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Spontaneous neural activity coherently relays information across the brain. Several efforts have been made to understand how spontaneous neural activity evolves at the macro-scale level as measured by resting-state functional magnetic resonance imaging (rsfMRI). Previous studies observe the global patterns and flow of information in rsfMRI using methods such as sliding window or temporal lags. However, to our knowledge, no studies have examined spatial propagation patterns evolving with time across multiple overlapping 4D networks. Here, we propose a novel approach to study how dynamic states of the brain networks spatially propagate and evaluate whether these propagating states contain information relevant to mental illness. We implement a lagged windowed correlation approach to capture voxel-wise network-specific spatial propagation patterns in dynamic states. Results show systematic spatial state changes over time, which we confirmed are replicable across multiple scan sessions using human connectome project data. We observe networks varying in propagation speed; for example, the default mode network (DMN) propagates slowly and remains positively correlated with blood oxygenation level-dependent (BOLD) signal for 6-8 s, whereas the visual network propagates much quicker. We also show that summaries of network-specific propagative patterns are linked to schizophrenia. More specifically, we find significant group differences in multiple dynamic parameters between patients with schizophrenia and controls within four large-scale networks: default mode, temporal lobe, subcortical, and visual network. Individuals with schizophrenia spend more time in certain propagating states. In summary, this study introduces a promising general approach to exploring the spatial propagation in dynamic states of brain networks and their associated complexity and reveals novel insights into the neurobiology of schizophrenia. more...

The behavioral variant of frontotemporal dementia (bvFTD) includes symptoms that reflect altered pursuit of rewards, including food, alcohol, and money. Little is known, however, about how these reward changes relate to atrophy and functional connectivity within reward-related regions. The goal of this study was to examine the structural and functional correlates of valence perception for olfactory rewards in 24 patients with bvFTD. Regression analysis of resting-state brain functional connectivity indicated that more positive valence ratings of olfactory stimuli were predicted by ventral pallidum connectivity to other reward circuit regions, particularly functional connectivity between ventral pallidum and bilateral anterior cingulate cortex/ventromedial prefrontal cortex. Structural analysis showed that atrophy of the anterior cingulate cortex was also significantly associated with perceiving stimuli as more rewarding. Finally, there was a significant interaction between ventral pallidum connectivity and atrophy of the anterior cingulate cortex. More specifically, the ventral pallidum connectivity had a greater effect on the positive perception of olfactory stimuli in the setting of low anterior cingulate cortex volume. These findings indicate that atrophy and functional connectivity within reward-relevant regions exert independent and interacting effects on the perception of pleasantness in bvFTD, potentially due to changes in hedonic liking signals. more...

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts. more...

Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is an agnostic method for broad-based diagnosis of central nervous system (CNS) infections. Here we analyzed the 7-year performance of clinical CSF mNGS testing of 4,828 samples from June 2016 to April 2023 performed by the University of California, San Francisco (UCSF) clinical microbiology laboratory. Overall, mNGS testing detected 797 organisms from 697 (14.4%) of 4,828 samples, consisting of 363 (45.5%) DNA viruses, 211 (26.4%) RNA viruses, 132 (16.6%) bacteria, 68 (8.5%) fungi and 23 (2.9%) parasites. We also extracted clinical and laboratory metadata from a subset of the samples (n = 1,164) from 1,053 UCSF patients. Among the 220 infectious diagnoses in this subset, 48 (21.8%) were identified by mNGS alone. The sensitivity, specificity and accuracy of mNGS testing for CNS infections were 63.1%, 99.6% and 92.9%, respectively. mNGS testing exhibited higher sensitivity (63.1%) than indirect serologic testing (28.8%) and direct detection testing from both CSF (45.9%) and non-CSF (15.0%) samples (P more...

Our understanding of brain iron regulation and its disruption in disease is limited. Excess iron affects motor circuitry, contributing to Parkinson's disease (PD) risk. The molecular mechanisms regulating central iron levels, beyond a few well-known genes controlling peripheral iron, remain unclear. We generated scores based on the archetypal brain iron accumulation observed in magnetic resonance imaging scans of individuals with excessive dietary iron absorption and hemochromatosis risk. Genome-wide analysis revealed that this score is highly heritable, identifying loci associated with iron homeostasis, and driven by peripheral iron levels. Our score predicted gait abnormalities and showed a U-shaped relationship with PD risk, identifying individuals with threefold increased risk. These results establish a hormetic relationship between brain iron and PD risk, where central iron levels are strongly determined by genetics via peripheral iron. This framework combining forward and reverse genetics is a powerful study design to understand genomic drivers underlying high dimensional phenotypes. more...

Tools for rapid identification of novel and/or emerging viruses are urgently needed for clinical diagnosis of unexplained infections and pandemic preparedness. Here we developed and clinically validated a largely automated metagenomic next-generation sequencing (mNGS) assay for agnostic detection of respiratory viral pathogens from upper respiratory swab and bronchoalveolar lavage samples in more...

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases. more...

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations. more...

Understanding the contribution of gene-environment interactions (GxE) to complex trait variation can provide insights into disease mechanisms, explain sources of heritability, and improve genetic risk prediction. While large biobanks with genetic and deep phenotypic data hold promise for obtaining novel insights into GxE, our understanding of GxE architecture in complex traits remains limited. We introduce a method to estimate the proportion of trait variance explained by GxE (GxE heritability) and additive genetic effects (additive heritability) across the genome and within specific genomic annotations. We show that our method is accurate in simulations and computationally efficient for biobank-scale datasets. We applied our method to common array SNPs (MAF ≥1%), fifty quantitative traits, and four environmental variables (smoking, sex, age, and statin usage) in unrelated white British individuals in the UK Biobank. We found 68 trait-E pairs with significant genome-wide GxE heritability (p more...

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for NTRK-positive solid tumors in academic cancer centers remains largely unknown. OBJECTIVE: To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with NTRK-positive solid tumors treated at US academic cancer centers. METHODS: This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an NTRK fusion-positive (NTRK1, NTRK2, NTRK3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, NTRK testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate. RESULTS: In total, 6 centers contributed data for 55 patients with NTRK-positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to NTRK testing was 85 days (IQR = 44-978). At the time of NTRK testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). NTRK1 fusions were most common (45%), followed by NTRK3 (40%) and NTRK2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive NTRK test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies. CONCLUSIONS: This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy. more...

BackgroundChildhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks.ObjectiveThis population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring.MethodsData on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers.ResultsOffspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth.ConclusionsIn this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer. more...

BACKGROUND: Female sex is a significant risk factor for pulmonary arterial hypertension (PAH), yet males with PAH have worse survival - a phenomenon referred to as the sex paradox in PAH. METHODS: All adult PAH patients in the Pulmonary Hypertension Association Registry (PHAR) with congruent sex and gender were included. Baseline differences in demographics, hemodynamics, functional parameters, and quality of life were assessed by sex. Kaplan-Meier survival analysis was used to evaluate survival by sex. Mediation analysis was conducted with Cox proportional hazards regression by comparing the unadjusted hazard ratios for sex before and after adjustment for covariates. The plausibility of collider-stratification bias was assessed by modeling how large an unmeasured factor would have to be to generate the observed sex-based mortality differences. Subgroup analysis was performed on idiopathic and incident patients. RESULTS: Among the 1,891 patients included, 75% were female. Compared to men, women had less favorable hemodynamics, lower 6-minute walk distance, more PAH therapies, and worse functional class; however, sex-based differences were less pronounced when accounting for body surface area or expected variability by gender. On multivariate analysis, women had a 48% lower risk of death compared to men (Hazard Ratio 0.52, 95% Confidence interval 0.36 - 0.74, p more...

BackgroundMaternal solvent exposure has been suspected to increase offspring cancer risk. The study aimed to evaluate the associations between maternal residential exposure to solvents from industrial pollution during pregnancy and childhood cancer.MethodsThe present study included 15,744 cancer cases (aged 0-19 years at diagnosis) identified from California Cancer Registry and 283,141 controls randomly selected from California Birth Registry (20:1 frequency-matched by birth year: 1998-2016). We examined industrial releases of tetrachloroethylene and 1,1,1-trichloroethane within 3 km of the birth address, while we used a 5 km buffer for carbon disulfide. We calculated the total exposure from all linked Toxic Release Inventory sites during each index pregnancy and assigned "ever/never" and "high/low exposed/unexposed" exposure, using median values. We performed quadratic decay models to estimate cancer risks associated with maternal solvent exposure in pregnancy.Results1,1,1-Trichloroethane was associated with rhabdomyosarcoma (adjusted Odds Ratio (aOR): 1.96; 95% Confidence Interval (CI): 1.16, 3.32) in the "ever exposed" group. Ever exposure to carbon disulfide was associated with increased risks of medulloblastoma (OR = 1.85, 95% CI 1.01, 3.40) and ependymoma (OR = 1.63, 95% CI 0.97, 2.74).ConclusionsOverall, our findings suggested maternal residential exposure to solvents from industrial sources might be associated with elevated childhood cancer risks. more...

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble models performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations. more...

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimers disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimers disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimers disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders. more...

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases. more...

Exposure to heat is associated with a substantial burden of disease and is an emerging issue in the context of climate change. Heat is of particular concern in India, which is one of the worlds hottest countries and also most populous, where relatively little is known about personal heat exposure, particularly in rural areas. Here, we leverage data collected as part of a randomized controlled trial to describe personal temperature exposures of adult women (40-79 years of age) in rural Tamil Nadu. We also characterize measurement error in heat exposure assessment by comparing personal exposure measurements to the nearest ambient monitoring stations and to commonly used modeled temperature data products. We find that temperatures differ across individuals in the same area on the same day, sometimes by more than 5 °C within the same hour, and that some individuals experience sharp increases in heat exposure in the early morning or evening, potentially a result of cooking with solid fuels. We find somewhat stronger correlations between the personal exposure measurements and the modeled products than with ambient monitors. We did not find evidence of systematic biases, which indicates that adjusting for discrepancies between different exposure measurement methods is not straightforward. more...

Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID-19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS-CoV-2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants. We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS-CoV-2 positive test March-August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS-CoV-2 infection. Patient-reported Long COVID symptoms, symptom rebound and test-positivity rebound were asked on subsequent surveys at least 3 months after SARS-CoV-2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median age was 55 years and 66% were female. At 5.4 ± 1.3 months after infection, nirmatrelvir treatment was not associated with subsequent Long COVID symptoms (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.80-1.64; p = 0.45). Among 666 treated who answered rebound questions, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR: 1.34; 95% CI: 0.74-2.41; p = 0.33). Within this cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS-CoV-2 infection and rebound after nirmatrelvir treatment were not associated with Long COVID symptoms more than 90 days after infection. more...

BackgroundWhereas clinical experience in dementia indicates high risk for financial mismanagement, there has been little formal study of real world financial errors in dementia.ObjectiveWe aimed to compare caregiver-reported financial mistakes among people with Alzheimer's disease, behavioral variant frontotemporal dementia (bvFTD), and primary progressive aphasia (PPA).MethodsCaregivers reported whether participants with dementia had made financial mistakes within the last year; and if so, categorized these as resulting from: (a) being too trusting or gullible, (b) being wasteful or careless with money, or (c) trouble with memory. In a pre-registered analysis https://archive.org/details/osf-registrations-vupj7-v1), we examined the hypotheses that (1) financial mistakes due to impaired socioemotional function and diminished sensitivity to negative outcomes are more prevalent in bvFTD than in Alzheimer's disease, and (2) financial mistakes due to memory are more prevalent in Alzheimer's disease than in bvFTD. Exploratory analyses addressed vulnerability in PPA and brain-behavior relationships using voxel-based morphometry.ResultsConcordant with our first hypothesis, bvFTD was more strongly associated than Alzheimer's disease with mistakes due to being too trusting/gullible or wasteful/careless; contrary to our second hypothesis, both groups were similarly likely to make mistakes due to memory. No differences were found between Alzheimer's disease and PPA. Exploratory analyses indicated associations between financial errors and atrophy in right prefrontal and insular cortex.ConclusionsOur findings cohere with documented socioemotional and valuation impairments in bvFTD, and with research indicating comparable memory impairment between bvFTD and Alzheimer's disease. more...

COVID-19 increased the prevalence of clinically significant anxiety in the United States. To investigate contributing factors we analyzed anxiety, reported online via monthly Generalized Anxiety Disorders-7 (GAD-7) surveys between April 2020 and May 2022, in association with self-reported worry about the health effects of COVID-19, economic difficulty, personal COVID-19 experience, and subjective social status. 333,292 anxiety surveys from 50,172 participants (82% non-Hispanic white; 73% female; median age 55, IQR 42-66) showed high levels of anxiety, especially early in the pandemic. Anxiety scores showed strong independent associations with worry about the health effects of COVID-19 for oneself or family members (GAD-7 score +3.28 for highest vs. lowest category; 95% confidence interval: 3.24, 3.33; p more...

PurposeClinical management of disc degeneration in patients with chronic low back pain (cLBP) is hampered by the challenge of distinguishing pathologic changes relating to pain from physiologic changes related to aging. The goal of this study was to use imaging biomarkers of disc biochemical composition to distinguish degenerative changes associated with cLBP from normal aging.MethodsT1ρ MRI data were acquired from 133 prospectively enrolled subjects for this observational study (80 cLBP, 53 controls; mean ± SD age = 43.9 ± 13.4 years; 61 females, 72 males). The mean T1ρ relaxation time in the nucleus pulposus (NP-T1ρ; n = 650 discs) was used as a quantitative biomarker of disc biochemical composition. Linear regression was used to assess associations between NP-T1ρ and age, sex, spinal level, and study group, and their interactions.ResultsNP-T1ρ values were lower in cLBP patients than controls (70.8 ± 22.8 vs. 76.4 ± 22.2 ms, p = 0.009). Group differences were largest at L5-S1 (ΔT1ρcLBP-control = -11.3 ms, p more...

BackgroundDesmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.MethodsWe conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.ResultsFrom May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P more...

ObjectivesThis double-blind randomized controlled trial investigated raising serum 25-hydroxyvitamin D (25D) with extended-release calcifediol (ERC) on time to symptom resolution in patients with mild to moderate COVID-19.MethodsCOVID-19 outpatients received oral ERC (300 mcg on days 1-3 and 60 mcg on days 4-27) or placebo (NCT04551911). Symptoms were self-reported daily. Primary end points were raising 25D to ≥50 ng/mL and decreasing resolution time for five aggregated symptoms (three respiratory).ResultsIn all, 171 patients were randomized, 160 treated and 134 (65 ERC, 69 placebo) retained. The average age was 43 y (range 18-71), 59% were women. The mean baseline 25D was 37 ± 1 (SE) ng/mL. In the full analysis set (FAS), 81% of patients in the ERC group achieved 25D levels of ≥50 ng/mL versus 15% in the placebo group (P < 0.0001). In the per-protocol (PP) population, mean 25D increased with ERC to 82 ± 4 (SE) ng/mL (P < 0.0001) by day 7; the placebo group trended lower. Symptom resolution time was unchanged in the FAS by ERC (hazard ratio [HR], 0.983; 95% confidence interval [CI], 0.695-1.390; P = 0.922). In the PP population, respiratory symptoms resolved 4 d faster when 25D was elevated above baseline level at both days 7 and 14 (median 6.5 versus 10.5 d; HR, 1.372; 95% CI, 0.945-1.991; P = 0.0962; Wilcoxon P = 0.0386). Symptoms resolved in both treatment groups to a similar extent by study end. Safety concerns including hypercalcemia were absent with ERC treatment.ConclusionERC safely raised serum 25D to ≥50 ng/mL in outpatients with COVID-19, possibly accelerating resolution of respiratory symptoms and mitigating the risk for pneumonia. These findings warrant further study. more...

BackgroundLittle is known about whether people who use both tobacco and cannabis (co-use) are more or less likely to have mental health disorders than single substance users or non-users. We aimed to examine associations between use of tobacco and/or cannabis with anxiety and depression.MethodsWe analyzed data from the COVID-19 Citizen Science Study, a digital cohort study, collected via online surveys during 2020-2022 from a convenience sample of 53,843 US adults (≥ 18 years old) nationwide. Past 30-day use of tobacco and cannabis was self-reported at baseline and categorized into four exclusive patterns: tobacco-only use, cannabis-only use, co-use of both substances, and non-use. Anxiety and depression were repeatedly measured in monthly surveys. To account for multiple assessments of mental health outcomes within a participant, we used Generalized Estimating Equations to examine associations between the patterns of tobacco and cannabis use with each outcome.ResultsIn the total sample (mean age 51.0 years old, 67.9% female), 4.9% reported tobacco-only use, 6.9% cannabis-only use, 1.6% co-use, and 86.6% non-use. Proportions of reporting anxiety and depression were highest for the co-use group (26.5% and 28.3%, respectively) and lowest for the non-use group (10.6% and 11.2%, respectively). Compared to non-use, the adjusted odds of mental health disorders were highest for co-use (Anxiety: OR = 1.89, 95%CI = 1.64-2.18; Depression: OR = 1.77, 95%CI = 1.46-2.16), followed by cannabis-only use, and tobacco-only use. Compared to tobacco-only use, co-use (OR = 1.35, 95%CI = 1.08-1.69) and cannabis-only use (OR = 1.17, 95%CI = 1.00-1.37) were associated with higher adjusted odds for anxiety, but not for depression. Daily use (vs. non-daily use) of cigarettes, e-cigarettes, and cannabis were associated with higher adjusted odds for anxiety and depression.ConclusionsUse of tobacco and/or cannabis, particularly co-use of both substances, were associated with poor mental health. Integrating mental health support with tobacco and cannabis cessation may address this co-morbidity. more...

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and its corresponding ligand PD-L1 are being increasingly used for a wide variety of cancers, including refractory sarcomas. Autoimmune hepatitis is a known side effect of ICIs, and is typically managed with broad, non-specific immunosuppression. Here, we report a case of severe autoimmune hepatitis occurring after anti-PD-1 therapy with nivolumab in a patient with osteosarcoma. Following prolonged unsuccessful treatment with intravenous immunoglobulin, steroids, everolimus, tacrolimus, mycophenolate, and anti-thymoglobulin, the patient was eventually treated with the anti-CD25 monoclonal antibody basiliximab. This resulted in prompt, sustained resolution of her hepatitis without significant side effects. Our case demonstrates that basiliximab may be an effective therapy for steroid-refractory severe ICI-associated hepatitis. more...

Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects. more...

This paper tested whether shift-&-persist coping, or coping involving the combination of cognitive reappraisal, acceptance, and optimism (Chen & Miller, Perspectives on Psychological Science, 2012, 7, 135), attenuates the risks presented by economic hardship and ethnic discrimination for change in depressive symptoms from 9th to 12th grade, in a sample of 674 Mexican American youth (Mage W1 = 10.86; 50% female; 72% US born) and whether this effect depends on ethnic pride. Structural equation modeling indicated that, when accounting for economic hardship, shift-&-persist was associated with fewer concurrent depression symptoms. Youth with lower ethnic pride who endorsed high levels of shift-&-persist were protected against the negative impacts of peer ethnic discrimination on depressive symptoms. Future research on ethnic discrimination should examine patterns of coping and identity that can mitigate risk. more...

BackgroundThe effect of maternal diabetes on childhood cancer has not been widely studied.MethodsWe examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child's sex, maternal age and birth order.ResultsGestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71-1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63-1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92-1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04-5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01-2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02-4.00).ConclusionsOur results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring. more...

PurposeThe composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration.MethodsMRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19-65 [mean ± SD, min-max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables.ResultsCEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43).ConclusionPoor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion. more...

BackgroundThe SARS-CoV-2 virus has infected and killed millions of people worldwide. Breast cancer is the most prevalent cancer in women and few studies have investigated the outcomes of patients with a history of breast cancer and COVID-19. We report the clinical outcomes of patients with invasive breast cancer who tested positive for SARS-CoV-2, including hospitalization and death, and evaluate demographic and cancer-related factors associated with these outcomes.PatientsPatients with a history of invasive breast cancer and positive SARS-CoV-2 test from January 1 to December 31, 2020 at two large, academic Los Angeles health systems were included.MethodsRetrospective chart review of the electronic medical record was performed. Data for demographic and cancer-related factors were manually abstracted. Relationships between outcomes and clinical variables were evaluated using Fisher's exact test and linear regression analysis.ResultsAmong a total of 132 patients, 40 (30.3%) were hospitalized, while 11 (8.3%) required intensive care support, and 8 patients (6.1%) died. Older age and presence of one or more additional comorbidities were associated with hospitalization and death (P = .010, P = .003, P = .034, P < .001). Hispanic/Latinx ethnicity was associated with hospitalization (P = .047). Cancer treatment was not associated with hospitalization or death.ConclusionIn our diverse, multi-center, breast cancer cohort, Hispanic/Latinx ethnicity, older age and presence of other comorbidities were associated with worse outcomes from COVID-19. Breast cancer treatment, including surgery, radiation, systemic therapy, and endocrine therapy, was not associated with hospitalization in our cohort. Further studies are needed to explore the relationship between breast cancer and COVID-19 outcomes. more...

The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from Caenorhabditis elegans to mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled. Together with our previous study implicating LZK in astrocytic reactivity and scar formation, these data illustrate the multicellular function of this pair of MAP3Ks in both neurons and glia in the injury response of the mammalian spinal cord.SIGNIFICANCE STATEMENT Functional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucine-zipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated. more...

BackgroundHidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk.ObjectiveTo provide evidence-based screening recommendations for comorbidities linked to HS.MethodsSystematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and magnitude of association, as well as benefits, harms, and feasibility of screening. The level of evidence and strength of corresponding screening recommendation were graded by using the Strength of Recommendation Taxonomy (SORT) criteria.ResultsScreening is recommended for the following comorbidities: acne, dissecting cellulitis of the scalp, pilonidal disease, pyoderma gangrenosum, depression, generalized anxiety disorder, suicide, smoking, substance use disorder, polycystic ovary syndrome, obesity, dyslipidemia, diabetes mellitus, metabolic syndrome, hypertension, cardiovascular disease, inflammatory bowel disease, spondyloarthritis, and sexual dysfunction. It is also recommended to screen patients with Down syndrome for HS. The decision to screen for specific comorbidities may vary with patient risk factors. The role of the dermatologist in screening varies according to comorbidity.LimitationsScreening recommendations represent one component of a comprehensive care strategy.ConclusionsDermatologists should support screening efforts to identify comorbid conditions in HS. more...

Study objectivesThe clinical benefits of positive airway pressure (PAP) therapy for obstructive sleep apnea are assumed to require adherent PAP usage, defined by the Centers for Medicare & Medicaid Services as ≥ 4 hours of use ≥ 70% of nights. However, this definition is based on early data and does not necessarily capture improvements at subthreshold adherence. We explored dose-response relationships between PAP adherence measures and excessive daytime sleepiness from the HomePAP randomized controlled trial.MethodsParticipants aged ≥ 18 years with an apnea-hypopnea index ≥ 15 events/h and baseline sleepiness (Epworth Sleepiness Scale [ESS] ≥ 12) received PAP therapy. Data were collected at baseline, 1-month follow-up, and 3-months follow-up. Regression models and receiver operating characteristic curves evaluated PAP measures as predictors of ESS change and normalization (ESS < 10).ResultsIn 119 participants (aged 49.4 ± 12.6 years, 66.4% male, 72.3% White), > 50% were PAP nonadherent per Centers for Medicare & Medicaid Services criteria at 3 months. The percentage of nights with PAP use ≥ 4 hours predicted ESS change (P = .023), but not when controlling for the apnea-hypopnea index. The percentage of nights with ≥ 4 hours and average PAP use provided the best discrimination for predicting ESS normalization; each 10% increase in PAP use ≥ 4 hours increased the odds of ESS normalization by 22% (P = .007); those using PAP ≥ 4 hours had a nearly 3-fold greater odds of ESS normalization (P = .025). PAP use for at least 4 hours and on 70% of nights provided the best balance between specificity (0.50) and sensitivity (0.73).ConclusionsAlthough subadherent PAP usage may still confer some benefit for patients with obstructive sleep apnea, adherence to current criteria confers the highest likelihood for ESS change and normalization.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Portable Monitoring for Diagnosis and Management of Sleep Apnea (HomePAP); URL: https://clinicaltrials.gov/ct2/show/NCT00642486; Identifier: NCT00642486.CitationPascoe M, Bena J, Andrews ND, et al. Dose-response relationship between positive airway pressure therapy and excessive daytime sleepiness: the HomePAP study. J Clin Sleep Med. 2022;18(4):1027-1034. more...

BackgroundAccess to primary care was hindered by the coronavirus disease 2019 (COVID-19) pandemic.ObjectiveEvaluate changes in health screening rates before and during the pandemic.DesignRetrospective analysis of health maintenance and disease management screening rates among primary care patients before and during the pandemic.ParticipantsOver 150,000 patients of a large, academic health system.Main measuresSix quality measures were analyzed: colon cancer, breast cancer, cervical cancer, diabetes Hgb A1C, diabetes eye, and diabetes nephropathy monitoring. Based on US Preventative Services Task Force screening guidelines, we determined which patients were due for at least one of the quality measures. We tracked completion rates during three time periods: pre-pandemic (January 1-March 3, 2020), stay-at-home (March 4-May 8, 2020), and phased reopening (May 9-July 8, 2020). Differences in quality measure completion rates were evaluated using mixed-effects logistic regression models.Key resultsCompared to pre-pandemic rates, completion of all health screenings declined during the stay-at-home period: mammograms (OR: 0.34; 95% CI: 0.31-0.37), cervical cancer (OR: 0.83; 95% CI: 0.76-0.91), colorectal cancer (OR: 0.25; 95% CI: 0.23-0.28), diabetes eye (OR: 0.34; 95% CI: 0.29-0.41), diabetes Hgb A1c (OR: 0.41; 95% CI: 0.37-0.46), and diabetes nephropathy (OR: 0.46, 95% CI: 0.41-0.53). During phased reopening, completion of all quality measures increased compared to the stay-at-home period, except for cervical cancer screening (OR: 0.83; 95% CI: 0.76-0.92). There was a persistent reduction in completion of all quality measures, except for diabetic nephropathy monitoring (OR: 0.99; 95% CI: 0.89-1.09), during phased reopening compared to pre-pandemic.ConclusionsHealthcare screening rates were reduced during the early part of the COVID-19 pandemic and did not fully recover to pre-pandemic rates by July 2020. Future research should aim to clarify the long-term impacts of delayed health screenings. New interventions should be considered for expanding remote preventative health services. more...

The COVID-19 pandemic has the potential to impact long-standing efforts to increase adherence to cancer screening guidelines. Healthcare workers (HCWs) experienced significant hardship, but generally have greater access to preventive services, making them a particularly relevant population in which to understand cancer screening behaviors during the pandemic. We report data from 794 HCWs enrolled in the NCI-funded Serological Sciences Network for Coronavirus Associations and Longitudinal Evaluation Study from December 2020 to April 2021. Participants reported lifestyle and screening behaviors during relevant look-back periods which included the pandemic timeframe. Among women between the ages of 40 and 74, 25.7% were overdue for mammographic breast cancer screening. Among participants 50-75 years old, 38.9% were overdue for colorectal cancer screening. The proportion over-due varied according to race/ethnicity. Lifetime low-dose computed tomography lung cancer screening among HCWs age 50-80 years who were smokers was 10.9%. Strategies to address screening disruptions are needed to minimize the impact of later stage of diagnosis. more...

Cardiac arrhythmias have been observed among patients hospitalised with acute COVID-19 infection, and palpitations remain a common symptom among the much larger outpatient population of COVID-19 survivors in the convalescent stage of the disease. To determine arrhythmia prevalence among outpatients after a COVID-19 diagnosis. Adults with a positive COVID-19 test and without a history of arrhythmia were prospectively evaluated with 14-day ambulatory electrocardiographic monitoring. Participants were instructed to trigger the monitor for palpitations. A total of 51 individuals (mean age 42±11 years, 65% women) underwent monitoring at a median 75 (IQR 34-126) days after a positive COVID-19 test. Median monitoring duration was 13.2 (IQR 10.5-13.8) days. No participant demonstrated atrial fibrillation, atrial flutter, sustained supraventricular tachycardia (SVT), sustained ventricular tachycardia or infranodal atrioventricular block. Nearly all participants (96%) had an ectopic burden of more...

Purpose: The aims of the current study were to better understand, from the perspective of adolescents and young adults (AYAs) with sarcoma, parents, and providers, the friendship support needs of AYAs with bone and soft tissue sarcoma and the role of social media in facilitating social support for AYAs with sarcoma. Methods: Semistructured interviews were conducted with 21 participants. AYA (n = 10) ranged in age from 14 to 23 years (mean 19.3, standard deviation 3.4 years; 50% female). All AYAs reported a current or past diagnosis of sarcoma, except for one patient who had another cancer diagnosis but was receiving treatment through the sarcoma clinic. Five parents of the adolescent participants were interviewed, as well as six health care providers. Data analysis was conducted using theory-driven immersion/crystallization, incorporating the Resilience in Illness Model as a framework to guide interpretation of the data. Results: Four main themes associated with social support from friends and social media were identified: (1) Social media provides a way to feel normal and connected to friends; (2) Social media accentuates the frustration of being left behind; (3) Social media facilitates the need to be understood by peers who have experienced sarcoma, and (4) Social media can lead to despair, and also provide hope for the future. Conclusions: Connecting with peers through social media can play an important role in providing support for AYAs with sarcoma, but it may also amplify feelings of frustration and anxiety. Future work is needed to determine intervention components that can maximize the benefits of social media for social support of AYAs with sarcoma. Clinical Trial Registration number: NCT03130751. more...

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P 80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last more...

ImportanceLittle is known about the factors associated with COVID-19 vaccine adverse effects in a real-world population.ObjectiveTo evaluate factors potentially associated with participant-reported adverse effects after COVID-19 vaccination.Design, setting, and participantsThe COVID-19 Citizen Science Study, an online cohort study, includes adults aged 18 years and older with a smartphone or internet access. Participants complete daily, weekly, and monthly surveys on health and COVID-19-related events. This analysis includes participants who provided consent between March 26, 2020, and May 19, 2021, and received at least 1 COVID-19 vaccine dose.ExposuresParticipant-reported COVID-19 vaccination.Main outcomes and measuresParticipant-reported adverse effects and adverse effect severity. Candidate factors in multivariable logistic regression models included age, sex, race, ethnicity, subjective social status, prior COVID-19 infection, medical conditions, substance use, vaccine dose, and vaccine brand.ResultsThe 19 586 participants had a median (IQR) age of 54 (38-66) years, and 13 420 (68.8%) were women. Allergic reaction or anaphylaxis was reported in 26 of 8680 participants (0.3%) after 1 dose of the BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccine, 27 of 11 141 (0.2%) after 2 doses of the BNT162b2 or mRNA-1273 vaccine or 1 dose of the JNJ-78436735 (Johnson & Johnson) vaccine. The strongest factors associated with adverse effects were vaccine dose (2 doses of BNT162b2 or mRNA-1273 or 1 dose of JNJ-78436735 vs 1 dose of BNT162b2 or mRNA-1273; odds ratio [OR], 3.10; 95% CI, 2.89-3.34; P more...

RNA, DNA, and protein molecules are highly organized within three-dimensional (3D) structures in the nucleus. Although RNA has been proposed to play a role in nuclear organization, exploring this has been challenging because existing methods cannot measure higher-order RNA and DNA contacts within 3D structures. To address this, we developed RNA & DNA SPRITE (RD-SPRITE) to comprehensively map the spatial organization of RNA and DNA. These maps reveal higher-order RNA-chromatin structures associated with three major classes of nuclear function: RNA processing, heterochromatin assembly, and gene regulation. These data demonstrate that hundreds of ncRNAs form high-concentration territories throughout the nucleus, that specific RNAs are required to recruit various regulators into these territories, and that these RNAs can shape long-range DNA contacts, heterochromatin assembly, and gene expression. These results demonstrate a mechanism where RNAs form high-concentration territories, bind to diffusible regulators, and guide them into compartments to regulate essential nuclear functions. more...

Color polymorphic species can offer exceptional insight into the ecology and genetics of adaptation. Although the genetic architecture of animal coloration is diverse, many color polymorphisms are associated with large structural variants and maintained by biotic interactions. Grasshoppers are notably polymorphic in both color and karyotype, which makes them excellent models for understanding the ecological drivers and genetic underpinnings of color variation. Banded and uniform morphs of the desert clicker grasshopper (Ligurotettix coquilletti) are found across the western deserts of North America. To address the hypothesis that predation maintains local color polymorphism and shapes regional crypsis variation, we surveyed morph frequencies and tested for covariation with two predation environments. Morphs coexisted at intermediate frequencies at most sites, consistent with local balancing selection. Morph frequencies covaried with the appearance of desert substrate-an environment used only by females-suggesting that ground-foraging predators are major agents of selection on crypsis. We next addressed the hypothesized link between morph variation and genome structure. To do so, we designed an approach for detecting inversions and indels using only RADseq data. The banded morph was perfectly correlated with a large putative indel. Remarkably, indel dominance differed among populations, a rare example of dominance evolution in nature. more...

Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2-anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade. more...

BackgroundTransgender and nonbinary (TNB) individuals assigned female sex at birth experience discrimination, misgendering, problems with insurance, and denial of services when accessing health care. This study aimed to understand the experiences of TNB young adults in accessing "women's" health care-a form of care that is structurally gendered that few studies have investigated.MethodsIn 2015, we conducted in-depth interviews with 20 TNB young (ages 18-29) adults assigned female sex at birth. We thematically analyzed the data.ResultsParticipants described feelings of comfort and trust-and lack thereof-at every step of the health care-seeking process, including scheduling, checking in, waiting, and interactions with clinicians and other staff. Gendered language served as a constant stressor; participants-especially nonbinary participants-noted few opportunities to provide their correct pronouns and names. Participants relayed negative experiences associated with waiting rooms in "women's" health care spaces, where TNB patients are forced to disclose their identity simply through their presence or owing to actions of staff that out them. These concerns deterred some from seeking care, with most expressing discomfort or anxiety that caused them to feel unsafe. Participants described "women's" health care providers making assumptions about their anatomy, reproductive desires, sexual orientation, and sexual practices, as well as inappropriately and harmfully emphasizing their bodies and TNB identities during health care interactions. Clinician competence and humility engendered participants' feelings of safety and undergirded their interest in engaging with "women's" health care.ConclusionsA lack of patient-centered, TNB-competent care in structurally gendered health settings exacerbates health care and health inequities for TNB young adults. more...

BackgroundWhile immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).ObjectiveWe aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.Design, setting, and participantsPatients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.Outcome measurements and statistical analysisWe used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.Results and limitationsAmong 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.ConclusionsWe developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.Patient summaryWith multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE  HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases each one point, with a higher score being associated with worse overall survival. more...

ImportanceActive SARS-CoV-2 (coronavirus) transmission continues in the US. It is unclear whether better access to coronavirus testing and more consistent use of testing could substantially reduce transmission.ObjectiveTo describe coronavirus testing in persons with new onset of febrile illness and analyze whether there are changes over time and differences by race and ethnicity.Design, setting, and participantsThis cohort study used data from the COVID-19 Citizen Science Study, launched in March 2020, which recruited participants via press release, word-of-mouth, and partner organizations. Participants completed daily surveys about COVID-19 symptoms and weekly surveys about coronavirus testing. All adults (aged at least 18 years) with a smartphone were eligible to join. For this analysis, US participants with new onset of febrile illness from April 2020 to October 2020 were included. Data analysis was performed from November 2020 to March 2021.Main outcomes and measuresReceipt of a coronavirus test result within 7 days of febrile illness onset.ResultsOf the 2679 participants included in this analysis, the mean (SD) age was 46.3 (13.4) years, 1983 were female (74%), 2017 were college educated (75%), and a total of 3865 distinct new febrile illness episodes were reported (300 episodes [7.8%] from Hispanic participants, 71 episodes [1.8%] from Black participants, and 3494 episodes [90.4%] from not Black, not Hispanic participants) between April 2 and October 23, 2020. In weekly surveys delivered during the 14 days after fever onset, 12% overall (753 participants) indicated receipt of a test result. Using serial survey responses and parametric time-to-event modeling, it was estimated that by 7 days after onset of febrile illness, a total of 20.5% (95% CI, 19.1%-22.0%) had received a test result. This proportion increased from 9.8% (95% CI, 7.5%-12.0%) early in the epidemic to 24.1% (95% CI, 21.5%-26.7%) at the end of July, but testing rates did not substantially improve since then, increasing to 25.9% (95% CI; 21.6%-30.3%) in late October at the start of the winter surge. Black participants reported receiving a test result about half as often as others (7% [7 of 103] of survey responses vs 12% [53 of 461] for Hispanic vs 13% [693 of 5516] for not Black, not Hispanic; P = .03). This association was not statistically significant in adjusted time-to-event models (hazard ratio = 0.59 vs not Black, not Hispanic participants; 95% CI, 0.26-1.34).Conclusions and relevanceSystematic underuse of coronavirus testing was observed in this cohort study through late October 2020, at the beginning of the winter COVID-19 surge, which may have contributed to preventable coronavirus transmission. more...

Despite widespread national, state, and local guidelines for COVID-19 prevention, including social distancing and mask orders, many people continue to not adhere to recommendations, including congregating in groups for non-essential activities, putting themselves and others at risk. A social psychological perspective can be used to understand reasons for lack of adherence to policies and methods for increasing adherence based on successes from other behavior change campaigns. This manuscript seeks to describe some of the social psychological research that may be relevant to COVID-19 prevention and behavior change, describe how these theories have been previously applied in various domains to change behavior, and provide examples of how these approaches might be similarly applied to control the pandemic. We provide concrete examples of actions that can be taken based on social psychological research that might help to increase adherence to COVID-19 recommendations and improve prevention and control of the virus. more...

IntroductionSmoking cigarettes under the influence of alcohol or cannabis is associated with perceived pleasure. However, it is unclear whether these changes in perceived reward impact the extent of concurrent use of cigarettes with alcohol or cannabis. The current study investigated if self-reported changes in perceived reward from concurrent use of cigarettes with alcohol or cannabis are related to the extent of concurrent use in real-world contexts using a smartphone-based Ecological Momentary Assessment (EMA) study.MethodsThe sample included 126 diverse young adult smokers in the San Francisco Bay Area who reported current alcohol or cannabis use at baseline (M = 22.8 years, 50.8% male, 40.5% sexual minority, 39.7% Non-Hispanic White). Participants completed an online baseline survey and 30 days of smartphone-based daily EMA surveys of cigarette, alcohol, and cannabis use. The baseline assessed self-reported changes in perceived pleasure of smoking cigarettes while using alcohol or cannabis separately. EMA surveys included detailed questions about concurrent use (i.e., the extent of smoking while using another substance) covering the previous day. A total of 2,600 daily assessments were analyzed using mixed models.ResultsHigher perceived pleasure from smoking cigarettes while drinking alcohol or using cannabis at baseline were both associated with a greater extent of concurrent use of cigarettes with alcohol (b = 0.140; SE = 0.066; t = 2.1; p = .035) and cannabis (b = 0.136; SE = 0.058; t = 2.4; p = .019) on a given day.ConclusionsResults suggest that perceived reward from concurrently using cigarettes with alcohol or cannabis is associated with the extent of concurrent use. Findings can inform tailored smoking cessation interventions. more...

PurposeDepression is increasingly common among US adolescents; the extent to which social media exposure contributes to this increase remains controversial.MethodsWe used Monitoring the Future data from 8th and 10th grade students (n = 74,472), 2009-2017, to assess the relationship between daily social media use and depressive symptoms. Self-reported depressive symptom score (range: 4-20) was assessed continuously using a log-transformed outcome and at varying cut scores with logistic regression analyses. First, these outcomes were examined overall, comparing adolescents using social media daily to adolescents who were not. We then estimated predicted depressive symptom scores using 26 predictors in order to establish underlying depression risk. We partitioned students into depression risk quintiles to control for confounding due to underlying depression risk and examine heterogeneity in the association between social media use and depressive symptoms. Sensitivity analyses were used to test the robustness of results with different configurations of the predicted score model, and overall associations were examined in two-year groups to identify differences in effects.ResultsFor girls, in adjusted risk-stratified analysis, daily social media use was not associated with high (vs. low) depressive symptoms. For boys, results were inconsistent, suggesting a protective effect of daily social media use at some cut scores. Results were consistent across sensitivity analyses, and any potential harmful effects appear to be limited to 2009-2010, limiting the evidence supporting social media as a current risk factor for depressive symptoms.ConclusionsAmong US adolescents, daily social media use is not a strong or consistent risk factor for depressive symptoms. more...

ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.SettingsA multisite healthcare delivery system located in Los Angeles County.ParticipantsA diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.Main outcomesUsing Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p more...

ObjectiveTo determine the effects of HIV serostatus and disease severity on endothelial function in a large pooled cohort study of people living with HIV infection and HIV- controls. Approach and Results: We used participant-level data from 9 studies: 7 included people living with HIV (2 treatment-naïve) and 4 had HIV- controls. Brachial artery flow-mediated dilation (FMD) was measured using a standardized ultrasound imaging protocol with central reading. After data harmonization, multiple linear regression was used to examine the effects of HIV- serostatus, HIV disease severity measures, and cardiovascular disease risk factors on FMD. Of 2533 participants, 986 were people living with HIV (mean 44.4 [SD 11.8] years old) and 1547 were HIV- controls (42.9 [12.2] years old). The strongest and most consistent associates of FMD were brachial artery diameter, age, sex, and body mass index. The effect of HIV+ serostatus on FMD was strongly influenced by kidney function. In the highest tertile of creatinine (1.0 mg/dL), the effect of HIV+ serostatus was strong (β=-1.59% [95% CI, -2.58% to -0.60%], P=0.002), even after covariate adjustment (β=-1.36% [95% CI, -2.46% to -0.47%], P=0.003). In the lowest tertile (0.8 mg/dL), the effect of HIV+ serostatus was strong (β=-1.90% [95% CI, -2.58% to -1.21%], P more...