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Early adolescent drinking onset is linked to myriad negative consequences. Using the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) baseline to year 8 data, this study (1) leveraged best subsets selection and Cox Proportional Hazards regressions to identify the most robust predictors of adolescent first and regular drinking onset, and (2) examined the clinical utility of drinking onset in forecasting later binge drinking and withdrawal effects. Baseline predictors included youth psychodevelopmental characteristics, cognition, brain structure, family, peer, and neighborhood domains. Participants (N=538) were alcohol-naïve at baseline. The strongest predictors of first and regular drinking onset were positive alcohol expectancies (Hazard Ratios [HRs]=1.67-1.87), easy home alcohol access (HRs=1.62-1.67), more parental solicitation (e.g., inquiring about activities; HRs=1.72-1.76), and less parental control and knowledge (HRs=.72-.73). Robust linear regressions showed earlier first and regular drinking onset predicted earlier transition into binge and regular binge drinking (βs=0.57-0.95). Zero-inflated Poisson regressions revealed that delayed first and regular drinking increased the likelihood (Incidence Rate Ratios [IRR]=1.62 and IRR=1.29, respectively) of never experiencing withdrawal. Findings identified behavioral and environmental factors predicting temporal paths to youthful drinking, dissociated first from regular drinking initiation, and revealed adverse sequelae of younger drinking initiation, supporting efforts to delay drinking onset.

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

AimThe current study investigated the prospective relationships between parental monitoring, family conflict, and screen time across six screen time modalities in early adolescents in the USA.MethodsWe utilised prospective cohort data of children (ages 10-14 years) from the Adolescent Brain Cognitive Development (ABCD) Study (years baseline to Year 2 of follow-up; 2016-2020; N = 10 757). Adjusted coefficients (B) and 95% confidence intervals (CIs) were estimated using mixed-effect models with robust standard errors.ResultsA higher parental monitoring score was associated with less total screen time (B = -0.37, 95% CI -0.58, -0.16), with the strongest associations being with video games and YouTube videos. Conversely, a higher family conflict score was associated with more total screen time (B = 0.08, 95% CI 0.03, 0.12), with the strongest associations being with YouTube videos, video games, and watching television shows/movies in Years 1 and 2.ConclusionThe current study found that greater parental monitoring was associated with less screen time, while greater family conflict was linked to more screen time. These results may inform strategies to reduce screen time in adolescence, such as improving communication between parents and their children to strengthen family relationships.

Study designRetrospective cohort study of prospectively accrued data.ObjectiveTo evaluate a large, prospective, multicentre dataset of surgically treated degenerative cervical myelopathy (DCM) cases on the contemporary risk of C5 palsy with surgical approach.Summary of background dataThe influence of surgical technique on postoperative C5 palsy after decompression for DCM is intensely debated. Comprehensive, covariate-adjusted analyses are needed using contemporary data.MethodsPatients with moderate to severe DCM were prospectively enrolled in the multicenter, randomized, Phase III CSM-Protect clinical trial and underwent either anterior or posterior decompression between Jan 31, 2012 and May 16, 2017. The primary outcome was the incidence of postoperative C5 palsy, defined as the onset of muscle weakness by at least one grade in manual muscle test at the C5 myotome with slight or absent sensory disruption after cervical surgery. Two comparative cohorts were made based on the anterior or posterior surgical approach. Multivariate hierarchical mixed-effects logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for C5 palsy.ResultsA total of 283 patients were included, and 53.4% underwent posterior decompression. The total incidence of postoperative C5 palsy was 7.4% and was significantly higher in patients who underwent posterior decompression compared with anterior decompression (11.26% vs. 3.03%, P =0.008). After multivariable regression, the posterior approach was independently associated with greater than four times the likelihood of postoperative C5 palsy ( P =0.017). Rates of C5 palsy recovery were comparable between the two surgical approaches.ConclusionThe odds of postoperative C5 palsy are significantly higher after posterior decompression compared to anterior decompression for DCM. This may influence surgical decision-making when there is equipoise in deciding between anterior and posterior treatment options for DCM.Level of evidenceTherapeutic Level-II.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

BackgroundPain is ubiquitous, yet understudied. The objective of this study was to analyze inequities in pain assessment and management for hospitalized older adults focusing on demographic and geriatric-related variables.MethodsThis was a retrospective cohort study from January 2013 through September 2021 of all adults 65 years or older on the general medicine service at UCSF Medical Center. Primary exposures included (1) demographic variables including race/ethnicity and limited English proficiency (LEP) status and (2) geriatric-related variables including age, dementia or mild cognitive impairment diagnosis, hearing or visual impairment, end-of-life care, and geriatrics consult involvement. Primary outcomes included (1) adjusted odds of numeric pain assessment versus other assessments and (2) adjusted opioids administered, measured by morphine milligram equivalents (MME).ResultsA total of 15,809 patients were included across 27,857 hospitalizations with 1,378,215 pain assessments, with a mean age of 77.8 years old. Patients were 47.4% White, 26.3% with LEP, 49.6% male, and 50.4% female. Asian (OR 0.75, 95% CI 0.70-0.80), Latinx (OR 0.90, 95% CI 0.83-0.99), and Native Hawaiian or Pacific Islander (OR 0.77, 95% CI 0.64-0.93) patients had lower odds of a numeric assessment, compared with White patients. Patients with LEP (OR 0.70, 95% CI 0.66-0.74) had lower odds of a numeric assessment, compared with English-speaking patients. Patients with dementia, hearing impairment, patients 75+, and at end-of-life were all less likely to receive a numeric assessment. Compared with White patients (86 MME, 95% CI 77-96), Asian patients (55 MME, 95% CI 46-65) received fewer opioids. Patients with LEP, dementia, hearing impairment and those 75+ years old also received significantly fewer opioids.ConclusionOlder, hospitalized, general medicine patients from minoritized groups and with geriatric-related conditions are uniquely vulnerable to inequitable pain assessment and management. These findings raise concerns for pain underassessment and undertreatment.

Substance use disparities among sexual and gender minority (SGM) people are attributed to minority stress, but few studies have examined minority stress and cannabis use over time or investigated differences in cannabis use trajectories by less-studied gender subgroups. We examined if longitudinal cannabis use trajectories are related to baseline minority stressors and if gender differences persisted after accounting for minority stress. Cannabis use risk was measured annually over four years (2017-2021) within a longitudinal cohort study of SGM adults in the United States (N = 11,813). Discrimination and victimization, internalized stigma, disclosure and concealment, and safety and acceptance comprised minority stress (n = 5,673). Latent class growth curve mixture models identified five cannabis use trajectories: 'low or no risk', 'low moderate risk', 'high moderate risk', 'steep risk increase', and 'highest risk'. Participants who reported past-year discrimination and/or victimization at baseline had greater odds of membership in any cannabis risk category compared to the 'low risk' category (odds ratios [OR] 1.17-1.33). Internalized stigma was related to 'high moderate' and 'highest risk' cannabis use (ORs 1.27-1.38). After accounting for minority stress, compared to cisgender men, gender expansive people and transgender men had higher odds of 'low moderate risk' (ORs 1.61, 1.67) or 'high moderate risk' (ORs 2.09, 1.99), and transgender men had higher odds of 'highest risk' (OR 2.36) cannabis use. This study indicates minority stress is related to prospective cannabis use risk trajectories among SGM people, and transgender men and gender expansive people have greater odds of trajectories reflecting cannabis use risk.

Food cue reactivity (FCR) is an appetitive trait associated with overeating and weight gain. We developed a laboratory craving assessment to objectively evaluate cognitive aspects of FCR. This study examined the preliminary construct and criterion validity of this craving assessment and evaluated 4 different interventions, 2 of which incorporated cue-exposure treatment for food, on craving over treatment and follow-up. 271 treatment-seeking adults with overweight/obesity (body mass index = 34.6[5.2]; age = 46.5[11.8]; 81.2% female; 61.6% non-Latinx White) completed the Food Cue Responsivity Scale and the laboratory craving assessment, during which they alternated holding and smelling a highly craved food and provided craving ratings over 5 min. Participants were subsequently randomized to 26 treatment sessions over 12-months of ROC, Behavioral Weight Loss (BWL), a combined arm (ROC+) and an active comparator (AC), and repeated the craving assessment at post-treatment and 12-month follow-up. Linear mixed-effects models assessed associations between trial type (holding vs. smelling), trial number, pre-treatment FCR, treatment arm, assessment time point, and craving. Cravings were greater when smelling vs. holding food (b = 0.31, p

Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear-distinct philosophical traditions suggest different views of wisdoms cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions-Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets-as perceived by participants-score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

IntroductionAlzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; ?-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed.MethodsA validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories.ResultsSAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive.DiscussionSAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression.HighlightsSAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

Heavy alcohol drinking is a major, preventable problem that adversely impacts the physical and mental health of US young adults. Studies seeking drinking risk factors typically focus on young adults who enrolled in 4-year residential college programs (4YCP) even though most high school graduates join the workforce, military, or community colleges. We examined 106 of these understudied young adults (USYA) and 453 4YCPs from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) by longitudinally following their drinking patterns for 8 years from adolescence to young adulthood. All participants were no-to-low drinkers during high school. Whereas 4YCP individuals were more likely to initiate heavy drinking during college years, USYA participants did so later. Using mental health metrics recorded during high school, machine learning forecasted individual-level risk for initiating heavy drinking after leaving high school. The risk factors differed between demographically matched USYA and 4YCP individuals and between sexes. Predictors for USYA drinkers were sexual abuse, physical abuse for girls, and extraversion for boys, whereas 4YCP drinkers were predicted by the ability to recognize facial emotion and, for boys, greater openness. Thus, alcohol prevention programs need to give special consideration to those joining the workforce, military, or community colleges, who make up the majority of this age group.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Delay discounting refers to the behavioral tendency to devalue rewards as a function of their delay in receipt. Heightened delay discounting has been associated with substance use disorders and multiple co-occurring psychopathologies. Human and animal genetic studies have established that delay discounting is heritable, but only a few associated genes have been identified. We aimed to identify novel genetic loci associated with delay discounting through a genome-wide association study (GWAS) using Heterogeneous Stock (HS) rats, a genetically diverse outbred population derived from eight inbred founder strains. We assessed delay discounting in 650 male and female HS rats using an adjusting amount procedure in which rats chose between smaller immediate sucrose rewards or a larger reward at various delays. Preference switch points were calculated and both exponential and hyperbolic functions were fitted to these indifference points. Area under the curve (AUC) and the discounting parameter k of both functions were used as delay discounting measures. GWAS for AUC, exponential k, and one indifference point identified significant loci on chromosomes 20 and 14. The gene Slc35f1, which encodes a member of the solute carrier family, was the sole gene within the chromosome 20 locus. That locus also contained an eQTL for Slc35f1, suggesting that heritable differences in the expression might be responsible for the association with behavior. Adgrl3, which encodes a latrophilin subfamily G-protein coupled receptor, was the sole gene within the chromosome 14 locus. These findings implicate novel genes in delay discounting and highlight the need for further exploration.

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

IntroductionThe understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.MethodsTo examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.ResultsUsing quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells.DiscussionBy combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients.HighlightsDual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.

BackgroundHIV testing rates among South African men lag behind rates for women and national targets. Community-based HIV self-screening (HIVSS) distribution and follow-up by community health workers (CHWs) is a scalable option to increase testing coverage, diagnosis, and treatment initiation. We provided HIVSS and assisted linkage to care to men not recently tested (within the past 12 months) residing in high-HIV-burden areas of Johannesburg.MethodsCHWs distributed HIVSS in 6 clinic catchment areas. Follow-up to encourage confirmatory testing and antiretroviral therapy initiation was conducted through personal support (PS) or an automated short message service (SMS) follow-up and linkage system in 3 clinic areas each. Using a quasi-experimental pre-post design, we compared differences in the proportion of men testing in the clinic catchment areas during the HIVSS campaign (June-August 2019) to the 3 months prior (March-May 2019) and compared treatment initiations by assisted linkage strategy.ResultsAmong 4793 participants accepting HIVSS, 62% had never tested. Among 3993 participants with follow-up data, 90.6% reported using their HIVSS kit. Testing coverage among men increased by 156%, from under 4% when only clinic-based HIV testing services were available to 9.5% when HIVSS and HIV testing services were available (z = -11.6; P < 0.01). Reported test use was higher for men followed through PS (99% vs. 68% in SMS); however, significantly more men reported reactive self-test results in the SMS group compared with PS (6.4% vs. 2.0%), resulting in more antiretroviral therapy initiations in the SMS group compared with PS (23 vs. 9; P < 0.01).ConclusionsCHW HIVSS distribution significantly increases testing among men. While PS enabled personalized follow-up, reporting differences indicate SMS is more acceptable and better aligned with expectations of privacy associated with HIVSS.

The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50 lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K, 53% for 1750 K). At the lowest intensity (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K, 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.

ObjectivePatients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need.MethodsThis is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome.ResultsTwenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities.DiscussionThe combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

PurposeTo compare rates of retinal nerve fiber layer change over time in healthy, eyes with nonprogressing glaucoma and eyes with progressing glaucoma using single wide-field (SWF) and optic nerve head (ONH) cube scan optical coherence tomography (OCT) images.MethodsForty-five eyes of 25 healthy individuals and 263 eyes of 161 glaucoma patients from the Diagnostic Innovations in Glaucoma Study were included. All eyes underwent 24-2 visual field testing and OCT (Spectralis SD-OCT) ONH and macular imaging. SWF images (up to 43° × 28°) were created by stitching together ONH cube scans centered on the optic disc and macular cube scans centered on the fovea. Visual field progression was defined as guided progression analysis likely progression and/or a significant (P < 0.01) mean deviation slope of less than -1.0 dB/year. Mixed effects models were used to compare rates of change. Highly myopic eyes were included.ResultsThirty glaucomatous eyes were classified as progressing. In eyes with glaucoma, mean global rate of change was -1.22 µm/year (P < 0.001) using SWF images and -0.83 µm/year (P = 0.003) using ONH cube scans. Rate of change was significantly greater in eyes with progressing glaucoma compared with eyes with nonprogressing glaucoma (-1.51 µm/year vs. -1.24 µm/year; P = 0.002) using SWF images and was similar using ONH cube scans (P = 0.27).ConclusionsIn this cohort that includes eyes with and without high axial myopia, the mean rate of retinal nerve fiber layer thinning measured using SWF images was faster in eyes with progressing glaucoma than in eyes with nonprogressing glaucoma. Wide-field OCT images including the ONH and macula can be effective for monitoring glaucomatous progression in patients with and without high myopia.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

ImportanceWomen account for only 28% of current US medical school deans. Studying the differences between women and men in their preparation to becoming deans might help to explain this discrepancy.ObjectiveTo identify differences in the leadership development experiences between women and men in their ascent to the medical school deanship.Design, setting, and participantsIn this qualitative study, volunteers from the roster of the Association of American Medical Colleges Council of Deans were solicited and interviewed from June 15 to November 9, 2023. Women deans were recruited first, then men who had been appointed to their deanships at a similar time to their women counterparts were recruited. Deans were interviewed on topics related to number of applications for deanships, prior leadership roles, leadership development, personal factors, and career trajectories. Interviews were coded, and themes were extracted through conventional content analysis.Main outcome and measuresCareer and leadership development experiences were elicited using a semistructured interview guide.ResultsWe interviewed 17 women and 17 men deans, representing 25.8% (34 of 132) of the total population of US medical school deans. Most deans (23 [67.6%]) practiced a medicine-based specialty or subspecialty. No statistically significant differences were found between women and men with regard to years to attain deanship (mean [SD], 2.7 [3.4] vs 3.7 [3.7] years), years as a dean (mean [SD], 5.7 [5.2] vs 6.0 [5.0] years), highest salary during career (mean [SD], $525 769 [$199 936] vs $416 923 [$195 848]), or medical school rankings (mean [SD], 315.5 [394.5] vs 480.5 [448.9]). Their reports indicated substantive gender differences in their paths to becoming a dean. Compared with men, women deans reported having to work harder to advance, while receiving less support and opportunities for leadership positions by their own institutions. Subsequently, women sought leadership development from external programs. Women deans also experienced gender bias when working with search firms.Conclusions and relevanceThis qualitative study of US medical school deans found that compared with men, women needed to be more proactive, had to participate in external leadership development programs, and had to confront biases during the search process. For rising women leaders, this lack of support had consequences, such as burnout and attrition, potentially affecting the makeup of future generations of medical school deans. Institutional initiatives centering on leadership development of women is needed to mitigate the gender biases and barriers faced by aspiring women leaders.

IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

BackgroundOne challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease.AimTo derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes.MethodsWe used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic fibrosis (> 8 kPa). Possible predictors included data from the EHR for age, gender, diabetes, hypertension, FIB-4, body mass index (BMI), LDL, HDL, and triglycerides.ResultsOf 344 patients (56.4% women), 34 had any hepatic fibrosis, and 15 significant hepatic fibrosis. Three variables (BMI, FIB-4, diabetes) were identified from both approaches. When we used variable cut-offs defined by Youden's index, the final model predicting any hepatic fibrosis had an AUC of 0.75 (95% CI 0.67-0.84), NPV of 91.5% and PPV of 40.0%. The final model with variable categories based on standard clinical thresholds (i.e., BMI ≥ 30 kg/m2; FIB-4 ≥ 1.45) had lower discriminatory ability (AUC 0.65), but higher PPV (50.0%) and similar NPV (91.3%). We observed similar findings for predicting significant hepatic fibrosis.ConclusionsOur results demonstrate that standard thresholds for clinical risk factors/biomarkers may need to be modified for greater discriminatory ability among populations with high prevalence of obesity and diabetes.

BackgroundSurvivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention for bowel dysfunction in survivors of rectal cancer.MethodsNinety-three posttreatment survivors were randomized to the AIMS-RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run-in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self-efficacy, and positive/negative affect.ResultsMost participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS-RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p = .01) and the frequency subscale of the bowel function index (p = .03). The AIMS-RC group reported significantly higher acceptability of the study.ConclusionsSWOG S1820 did not provide evidence of benefit from the AIMS-RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS-RC intervention.

PurposeAnterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation.Materials and methodsMen with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation.ResultsOf 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures (P = .036). Stricture fibrosis did not significantly differ between cohorts (P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: interleukin-9 (IL-9; P = .001), platelet-derived growth factor-BB (P = .004), and CCL5 (P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation (P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014).ConclusionsThe most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.

Adaptation is a universal aspect of neural systems that changes circuit computations to match prevailing inputs. These changes facilitate efficient encoding of sensory inputs while avoiding saturation. Conventional artificial neural networks (ANNs) have limited adaptive capabilities, hindering their ability to reliably predict neural output under dynamic input conditions. Can embedding neural adaptive mechanisms in ANNs improve their performance? To answer this question, we develop a new deep learning model of the retina that incorporates the biophysics of photoreceptor adaptation at the front-end of conventional convolutional neural networks (CNNs). These conventional CNNs build on 'Deep Retina,' a previously developed model of retinal ganglion cell (RGC) activity. CNNs that include this new photoreceptor layer outperform conventional CNN models at predicting male and female primate and rat RGC responses to naturalistic stimuli that include dynamic local intensity changes and large changes in the ambient illumination. These improved predictions result directly from adaptation within the phototransduction cascade. This research underscores the potential of embedding models of neural adaptation in ANNs and using them to determine how neural circuits manage the complexities of encoding natural inputs that are dynamic and span a large range of light levels.

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity-up to 3,000-fold in 15 min-enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals-two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision-between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.

ObjectiveHispanic/Latino individuals in the U.S. have the highest prevalence of undiagnosed and untreated diabetes and are at increased risk for cognitive impairment. In this study, we examine glycemic control in relation to cognitive aging and impairment in a large prospective cohort of middle-aged and older Hispanic/Latino individuals of diverse heritages.Research design and methodsStudy of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) is a Hispanic Community Health Study/Study of Latinos (HCHS/SOL) ancillary study. HCHS/SOL is a multisite (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA), probability sampled prospective cohort study. SOL-INCA enrolled 6,377 diverse Hispanic/Latino individuals aged 50 years and older (2016-2018). The primary outcomes were cognitive function, 7-year cognitive decline, and mild cognitive impairment (MCI). The primary glycemia exposure variables were measured from fasting blood samples collected at HCHS/SOL visit 1 (2008-2011).ResultsVisit 1 mean age was 56.5 years ± 8.2 SD, and the average glycosylated hemoglobin A1C (HbA1c) was 6.12% (43.5 ± 14.6 mmol/mol). After covariate adjustment, higher HbA1c was associated with accelerated 7-year global (b = -0.045; 95% CI -0.070; -0.021; in z score units) and executive cognitive decline and a higher prevalence of MCI (odds ratio 1.20; 95% CI 1.11; 1.29).ConclusionsElevated HbA1c levels were associated with 7-year executive cognitive decline and increased MCI risk among diverse middle-aged and older Hispanic/Latino individuals. Our findings indicate that poor glycemic control in midlife may pose significant risks for cognitive decline and MCI later in life among Hispanic/Latino individuals of diverse heritages.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

ImportanceUrinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020).InterventionsCPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (

ImportancePneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed.ObjectiveTo evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia.Design, setting, and participantsCluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020.InterventionCPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (

IntroductionGlobally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the 'most at-risk' group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.Methods and analysisWe are conducting a two-arm randomised wait-list controlled trial of the intervention's efficacy in São Paulo, Brazil, to improve uptake of HIV testing and PrEP among transgender women (N=400). The primary outcomes are changes in HIV testing (self-testing and clinic based), changes in PrEP uptake and changes in PrEP persistence at baseline and follow-up assessment for 12 months at 3-month intervals.Ethics and disseminationThis study was approved by University of California, San Francisco Institutional Review Board (15-17910) and Comissão Nacional de Ética em Pesquisa (Research Ethics National Commission, CAAE: 25215219.8.0000.5479) in Brazil. Participants provided informed consent before enrolment. We are committed to collaboration with National Institutes of Health officials, other researchers, and health and social services communities for rapid dissemination of data and sharing of materials. The results will be published in peer-reviewed academic journals and scientific presentations.Trial registration numberNCT03081559.

Several studies demonstrate gender and partisan differences among Americans in COVID-19 socioeconomic consequences, attitudes, and behaviors. The authors of this study use six waves of panel survey data to explore the intersection of gender and party across COVID-19 mitigation behaviors, concerns, and policy preferences. The authors observe small gender gaps on several measures; however, partisan differences are larger than gender differences when considering the interaction between gender and partisanship. Democratic women are more similar to Democratic men on these measures than to Republican women. On virtually all measures, Republican women report lower levels of mitigation behaviors, worries, and support for expansive government policies compared to Democratic women and men. Analyzing the interaction of gender and partisanship illuminates how individuals navigated the pandemic with respect to identity factors that often pull in different directions. These findings suggest that one's partisan identity is more consequential than gender when it comes to COVID behaviors, concerns, and policy preferences.

Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective electronic health record (EHR) cohort study of 2,391,006 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 76 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28-120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There were significant associations between a diagnosis of any psychiatric disease and five categories of PASC-AMs with odds ratios highest for neurological, cardiovascular, and constitutional PASC-AMs with odds ratios of 1.31, 1.29, and 1.23 respectively. Secondary analysis revealed that the proportions of 50 individual clinical features significantly differed between patients diagnosed with different psychiatric diseases. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.

BackgroundLow grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited.AimWe examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors.MethodsParticipants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index).ResultsMean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed.ConclusionsGrip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

BackgroundSkeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD.MethodsForty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype.ResultsAbnormal myofibre proportion was defined in males with COPD (n = 29) as 22% type IIx/IIax fibres and in females with COPD (n = 17) as 12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density.ConclusionsOur findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

PurposeMany survivors of rectal cancer experience persistent bowel dysfunction. There are few evidence-based symptom management interventions to improve bowel control. The purpose of this study is to describe recruitment and pre-randomization baseline sociodemographic, health status, and clinical characteristics for SWOG S1820, a trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention.MethodsSWOG S1820 aimed to determine the preliminary efficacy, feasibility, and acceptability of AIMS-RC, a symptom management intervention for bowel health, comparing intervention to attention control. Survivors with a history of cancers of the rectosigmoid colon or rectum, within 6-24 months of primary treatment completion, with a post-surgical permanent ostomy or anastomosis, and over 18 years of age were enrolled. Outcomes included total bowel function, low anterior resection syndrome, quality of life, motivation for managing bowel health, self-efficacy for managing symptoms, positive and negative affect, and study feasibility and acceptability.ResultsThe trial completed accrual over a 29-month period and enrolled 117 participants from 34 institutions across 17 states and one US Pacific territory. At baseline, most enrolled participants reported self-imposed diet adjustments after surgery, persistent dietary intolerances, and bowel discomfort post-treatment, with high levels of constipation and diarrhea (grades 1-4).ConclusionsSWOG S1820 was able to recruit, in a timely manner, a study cohort that is demographically representative of US survivors of rectal cancer. Baseline characteristics illustrate the connection between diet/eating and bowel symptoms post-treatment, with many participants reporting diet adjustments and persistent inability to be comfortable with dietary intake.ClinicaltrialsGov registration date12/19/2019.ClinicaltrialsGov identifierNCT#04205955.

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5'UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

Purpose: Sexual and gender minority (SGM) people are at greater risk for substance use than heterosexual and cisgender people, but most prior work is limited by cross-sectional analyses or the examination of single substance use. This study examined substance use over time among SGM people to identify patterns of polysubstance use at the intersection of sex and gender. Methods: Data were collected annually over 4 years from SGM respondents (n = 11,822) in The Population Research in Identity and Disparities for Equality (PRIDE) Study. Differences in substance use patterns (any prior 30-day use of 15 substances) by gender subgroup were examined with latent class analysis, and multinomial regression models tested relationships between gender subgroup and substance use. Results: Eight classes of substance use were observed. The three most common patterns were low substance use (49%), heavy episodic alcohol use (≥5 alcoholic drinks on one occasion) with some cannabis and tobacco use (14%), and cannabis use with some tobacco and declining heavy episodic alcohol use (13%). Differences observed included lower odds of patterns defined by heavy episodic alcohol use with some cannabis and tobacco use in all gender subgroups relative to cisgender men and persons with low substance use (odds ratios [ORs] 0.26-0.60). Gender expansive people assigned female at birth, gender expansive people assigned male at birth, and transgender men had greater odds of reporting cannabis use with small percentages of heavy episodic alcohol and tobacco use (ORs: 1.41-1.60). Conclusion: This study suggests that there are unique patterns of polysubstance use over time among gender subgroups of SGM people.

Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

PurposeEffective visual perceptual processing is one of the many components of surgical competence. Human face identification is most efficient when viewed upright. However, it is not yet clear how this perception sensitivity impacts eyelid symmetry. This study investigates surgeons' and laypeople's accuracy and efficiency in perceiving eyelid asymmetry from different spatial perspectives.MethodsA prospective psychometric experiment was conducted where oculoplastic surgeons were recruited from the American Society of Ophthalmic Plastic and Reconstructive Surgery and the Brazilian Oculoplastic Surgery Society, and control participants were recruited via crowdsourcing (Amazon's Mechanical Turk). Standard illustrations of the human face with varying degrees of eyelid abnormality, laterality, gender and rotation were presented to participants who were asked to judge whether the eyelids were symmetric or asymmetric.ResultsThe survey was completed by 75 oculoplastic surgeons (49.33% male; mean age of 46.9±10.7) and 192 lay individuals (54.6% male; mean age 34.6±11.3 years). Among oculoplastic surgeons, deviation from upright was significantly associated with increased reaction time and decreased proportion correct (OR per 45° for peak 0.68, 95% CI 0.60 to 0.77, p