Prospective comparison of risk factors for firearm suicide and non-firearm suicide in a large population-based cohort of current and former US service members: findings from the Millennium Cohort Study.

Background: Suicide is a leading cause of death among service members and veterans. Among suicide methods, firearms are the most lethal and commonly used method among military populations. Limited research has compared risk factors for the various suicide methods. This study evaluated and compared risk factors for firearm versus non-firearm suicides using data from the Millennium Cohort Study, a large longitudinal military cohort. Methods: Using a competing risk approach, we identified factors associated with each suicide method. Risk factors included demographics, mental health diagnoses, mental health symptoms, military-specific characteristics, health behaviors, and psychosocial factors. Cause of death was assessed from July 1, 2001, through December 31, 2018. Findings: Among 201,565 eligible participants with a mean [SD] age of 29.0 [58.1] years, there were 139,789 (69.3%) male, 61,776 (30.7%) female, 15,927 (7.9%) Hispanic, 24,667 (12.3%) non-Hispanic Black, 14,138 (7.0%) Asian, Pacific Islander, American Indian or Multiracial, and 146,736 (72.8%) non-Hispanic White participants. During the study period, 330 died by firearm suicide and 168 died by non-firearm suicide. Overall, effect estimates for risk factors were similar across both methods of suicide. After adjustment, men (HR: 3.69, 95% CI: 2.59, 5.24) and those who screened positive for depression (HR: 1.97, 95% CI: 1.36, 2.87) had an elevated risk for firearm suicide. In contrast, those who self-reported a history of bipolar diagnosis (HR: 3.40, 95% CI: 1.76, 6.55) had significantly increased risk for non-firearm suicide. Interpretation: Findings suggest that prevention and intervention strategies overall may not need to be differentiated by specific demographic, military, or health factors. Targeted interventions that consider sex and mental health screens might have relative utility in preventing firearm related suicide risk compared with non-firearm suicide. Funding: Military Operational Medicine Research Program, Defense Health Program, and Department of Veterans Affairs.

Comparative Analysis of Performance of Large Language Models in Urogynecology.

IMPORTANCE: Despite growing popularity in medicine, data on large language models in urogynecology are lacking. OBJECTIVE: The aim of this study was to compare the performance of ChatGPT-3.5, GPT-4, and Bard on the American Urogynecologic Society self-assessment examination. STUDY DESIGN: The examination features 185 questions with a passing score of 80. We tested 3 models-ChatGPT-3.5, GPT-4, and Bard on every question. Dedicated accounts enabled controlled comparisons. Questions with prompts were inputted into each model's interface, and responses were evaluated for correctness, logical reasoning behind answer choice, and sourcing. Data on subcategory, question type, correctness rate, question difficulty, and reference quality were noted. The Fisher exact or χ2 test was used for statistical analysis. RESULTS: Out of 185 questions, GPT-4 answered 61.6% questions correctly compared with 54.6% for GPT-3.5 and 42.7% for Bard. GPT-4 answered all questions, whereas GPT-3.5 and Bard declined to answer 4 and 25 questions, respectively. All models demonstrated logical reasoning in their correct responses. Performance of all large language models was inversely proportional to the difficulty level of the questions. Bard referenced sources 97.5% of the time, more often than GPT-4 (83.3%) and GPT-3.5 (39%). GPT-3.5 cited books and websites, whereas GPT-4 and Bard additionally cited journal articles and society guidelines. Median journal impact factor and number of citations were 3.6 with 20 citations for GPT-4 and 2.6 with 25 citations for Bard. CONCLUSIONS: Although GPT-4 outperformed GPT-3.5 and Bard, none of the models achieved a passing score. Clinicians should use language models cautiously in patient care scenarios until more evidence emerges.

Defining blood hematology reference values in female pig-tailed macaques (Macaca nemestrina) using the Isolation Forest algorithm.

BACKGROUND: Pig-tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm. METHODS: Eighteen female PTMs were evaluated. Blood was collected 1-24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers. RESULTS: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index. CONCLUSIONS: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs.

Reinforcing effects of fentanyl analogs found in illicit drug markets.

RATIONALE: The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs). OBJECTIVES: Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold. METHODS: Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction. RESULTS: Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction. CONCLUSIONS: Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.

Cytoprotective Small Compound M109S Attenuated Retinal Ganglion Cell Degeneration Induced by Optic Nerve Crush in Mice.

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.

Machine Learning Methods Using Artificial Intelligence Deployed on Electronic Health Record Data for Identification and Referral of At-Risk Patients From Primary Care Physicians to Eye Care Specialists: Retrospective, Case-Controlled Study.

BACKGROUND: Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans suffer from vision loss as a result of undiagnosed or untreated ophthalmic conditions. In ophthalmology, artificial intelligence (AI) is used to predict glaucoma progression, recognize diabetic retinopathy (DR), and classify ocular tumors; however, AI has not yet been used to triage primary care patients for ophthalmology referral. OBJECTIVE: This study aimed to build and compare machine learning (ML) methods, applicable to electronic health records (EHRs) of PCPs, capable of triaging patients for referral to eye care specialists. METHODS: Accessing the Optum deidentified EHR data set, 743,039 patients with 5 leading vision conditions (age-related macular degeneration [AMD], visually significant cataract, DR, glaucoma, or ocular surface disease [OSD]) were exact-matched on age and gender to 743,039 controls without eye conditions. Between 142 and 182 non-ophthalmic parameters per patient were input into 5 ML methods: generalized linear model, L1-regularized logistic regression, random forest, Extreme Gradient Boosting (XGBoost), and J48 decision tree. Model performance was compared for each pathology to select the most predictive algorithm. The area under the curve (AUC) was assessed for all algorithms for each outcome. RESULTS: XGBoost demonstrated the best performance, showing, respectively, a prediction accuracy and an AUC of 78.6% (95% CI 78.3%-78.9%) and 0.878 for visually significant cataract, 77.4% (95% CI 76.7%-78.1%) and 0.858 for exudative AMD, 79.2% (95% CI 78.8%-79.6%) and 0.879 for nonexudative AMD, 72.2% (95% CI 69.9%-74.5%) and 0.803 for OSD requiring medication, 70.8% (95% CI 70.5%-71.1%) and 0.785 for glaucoma, 85.0% (95% CI 84.2%-85.8%) and 0.924 for type 1 nonproliferative diabetic retinopathy (NPDR), 82.2% (95% CI 80.4%-84.0%) and 0.911 for type 1 proliferative diabetic retinopathy (PDR), 81.3% (95% CI 81.0%-81.6%) and 0.891 for type 2 NPDR, and 82.1% (95% CI 81.3%-82.9%) and 0.900 for type 2 PDR. CONCLUSIONS: The 5 ML methods deployed were able to successfully identify patients with elevated odds ratios (ORs), thus capable of patient triage, for ocular pathology ranging from 2.4 (95% CI 2.4-2.5) for glaucoma to 5.7 (95% CI 5.0-6.4) for type 1 NPDR, with an average OR of 3.9. The application of these models could enable PCPs to better identify and triage patients at risk for treatable ophthalmic pathology. Early identification of patients with unrecognized sight-threatening conditions may lead to earlier treatment and a reduced economic burden. More importantly, such triage may improve patients' lives.

Probing the mechanism of guest-framework bonding interactions through a first-principles study on the structural and electronic properties of type-II clathrate A x Si136 (A = Na, K, Rb; 0 ≤ x ≤ 24) under pressure.

The role of noncovalent bonding, including multiatomic interactions (van der Waals-like forces) and ionic characteristics, in the intermetallic clathrate A x Si136 (A = Na, K, Rb; 0 < x ≤ 24) is qualitatively discussed. Using the local density approximation (LDA) to density functional theory (DFT), we investigated the effect of different guest filling and pressure parameters on the structural and electronic properties of these materials. In the context of the rigid-band model, we first noted that the competition between van der Waals-like multiatomic interactions and ionicity due to the extent of charge transfer responsible for guest-framework complexes accounts for the nonmonotonic structural response upon guest filling in A x Si136 (0 ≤ x ≤ 8), which is in good agreement with previous experimental findings as well as theoretical predictions. In comparison with computational work initiated under zero temperature and pressure conditions, the DFT calculations at high pressure (P = 3 GPa) show no apparent variation with respect to the electronic structure. Regarding the A16Si136 compound, the encapsulated sodium atoms residing in the 20-atom cage cavity act as centers of somewhat localized electrons compared with the alkaline metal sites inside Si28 cage voids. Moreover, the substitution of heavier guest atoms (e.g., Rb) for all the Na atoms in Na8Si136 yields less significant charge transfer between the guest and framework constituents. The net effect of quickly increasing multiatomic interactions and slowly decreasing ionic bonding between the encapsulated atom and Si28 cage may prevent the entire lattice configuration from contracting in a more rapid way when guest species are tuned from Na to Rb in A x Si136 (A = Na, Rb; 0 < x ≤ 8) with increased composition x. In other words, the coulombic attraction due to ionic bonding slightly outweighs the repulsive interaction between the Rb atom and Si28 cage. In addition, the determined formation energy per conventional unit cell in K8Si136, Rb8Si136 and Na12Si136 attains a minimum value, demonstrating the stabilizing effect of guests incorporated into "oversized" cage cavities.

Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.Trial Registration: ClinicalTrials.gov identifier: NCT04688164.

Machine Learning in Electroconvulsive Therapy: A Systematic Review.

ABSTRACT: Despite years of research, we are still not able to reliably predict who might benefit from electroconvulsive therapy (ECT) treatment. As we exhaust what is possible using traditional statistical analysis, ECT remains a good candidate for machine learning approaches due to the large data sets with data captured through electroencephalography (EEG) and other objective measures. A systematic review of 6 databases led to the full-text examination of 26 articles using machine learning approaches in examining data predicting response to ECT treatment. The identified articles used a wide variety of data types covering structural and functional imaging data (n = 15), clinical data (n = 5), a combination of clinical and imaging data (n = 2), EEG (n = 3), and social media posts (n = 1). The clinical indications in which response prediction was assessed were depression (n = 21) and psychosis (n = 4). Changes in multiple anatomical regions in the brain were identified as holding a predictive value for response to ECT. These primarily centered on the limbic system and associated networks. Clinical features predicting good response to ECT in depression included shorter duration, lower severity, higher medication dose, psychotic features, low cortisol levels, and positive family history. It has also been possible to predict the likelihood of relapse of readmission with psychosis after ECT treatment, including a better response if higher transfer entropy was calculated from EEG signals. A transdisciplinary approach with an international consortium collecting a wide range of retrospective and prospective data may help to refine and extend these outcomes and translate them into clinical practice.

Dissemination and implementation research coordination and training to improve cardiovascular health in people living with HIV in sub-Saharan Africa: the research coordinating center of the HLB-SIMPLe Alliance.

As global adoption of antiretroviral therapy extends the lifespan of People Living with HIV (PLHIV) through viral suppression, the risk of comorbid conditions such as hypertension has risen, creating a need for effective, scalable interventions to manage comorbidities in PLHIV. The Heart, Lung, and Blood Co-morbiditieS Implementation Models in People Living with HIV (HLB-SIMPLe) Alliance has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Fogarty International Center (FIC) since September 2020. The Alliance was created to conduct late-stage implementation research to contextualize, implement, and evaluate evidence-based strategies to integrate the diagnosis, treatment, and control of cardiovascular diseases, particularly hypertension, in PLHIV in low- and middle-income countries (LMICs).The Alliance consists of six individually-funded clinical trial cooperative agreement research projects based in Botswana, Mozambique, Nigeria, South Africa, Uganda, and Zambia; the Research Coordinating Center; and personnel from NIH, NHLBI, and FIC (the Federal Team). The Federal Team works together with the members of the seven cooperative agreements which comprise the alliance. The Federal Team includes program officials, project scientists, grant management officials and clinical trial specialists. This Alliance of research scientists, trainees, and administrators works collaboratively to provide and support venues for ongoing information sharing within and across the clinical trials, training and capacity building in research methods, publications, data harmonization, and community engagement. The goal is to leverage shared learning to achieve collective success, where the resulting science and training are greater with an Alliance structure rather than what would be expected from isolated and unconnected individual research projects.In this manuscript, we describe how the Research Coordinating Center performs the role of providing organizational efficiencies, scientific technical assistance, research capacity building, operational coordination, and leadership to support research and training activities in this multi-project cooperative research Alliance. We outline challenges and opportunities during the initial phases of coordinating research and training in the HLB-SIMPLe Alliance, including those most relevant to dissemination and implementation researchers.

Strategies and outcomes of extracorporeal membrane oxygenation use in peripartum patients: a single institution experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) use in peripartum patients is rare, and there is a gap in the literature on the outcomes and guidance on using ECMO in peripartum patients. This study describes ECMO strategies our institution uses for peripartum patients and reports outcomes of ECMO use in peripartum patients with respiratory and/or cardiac failure. METHODS: A case series of all peripartum patients, defined as pregnant or up to 6 weeks after delivery of an infant >20 weeks gestation, from 2018 to 2023 from a single center requiring ECMO support. Patients were included if ECMO was initiated in the setting of cardiac, pulmonary, or combined failure. Patient demographics, operative details, ECMO data, and adverse outcomes for maternal, fetus, and neonates were all collected. RESULTS: Eighteen patients met the inclusion criteria. The cohort had a mean maternal age of 30.7 years old and was racially diverse. A majority of this cohort tested positive for COVID-19 (n = 10, 55%). ECMO was a bridge to recovery for all patients, of whom 14 (78%) were discharged out of the hospital alive. No patients received transplantation or a durable mechanical device. The most common complications were infection (25%) and postpartum hemorrhage (22%). CONCLUSIONS: ECMO use in peripartum patients in a single tertiary center was associated with a high survival rate. Furthermore, a strong multidisciplinary team, careful reevaluation of clinical trajectory, and consideration of complications and risks associated with using ECMO in peripartum patients are possible frameworks to use when challenged with critically ill peripartum patients.

Confirmation and inheritance of glufosinate resistance in an Amaranthus palmeri population from North Carolina.

A putative glufosinate-resistant Amaranthus palmeri population was reported in 2015 in Anson County, North Carolina. The results from dose-response assays conducted in the field suggested plants were surviving lethal rates of glufosinate. Dose-response assays conducted in the glasshouse determined the Anson County accession exhibited reduced susceptibility to glufosinate compared to three glufosinate-susceptible populations. The LD50 values (210-316 g ai ha-1) for the Anson County population were always higher than the LD50 values (118-158 g ai ha-1) for the tested susceptible populations from the dose-response assays. Anson County plants that survived lethal glufosinate rates were reciprocally crossed with susceptible plants to create F1 genotypes and treated with a lethal rate of glufosinate (267 g ai ha-1; ascertained from glasshouse dose-response assay) to determine the distribution of injury and survival for each cross compared to a cross of susceptible parents. The distribution of injury was non-normal for the crosses containing an Anson County plant compared to the cross with a susceptible parent. Survival was 68%-84% for crosses containing an Anson County plant, whereas the survival was significantly reduced to 35% for the susceptible plant cross. Chi-square goodness of fit tests were used to test inheritance models to describe the responses of the genotypes. The resistant × susceptible crosses were best described with a heterozygous two loci with incomplete dominance model compared to the resistant × resistant cross that was best described with a heterozygous single locus with incomplete dominance model. The Anson County population has evolved resistance to glufosinate that is heritable and likely conferred by an oligogenic mechanism with incomplete dominance.

Certolizumab Pegol for the Treatment of Plaque Psoriasis in Routine Clinical Practice: One-Year Results from the CIMREAL Study.

INTRODUCTION: Certolizumab pegol (CZP) is an anti-tumor necrosis factor alpha (TNFα) approved for the treatment of moderate to severe plaque psoriasis (PSO). However, data on its real-world use is currently limited. The objective of this study was to describe the 1-year real-world effectiveness of CZP, its impact on health-related quality of life (HRQoL), and safety outcomes in patients with moderate to severe PSO in multi-country settings. METHODS: CIMREAL, a prospective, noninterventional study, was conducted across Europe and Canada from August 2019 to December 2022. Patients were followed for 1-year, receiving CZP 400 mg initial doses at weeks 0, 2, and 4, followed by CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg Q2W maintenance dosing. Effectiveness was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). Safety was also evaluated. RESULTS: Overall, 399 patients with moderate to severe PSO were included. Of these, 93.7% (374/399) and 77.9% (311/399) completed months 3 and 12, respectively. Mean age (± standard deviation) was 42.9 ± 13.5 years and body mass index was 28.5 ± 6.8 kg/m2, with the majority of patients being female (68.2%). At 12 months, CZP showed substantial effectiveness, achieving PASI 75 and PASI 90 response rates (≥ 75% and ≥ 90% improvement from baseline, respectively) of 77% and 56.5%, respectively. Patients with PASI score of ≤ 3 and ≤ 2 experienced improvement from 3 months (49.8% and 41.1%, respectively) to 12 months (82.0% and 75.3%, respectively). HRQoL considerably improved, with mean DLQI scores decreasing from 12.4 to 2.3 after 12 months of treatment, and the proportion of patients with DLQI 0/1 increased from 28.6% at 3 months to 59.4% at 12 months. The 1-year probability of persistence was approximately 85%. Overall, 30.6% of the patients experienced any adverse events and 9.3% had serious adverse events. CONCLUSION: In routine clinical practice, CZP exhibited consistent effectiveness, positively impacting both skin psoriasis activity and HRQoL. The 1-year persistence of CZP was high, and no new safety signals were identified. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04053881 https://www. CLINICALTRIALS: gov/study/NCT04053881 .

Self-perceived upper extremity motor function predicts health-related quality of life in chronic stroke survivors.

PURPOSE: To examine whether the Upper Extremity Functional Index (UEFI) score independently contributes to the Stroke Impact Scale (SIS) score and quantified its relative contribution to SIS scores in chronic stroke survivors. MATERIALS AND METHODS: A cross-sectional study in a university-based rehabilitation centre with people with chronic stroke (N = 95) aged ≥ 50 years. The outcome measures included paretic hand grip strength, Fugl-Meyer Upper Extremity Assessment (FMA-UE), Wolf Motor Function Test (WMFT), UEFI, and SIS. RESULTS: Correlation analysis revealed that paretic hand grip strength, FMA-UE, UEFI, and WMFT scores exhibited a significant moderate positive correlation with SIS scores (r = 0.544-0.687, p < 0.001). The results of a regression model indicated that after adjustment for demographic factors and stroke-related impairments, the UEFI scores remained independently associated with SIS scores, accounting for 18.8% of the variance. The entire model explained 60.3% of the variance in SIS scores. CONCLUSIONS: Self-perceived UE motor function is a crucial component to be included in rehabilitation programmes aimed at enhancing quality of life and participation among chronic stroke survivors.

Observation-based outcome measures, e.g., Fugl­Meyer Assessment for Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT) could not predict the health-related quality of life (Stroke Impact scale (SIS)) in chronic stroke survivors in our study, which was contradictory with current studies.A self-perceived outcome measure to evaluate upper extremity function (Upper Extremity Functional Index (UEFI)) could independently predict the health-related quality of life (SIS), accounting for 18.8% of the variance.Our study demonstrated that self-perceived UE motor function would be an important component to optimize the rehabilitation programmes aimed at enhancing quality of life and social participation among chronic stroke survivors.

Acute exposure to hydrazine reported to four United States regional poison centers: reconsidering a paradigm.

INTRODUCTION: Exposures to hydrazines occur during aeronautic and space operations and pose a potential risk to personnel. Historically, extensive preparatory countermeasures have been taken due to concern for severe toxicity. This study seeks to better understand manifestations of acute occupational exposures to hydrazine to guide recommendations for management. MATERIALS AND METHODS: A retrospective database review of records from four United States regional poison centers was conducted of all human exposures to hydrazine, monomethylhydrazine, or 1,1-dimethylhydrazine over two decades. Following case abstraction, descriptive statistics were performed to characterize demographics, manifestations, treatments, and outcomes. RESULTS: One hundred and thirty-five cases were identified, and most were adult males exposed to inhaled hydrazine propellant vapors. Fifty-seven percent of patients were asymptomatic following exposure; otherwise, common symptoms were dyspnea, throat irritation, cough, ocular irritation, and headache. All patients were evacuated or received decontamination, with a few reports of symptomatic treatments, including oxygen supplementation and salbutamol (albuterol). Patients usually recovered quickly and were released after a brief healthcare facility evaluation or observed locally. No patients developed delayed symptoms. Symptoms of severe toxicity were not observed, and there were no deaths. DISCUSSION: Acute exposures to hydrazines during operations within the aerospace industry appear to be limited primarily to mucosal and mild pulmonary irritation without significant neurologic, hepatic, or hematologic toxicity. These findings are contrary to previously established expectations and may be related to low-level exposures or possibly due to current emergency countermeasures. CONCLUSIONS: Care in occupational hydrazine exposure will focus on evacuation, decontamination, and symptomatic management of chemical irritant properties of hydrazines. It is reasonable to manage mild cases outside of a healthcare facility. Continued endeavors in human space exploration and habitation will increase the risk of these exposures, making it imperative that clinicians be comfortable with the care and management of these patients.

Developmental origins shape the paediatric cancer genome.

In the past two decades, technological advances have brought unprecedented insights into the paediatric cancer genome revealing characteristics distinct from those of adult cancer. Originating from developing tissues, paediatric cancers generally have low mutation burden and are driven by variants that disrupt the transcriptional activity, chromatin state, non-coding cis-regulatory regions and other biological functions. Within each tumour, there are multiple populations of cells with varying states, and the lineages of some can be tracked to their fetal origins. Genome-wide genetic screening has identified vulnerabilities associated with both the cell of origin and transcription deregulation in paediatric cancer, which have become a valuable resource for designing new therapeutic approaches including those for small molecules, immunotherapy and targeted protein degradation. In this Review, we present recent findings on these facets of paediatric cancer from a pan-cancer perspective and provide an outlook on future investigations.

Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development.

Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or antiviral drugs have been developed to prevent or treat ZIKV infections. The viral protease NS3 and its co-factor NS2B are essential for the cleavage of the Zika polyprotein precursor into individual structural and non-structural proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 48 binders with diverse chemical scaffolds were identified in the active site of the protease, with another 6 fragment hits observed in a potential allosteric binding site. Our work provides potential starting points for the development of potent NS2B-NS3 protease inhibitors. Furthermore, we have structurally characterized a potential allosteric binding pocket, identifying opportunities for allosteric inhibitor development.

Crystallographic Fragment Screen of Coxsackievirus A16 2A Protease identifies new opportunities for the development of broad-spectrum anti-enterovirals.

Enteroviruses are the causative agents of paediatric hand-foot-and-mouth disease, and a target for pandemic preparedness due to the risk of higher order complications in a large-scale outbreak. The 2A protease of these viruses is responsible for the self-cleavage of the poly protein, allowing for correct folding and assembly of capsid proteins in the final stages of viral replication. These 2A proteases are highly conserved between Enterovirus species, such as Enterovirus A71 and Coxsackievirus A16 . Inhibition of the 2A protease deranges capsid folding and assembly, preventing formation of mature virions in host cells and making the protease a valuable target for antiviral activity. Herein, we describe a crystallographic fragment screening campaign that identified 75 fragments which bind to the 2A protease including 38 unique compounds shown to bind within the active site. These fragments reveal a path for the development of non-peptidomimetic inhibitors of the 2A protease with broad-spectrum anti-enteroviral activity.