, the authors' understanding of apoptosis, especially in the multi-cell regime, is incomplete because of the difficulty of identifying dying cells by conventional strategies. Real-time in vivo microscopy of Drosophila , an excellent model system for studying the PCD during development, has been used to uncover plausible collective apoptosis at the tissue level, although the dynamic regulation of the process remains to be deciphered. In this work, the authors have developed an image-analysis program that can quantitatively analyse time-lapse microscopy of live tissues undergoing apoptosis with a fluorescent nuclear marker, and subsequently extract the spatiotemporal patterns of multicellular response. The program can process a large number of cells (>10 3 ) automatically tracked across sets of image frames. It is applied to characterise the apoptosis of Drosophila wing epithelium at eclosion. Using the natural anatomic structures as reference, the authors identify dynamic patterns in the progression of PCD within the Drosophila tissues. The results not only confirm the previously observed collective multi-cell behaviour from a quantitative perspective, but also reveal a plausible role played by the anatomic structures, such as the wing veins, in the PCD propagation across the Drosophila wing.

In late October 2014, Ebola virus disease (Ebola) was diagnosed in a humanitarian aid worker who recently returned from West Africa to New York City (NYC). The NYC Department of Health and Mental Hygiene (DOHMH) actively monitored three close contacts of the patient and 114 health care personnel. No secondary cases of Ebola were detected. In collaboration with local and state partners, DOHMH had developed protocols to respond to such an event beginning in July 2014. These protocols included safely transporting a person at the first report of symptoms to a local hospital prepared to treat a patient with Ebola, laboratory testing for Ebola, and monitoring of contacts. In response to this single case of Ebola, initial health care worker active monitoring protocols needed modification to improve clarity about what types of exposure should be monitored. The response costs were high in both human resources and money: DOHMH alone spent $4.3 million. However, preparedness activities that include planning and practice in effectively monitoring the health of workers involved in Ebola patient care can help prevent transmission of Ebola.

The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras-expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)