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INTRODUCTION: It remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial II (DETECT II), a multicentre, outcome-masked, randomised, placebo-controlled, clinical trial comparing DMEK to DSO with ripasudil (DSO-R) for this patient population. METHODS AND ANALYSIS: A total of 60 patients with endothelial dysfunction due to symptomatic FECD will be enrolled from seven participating sites in the USA. The patients will be randomly assigned in a 1:1 ratio to one of the following treatment groups: group 1-DMEK plus topical placebo and group 2-DSO plus topical ripasudil 0.4%. The enrolment period is 24 months. The primary outcome is best spectacle-corrected visual acuity at 12 months. Secondary outcomes include peripheral and central endothelial cell density, visual acuity, vision-related quality of life and Pentacam Scheimpflug tomography. Study outcomes will be analysed using mixed effects linear regression. Adverse events, including rebubble procedures, endothelial failure and graft rejection, will be documented and analysed using appropriate statistical methods. DETECT II aims to provide evidence on the comparative effectiveness of DMEK and DSO-R. The results of this trial will contribute to optimising the treatment of FECD, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee has been empanelled by the National Eye Institute. All study protocols will be subject to review and approval by WCG IRB as the single IRB of record. This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request. TRIAL REGISTRATION NUMBER: NCT05275972.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

IntroductionSchool-based social support for Black students may mediate or modify the association between school segregation and late-life cognition.MethodsStudy of Healthy Aging in African Americans participants (n = 574) reported segregated school attendance and school-based social support. Associations of segregated schooling with domain-specific cognitive outcomes and effect modification or mediation by school-based social support were evaluated with linear mixed models.ResultsSegregated school attendance was associated with increased likelihood of school-based social support. Segregated (vs. desegregated in 6th grade) school attendance was associated with lower executive function (β = -0.18 [-0.34, -0.02]) and semantic memory z-scores (β = -0.31 [-0.48, -0.13]). Social support did not mediate these associations. Estimates for segregated school attendance were attenuated among those who felt supported, although there was limited evidence of statistically significant effect modification.DiscussionEarly-childhood school segregation was associated with poorer cognitive function. Sources of resilience within racialized educational experiences should be further evaluated to bridge inequities.HighlightsSchool segregation is a form of structural racism that affected the educational experiences of Black youth with potentially lasting consequences for healthy brain aging. Black students who attended a segregated school experienced greater school-based social support, which may highlight a potential source of resilience and resistance against the effects of racism-related stressors on cognitive function. The estimated adverse association between attending a segregated school on cognition was larger for students without an adult at school who cared about them versus those with an adult at school who cared about them, but estimates were imprecise.

Contemporary research has begun to show a strong relationship between movements and the perception of time. More specifically, concurrent movements serve to both bias and enhance time estimates. To explain these effects, we recently proposed a mechanism by which movements provide a secondary channel for estimating duration that is combined optimally with sensory estimates. However, a critical test of this framework is that by introducing noise into movements, sensory estimates of time should similarly become noisier. To accomplish this, we had human participants move a robotic arm while estimating intervals of time in either auditory or visual modalities (n = 24, ea.). Crucially, we introduced an artificial tremor in the arm while subjects were moving, that varied across three levels of amplitude (1-3 N) or frequency (4-12 Hz). The results of both experiments revealed that increasing the frequency of the tremor led to noisier estimates of duration. Further, the effect of noise varied with the base precision of the interval, such that a naturally less precise timing (i.e., visual) was more influenced by the tremor than a naturally more precise modality (i.e., auditory). To explain these findings, we fit the data with a recently developed drift-diffusion model of perceptual decision-making, in which the momentary, within-trial variance was allowed to vary across conditions. Here, we found that the model could recapitulate the observed findings, further supporting the theory that movements influence perception directly. Overall, our findings support the proposed framework, and demonstrate the utility of inducing motor noise via artificial tremors.

IntroductionGlobalization has increased the importance of multicultural research to address health disparities and improve healthcare outcomes for underrepresented communities. The International Nursing Network for HIV Research (The Network) serves as a platform for researchers to collaborate on cross-cultural and cross-national HIV studies. This article discusses the Network's approach to overcoming barriers in multicultural and multinational research in a qualitative context.MethodsThe network created a protocol to guide decision-making throughout the translation process of qualitative data collected from participants in their native languages. The protocol includes aspects of why, when, what, who, how, where, and by what means the translation is completed.ResultsThe protocol has allowed researchers to enhance the validity, reliability, and cultural sensitivity of translation process, ensuring the clarity and impact of their research findings.DiscussionRigorous translation practices promote cross-cultural understanding and respect for participants' perspectives, fostering global collaborations and knowledge exchange.

Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo-IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states and was upregulated in astrocytes in multiple sclerosis lesions. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.

An increasing amount of Californias landscape has burned in wildfires in recent decades, in conjunction with increasing temperatures and vapor pressure deficit due to climate change. As the wildland-urban interface expands, more people are exposed to and harmed by these extensive wildfires, which are also eroding the resilience of terrestrial ecosystems. With future wildfire activity expected to increase, there is an urgent demand for solutions that sustain healthy ecosystems and wildfire-resilient human communities. Those who manage disaster response, landscapes, and biodiversity rely on mapped projections of how fire activity may respond to climate change and other human factors. California wildfire is complex, however, and climate-fire relationships vary across the state. Given known geographical variability in drivers of fire activity, we asked whether the geographical extent of fire models used to create these projections may alter the interpretation of predictions. We compared models of fire occurrence spanning the entire state of California to models developed for individual ecoregions and then projected end-of-century future fire patterns under climate change scenarios. We trained a Maximum Entropy model with fire records and hydroclimatological variables from recent decades (1981 to 2010) as well as topographic and human infrastructure predictors. Results showed substantial variation in predictors of fire probability and mapped future projections of fire depending upon geographical extents of model boundaries. Only the ecoregion models, accounting for the unique patterns of vegetation, climate, and human infrastructure, projected an increase in fire in most forested regions of the state, congruent with predictions from other studies.

BackgroundIntersectionality has rarely been considered in research studies of cognitive ageing. We investigated whether life-course financial mobility is differentially associated with later-life memory function and decline across intersectional identities defined by gender, and race and ethnicity.MethodsData were from two harmonised multiethnic cohorts (the Kaiser Healthy Aging and Diverse Life Experiences cohort and the Study of Healthy Aging in African Americans cohort) in northern California, USA (n=2340). Life-course financial mobility, measured using a combination of self-reported financial capital measures in childhood (from birth to age 16 years) and later adulthood (at the cohort baseline) was defined as consistently high, upwardly mobile, downwardly mobile, or consistently low. We clustered individuals into 32 strata representing intersectional identities defined by life-course financial mobility combined with gender, and race and ethnicity. Verbal episodic memory was assessed using the Spanish and English Neuropsychological Assessment Scales over four waves from 2017 to 2023. Adjusted mixed-effects linear regression models were estimated with and without fixed effects of gender, race and ethnicity, and financial mobility, to evaluate whether the random effects of the intersectional identity strata contributed variance to memory beyond individual fixed effects.FindingsMean age was 73·6 years (SD 8·1). Of 2340 individuals, 1460 (62·4%) were women, 880 (37·6%) were men, 388 (16·6%) were Asian, 1136 (48·5%) were Black, 334 (14·3%) were Latinx, and 482 (20·6%) were White. Consistently low and downwardly mobile financial capital were strongly negatively associated with later-life memory at baseline (-0·162 SD units [95% CI -0·273 to -0·051] for consistently low and -0·171 [-0·250 to -0·092] for downwardly mobile), but not rate of change over time. Intersectional identities contributed 0·2% of memory variance after accounting for the fixed effects of gender, race and ethnicity, and financial mobility.InterpretationConsistently low and downward life-course financial mobility are associated with lower later-life memory function. Intersectional identities defined by financial mobility in addition to gender, and race and ethnicity, contribute negligible additional variance to later-life memory in this study setting.FundingUS National Institute on Aging, US National Institutes of Health.

Media exposure to graphic images of violence has proliferated in contemporary society, particularly with the advent of social media. Extensive exposure to media coverage immediately after the 9/11 attacks and the Boston Marathon bombings (BMB) was associated with more early traumatic stress symptoms; in fact, several hours of BMB-related daily media exposure was a stronger correlate of distress than being directly exposed to the bombings themselves. Researchers have replicated these findings across different traumatic events, extending this work to document that exposure to graphic images is independently and significantly associated with stress symptoms and poorer functioning. The media exposure-distress association also appears to be cyclical over time, with increased exposure predicting greater distress and greater distress predicting more media exposure following subsequent tragedies. The war in Israel and Gaza, which began on October 7, 2023, provides a current, real-time context to further explore these issues as journalists often share graphic images of death and destruction, making media-based graphic images once again ubiquitous and potentially challenging public well-being. For individuals sharing an identity with the victims or otherwise feeling emotionally connected to the Middle East, it may be difficult to avoid viewing these images. Through a review of research on the association between exposure to graphic images and public health, we discuss differing views on the societal implications of viewing such images and advocate for media literacy campaigns to educate the public to identify mis/disinformation and understand the risks of viewing and sharing graphic images with others.

Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was

The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimers disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.

Background/objectivesTrait mindfulness (TM) may protect against post-trauma mental health ailments and related impairment. Few studies have evaluated this association in the context of collective traumas using representative samples or longitudinal designs.Design/methodWe explored relationships between TM and collective trauma-related outcomes in a prospective, representative, probability-based sample of 1846 U.S. Gulf Coast residents repeatedly exposed to catastrophic hurricanes, assessed twice during the COVID-19 outbreak (Wave 1: 5/14/20-5/27/20; Wave 2: 12/21/21-1/11/22). Generalized estimating equations examined longitudinal relationships between TM, COVID-19-related fear/worry, hurricane-related fear/worry, global distress, and functional impairment; ordinary least squares regression analyses examined the cross-sectional association between TM and COVID-19-related posttraumatic stress symptoms (PTSS) at Wave 1. Event-related stressor exposure was explored as a moderator.ResultsIn covariate-adjusted models including pre-event mental health ailments and demographics, TM was negatively associated with COVID-19-related fear/worry, hurricane-related fear/worry, global distress, and functional impairment over time; in cross-sectional analyses, TM was negatively associated with COVID-19-related PTSS. TM moderated the relationship between COVID-19 secondary stressor exposure (e.g., lost job/wages) and both global distress and functional impairment over time.ConclusionsResults suggest TM may buffer adverse psychosocial outcomes following collective trauma, with some evidence TM may protect against negative effects of secondary stressor exposure.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the WIN site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

PURPOSE: This study sought to identify the sources of differential performance and misclassification error among local (Indian) and external (non-Indian) corneal specialists in identifying bacterial and fungal keratitis based on corneal photography. METHODS: This study is a secondary analysis of survey data assessing the ability of corneal specialists to identify acute bacterial versus fungal keratitis by using corneal photography. One-hundred images of 100 eyes from 100 patients with acute bacterial or fungal keratitis in South India were previously presented to an international cohort of cornea specialists for interpretation over the span of April to July 2021. Each expert provided a predicted probability that the ulcer was either bacterial or fungal. Using these data, we performed multivariable linear regression to identify factors predictive of expert performance, accounting for primary practice location and surrogate measures to infer local fungal ulcer prevalence, including locality, latitude, and dew point. In addition, Brier score decomposition was used to determine experts reliability (calibration) and resolution (boldness) and were compared between local (Indian) and external (non-Indian) experts. RESULTS: Sixty-six experts from 16 countries participated. Indian practice location was the only independently significant predictor of performance in multivariable linear regression. Resolution among Indian experts was significantly better (0.08) than among non-Indian experts (0.01; P < 0.001), indicating greater confidence in their predictions. There was no significant difference in reliability between the two groups ( P = 0.40). CONCLUSION: Local cornea experts outperformed their international counterparts independent of regional variability in tropical risk factors for fungal keratitis. This may be explained by regional characteristics of infectious ulcers with which local corneal specialists are familiar.

BackgroundIndividuals confronting health threats may display an optimistic bias such that judgments of their risk for illness or death are unrealistically positive given their objective circumstances.PurposeWe explored optimistic bias for health risks using k-means clustering in the context of COVID-19. We identified risk profiles using subjective and objective indicators of severity and susceptibility risk for COVID-19.MethodsBetween 3/18/2020-4/18/2020, a national probability sample of 6,514 U.S. residents reported both their subjective risk perceptions (e.g., perceived likelihood of illness or death) and objective risk indices (e.g., age, weight, pre-existing conditions) of COVID-19-related susceptibility and severity, alongside other pandemic-related experiences. Six months later, a subsample (N = 5,661) completed a follow-up survey with questions about their frequency of engagement in recommended health protective behaviors (social distancing, mask wearing, risk behaviors, vaccination intentions).ResultsThe k-means clustering procedure identified five risk profiles in the Wave 1 sample; two of these demonstrated aspects of optimistic bias, representing almost 44% of the sample. In OLS regression models predicting health protective behavior adoption at Wave 2, clusters representing individuals with high perceived severity risk were most likely to report engagement in social distancing, but many individuals who were objectively at high risk for illness and death did not report engaging in self-protective behaviors.ConclusionsObjective risk of disease severity only inconsistently predicted health protective behavior. Risk profiles may help identify groups that need more targeted interventions to increase their support for public health policy and health enhancing recommendations more broadly.

Poor bone quality is a major factor in skeletal fragility in elderly individuals. The molecular mechanisms that establish and maintain bone quality, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with osteocyte-intrinsic repression of TGFβ signaling (TβRIIocy-/-) that suppresses PLR. The control aged bone displayed decreased TGFβ signaling and PLR, but aging did not worsen the existing PLR suppression in male TβRIIocy-/- bone. This relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFβ. We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of TGFβ-dependent maintenance of collagen integrity.

Wildfires have become more frequent and intense due to climate change and outdoor wildfire fine particulate matter (PM2.5) concentrations differ from relatively smoothly varying total PM2.5. Thus, we introduced a conceptual model for computing long-term wildfire PM2.5 and assessed disproportionate exposures among marginalized communities. We used monitoring data and statistical techniques to characterize annual wildfire PM2.5 exposure based on intermittent and extreme daily wildfire PM2.5 concentrations in California census tracts (2006 to 2020). Metrics included: 1) weeks with wildfire PM2.5 < 5 μg/m3; 2) days with non-zero wildfire PM2.5; 3) mean wildfire PM2.5 during peak exposure week; 4) smoke waves (≥2 consecutive days with

Reductions in nonresidential water demand during the COVID-19 pandemic highlighted the importance of understanding how water age impacts drinking water quality and microbiota in piped distribution systems. Using benchtop model distribution systems, we aimed to characterize the impacts of elevated water age on microbiota in bulk water and pipe wall biofilms. Five replicate constant-flow reactors were fed with municipal chloraminated tap water for 6 months prior to building closures and 7 months after. After building closures, chloramine levels entering the reactors dropped; in the reactor bulk water and biofilms the mean cell counts and ATP concentrations increased over an order of magnitude while the detection of opportunistic pathogens remained low. Water age, and the corresponding physicochemical changes, strongly influenced microbial abundance and community composition. Differential initial microbial colonization also had a lasting influence on microbial communities in each reactor (i.e., historical contingency).

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

The objective of this study was to identify the prevalence and correlates of phosphatidylethanol (PEth) levels suggestive of unhealthy alcohol use among women living with and without HIV who self-reported no or low-risk drinking. We analyzed data from a cross-sectional study among women enrolled in the San Francisco Bay Area site of the Womens Interagency HIV Study (WIHS). Between October 2017 and March 2018, PEth was tested from dried blood spots in 192 women enrolled in the San Francisco site of the WIHS. Using multivariable logistic regression, we identified the correlates of PEth levels suggestive of unhealthy alcohol use (>50 ng/ml) among the 168 women who reported no or low-risk drinking ( 1 (aOR = 3.10, 95% CI = 1.18-8.13), higher high-density lipoprotein levels (aOR = 1.31 per 10 mg/dL increase, 95% CI = 1.01-1.70), and consuming a greater number of drinks per week in the past six months (aOR = 1.40, 95% CI = 1.10-1.78). Nearly a third of women in this study had PEth levels suggestive of unhealthy alcohol use and potentially under-reported their use. To optimize alcohol related health care, there is a need to consider approaches to improve ascertainment of unhealthy alcohol use, especially among Black/African American women and those living with liver disease, so that interventions can be initiated.

BACKGROUND: Almost half of all women in the US experience intimate partner violence (IPV) in their lifetime. The US Preventive Services Task Force recommends IPV screening paired with intervention for women of reproductive age. We aim to understand clinical practices and policies that are beneficial, detrimental, or insufficient to support survivors of IPV in a safety-net healthcare system. METHODS: We sampled 45 women who were 18-64 years old, had experienced IPV within the prior year and were patients in the San Francisco Health Network. We conducted in-depth, semi-structured interviews to elicit their perspectives on disclosing IPV and obtaining support within the healthcare system. We analyzed our data using thematic analysis and grounded theory practices informed by ecological systems theory. FINDINGS: We identified four themes regarding factors that impeded or facilitated discussing and addressing IPV across interpersonal and systemic levels relating to relationship-building, respect, autonomy and resources. (1) Interpersonal barriers included insufficient attention to relationship-building, lack of respect or concern for survivor circumstances, and feeling pressured to disclose IPV or to comply with clinicians recommended interventions. (2) Interpersonal facilitators consisted of patient-centered IPV inquiry, attentive listening, strength-based counseling and transparency regarding confidentiality. (3) Systemic barriers such as visit time limitations, clinician turn-over and feared loss of autonomy from involvement of governmental systems leading to separation from children or harm to partners, negatively affected interpersonal dynamics. (4) Systemic facilitators involved provision of resources through IPV universal education, on-site access to IPV services, and community partnerships. CONCLUSIONS: Women experiencing IPV in our study reported that relationship-building, respect, autonomy, and IPV-related resources were essential components to providing support, promoting safety, and enabling healing in the healthcare setting. Successful trauma-informed transformation of healthcare systems must optimize interpersonal and systemic factors that improve survivor wellbeing while eliminating barriers.

Despite decades of stress research, there still exist substantial gaps in our understanding of how social, environmental, and biological factors interact and combine with developmental stressor exposures, cognitive appraisals of stressors, and psychosocial coping processes to shape individuals stress reactivity, health, and disease risk. Relatively new biological profiling approaches, called multi-omics, are helping address these issues by enabling researchers to quantify thousands of molecules from a single blood or tissue sample, thus providing a panoramic snapshot of the molecular processes occurring in an organism from a systems perspective. In this review, we summarize two types of research designs for which multi-omics approaches are best suited, and describe how these approaches can help advance our understanding of stress processes and the development, prevention, and treatment of stress-related pathologies. We first discuss incorporating multi-omics approaches into theory-rich, intensive longitudinal study designs to characterize, in high-resolution, the transition to stress-related multisystem dysfunction and disease throughout development. Next, we discuss how multi-omics approaches should be incorporated into intervention research to better understand the transition from stress-related dysfunction back to health, which can help inform novel precision medicine approaches to managing stress and fostering biopsychosocial resilience. Throughout, we provide concrete recommendations for types of studies that will help advance stress research, and translate multi-omics data into better health and health care.

Translational medicine has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new bench-to-bedside approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

BackgroundThe US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.Patients and methodsParticipants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.Results and interpretationOn univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09,

INTRODUCTION: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. RESULTS: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

BackgroundA subgroup of adults with celiac disease experience persistent gastrointestinal and extraintestinal symptoms, which vary between individuals and the cause(s) for which are often unclear.MethodsThe present observational study sought to elucidate patterns of persistent symptoms and the relationship between those patterns and gluten-free diet adherence, psychiatric symptoms, and various aspects of quality of life (QOL) in an online sample of adults with celiac disease. U.S. adults with self-reported, biopsy-confirmed celiac disease (N = 523; Mage = 40.3 years; 88% women; 93.5% White) voluntarily completed questionnaires as part of the iCureCeliac® research network: (a) Celiac Symptoms Index (CSI) for physical symptoms and subjective health; (b) Celiac Dietary Adherence Test for gluten-free diet adherence; (c) PROMIS-29, SF-36, and Celiac Disease Quality of Life Survey for psychiatric symptoms and QOL. Symptom profiles were derived using latent profile analysis and profile differences were examined using auxiliary analyses.ResultsLatent profile analysis of CSI items determined a four-profile solution fit best. Profiles were characterized by: (1) little to no symptoms and excellent subjective health (37% of sample); (2) infrequent symptoms and good subjective health (33%); (3) occasional symptoms and fair to poor subjective health (24%); (4) frequent to constant symptoms and fair to poor subjective health (6%). Profiles 2 and 3 reported moderate overall symptomology though Profile 2 reported relatively greater extraintestinal symptoms and Profile 3 reported relatively greater gastrointestinal symptoms, physical pain, and worse subjective health. Profiles differed on anxiety and depression symptoms, limitations due to physical and emotional health, social functioning, and sleep, but not clinical characteristics, gluten-free diet adherence, or QOL. Despite Profile 3's moderate symptom burden and low subjective health as reported on the CSI, Profile 3 reported the lowest psychiatric symptoms and highest quality of life on standardized measures.ConclusionsAdults with celiac disease reported variable patterns of persistent symptoms, symptom severity, and subjective health. Lack of profile differences in gluten-free diet adherence suggests that adjunctive dietary or medical assessment and intervention may be warranted. Lower persistent symptom burden did not necessarily translate to better mental health and QOL, suggesting that behavioral intervention may be helpful even for those with lower celiac symptom burden.

AbstractAs the COVID-19 pandemic spread across the world, immunocompromised individuals such as people with HIV (PWH) may have faced a disproportionate impact on their health and HIV outcomes, both from COVID-19 and from the strategies enacted to contain it. Based on the SPIRIT guidelines, we describe the protocol for an international multisite observational study being conducted by The International Nursing Network for HIV Research, with the Coordinating Center based at the University of California, San Francisco (UCSF) School of Nursing. Site Principal Investigators implement a standardized protocol to recruit PWH to complete the study online or in-person. Questions address demographics; HIV continuum of care indicators; mental and social health; COVID-19 and vaccination knowledge, attitudes, behaviors, and fears; and overall outcomes. Results of this study will contribute to knowledge that can inform responses to future public health crises to minimize their impacts on vulnerable populations such as PWH.

Opinion statementThe treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates2. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

Incomplete longitudinal data are common in life-course epidemiology and may induce bias leading to incorrect inference. Multiple imputation (MI) is increasingly preferred for handling missing data, but few studies explore MI-method performance and feasibility in real-data settings. We compared 3 MI methods using real data under 9 missing-data scenarios, representing combinations of 10%, 20%, and 30% missingness and missing completely at random, at random, and not at random. Using data from Health and Retirement Study (HRS) participants, we introduced record-level missingness to a sample of participants with complete data on depressive symptoms (1998-2008), mortality (2008-2018), and relevant covariates. We then imputed missing data using 3 MI methods (normal linear regression, predictive mean matching, variable-tailored specification), and fitted Cox proportional hazards models to estimate effects of 4 operationalizations of longitudinal depressive symptoms on mortality. We compared bias in hazard ratios, root mean square error, and computation time for each method. Bias was similar across MI methods, and results were consistent across operationalizations of the longitudinal exposure variable. However, our results suggest that predictive mean matching may be an appealing strategy for imputing life-course exposure data, given consistently low root mean square error, competitive computation times, and few implementation challenges.

OBJECTIVE: Nurse turnover can compromise the quality and continuity of home health care. Scope of practice laws, which determine the tasks nurses are allowed to perform and delegate, are an important element of autonomy and vary across states. In this study, we used human resource records from a multistate home health organization to examine the relationship between nurse turnover and whether nurses can delegate tasks to unlicensed aides. DESIGN: A retrospective, cross-sectional analysis. SETTING AND PARTICIPANTS: The study sample included 1820 licensed practical nurses and 3309 registered nurses, who spanned 30 states. The study period was 2016 through 2018. METHODS: We used weighted least squares to study the relationship between nurse turnover for registered and licensed practical nurses and task delegation across state-years. We measured task delegation continuously (0-16 tasks) and as a binary variable (14 or more tasks, which indicated the state was in the top half of the distribution). RESULTS: Across state-years, the turnover rate was 30.8% for licensed practical nurses and 36.8% for registered nurses. Although there was no significant relationship between task delegation and turnover among registered nurses, we found that states in which nurses could delegate the most tasks had lower turnover rates among licensed practical nurses. CONCLUSION AND IMPLICATIONS: The ability to delegate tasks to unlicensed aides was correlated with lower turnover rates among licensed practical nurses, but not among registered nurses. This suggests that the ability to delegate tasks is more likely to affect the workload of licensed practical nurses. This also points to a potential and unexplored element of expanding the scope of practice for nurses: reduced turnover. Given the added work-related hazards associated with home health care, including working in isolation, a lack of social recognition, and inadequate reimbursement, states should consider whether changes in their policy environment could benefit nurses working in home health.

The field of psychoneuroimmunology (PNI) has grown substantially in both relevance and prominence over the past 40 years. Notwithstanding its impressive trajectory, a majority of PNI studies are still based on a relatively small number of analytes. To advance this work, we suggest that PNI, and health research in general, can benefit greatly from adopting a multi-omics approach, which involves integrating data across multiple biological levels (e.g., the genome, proteome, transcriptome, metabolome, lipidome, and microbiome/metagenome) to more comprehensively profile biological functions and relate these profiles to clinical and behavioral outcomes. To assist investigators in this endeavor, we provide an overview of multi-omics research, highlight recent landmark multi-omics studies investigating human health and disease risk, and discuss how multi-omics can be applied to better elucidate links between psychological, nervous system, and immune system activity. In doing so, we describe how to design high-quality multi-omics studies, decide which biological samples (e.g., blood, stool, urine, saliva, solid tissue) are most relevant, incorporate behavioral and wearable sensing data into multi-omics research, and understand key data quality, integration, analysis, and interpretation issues. PNI researchers are addressing some of the most interesting and important questions at the intersection of psychology, neuroscience, and immunology. Applying a multi-omics approach to this work will greatly expand the horizon of what is possible in PNI and has the potential to revolutionize our understanding of mind-body medicine.

BACKGROUND: HIV subtype is associated with varied rates of disease progression. The HIV accessory protein, Nef, continues to be present during antiretroviral therapy (ART) where it has numerous immunoregulatory effects. In this study, we analyzed Nef sequences from HIV subtypes A1, B, C, and D using a machine learning approach that integrates functional amino acid information to identify if unique physicochemical features are associated with Nef functional/structural domains in a subtype-specific manner. METHODS: 2253 sequences representing subtypes A1, B, C, and D were aligned and domains with known functional properties were scored based on amino acid physicochemical properties. Following feature generation, we used statistical pruning and evolved neural networks (ENNs) to determine if we could successfully classify subtypes. Next, we used ENNs to identify the top five key Nef physicochemical features applied to specific immunoregulatory domains that differentiated subtypes. A signature pattern analysis was performed to the assess amino acid diversity in sub-domains that differentiated each subtype. RESULTS: In validation studies, ENNs successfully differentiated each subtype at A1 (87.2%), subtype B (89.5%), subtype C (91.7%), and subtype D (85.1%). Our feature-based domain scoring, followed by t-tests, and a similar ENN identified subtype-specific domain-associated features. Subtype A1 was associated with alterations in Nef CD4 binding domain; subtype B was associated with alterations with the AP-2 Binding domain; subtype C was associated with alterations in a structural Alpha Helix domain; and, subtype D was associated with alterations in a Beta-Sheet domain. CONCLUSIONS: Recent studies have focused on HIV Nef as a driver of immunoregulatory disease in those HIV infected and on ART. Nef acts through a complex mixture of interactions that are directly linked to the key features of the subtype-specific domains we identified with the ENN. The study supports the hypothesis that varied Nef subtypes contribute to subtype-specific disease progression.

Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome.

Exclusive breastfeeding for the first 6 months and continued breastfeeding for 24 months or longer is recommended for all mothers world-wide, including women living with HIV (WLWH). Given evidence of suboptimal infant feeding and the need to understand context specific barriers, we explored experiences of perinatal WLWH in Kisumu, Kenya. We applied a longitudinal qualitative approach (4 in-depth interviews) with 30 women from pregnancy to 14-18 months postpartum. Cross-sectional profiling led to a narrative description of infant feeding across time. The majority of women breastfed exclusively for 6 months and weaned by 18 months. Severe financial and food insecurity were primary challenges as women worked through when/how to breastfeed or stop breastfeeding in the setting of multiple competing priorities/pressures across time. Financial and food support and increased support for breastfeeding beyond 18 months have the potential to reduce women's stress and uncertainty associated with infant feeding as well as optimize infant health and nutrition in this setting.

BACKGROUND: After lung transplantation, both frailty and chronic lung allograft dysfunction (CLAD) commonly develop, and when they do, are associated with poorer outcomes. Given their potential shared mechanisms, we sought to explore the temporal relationship between frailty and CLAD onset. METHODS: In a single center, we prospectively measured frailty by the short physical performance battery (SPPB) repeatedly after transplant. Because of the nature of the relationship between frailty and CLAD is unknown, we tested the association between frailty, modeled as a time-dependent predictor, and CLAD development as well as CLAD development, modeled as a time-dependent predictor, and frailty development. To do so, we used Cox proportional cause-specific hazards and conditional logistic regression models adjusted for age, sex, race, diagnosis, cytomegalovirus serostatus, posttransplant body mass index, and acute cellular rejection episodes as time-dependent covariates. We tested SPPB frailty as a binary (≤9 points) and continuous predictor (12-point scale); as an outcome, we defined frailty as SPPB ≤9. RESULTS: The 231 participants were a mean age of 55.7 y (SD 12.1). After adjusting for covariates, the development of frailty within 3 y after lung transplant was associated with cause-specific CLAD risk (adjusted cause-specific hazard ratio: 1.76; 95% confidence interval [CI], 1.05-2.92 when defining frailty as SPPB ≤9 and adjusted cause-specific hazard ratio: 1.10, 95% CI, 1.03-1.18 per 1-point worsening in SPPB). CLAD onset did not appear to be a risk factor for subsequent frailty (odds ratio, 4.0; 95% CI, 0.4-197.0). CONCLUSIONS: Studying the mechanisms underlying frailty and CLAD could provide new insights into the pathobiology of both and potential targets for intervention.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

IntroductionHigher occupational complexity has been linked to favorable cognitive outcomes, but rarely examined in racially and ethnically diverse populations.MethodsIn a diverse cohort (n = 1536), linear mixed-effects models estimated associations between main lifetime occupational complexity and domain-specific cognitive decline (z-standardized). Occupational complexity with data, people, and things were classified using the Dictionary of Occupational Titles.ResultsFor occupational complexity with data, highest tertile (vs. lowest) was associated with higher baseline executive function (β = 0.11; 95% confidence interval [CI] 0.00-0.22) and slower annual rate of decline (β = 0.03; 95% CI 0.01-0.06), and higher baseline semantic memory (β = 0.14; 95% CI 0.04-0.25). Highest tertile of occupational complexity with people was associated with higher baseline executive function (β = 0.29; 95% CI 0.18-0.40), verbal episodic memory (β = 0.12; 95% CI 0.00-0.24), and semantic memory (β = 0.23; 95% CI 0.12-0.34).DiscussionIn a diverse cohort, higher occupational complexity is associated with better cognition. Findings should be verified in larger cohorts.HighlightFew studies have examined associations of occupational complexity with cognition in diverse populations. Racial and ethnic minorities are disproportionately exposed to lower occupational complexity. Occupational complexity with data and people are associated with better cognition.

IntroductionThe challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory.MethodsIn three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data.ResultsAPM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used.DiscussionConstraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change.HighlightsThe magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

BACKGROUND: Persons who experience homelessness (PEH) have high rates of depression and incur challenges accessing high-quality health care. Some Veterans Affairs (VA) facilities offer homeless-tailored primary care clinics, although such tailoring is not required, within or outside VA. Whether services tailoring enhances care for depression is unstudied. OBJECTIVE: To determine whether PEH in homeless-tailored primary care settings receive higher quality of depression care, compared to PEH in usual VA primary care. DESIGN: Retrospective cohort study of depression treatment among a regional cohort of VA primary care patients (2016-2019). PARTICIPANTS: PEH diagnosed or treated for a depressive disorder. MAIN MEASURES: The quality measures were timely follow-up care (3 + completed visits with a primary care or mental health specialist provider, or 3 + psychotherapy sessions) within 84 days of a positive PHQ-2 screen result, timely follow-up care within 180 days, and minimally appropriate treatment (4 + mental health visits, 3 + psychotherapy visits, 60 + days antidepressant) within 365 days. We applied multivariable mixed-effect logistic regressions to model differences in care quality for PEH in homeless-tailored versus usual primary care settings. KEY RESULTS: Thirteen percent of PEH with depressive disorders received homeless-tailored primary care (n = 374), compared to usual VA primary care (n = 2469). Tailored clinics served more PEH who were Black, who were non-married, and who had low income, serious mental illness, and substance use disorders. Among all PEH, 48% received timely follow-up care within 84 days of depression screening, 67% within 180 days, and 83% received minimally appropriate treatment. Quality metric attainment was higher for PEH in homeless-tailored clinics, compared to PEH in usual VA primary care: follow-up within 84 days (63% versus 46%; adjusted odds ratio [AOR] = 1.61, p = .001), follow-up within 180 days (78% versus 66%; AOR = 1.51, p = .003), and minimally appropriate treatment (89% versus 82%; AOR = 1.58, p = .004). CONCLUSIONS: Homeless-tailored primary care approaches may improve depression care for PEH.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

IntroductionBlack students attending predominantly White institutions (PWIs) versus historically Black colleges and universities (HBCUs) report more harmful discrimination and develop worse mental health outcomes, potentially offsetting the established benefits of college for lowering dementia incidence.MethodsBlack participants in two cohorts (the Kaiser Healthy Aging and Diverse Life Experiences [KHANDLE] and the Study of Healthy Aging in African Americans [STAR]) who had attended college (N = 716) self-reported the college name (classified as HBCU vs. PWI) and completed three waves of executive function (EF) and verbal episodic memory (VEM) assessments. HBCU effects on cognitive level and decline were estimated using adjusted linear mixed-effects models.ResultsHBCU (vs. PWI) attendees averaged better EF (β = 0.05 [-0.22, 0.32]) and VEM (β = 0.21 [-0.06, 0.46]) at age 70 though neither association was statistically significant. HBCU attendance was associated with slightly faster VEM decline (β = -0.03 [-0.05, 0.00]).DiscussionHarmonized analyses with larger studies are needed to estimate important effects of HBCU attendance.HighlightsHigher education is robustly linked to lower dementia risk, yet Black-White inequities persist among college-educated adults. Black students attending predominantly White institutions (PWIs) versus historically Black colleges and universities (HBCUs) report more harmful discrimination and develop worse mental health outcomes, which may offset the established benefits of college for lowering dementia incidence. HBCU (vs. non-HBCU) attendees averaged better executive function and verbal episodic memory (VEM) at average age 70, though confidence intervals were wide and associations were not statistically significant, and averaged slightly faster decline in VEM. Harmonized analyses using larger nationally representative studies are likely needed to avoid underestimating the health effects of HBCU attendance.

BACKGROUND: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments. PATIENTS AND METHODS: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment. RESULTS: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9). CONCLUSIONS: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice.

Inspired by advances in wearable technologies, we design and perform human-subject experiments. We aim to investigate the effects of applying safe actuation (i.e., auditory, gustatory, and olfactory) for the purpose of regulating cognitive arousal and enhancing the performance states. In two proposed experiments, subjects are asked to perform a working memory experiment called n-back tasks. Next, we incorporate listening to different types of music, drinking coffee, and smelling perfume as safe actuators. We employ signal processing methods to seamlessly infer participants' brain cognitive states. The results demonstrate the effectiveness of the proposed safe actuation in regulating the arousal state and enhancing performance levels. Employing only wearable devices for human monitoring and using safe actuation intervention are the key components of the proposed experiments. Our dataset fills the existing gap of the lack of publicly available datasets for the self-management of internal brain states using wearable devices and safe everyday actuators. This dataset enables further machine learning and system identification investigations to facilitate future smart work environments. This would lead us to the ultimate idea of developing practical automated personalized closed-loop architectures for managing internal brain states and enhancing the quality of life.

In the last 30 years, 25 US states have relaxed laws regulating the concealed carrying of firearms (concealed-carry weapons (CCW) laws). These changes may have substantial impacts on violent crime. In a recent study, Doucette et al. (Am J Epidemiol. 2023;192(3):342-355) used a synthetic control approach to assess the effects of shifting from more restrictive may/no-issue CCW laws to less restrictive shall-issue CCW laws on homicides, aggravated assaults, and robberies involving a gun or committed by other means. The study adds to the evidence that more permissive CCW laws have probably increased rates of firearm assault in states adopting these laws. Importantly, this study is the first to identify that specific provisions of shall-issue CCW laws-including denying permits to persons with violent misdemeanor convictions, a history of dangerous behavior, or questionable character and live-fire training requirements-may help mitigate harms associated with shall-issue CCW laws. These findings are timely and salient given the recent Supreme Court ruling striking down a defining element of may-issue laws. This thorough study offers actionable results and provides a methodological model for state firearm policy evaluations. Its limitations reflect the needs of the field more broadly: greater focus on racial/ethnic equity and within-state variation, plus strengthening the data infrastructure on firearm violence and crime.