Search

Fine particulate matter (PM2.5) exposure can induce immune system pathology via epigenetic modification, affecting pregnancy outcomes. Our study investigated the association between PM2.5 exposure and immune response, as well as epigenetic changes using high-dimensional epigenetic landscape profiling using cytometry by time-of-flight (EpiTOF) at the single cell. We found statistically significant associations between PM2.5 exposure and levels of certain cytokines [interleukin-1RA (IL-1RA), IL-8/CXCL8, IL-18, and IL-27)] and histone posttranslational modifications (HPTMs) in immune cells (HPTMs: H3K9ac, H3K23ac, H3K27ac, H2BK120ub, H4K20me1/3, and H3K9me1/2) among pregnant and nonpregnant women. The cord blood of neonates with high maternal PM2.5 exposure showed lower IL-27 than those with low exposure. Furthermore, PM2.5 exposure affects the co-modification profiles of cytokines between pregnant women and their neonates, along with HPTMs in each immune cell type between pregnant and nonpregnant women. These modifications in specific histones and cytokines could indicate the toxicological mechanism of PM2.5 exposure in inflammation, inflammasome pathway, and pregnancy complications.

BACKGROUND AND AIMS: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations. METHODS: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. RESULTS: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% confidence interval 76%-83%, P < .001) and hs-cTnI by 41% (95% confidence interval 32%-49%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. N-Terminal pro-B-type natriuretic peptide reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. CONCLUSIONS: N-Terminal pro-B-type natriuretic peptide and hs-cTnI concentrations are associated with key variables in obstructive hypertrophic cardiomyopathy. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The HBCD Study aims to reflect the sociodemographic diversity of pregnant individuals in the U.S. The study will also oversample individuals who use substances during pregnancy and enroll similar individuals who do not use to allow for generalizable inferences of the impact of prenatal substance use on trajectories of child development. Without probability sampling or a randomization-based design, the study requires innovation during enrollment, close monitoring of group differences, and rigorous evaluation of external and internal validity across the enrollment period. In this article, we discuss the HBCD Study recruitment and enrollment data collection processes and potential analytic strategies to account for sources of heterogeneity and potential bias. First, we introduce the adaptive design and enrollment monitoring indices to assess and enhance external and internal validity. Second, we describe the visit schedule for in-person and remote data collection where dyads are randomly assigned to visit windows based on a jittered design to optimize longitudinal trajectory estimation. Lastly, we provide an overview of analytic procedures planned for estimating trajectories.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.

Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

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.

PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institutions review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.

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/ ).

OBJECTIVE: Extending collaborative care, a model integrating mental health services into primary care, to include community-based organisations (CBOs) may improve older patient health outcomes by increasing access to care and addressing patients social needs; however, little is known about how CBOs contribute to such partnered depression care. We explored how six primary care clinic and CBO partnerships came together to provide late-life depression care through the Care Partners funded in 2014. DESIGN: 43 key informant interviews and 15 focus groups were conducted with care managers, administrators and primary care providers partnering to provide late-life depression care. Data were coded and analysed iteratively using qualitative thematic analysis. SETTING: Six primary care clinic-CBO sites across California. PARTICIPANTS: Care managers, administrators and primary care providers participated in this study. RESULTS: Three unique contributions of CBOs to depression care in these clinic-CBO partnerships were identified: (1) CBOs added new services that focus on social needs and enhanced depression care; (2) CBOs strengthened core aspects of collaborative care for depression; (3) CBOs provided new avenues for building connections and trust with underserved patients. CONCLUSIONS: CBOs, when partnered with clinics, enhanced both medical and social aspects of depression treatment for older adults. CBOs are well positioned to assist primary care clinics in treating the complex health needs of older adults by providing new and strengthening existing aspects of partnered depression care while building patient trust among culturally diverse populations.

Embryo-maternal crosstalk is essential to establish pregnancy, with the equine embryo moving throughout the uterus on days 9-15 (ovulation = day 0) as part of this interaction. We hypothesized that the presence of a mobile embryo induces local changes in the gene expression of the endometrium. On Day 12, the endometrial transcripts were compared among three groups: uterine horn with an embryo (P+, n = 7), without an embryo (P-, n = 7) in pregnant mares, and both uterine horns of nonbred mares (NB, n = 6). We identified 1,101 differentially expressed genes (DEGs) between P+ vs. NB and 1,229 DEGs between P- vs. NB. The genes upregulated in both P+ and P- relative to NB were involved in growth factor pathway and fatty acid activation, while downregulated genes were associated with oxytocin signaling pathway and estrogen receptor signaling. Comparing the transcriptome of P+ to that of P-, we found 59 DEGs, of which 30 genes had a higher expression in P+. These genes are associated with regulating vascular growth factors and the immune system, all known to be essential in early pregnancy. Overall, this study suggests that the mobile embryo influences the endometrial gene expression locally.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or Long COVID) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIHs REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC Kd = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter VOS, formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

IntroductionRetrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19.MethodsEligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14.ResultsBetween 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19.ConclusionDe novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19.Trial registrationClinicaltrials.gov NCT04366050.

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Maturation is a critical step in the development of an oocyte, and it is during this time that the oocyte advances to metaphase II (MII) of the meiotic cycle and acquires developmental competence to be fertilized and become an embryo. However, in vitro maturation (IVM) remains one of the limiting steps in the in vitro production of embryos (IVP), with a variable percentage of oocytes reaching the MII stage and unpredictable levels of developmental competence. Understanding the dynamics of oocyte maturation is essential for the optimization of IVM culture conditions and subsequent IVP outcomes. Thus, the aim of this study was to elucidate the transcriptome dynamics of oocyte maturation by comparing transcriptomic changes during in vitro maturation in both oocytes and their surrounding cumulus cells. Cumulus-oocyte complexes were obtained from antral follicles and divided into two groups: immature and in vitro-matured (MII). RNA was extracted separately from oocytes (OC) and cumulus cells (CC), followed by library preparation and RNA sequencing. A total of 13,918 gene transcripts were identified in OC, with 538 differentially expressed genes (DEG) between immature OC and in vitro-matured OC. In CC, 13,104 genes were expressed with 871 DEG. Gene ontology (GO) analysis showed an association between the DEGs and pathways relating to nuclear maturation in OC and GTPase activity, extracellular matrix organization, and collagen trimers in CC. Additionally, the follicle-stimulating hormone receptor gene (FSHR) and luteinizing hormone/choriogonadotropin receptor gene (LHCGR) showed differential expressions between CC-MII and immature CC samples. Overall, these results serve as a foundation to further investigate the biological pathways relevant to oocyte maturation in horses and pave the road to improve the IVP outcomes and the overall clinical management of equine assisted reproductive technologies (ART).

OBJECTIVE: The Eating Disorder Examination-Questionnaire (EDE-Q) is one of the most widely used self-report assessments of eating disorder symptoms. However, evidence indicates potential problems with its original factor structure and associated psychometric properties in a variety of populations, including gender minority populations. The aim of the current investigation was to explore several previously published EDE-Q factor structures and to examine internal consistency and measurement invariance of the best-fitting EDE-Q model in a large community sample of gender minority adults. METHODS: Data were drawn from 1567 adults (337 transgender men, 180 transgender women, and 1050 gender-expansive individuals) who participated in The PRIDE Study, a large-scale longitudinal cohort study of sexual and gender minorities from the United States. A series of confirmatory factor analyses (CFAs) were conducted to explore the fit of eight proposed EDE-Q models; internal consistency (Cronbachs alphas, Omega coefficients) and measurement invariance (multi-group CFA) were subsequently evaluated. RESULTS: A brief seven-item, three-factor (dietary restraint, shape/weight overvaluation, body dissatisfaction) model of the EDE-Q consistently evidenced the best fit across gender minority groups (transgender men, transgender women, gender-expansive individuals). The internal consistencies of the three subscales were adequate in all groups, and measurement invariance across the groups was supported. DISCUSSION: Taken together, these findings support the use of the seven-item, three-factor version of the EDE-Q for assessing eating disorder symptomatology in gender minority populations. Future studies can confirm the current findings in focused examinations of the seven-item, three-factor EDE-Q in diverse gender minority samples across race, ethnicity, socioeconomic status, and age ranges. PUBLIC SIGNIFICANCE STATEMENT: Although transgender individuals have greater risk of developing an eating disorder, the factor structure of the Eating Disorder Examination-Questionnaire, one of the most widely used eating disorder assessment measures, has not been explored in transgender adults. We found that a seven-item model including three factors of dietary restraint, shape and weight overvaluation, and body dissatisfaction had the best fit among transgender and nonbinary adults.

OBJECTIVE: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. METHODS: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages

BACKGROUND: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). OBJECTIVES: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. METHODS: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. RESULTS: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. CONCLUSIONS: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ42) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ42, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

BackgroundOsteoporosis is often considered to be a disease of women. Over the last few years, owing to the increasing clinical and economic burden, the awareness and imperative for identifying and managing osteoporosis in men have increased substantially. With the approval of agents to treat men with osteoporosis, more economic evaluations have been conducted to assess the potential economic benefits of these interventions. Despite this concern, there is no specific overview of cost-effectiveness analyses for the treatment of osteoporosis in men.ObjectivesThis study aims (1) to systematically review economic evaluations of interventions for osteoporosis in men; (2) to critically appraise the quality of included studies and the source of model input data; and (3) to investigate the comparability of results for studies including both men and women.MethodsA literature search mainly using MEDLINE (via Ovid) and Embase databases was undertaken to identify original articles published between 1 January, 2000 and 30 June, 2022. Studies that assessed the cost effectiveness of interventions for osteoporosis in men were included. The Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the International Osteoporosis Foundation osteoporosis-specific guideline was used to assess the quality of design, conduct, and reporting of included studies.ResultsOf 2973 articles identified, 25 studies fulfilled the inclusion criteria, classified into economic evaluations of active drugs (n = 8) or nutritional supplements (n = 4), intervention thresholds (n = 5), screening strategies (n = 6), and post-fracture care programs (n = 2). Most studies were conducted in European countries (n = 15), followed by North America (n = 9). Bisphosphonates (namely alendronate) and nutritional supplements were shown to be generally cost effective compared with no treatment in men over 60 years of age with osteoporosis or prior fractures. Two other studies suggested that denosumab was cost effective in men aged 75 years and older with osteoporosis compared with bisphosphates and teriparatide. Intervention thresholds at which bisphosphonates were found to be cost effective varied among studies with a 10-year probability of a major osteoporotic fracture that ranged from 8.9 to 34.2% for different age categories. A few studies suggested cost effectiveness of screening strategies and post-fracture care programs in men. Similar findings regarding the cost effectiveness of drugs and intervention thresholds in women and men were captured, with slightly greater incremental cost-effectiveness ratios in men. The quality of the studies included had an average score of 18.8 out of 25 (range 13-23.5). Hip fracture incidence and mortality risk were mainly derived from studies in men, while fracture cost, treatment efficacy, and disutility were commonly derived from studies in women or studies combining both sexes.ConclusionsAnti-osteoporosis drugs and nutritional supplements are generally cost effective in men with osteoporosis. Screening strategies and post-fracture care programs also showed economic benefits for men. Cost-effectiveness and intervention thresholds were generally similar in studies conducted in both men and women, with slightly greater incremental cost-effectiveness ratios in men.

BACKGROUND: Zika virus (ZIKV) epidemics with infections in pregnant women are associated with severe neurological disease in newborns. Although an arbovirus, ZIKV is also blood transfusion-transmitted (TT). Greater knowledge of the efficiency of ZIKV TT would aid decisions on testing and pathogen reduction technologies (PRT). STUDY DESIGN AND METHODS: Plasma units from ZIKV RNA-reactive blood donors were used to study infectivity in vitro, in mice, and in macaques. Furthermore, plasma units were subjected to PRT using amotosalen/ultraviolet light A (A/UVA) before transfusion. RESULTS: In vitro infectivity of ZIKV RNA-reactive plasma varied between 100 and 1000 international units (IU) of ZIKV RNA. Immunodeficient mice were more sensitive with as low as 32 IU sufficient to infect 50% of mice. 50-5500 IU of RNA led to TT in macaques using dose escalation of three different RNA-positive, seronegative plasma units. In contrast, RNA-reactive units collected postseroconversion were not infectious in macaques, even at a dose of 9 million IU RNA. After A/UVA PRT, transfusion of plasma containing up to 18 million IU was no longer infectious in vitro and did not result in ZIKV TT in macaques. CONCLUSION: Significant risks of ZIKV TT are likely confined to a relatively short viremic window before seroconversion, and that sensitive nucleic acid amplification testing likely identifies the majority of infectious plasma. PRT was demonstrated to be effective at preventing ZIKV TT. Considering that there is no approved ZIKV vaccine, these data are relevant to mitigate the risk of TT during the future ZIKV outbreaks.

PurposeThe aim of this study is to determine the prospective associations between baseline screen time and obsessive-compulsive disorder (OCD) at 2-year follow-up in a national (United States) cohort of 9- to 10-year-old children.MethodsWe analyzed prospective cohort data from the Adolescent Brain Cognitive Development study (n = 9,208). Logistic regression analyses were used to determine the associations between baseline self-reported screen time (exposure) and OCD, based on the Kiddie Schedule for Affective Disorders and Schizophrenia (outcome), at 2-year-follow-up, adjusting for race/ethnicity, sex, household income, parent education, family history of psychopathology, and study site, excluding participants with baseline OCD.ResultsThe sample was 48.9% female and racially and ethnically diverse (43.5% non-White). Each additional hour of total screen time was prospectively associated with 1.05 higher odds of OCD at 2-year follow-up (95% confidence interval [CI] 1.01-1.09). For specific screen time modalities, each additional hour of playing video games (adjusted odds ratio 1.15, 95% CI 1.03-1.28) and watching videos (adjusted odds ratio 1.11, 95% CI 1.01-1.23) was associated with a subsequent OCD diagnosis.ConclusionVideo games and watching videos are prospectively associated with new-onset OCD in early adolescents. Future research should examine mechanisms linking these specific screen modalities to OCD development to inform future prevention and intervention efforts.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

BACKGROUND: Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status. METHODS: Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Childrens Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease. FINDINGS: Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 [65·6%]), followed by Hispanic patients (4354 [20·6%]), non-Hispanic Black patients (1517 [7·2%]), non-Hispanic Asian (n=1071 [5·1%]), and non-Hispanic other (n=338 [1·6%]). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1%; hazard ratio [HR] 1·37, 95% CI 1·26-1·49; p

BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. FUNDING: National Cancer Institute and Novartis.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Aims/hypothesisSouth Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors.MethodsWe performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ).ResultsWe summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women.Conclusions/interpretationSouth Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians.FundingThere was no primary direct funding for undertaking the systematic review and meta-analysis.

Background Acne is common, can cause significant impact on quality of life and is a frequent reason for long-term antibiotic use. Spironolactone has been prescribed for acne in women for many years, but robust evidence is lacking. Objective To evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. Design Pragmatic, parallel, double-blind, randomised superiority trial. Setting Primary and secondary healthcare and community settings (community and social media advertising). Participants Women aged 18 years and older with facial acne persisting for at least 6 months, judged to potentially warrant oral antibiotic treatment. Interventions Participants were randomised 1 : 1, using an independent web-based procedure, to either 50 mg/day spironolactone or matched placebo until week 6, increasing to 100 mg/day spironolactone or matched placebo until week 24. Participants continued usual topical treatment. Main outcome measures Primary outcome was the adjusted mean difference in Acne-Specific Quality of Life symptom subscale score at 12 weeks. Secondary outcomes included Acne-Specific Quality of Life total and subscales; participant self-assessed improvement; Investigator’s Global Assessment; Participant’s Global Assessment; satisfaction; adverse effects and cost-effectiveness. Results Of 1267 women assessed for eligibility, 410 were randomised (201 intervention, 209 control), 342 in the primary analysis (176 intervention, 166 control). Mean age was 29.2 years (standard deviation 7.2) and 7.9% (28/356) were from non-white backgrounds. At baseline, Investigator’s Global Assessment classified acne as mild in 46%, moderate in 40% and severe in 13%. At baseline, 82.9% were using topical treatments. Over 95% of participants in both groups tolerated the treatment and increased their dose. Mean baseline Acne-Specific Quality of Life symptom subscale was 13.0 (standard deviation 4.7) across both groups. Mean scores at week 12 were 19.2 (standard deviation 6.1) for spironolactone and 17.8 (standard deviation 5.6) for placebo [difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46) adjusting for baseline variables]. Mean scores at week 24 were 21.2 (standard deviation 5.9) in spironolactone group and 17.4 (standard deviation 5.8) in placebo group [adjusted difference 3.77 (95% confidence interval 2.50 to 5.03) adjusted]. Secondary outcomes also favoured spironolactone at 12 weeks with greater differences at 24 weeks. Participants taking spironolactone were more likely than those taking placebo to report overall acne improvement at 12 weeks {72.2% vs. 67.9% [adjusted odds ratio 1.16 (95% confidence interval 0.70 to 1.91)]} and at 24 weeks {81.9% vs. 63.3% [adjusted odds ratio 2.72 (95% confidence interval 1.50 to 4.93)]}. Investigator’s Global Assessment was judged successful at week 12 for 31/201 (18.5%) taking spironolactone and 9/209 (5.6%) taking placebo [adjusted odds ratio 5.18 (95% confidence interval 2.18 to 12.28)]. Satisfaction with treatment improved in 70.6% of participants taking spironolactone compared with 43.1% taking placebo [adjusted odds ratio 3.12 (95% confidence interval 1.80 to 5.41)]. Adverse reactions were similar between groups, but headaches were reported more commonly on spironolactone (20.4% vs. 12.0%). No serious adverse reactions were reported. Taking account for missing data through multiple imputation gave an incremental cost per quality-adjusted life-year of £27,879 (adjusted) compared to placebo or £2683 per quality-adjusted life-year compared to oral antibiotics. Conclusions Spironolactone resulted in better participant-reported and investigator-reported outcomes than placebo, with greater differences at week 24 than week 12. Trial registration This trial is registered as ISRCTN12892056 and EudraCT (2018-003630-33). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/13/02) and is published in full in Health Technology Assessment; Vol. 28, No. 56. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Acne (or spots) is common and often persists into adulthood. Many people take long courses of antibiotic tablets, but concerns about antibiotic resistance mean alternatives are needed. Spironolactone is a medicine that is sometimes used for acne in women. However, we do not know whether it works. This trial aimed to answer this question. What did we do? We invited women aged over 18 who had acne on their face for at least 6 months to take part via their general practitioner surgery, hospital or advertising. Women were randomly assigned to two groups: one group was given spironolactone and the other group was given identical-looking placebo (‘dummy pill’) daily for 24 weeks. Women in both groups could continue using acne treatments applied to the skin (gels/creams/lotions). We asked participants to rate their acne using a questionnaire called Acne-Specific Quality of Life, asked whether they felt their skin had improved and asked skin specialists to assess their skin. What did we find? Four hundred and ten women took part, many of whom had had acne for a long time. Acne-Specific Quality of Life scores improved in both groups by 12 weeks but improved more in the spironolactone group at 12 and 24 weeks. When asked directly whether their skin had improved, 71% of participants in the spironolactone group said it had, compared with 43% on placebo. Skin specialists were also more likely to report that the acne had improved in the spironolactone group. Side effects were mild and similar in both groups but there were slightly more headaches on spironolactone (20% compared with 12%). Spironolactone is likely to represent value for money for the National Health Service, though this depends on a number of factors including what it is compared to. What does this mean? This trial suggests that spironolactone is a useful additional treatment for women with persistent acne. Scientific summary Background Acne vulgaris (hereon ‘acne’) is common, can cause significant psychosocial impact and risks permanent scarring. Topical treatments are first line, but people commonly receive long courses of oral antibiotics, raising concerns regarding antimicrobial resistance. Spironolactone, a potassium-sparing diuretic, is widely used for other conditions, such as hypertension. Spironolactone has anti-androgenic properties and is prescribed by dermatologists to treat acne in women, but robust evidence of effectiveness is lacking. Objective To evaluate whether spironolactone is clinically effective and cost-effective in treating persistent facial acne in women. Methods Design This was a pragmatic, multicentre, participant-blinded and clinician-blinded, placebo-controlled randomised trial. Participants were recruited through primary care (search and mail-out or opportunistic recruitment), secondary care (opportunistic recruitment) and advertising, including community and social media advertising. Trial participants were randomised to receive either 50 mg spironolactone or matched placebo one tablet daily for the first 6 weeks and then two tablets daily (total 100 mg spironolactone or matched placebo) at (or after) week 6, providing the participant was tolerating any side effects. Treatment continued for 24 weeks in both groups. Participants in both groups could continue to use usual topical treatments throughout the trial but adherence to topicals was not promoted beyond usual care. Between baseline and week 12, participants were asked not to change their topical treatments and not to take oral treatments for acne such as oral antibiotics, hormonal treatments or isotretinoin. After week 12, participants could change usual acne care, including oral treatments, if needed. In both groups, spironolactone or placebo was stopped at week 24, participants were informed of their treatment allocation and entered an unblinded follow-up period up to week 52. After week 24, participants could seek any treatment from their usual clinical team, including spironolactone. Baseline assessment was carried out in secondary care to ensure standardisation of clinical assessments, as the Investigator’s Global Assessment (IGA) for acne is not commonly used in primary care and was an important secondary outcome. The baseline appointment included pregnancy test, blood test (to exclude renal impairment or raised serum potassium), participant photo to aid recall about changes in acne, and contraceptive counselling. Baseline visits were conducted by research nurses and/or dermatologists. Participants were followed up face-to-face (or by video call or telephone due to the COVID-19 pandemic) in secondary care at week 6 and week 12, with primary outcome assessment at week 12, and longer-term follow-up by questionnaires at week 24 and up to week 52. Participants Participants eligible for inclusion were women aged 18 years or over: with facial acne vulgaris for at least 6 months acne of sufficient severity to warrant oral antibiotics, as judged by trial clinician; and with IGA ≥ 2 (mild or worse) women of childbearing potential at risk of pregnancy had to be willing to use their usual hormonal or barrier method of contraception for the first 6 months of the trial and for at least 4 weeks afterwards willing to be randomised sufficient English to self-complete acne-specific quality of life (Acne-QoL). Potential participants were excluded if: IGA acne grade was 0–1 (clear or almost clear) ever taken spironolactone taken oral isotretinoin within past 6 months taken oral antibiotics (lasting longer than 1 week) for acne within previous month started, stopped or changed hormonal contraception, co-cyprindiol or other hormonal treatment within past 3 months or planning to start, stop or change within the next 3 months intending to become pregnant in next 6 months spironolactone contraindicated: currently taking potassium-sparing diuretic, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker or digoxin hereditary problems of galactose intolerance, lactase deficiency or glucose–galactose malabsorption (as the spironolactone and placebo tablets contain lactose) androgen-secreting adrenal or ovarian tumour Cushing syndrome congenital adrenal hyperplasia estimated glomerular filtration rate below 60 ml/minute/1.73 m2 serum potassium level above upper limit of reference range for laboratory. Outcomes Primary outcome was comparison of mean Acne-QoL symptom subscale scores between groups at week 12. Acne-QoL contains 19 questions with seven response categories, each referring to the past week, reported in four domains (acne symptoms, self-perception, role-social, role-emotional). Secondary outcomes included: Acne-QoL symptom subscale score at week 24 and up to week 52 Acne-QoL other subscales (self-perception, role-emotional and role-social) at week 12, week 24 and up to week 52 participant self-assessed overall improvement at week 12 recorded on six-point Likert scale (with baseline photo to aid recall) IGA change from baseline to week 12 Participant’s Global Assessment (PGA) change at week 12 and week 24 generic health-related quality of life at week 6, week 12, week 24 and up to week 52 [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)] adverse reactions use of oral acne treatment during follow-up (e.g. antibiotics, isotretinoin) resource use. Sample size Sample size calculation was based on Acne-QoL symptom subscale scores as recommended by the questionnaire developer. Based on comparison Acne-QoL symptom subscale scores between groups at week 12, power 90%, alpha 0.05 and seeking a difference of 2 points between groups (effect size 0.35), a target sample size of 346 participants was initially estimated, or 434 participants allowing for 20% loss to follow-up. During the trial, the target sample size was revised to allow for correlation between baseline and follow-up measures, following discussion with trial monitoring committees and funder. Allowing for a correlation with baseline of 0.293 and a deflation factor of 1-ρ2, gave a revised target sample size of 398 participants (including allowing for 20% loss to follow-up). Randomisation and blinding Participants were randomised in a 1 : 1 ratio to either spironolactone or matched placebo using an independent web-based system (block sizes 2 and 4). Participants were stratified by recruitment centre and baseline acne severity (IGA

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

BackgroundRecent research has emphasized a growing trend of weight gain attempts, particularly among adolescents and boys and young men. Little research has investigated these efforts among adults, as well as the specific diet modifications individuals who are trying to gain weight engage in. Therefore, the aims of this study were to characterize the diet modification efforts used by adults across five countries who reported engaging in weight gain attempts and to determine the associations between weight gain attempts and concerted diet modification efforts.MethodsCross-sectional data from the 2018 and 2019 International Food Policy Study, including participants from Australia, Canada, Mexico, the United Kingdom, and the United States (N = 42,108), were analyzed. In reference to the past 12 months, participants reported on weight gain attempts and diet modification efforts related to increased consumption of calories, protein, fiber, fruits and vegetables, whole grains, dairy products, all meats, red meat only, fats, sugar/added sugar, salt/sodium, and processed foods. Unadjusted (chi-square tests) and adjusted (modified Poisson regressions) analyses were conducted to examine associations between weight gain attempts and diet modification efforts.ResultsWeight gain attempts were significantly associated with higher likelihood of each of the 12 forms of diet modification efforts among male participants, and 10 of the diet modification efforts among female participants. Notably, this included higher likelihood of efforts to consume more calories (males: adjusted prevalence ratio [aPR] 3.25, 95% confidence interval [CI] 2.94-3.59; females: aPR 4.05, 95% CI 3.50-4.70) and fats (males: aPR 2.71, 95% CI 2.42-3.03; females: aPR 3.03, 95% CI 2.58-3.55).ConclusionsOverall, the patterns of association between weight gain attempts and diet modification efforts may be indicative of the phenomenon of muscularity-oriented eating behaviors. Findings further highlight the types of foods and nutrients adults from five countries may try to consume in attempts to gain weight.

DescriptionThe purpose of this best practice advice (BPA) article from the Clinical Practice Update Committee of the American Gastroenterological Association is to provide an update on advances and innovation regarding the screening and surveillance of Barrett's esophagus.MethodsThe BPA statements presented here were developed from expert review of existing literature combined with discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of BPAs was not the intent of this clinical practice update. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. BEST PRACTICE ADVICE 1: Screening with standard upper endoscopy may be considered in individuals with at least 3 established risk factors for Barrett's esophagus (BE) and esophageal adenocarcinoma, including individuals who are male, non-Hispanic white, age >50 years, have a history of smoking, chronic gastroesophageal reflux disease, obesity, or a family history of BE or esophageal adenocarcinoma. BEST PRACTICE ADVICE 2: Nonendoscopic cell-collection devices may be considered as an option to screen for BE. BEST PRACTICE ADVICE 3: Screening and surveillance endoscopic examination should be performed using high-definition white light endoscopy and virtual chromoendoscopy, with endoscopists spending adequate time inspecting the Barrett's segment. BEST PRACTICE ADVICE 4: Screening and surveillance exams should define the extent of BE using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and the location and characteristics of visible lesions (nodularity, ulceration), when present. BEST PRACTICE ADVICE 5: Advanced imaging technologies such as endomicroscopy may be used as adjunctive techniques to identify dysplasia. BEST PRACTICE ADVICE 6: Sampling during screening and surveillance exams should be performed using the Seattle biopsy protocol (4-quadrant biopsies every 1-2 cm and target biopsies from any visible lesion). BEST PRACTICE ADVICE 7: Wide-area transepithelial sampling may be used as an adjunctive technique to sample the suspected or established Barrett's segment (in addition to the Seattle biopsy protocol). BEST PRACTICE ADVICE 8: Patients with erosive esophagitis should be biopsied when concern of dysplasia or malignancy exists. A repeat endoscopy should be performed after 8 weeks of twice a day proton pump inhibitor therapy. BEST PRACTICE ADVICE 9: Tissue systems pathology-based prediction assay may be utilized for risk stratification of patients with nondysplastic BE. BEST PRACTICE ADVICE 10: Risk stratification models may be utilized to selectively identify individuals at risk for Barrett's associated neoplasia. BEST PRACTICE ADVICE 11: Given the significant interobserver variability among pathologists, the diagnosis of BE-related neoplasia should be confirmed by an expert pathology review. BEST PRACTICE ADVICE 12: Patients with BE-related neoplasia should be referred to endoscopists with expertise in advanced imaging, resection, and ablation. BEST PRACTICE ADVICE 13: All patients with BE should be placed on at least daily proton pump inhibitor therapy. BEST PRACTICE ADVICE 14: Patients with nondysplastic BE should undergo surveillance endoscopy in 3 to 5 years. BEST PRACTICE ADVICE 15: In patients undergoing surveillance after endoscopic eradication therapy, random biopsies should be taken of the esophagogastric junction, gastric cardia, and the distal 2 cm of the neosquamous epithelium as well as from all visible lesions, independent of the length of the original BE segment.

ObjectiveTo determine the prevalence and sociodemographic correlates of cyberbullying victimization and perpetration among a racially, ethnically and socioeconomically diverse population-based sample of 11-12-year-old early adolescents.MethodsWe analyzed cross-sectional data from the Adolescent Brain Cognitive Development (ABCD) Study (Year 2; N = 9429). Multiple logistic regression analyses were used to estimate associations between sociodemographic factors (sex, race/ethnicity, sexual orientation, country of birth, household income, parental education) and adolescent-reported cyberbullying victimization and perpetration.ResultsIn the overall sample, lifetime prevalence of cyberbullying victimization was 9.6%, with 65.8% occurring in the past 12 months, while lifetime prevalence of cyberbullying perpetration was 1.1%, with 59.8% occurring in the past 12 months. Boys reported higher odds of cyberbullying perpetration (AOR 1.71, 95% CI 1.01-2.92) but lower odds of cyberbullying victimization (AOR 0.80, 95% CI 0.68-0.94) than girls. Sexual minorities reported 2.83 higher odds of cyberbullying victimization (95% CI 1.69-4.75) than nonsexual minorities. Lower household income was associated with 1.64 (95% CI 1.34-2.00) higher odds of cyberbullying victimization than higher household income, however household income was not associated with cyberbullying perpetration. Total screen time, particularly on the internet and social media, was associated with both cyberbullying victimization and perpetration.ConclusionsNearly one in 10 early adolescents reported cyberbullying victimization. Pediatricians, parents, teachers, and online platforms can provide education to support victims and prevent perpetration for early adolescents at the highest risk of cyberbullying.

ObjectiveTo determine sociodemographic correlates of problematic screen use (social media, video games, mobile phones) among a racially/ethnically and socioeconomically diverse population-based sample of 10-14-year-old early adolescents.Study designWe analyzed cross-sectional data from the Adolescent Brain Cognitive Development Study (Year 2, 2018-2020; N = 8753). Multiple linear regression analyses were used to estimate associations between sociodemographic factors (age, sex, race/ethnicity, primary language, household income, parental education) and adolescent-reported problematic video game (Video Game Addiction Questionnaire), social media (Social Media Addiction Questionnaire), and mobile phone use (Mobile Phone Involvement Questionnaire).ResultsBoys reported higher problematic video game use while girls reported higher problematic social media and mobile phone use. Native American, black, and Latinx adolescents reported higher scores across all problematic screen measures compared to non-Latinx white adolescents. Having unmarried/unpartnered parents was associated with higher problematic social media use. Although higher household income was generally protective against problematic video game use, these associations were weaker for black than white adolescents (p for interaction

Background and aimsPatients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD.MethodsAdult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort.Results147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89).ConclusionsThis cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and

OBJECTIVE: Appearance and performance-enhancing drugs and supplements (APEDS) can be used to enhance muscle growth, athletic performance, and physical appearance. The aim of this study was to examine the lifetime use of APEDS and associations with eating disorder and muscle dysmorphia symptoms among gender minority people. METHOD: Participants were 1653 gender minority individuals (1120 gender-expansive [defined as a broad range of gender identities that are generally situated outside of the woman-man gender binary, e.g., genderqueer, nonbinary] people, 352 transgender men, and 181 transgender women) recruited from The Population Research in Identity and Disparities for Equality Study in 2018. Regression analyses stratified by gender identity examined associations of any APEDS use with eating disorder and muscle dysmorphia symptom scores. RESULTS: Lifetime APEDS use was common across groups (30.7% of gender-expansive people, 45.2% of transgender men, and 14.9% of transgender women). Protein supplements and creatine supplements were the most commonly used APEDS. Among gender-expansive people and transgender men, lifetime use of any APEDS was significantly associated with higher eating disorder scores, dietary restraint, binge eating, compelled/driven exercise, and muscle dysmorphia symptoms. Any APEDS use was additionally associated with laxative use among gender-expansive people. Among transgender women, use of any APEDS was not significantly associated with eating disorder or muscle dysmorphia symptoms. DISCUSSION: APEDS use is common and associated with eating disorder and muscle dysmorphia symptoms in gender-expansive people and transgender men, thus highlighting the importance of assessing for these behaviors and symptoms among these populations, particularly in clinical settings. PUBLIC SIGNIFICANCE: This study aimed to examine APEDS use among gender minority people. We found that 30.7% of gender-expansive (e.g., nonbinary) people, 45.2% of transgender men, and 14.9% of transgender women reported lifetime APEDS use, which was associated with eating disorder and muscle dysmorphia symptoms in transgender men and gender-expansive people. Clinicians should assess for these behaviors in gender minority populations.

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.SIGNIFICANCE STATEMENT In Parkinson's disease and Lewy body dementia, dysfunctional autophagy contributes to accumulation and spread of aggregated α-synuclein. Here, we provide evidence that protein S-nitrosylation of p62 inhibits autophagic flux, contributing to α-synuclein aggregation and spread.

ObjectiveTo examine the effect of severe lower extremity trauma on meeting Physical Activity Guidelines for Americans (PAGA) 18 months after injury and perform an exploratory analysis to identify demographic, clinical, and psychosocial factors associated with meeting PAGA.DesignSecondary analysis of observational cohort study.SettingA total of 34 United States trauma centers PARTICIPANTS: A total of 328 adults with severe distal tibia, ankle and mid- to hindfoot injuries treated with limb reconstruction (N=328).InterventionsNone.Main outcome measuresThe Paffenbarger Physical Activity Questionnaire was used to assess physical activity levels 18 months after injury. Meeting PAGA was defined as combined moderate- and vigorous-intensity activity ≥150 minutes per week or vigorous-intensity activity ≥75 minutes per week.ResultsFewer patients engaged in moderate- or vigorous-intensity activity after injury compared with before injury (moderate: 44% vs 66%, P

Despite their importance in tissue homeostasis and renewal, human pituitary stem cells (PSCs) are incompletely characterized. We describe a human single nucleus RNA-seq and ATAC-seq resource from pediatric, adult, and aged postmortem pituitaries (snpituitaryatlas.princeton.edu) and characterize cell-type-specific gene expression and chromatin accessibility programs for all major pituitary cell lineages. We identify uncommitted PSCs, committing progenitor cells, and sex differences. Pseudotime trajectory analysis indicates that early-life PSCs are distinct from the other age groups. Linear modeling of same-cell multiome data identifies regulatory domain accessibility sites and transcription factors that are significantly associated with gene expression in PSCs compared with other cell types and within PSCs. We identify distinct deterministic mechanisms that contribute to heterogeneous marker expression within PSCs. These findings characterize human stem cell lineages and reveal diverse mechanisms regulating key PSC genes and cell type identity.

ObjectiveCognitive impairment in schizophrenia predicts functional outcomes and is largely unresponsive to pharmacology or psychotherapy; it is thus a critical unmet treatment need. This article presents the impact of remotely completed, intensive, targeted auditory training (AT) vs control condition computer games (CG) in a double-blind randomized trial in young adults with recent-onset schizophrenia.MethodParticipants (N = 147) were assessed for cognition, symptoms, and functioning at baseline, post-intervention, and at 6-month follow-up. All participants were provided with laptop computers and were instructed to complete 40 hours remotely of training or computer games. An intent-to-treat analysis (N = 145) was performed using linear mixed models with time modeled as a continuous variable. Planned contrasts tested the change from baseline to post-training, baseline to 6-month follow-up, and post-training to 6-month follow-up.ResultsGlobal Cognition, which had improved in the AT group relative to the CG group at post-training, showed durable gains at 6-month follow-up in an omnibus group-by-time interaction test (F(1,179) = 4.80, P = .030), as did Problem-Solving (F(1,179) = 5.13, P = .025), and Speed of Processing improved at trend level significance (F(1,170) = 3.80, P = .053). Furthermore, the AT group showed significantly greater improvement than the CG group in positive symptoms (F(1,179) = 4.06, P = .045).ConclusionsThese results provide the first evidence of durable cognitive gains and symptom improvement at follow-up of cognitive training (CT) in early schizophrenia completed independently and remotely. While functioning did not show significant improvement, these findings suggest that intensive targeted CT of auditory processing is a promising component of early intervention to promote recovery from psychosis.

PURPOSE: Appearance and performance-enhancing drugs and supplements (APEDS) are used to enhance muscle growth, athletic performance, and physical appearance. The aim of this study was to examine the lifetime use of APEDS and associations with eating disorder and muscle dysmorphia symptoms among cisgender sexual minority people. METHODS: Participants were cisgender sexual minority people (1090 gay men, 100 bisexual plus men, 564 lesbian women, and 507 bisexual plus women) recruited from The PRIDE Study in 2018 who reported lifetime APEDS use and completed the Eating Disorder Examination-Questionnaire (EDE-Q) and the Muscle Dysmorphic Disorder Inventory (MDDI). Regression analyses stratified by gender and sexual orientation examined associations of any APEDS use with EDE-Q and MDDI scores. RESULTS: Lifetime APEDS use was common across the four groups of cisgender sexual minority people (44% of gay men, 42% of bisexual plus men, 29% of lesbian women, and 30% of bisexual plus women). Protein supplements and creatine supplements were the most commonly used APEDS. Any APEDS use was associated with higher EDE-Q scores on one or more subscales in all sexual minority groups. Further, any APEDS use was associated with higher MDDI Total Scores in all groups; any APEDS use was associated with all MDDI subscale scores in cisgender gay men only. DISCUSSION: APEDS use is common and associated with eating disorder and muscle dysmorphia symptoms in sexual minority men and women, thus highlighting the importance of assessing for these behaviors and symptoms among these populations in clinical settings.

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Increasing numbers of compatible pairs are choosing to enter paired exchange programs, but motivations, outcomes, and system-level effects of participation are not well described. Using a linkage of the Scientific Registry of Transplant Recipients and National Kidney Registry, we compared outcomes of traditional (originally incompatible) recipients to originally compatible recipients using the Kaplan-Meier method. We identified 154 compatible pairs. Most pairs sought to improve HLA matching. Compared to the original donor, actual donors were younger (39 vs. 50 years, p

ObjectiveTo determine sociodemographic correlates of contemporary screen time use among a diverse population-based sample of 9- and 10-year-old children.Study designIn 2021, we analyzed cross-sectional baseline (2016-2018) data from the Adolescent Brain Cognitive Development study (n = 10 755). Multiple linear regression analyses were conducted to estimate associations between sociodemographic factors (sex, race/ethnicity, country of birth, household income, parental education) and 6 contemporary forms of screen time (television, videos [eg, YouTube], video games, social networking, texting, and video chat).ResultsOn average, children reported 3.99 hours of screen time per day across 6 modalities, with the most time spent watching/streaming television shows/movies (1.31 hours), playing video games (1.06 hours), and watching/streaming videos (1.05 hours). On average, Black children reported 1.58 more hours of screen time per day and Asian children reported 0.35 less hours of screen time per day compared with White children (mean 3.46 hours per day), and these trends persisted across most modalities. Boys reported higher overall screen time (0.75 hours more) than girls, which was primarily attributed to video games and videos. Girls reported more time texting, social networking, and video chatting than boys. Higher income was associated with lower screen time usage across all modalities except video chat. However, in high-income households, Latinx children reported 0.65 more hours of screen time per day than White children.ConclusionsGiven the sociodemographic differences in child screen use, guideline implementation strategies can focus on key populations, encourage targeted counseling by pediatricians, and adapt Family Media Use Plans for diverse backgrounds.

BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.ResultsAcross disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers (controls) and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.