Microbiota-derived proteins synergize with IL-23 to drive IL22 production in model type 3 innate lymphoid cells.

Microbiota-induced production of IL-22 by type 3 innate lymphoid cells (ILC3) plays an important role in maintaining intestinal health. Such IL-22 production is driven, in part, by IL-23 produced by gut myeloid cells that have sensed select microbial-derived mediators. The extent to which ILC3 can directly respond to microbial metabolites via IL-22 production is less clear, in part due to the difficulty of isolating and maintaining sufficient numbers of viable ILC3 ex vivo.

Cigar, Pipe, and Smokeless Tobacco Use and Cardiovascular Outcomes From Cross Cohort Collaboration.

Importance: Cardiovascular health outcomes associated with noncigarette tobacco products (cigar, pipe, and smokeless tobacco) remain unclear, yet such data are required for evidence-based regulation.

Objective: To investigate the association of noncigarette tobacco products with cardiovascular health outcomes.

Design, Setting, And Participants: This cohort study was conducted within the Cross Cohort Collaboration Tobacco Working Group by harmonizing tobacco-related data and conducting a pooled analysis from 15 US-based prospective cohorts with data on the use of at least 1 noncigarette tobacco product ranging between 1948 and 2015.

Electrocardiogram-based machine learning for risk stratification of patients with suspected acute coronary syndrome.

Background And Aims: The importance of risk stratification in patients with chest pain extends beyond diagnosis and immediate treatment. This study sought to evaluate the prognostic value of electrocardiogram feature-based machine learning models to risk-stratify all-cause mortality in those with chest pain.

Methods: This was a prospective observational cohort study of consecutive, non-traumatic patients with chest pain.

Liver Injury due to Intravenous Methylprednisolone in the Drug-Induced Liver Injury Network.

Background And Aims: Short courses of intravenous (iv) methylprednisolone (MP) can cause drug induced liver injury (DILI). The aim of this study was to assess the clinical features and HLA associations of MP-related DILI enrolled in the US DILI Network (DILIN).

Methods: DILIN cases with MP as a suspected drug were reviewed.

Maintenance of neuronal TDP-43 expression requires axonal lysosome transport.

TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified both specific hits and pathways present across multiple screens, the latter likely responsible for generic protein level maintenance.

The homolog of Sjögren's Syndrome Nuclear Antigen 1 is required for the structural integrity of the centriole and bipolar mitotic spindle assembly.

Centrioles play central roles in ciliogenesis and mitotic spindle assembly. Once assembled, centrioles exhibit long-term stability, a property essential for maintaining numerical control. How centriole stability is achieved and how it is lost in certain biological contexts are still not completely understood.

Structural insights into SSNA1 self-assembly and its microtubule binding for centriole maintenance.

SSNA-1 is a fibrillar protein localized at the area where dynamic microtubule remodeling occurs including centrosomes. Despite the important activities of SSNA1 to microtubules such as nucleation, co-polymerization, and lattice sharing microtubule branching, the underlying molecular mechanism have remained unclear due to a lack of structural information. Here, we determined the cryo-EM structure of SSNA-1 at 4.

In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia.

Background: High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Septic patients are routinely exposed to endogenously released and exogenously administered catecholamines, which may alter cardiac function and perfusion causing ischemia. Early during human septic shock, left ventricular ejection fraction (LVEF) decreases but normalizes in survivors over 7-10 days.

Localizing and Tailoring the Debriefing Assessment for Simulation in Healthcare to Optimize Fit.

Introduction Debriefing in healthcare simulation is helpful in reinforcing learning objectives, closing performance gaps, and improving future practice and patient care. The Debriefing Assessment for Simulation in Healthcare (DASH) is a validated tool. However, localized rater training for the DASH has not been described.

Combining a WT1 Vaccine (Galinpepimut-S) With Checkpoint Inhibition (Nivolumab) in Patients With WT1-Expressing Diffuse Pleural Mesothelioma: A Phase 1 Study.

Introduction: WT1 often presents on the surface of diffuse pleural mesotheliomas (DPMs) and is an ideal therapeutic target. Galinpepimut-S (GPS), a tetravalent, non-human leukocyte antigen-restricted, heteroclitic WT1-specific peptide vaccine was safe and effective in early phase clinical trials and upregulates T-cell suppressive programmed death-ligand 1 in the tumor microenvironment of other malignancies. A randomized phase 2 study of adjuvant GPS in patients with DPM trended toward improved median overall survival.

Associations of perceived discrimination with health outcomes and health disparities in the cohort.

Objective: The goal of this study was to investigate the association of perceived discrimination with health outcomes and disparities.

Materials And Methods: The study cohort consists of 60,180 participants from the four largest SIRE groups in the Research Program participant body: Asian (1,291), Black (4,726), Hispanic (5,336), and White (48,827). A perceived discrimination index (PDI) was derived from participant responses to the "Social Determinants of Health" survey, and the Researcher Workbench was used to analyze associations and mediation effects of PDI and self-identified race and ethnicity (SIRE) with 1,755 diseases.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in .

Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (). This variant (rs3115534-G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations.

Structural variation in nebulin and its implications on phenotype and inheritance: establishing a dominant distal phenotype caused by large deletions.

Introduction: Structural variants (SVs) of the nebulin gene (), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in .

PET/CT guided tuberculosis treatment shortening: a randomized trial.

Six months of chemotherapy using current agents is standard of care for pulmonary, drug-sensitive tuberculosis (TB), even though some are believed to be cured more rapidly and others require longer therapy. Understanding what factors determine the length of treatment required for durable cure in individual patients would allow individualization of treatment durations, provide better clinical tools to determine the of appropriate duration of new regimens, as well as reduce the cost of large Phase III studies to determine the optimal combinations to use in TB control programs. We conducted a randomized clinical trial in South Africa and China that recruited 704 participants with newly diagnosed, drug-sensitive pulmonary tuberculosis and stratified them based on radiographic disease characteristics as assessed by FDG PET/CT scan readers.

Differences in US Adult Dietary Patterns by Cardiovascular Health and Socioeconomic Vulnerability.

Background: Naturally occurring dietary patterns, a major contributor to health, are not well described among those with cardiovascular disease (CVD) - particularly in light of socioeconomic vulnerability. We sought to identify major dietary patterns in the US and their distribution by CVD, social risk factors, and Supplemental Nutrition Assistance Program (SNAP) participation.

Methods: This was a cross-sectional study among 32,498 noninstitutionalized adults from the National Health and Nutrition Examination Survey (2009-2020).

High versus low dose of 14 days treatment of primaquine in infected patients in Cambodia: a randomised open-label efficacy study.

Background: The WHO malaria treatment guidelines recommend a total dose in the range of 3·5 to 7·0 mg/kg of primaquine to eliminate () hypnozoites and prevent relapses. There are however indications that for tropical isolates, notably from Southeast Asia, the lower dose of 3·5 mg/kg is insufficient. Determining the most effective regimen to eliminate hypnozoites is needed to achieve elimination of this malaria parasite.

Increasing Representativeness in the Cohort Using Inverse Probability Weighting.

Large-scale population biobanks rely on volunteer participants, which may introduce biases that compromise the external validity of epidemiological studies. We characterized the volunteer participant bias for the Research Program cohort and developed a set of inverse probability (IP) weights that can be used to mitigate this bias. The cohort is older, more female, more educated, more likely to be covered by health insurance, less White, less likely to drink or smoke, and less healthy compared to the US population.

Demographics, Epidemiology, Mortality, and Difficult-To-Treat Resistance Patterns of Bacterial Bloodstream Infections in the Global United States Military Health System from 2010-2019: A Retrospective Cohort Study.

Objective: To describe demographics, causative pathogens, hospitalization, mortality, and antimicrobial resistance of bacterial bloodstream infections (BSIs) among beneficiaries in the global U.S. Military Health System (MHS), a single-provider healthcare system with 10-year longitudinal follow-up.

A composite socioeconomic deprivation index from survey data: associations with health outcomes and disparities.

Socioeconomic deprivation - defined as a lack of social, economic and material resources - is associated with poor health outcomes and health disparities between population groups. The Research Program is a longitudinal cohort study of diverse participants from the United States, with demographic and social determinants of health data gleaned from participant surveys and health outcome data derived from electronic health records. We developed a composite index of socioeconomic deprivation (iSDI) using a cohort of 202,919 participants - based on education, employment, health insurance, housing, and income data - and we associated iSDI with health outcomes and disparities.

Developing a Research Center for Artificial Intelligence in Medicine.

Artificial intelligence (AI) and machine learning (ML) are driving innovation in biosciences and are already affecting key elements of medical scholarship and clinical care. Many schools of medicine are capitalizing on the promise of these new technologies by establishing academic units to catalyze and grow research and innovation in AI/ML. At Stanford University, we have developed a successful model for an AI/ML research center with support from academic leaders, clinical departments, extramural grants, and industry partners.

Sex-specific associations between self-reported sleep characteristics and 10-year cardiovascular disease risk in men and women of African descent living in a low socioeconomic status environment.

Background: Risk factors for cardiovascular disease (CVD) and sleep health are well-known to be sex- and race-specific. To build on the established relationship between sleep duration and CVD risk, this cross-sectional study aimed to describe sex-specific associations between CVD risk and other sleep characteristics (sleep quality, sleep timing and sleep onset latency) in low-income adults of African descent.

Methods: Self-reported sleep (Pittsburgh Sleep Quality Index [PSQI], Epworth Sleepiness Scale [ESS], Insomnia Severity Index [ISI]), demographic and lifestyle data were collected in 412 adults (56 % women, 35.

TBAT-Catalyzed Dioxasilinane Formation from Beta-Hydroxy Ketones.

Beta-hydroxy ketones can be reduced using a sequence of ruthenium-catalyzed silyl etherification followed by tetrabutylammonium fluoride (TBAF) promoted intramolecular hydrosilylation. Switching from TBAF to tetrabutylammonium difluorotriphenylsilicate (TBAT), even without first forming the silyl ether, gave cyclic dioxasilinane products. These somewhat sensitive compounds could be isolated pure by column chromatography using florisil as the stationary phase.

Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels.