Search

BACKGROUND: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. METHODS: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. RESULTS: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p

IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

BACKGROUND: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO. METHODS: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed. RESULTS: The incidence of vessel perforation was 4.8% (66/1373). Notably, our analysis indicates variations in perforation rates across different arterial segments: 8.9% in M3 segments, 4.3% in M2 segments, and 8.3% in A2 segments (p = 0.612). Patients with perforation had significantly worse outcomes, with lower rates of favorable angiographic outcomes (TICI 2c-3: 23% vs 58.9%, p

The gut microbiome (GM) modulates body weight/composition and gastrointestinal functioning; therefore, approaches targeting resident gut microbes have attracted considerable interest. Intermittent fasting (IF) and protein pacing (P) regimens are effective in facilitating weight loss (WL) and enhancing body composition. However, the interrelationships between IF- and P-induced WL and the GM are unknown. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks. Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P (p

Stromal fibroblasts are a major stem cell niche component essential for organ formation and cancer development. Fibroblast heterogeneity, as revealed by recent advances in single-cell techniques, has raised important questions about the origin, differentiation, and function of fibroblast subtypes. In this study, we show in mammary stromal fibroblasts that loss of the receptor tyrosine kinase (RTK) negative feedback regulators encoded by Spry1, Spry2, and Spry4 causes upregulation of signaling in multiple RTK pathways and increased extracellular matrix remodeling, resulting in accelerated epithelial branching. Single-cell transcriptomic analysis demonstrated that increased production of FGF10 due to Sprouty (Spry) loss results from expansion of a functionally distinct subgroup of fibroblasts with the most potent branching-promoting ability. Compared to their three independent lineage precursors, fibroblasts in this subgroup are activated, as they are located immediately adjacent to the epithelium that is actively undergoing branching and invasion. Spry genes are downregulated, and activated fibroblasts are expanded, in all three of the major human breast cancer subtypes. Together, our data highlight the regulation of a functional subtype of mammary fibroblasts by Spry genes and their essential role in epithelial morphogenesis and cancer development.

Localized sources of morphogens, called signalling centres, play a fundamental role in coordinating tissue growth and cell fate specification during organogenesis. However, how these signalling centres are established in tissues during embryonic development is still unclear. Here we show that the main signalling centre orchestrating development of rodent incisors, the enamel knot (EK), is specified by a cell proliferation-driven buildup in compressive stresses (mechanical pressure) in the tissue. Direct mechanical measurements indicate that the stresses generated by cell proliferation are resisted by the surrounding tissue, creating a circular pattern of mechanical anisotropy with a region of high compressive stress at its centre that becomes the EK. Pharmacological inhibition of proliferation reduces stresses and suppresses EK formation, and application of external pressure in proliferation-inhibited conditions rescues the formation of the EK. Mechanical information is relayed intracellularly through YAP protein localization, which is cytoplasmic in the region of compressive stress that establishes the EK and nuclear in the stretched anisotropic cells that resist the pressure buildup around the EK. Together, our data identify a new role for proliferation-driven mechanical compression in the specification of a model signalling centre during mammalian organ development.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

PURPOSE: Mental health inequalities continue to persist among American Indian/Alaska Native (AI/AN) people. However, few studies have examined the association of social networks and depression and anxiety among urban emerging AI/AN adults. METHODS: This study analyzes the association of social network characteristics with depression and anxiety among a sample of urban AI/AN emerging adults. A second set of regression models tested the same associations but controlling for respondent sexual and gender minority (SGM) status. Data were from a sample of 150 AI/AN emerging adults residing in urban areas from 20 different states (86% female; mean age 21.8; 48.0% SGM) who participated in a randomized controlled trial analyzing the effects of culturally grounded interventions on alcohol and other drug use and cultural connectedness. RESULTS: Participants with a higher proportion of network members who were around the same age reported significantly less anxiety. Those who had a higher proportion of network members who they sometimes/often argue/fight with were more likely to report greater depression and anxiety. Participants with higher proportions of social network members who have ever lived on a reservation/Rancheria/tribal land/tribal village reported significantly less depression. However, participants with higher proportions of social network members who lived 50 miles away or more reported significantly more depression. Controlling for SGM status, results were largely similar. DISCUSSION: Results highlight the role of social connections on the mental well-being of urban AI/AN emerging adults.

BACKGROUND: Equitable assessment is critical in competency-based medical education. This study explores differences in key characteristics of qualitative assessments (i.e., narrative comments or assessment feedback) of internal medicine postgraduate resident performance associated with gender and race and ethnicity. METHODS: Analysis of narrative comments included in faculty assessments of resident performance from six internal medicine residency programs was conducted. Content analysis was used to assess two key characteristics of comments- valence (overall positive or negative orientation) and specificity (detailed nature and actionability of comment) - via a blinded, multi-analyst approach. Differences in comment valence and specificity with gender and race and ethnicity were assessed using multilevel regression, controlling for multiple covariates including quantitative competency ratings. RESULTS: Data included 3,383 evaluations with narrative comments by 597 faculty of 698 residents, including 45% of comments about women residents and 13.2% about residents who identified with race and ethnicities underrepresented in medicine. Most comments were moderately specific and positive. Comments about women residents were more positive (estimate 0.06, p 0.045) but less specific (estimate - 0.07, p 0.002) compared to men. Women residents were more likely to receive non-specific, weakly specific or no comments (adjusted OR 1.29, p 0.012) and less likely to receive highly specific comments (adjusted OR 0.71, p 0.003) or comments with specific examples of things done well or areas for growth (adjusted OR 0.74, p 0.003) than men. Gendered differences in comment specificity and valence were most notable early in training. Comment specificity and valence did not differ with resident race and ethnicity (specificity: estimate 0.03, p 0.32; valence: estimate - 0.05, p 0.26) or faculty gender (specificity: estimate 0.06, p 0.15; valence: estimate 0.02 p 0.54). CONCLUSION: There were significant differences in the specificity and valence of qualitative assessments associated with resident gender with women receiving more praising but less specific and actionable comments. This suggests a lost opportunity for well-rounded assessment feedback to the disadvantage of women.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (

INTRODUCTION: Evidence suggests gender disparities in medical education assessment, including differences in ratings of competency and narrative comments provided in resident performance assessments. This study explores how gender manifests within the content of qualitative assessments (i.e., narrative comments or performance feedback) of resident performance. METHODS: Qualitative content analysis was used to explore gender-based differences in narrative comments included in faculty assessments of resident performance during inpatient medicine rotations at six Internal Medicine residency programs, 2016-2017. A blinded, multi-analyst approach was employed to identify themes across comments. Patterns in themes with resident gender and post-graduate year (PGY) were explored, focusing on PGY2 and PGY3 when residents are serving in the team leader role. RESULTS: Data included 3,383 evaluations with narrative comments of 385 men (55.2%) and 313 women residents (44.8%). There were thematic differences in narrative comments received by men and women residents and how these themes manifested within comments changed with training time. Compared to men, comments about women had a persistent relationship-orientation and emphasized confidence over training including as interns and in PGY2 and PGY3, when serving as team leader. The relationship-orientation was characterized not only by the residents communal attributes but also their interpersonal and communication skills, including efforts supporting others and establishing the tone for the team. Comments about women residents often highlighted confidence, including recommendations around behaviors that convey confidence in decision-making and team leadership. DISCUSSION: There were gender-based thematic differences in qualitative assessments. Comments about women resident team leaders highlight relationship building skills and urge confidence and actions that convey confidence as team leader. Persistent attention to communal skills suggests gendered expectations for women resident team leaders and a lost opportunity for well-rounded feedback to the disadvantage of women residents. These findings may inform interventions to promote equitable assessment, such as providing feedback across the competencies.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms nonalcoholic and fatty were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA in children with headaches based on clinically sensible and reliable variables. METHODS AND ANALYSIS: Prospective cohort study of 28 000 children with headaches presenting to any of 18 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). We include children aged 2-17 years with a chief complaint of headache. We exclude children with a clear non-intracranial alternative diagnosis, fever, neuroimaging within previous year, neurological or developmental condition such that patient history or physical examination may be unreliable, Glasgow Coma Scale score

Study participants (n = 272) completed 12 Patient-Reported Outcomes Measurement Information System (PROMIS) physical, mental and social health measures (questionnaires) prior to implantation of a left ventricular assist device (LVAD) and again at 3 and 6 months postimplant. All but 1 PROMIS measure demonstrated significant improvement from pre-implant to 3 months; there was little change between 3 and 6 months. Because PROMIS measures were developed in the general population, patients with an LVAD, their caregivers and their clinicians can interpret the meaning of PROMIS scores in relation to the general population, helping them to monitor a return to normalcy in everyday life.

Facial recognition technology (FRT) has been adopted as a precision medicine tool. The medical genetics field highlights both the clinical potential and privacy risks of this technology, putting the discipline at the forefront of a new digital privacy debate. Investigating how geneticists perceive the privacy concerns surrounding FRT can help shape the evolution and regulation of the field, and provide lessons for medicine and research more broadly. Five hundred and sixty-two genetics clinicians and researchers were approached to fill out a survey, 105 responded, and 80% of these completed. The survey consisted of 48 questions covering demographics, relationship to new technologies, views on privacy, views on FRT, and views on regulation. Genetics professionals generally placed a high value on privacy, although specific views differed, were context-specific, and covaried with demographic factors. Most respondents (88%) agreed that privacy is a basic human right, but only 37% placed greater weight on it than other values such as freedom of speech. Most respondents (80%) supported FRT use in genetics, but not necessarily for broader clinical use. A sizeable percentage (39%) were unaware of FRT's lower accuracy rates in marginalized communities and of the mental health effects of privacy violations (62%), but most (76% and 75%, respectively) expressed concern when informed. Overall, women and those who self-identified as politically progressive were more concerned about the lower accuracy rates in marginalized groups (88% vs. 64% and 83% vs. 63%, respectively). Younger geneticists were more wary than older geneticists about using FRT in genetics (28% compared to 56% "strongly" supported such use). There was an overall preference for more regulation, but respondents had low confidence in governments' or technology companies' ability to accomplish this. Privacy views are nuanced and context-dependent. Support for privacy was high but not absolute, and clear deficits existed in awareness of crucial FRT-related discrimination potential and mental health impacts. Education and professional guidelines may help to evolve views and practices within the field.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

OBJECTIVES: Assess associations between social networks and urban American Indian/Alaska Native emerging adults alcohol, cannabis, and opioid use and intentions. METHOD: American Indian/Alaska Native participants ages 18-25 (N = 150; 86% female) were recruited across the United States from 12/20 to 10/21 via social media. Participants named up to 15 people whom they talked with most over the past 3 months and reported who (a) used alcohol and cannabis heavily or used other drugs (e.g., opioid use), (b) engaged in traditional practices, and (c) provided support. They also reported past 3-month alcohol, cannabis, and opioid use and intentions to use. RESULTS: Having a higher proportion of network members engaging in regular cannabis and heavy alcohol use (but not other drugs) was associated with more frequent cannabis use and stronger cannabis use intentions. Participants with higher proportions of members engaging in heavy alcohol use, regular cannabis use, or other drug use and who did not engage in traditional practices were more likely to report cannabis use and greater intentions to use cannabis and drink alcohol. In contrast, participants with higher proportions of network members engaging in traditional practices and who did not report heavy alcohol use, regular cannabis use, or other drug use were less likely to report intentions to use cannabis or drink alcohol. CONCLUSIONS: Findings emphasize what many studies have shown among various racial/ethnic groups-having network members who use substances increases the chance of use. Findings also highlight that traditional practices may be an important part of the prevention approach for this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND AND AIMS: Despite its inclusion in the 11th revision of the International Classification of Diseases, there is a virtual paucity of high-quality scientific evidence about compulsive sexual behavior disorder (CSBD), especially in underrepresented and underserved populations. Therefore, we comprehensively examined CSBD across 42 countries, genders, and sexual orientations, and validated the original (CSBD-19) and short (CSBD-7) versions of the Compulsive Sexual Behavior Disorder Scale to provide standardized, state-of-the-art screening tools for research and clinical practice. METHOD: Using data from the International Sex Survey (N = 82,243; Mage = 32.39 years, SD = 12.52), we evaluated the psychometric properties of the CSBD-19 and CSBD-7 and compared CSBD across 42 countries, three genders, eight sexual orientations, and individuals with low vs. high risk of experiencing CSBD. RESULTS: A total of 4.8% of the participants were at high risk of experiencing CSBD. Country- and gender-based differences were observed, while no sexual-orientation-based differences were present in CSBD levels. Only 14% of individuals with CSBD have ever sought treatment for this disorder, with an additional 33% not having sought treatment because of various reasons. Both versions of the scale demonstrated excellent validity and reliability. DISCUSSION AND CONCLUSIONS: This study contributes to a better understanding of CSBD in underrepresented and underserved populations and facilitates its identification in diverse populations by providing freely accessible ICD-11-based screening tools in 26 languages. The findings may also serve as a crucial building block to stimulate research into evidence-based, culturally sensitive prevention and intervention strategies for CSBD that are currently missing from the literature.

BACKGROUND: Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes. OBJECTIVE: We sought to identify the most promising interventions that are not yet included in the policy recommendations of the World Health Organization (WHO) but could complement antenatal care and reduce the prevalence of LBW and related adverse birth outcomes in low- and middle-income settings. METHODS: We utilized an adapted Child Health and Nutrition Research Initiative (CHNRI) prioritization method. RESULTS: In addition to procedures already recommended by WHO for the prevention of LBW, we identified six promising antenatal interventions that are not currently recommended by WHO with an indication for LBW prevention, namely: (1) provision of multiple micronutrients; (2) low-dose aspirin; (3) high-dose calcium; (4) prophylactic cervical cerclage; (5) psychosocial support for smoking cessation; and (6) other psychosocial support for targeted populations and settings. We also identified seven interventions for further implementation research and six interventions for efficacy research. CONCLUSION: These promising interventions, coupled with increasing coverage of currently recommended antenatal care, could accelerate progress toward the global target of a 30% reduction in the number of LBW infants born in 2025 compared to 2006-10.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

ObjectivesIt is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care.MethodsChanges in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3 years preceding the first observed BA of ≥12 years. Relationships were characterized using plot inspection and linear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models.ResultsBA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6-18 months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of ≥33/≥55 months).ConclusionsThese findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6-18 months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Histone variant H3.3 is encoded by two genes, H3f3a and H3f3b, which can be expressed differentially depending on tissue type. Previous work in our lab has shown that knockout of H3f3b causes some neonatal lethality and infertility in mice, and chromosomal defects in mouse embryonic fibroblasts (MEFs). Studies of H3f3a and H3f3b null mice by others have produced generally similar phenotypes to what we found in our H3f3b nulls, but the relative impacts of the loss of either H3f3a or H3f3b have varied depending on the approach and genetic background. Here we used a knockout-first approach to target the H3f3a gene for inactivation in C57BL6 mice. Homozygous H3f3a targeting produced a lethal phenotype at or before birth. E13.5 null embryos had some potential morphological differences from WT littermates including smaller size and reduced head size. An E18.5 null embryo was smaller than its control littermates with several potential defects including small head and brain size as well as small lungs, which would be consistent with a late gestation lethal phenotype. Despite a reduction in H3.3 and total H3 protein levels, the only histone H3 post-translational modification in the small panel assessed that was significantly altered was the unique H3.3 mark phospho-Serine31, which was consistently increased in null neurospheres. H3f3a null neurospheres also exhibited consistent gene expression changes including in protocadherins. Overall, our findings are consistent with the model that there are differential, cell-type-specific contributions of H3f3a and H3f3b to H3.3 functions in epigenetic and developmental processes.

BackgroundA better understanding is needed of the burdens and benefits of left ventricular assist device (LVAD) implantation on patients' physical, mental, and social well-being. The purpose of this report was to evaluate the validity of Patient-Reported Outcomes Measurement Information System (PROMIS) measures for LVAD patients and to estimate clinically important score differences likely to have implications for patient treatment or care.MethodsAdults from 12 sites across all US geographic regions completed PROMIS measures ≥3 months post-LVAD implantation. Other patient-reported outcomes (eg, Kansas City Cardiomyopathy Questionnaire-12 item), clinician ratings, performance tests, and clinical adverse events were used as validity indicators. Criterion and construct validity and clinically important differences were estimated with Pearson correlations, ANOVA methods, and Cohen d effect sizes.ResultsParticipants' (n=648) mean age was 58 years, and the majority were men (78%), non-Hispanic White people (68%), with dilated cardiomyopathy (55%), long-term implantation strategy (57%), and New York Heart Association classes I and II (54%). Most correlations between validity indicators and PROMIS measures were medium to large (≥0.3; p

A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0-91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2-59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5-42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step.

BackgroundLimited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.MethodsThis is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.Results1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.ConclusionsUsing one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.FundingThis study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.Clinical trial numberCCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur ( 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted.

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is a rare cause of stroke carrying a nearly 4% risk of recurrence after 1 year. There are limited data on predictors of recurrent venous thrombosis in patients with CVT. In this study, we aim to identify those predictors. METHODS: This is a secondary analysis of the ACTION-CVT study which is a multicenter international study of consecutive patients hospitalized with a diagnosis of CVT over a 6-year period. Patients with cancer-associated CVT, CVT during pregnancy, or CVT in the setting of known antiphospholipid antibody syndrome were excluded per the ACTION-CVT protocol. The study outcome was recurrent venous thrombosis defined as recurrent venous thromboembolism (VTE) or de novo CVT. We compared characteristics between patients with vs without recurrent venous thrombosis during follow-up and performed adjusted Cox regression analyses to determine important predictors of recurrent venous thrombosis. RESULTS: Nine hundred forty-seven patients were included with a mean age of 45.2 years, 63.9% were women, and 83.6% had at least 3 months of follow-up. During a median follow-up of 308 (interquartile range 120-700) days, there were 5.05 recurrent venous thromboses (37 VTE and 24 de novo CVT) per 100 patient-years. Predictors of recurrent venous thrombosis were Black race (adjusted hazard ratio [aHR] 2.13, 95% CI 1.14-3.98, p = 0.018), history of VTE (aHR 3.40, 95% CI 1.80-6.42, p < 0.001), and the presence of one or more positive antiphospholipid antibodies (aHR 3.85, 95% CI 1.97-7.50, p < 0.001). Sensitivity analyses including events only occurring on oral anticoagulation yielded similar findings. DISCUSSION: Black race, history of VTE, and the presence of one or more antiphospholipid antibodies are associated with recurrent venous thrombosis among patients with CVT. Future studies are needed to validate our findings to better understand mechanisms and treatment strategies in patients with CVT.

ObjectivesTo study total growth, rate of bone maturation, and menarche after discontinuation of Gonadotropin releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP).MethodsTwenty girls with CPP on treatment with GnRHa were followed from discontinuation of treatment to final height (FH). Height, height velocity (HV), and bone age were measured every 6 months. Age at menarche was collected.ResultsOnce treatment is discontinued, rate of bone maturation (bone age [BA]/chronological [CA]) accelerated from 0.7 ± 0.3 at end of treatment to 1.2 ± 0.8 post treatment, similar to BA/CA prior to treatment. BA at treatment discontinuation ranged from 11-14 years. On average, treatment was stopped when CA was within 9 months of BA. All girls continued to grow from end of treatment to menarche averaging an increase of 4.7 ± 3.7 cm, with HV 3.2 ± 2.0 cm/year. Post-menarche they grew an additional 4.6 ± 2.1 cm, with HV 2.4 ± 1.9 cm/year. Acceleration of HV was not seen post treatment. The younger the BA at initiation or completion of treatment, the longer time to menarche. No one had menarche prior to a BA of 12.5 year.ConclusionsA pubertal growth spurt does not usually occur after treatment with GnRHa in girls with CPP. Rate of bone maturation accelerates post treatment. These factors are important in assessing optimal height outcome and decisions regarding cessation of treatment. This study will help clinicians give patients and families better estimates of growth and onset of menarche post treatment.

People sometimes prefer groups to which they do not belong (outgroups) over their own groups (ingroups). Many long-standing theoretical perspectives assume that this outgroup favorability bias primarily reflects negative ingroup evaluations rather than positive outgroup evaluations. To examine the contributions of negative ingroup versus positive outgroup evaluations to outgroup bias, we examined participants' data (total n > 879,000) from Implicit Association Tests [A. G. Greenwald, D. E. McGhee, J. L. K. Schwartz, J. Pers. Soc. Psychol. 74, 1464-1480 (1998)] measuring intergroup attitudes across four social domains in exploratory and preregistered confirmatory analyses. Process modeling [F. R. Conrey, J. W. Sherman, B. Gawronski, K. Hugenberg, C. J. Groom, J. Pers. Soc. Psychol. 89, 469-487 (2005)] was applied to the responses of participants who demonstrated implicit outgroup bias to separately estimate the contributions of negative ingroup and positive outgroup evaluations. The outgroup biases of lower-status group members (i.e., Asian, Black, gay and lesbian, and older people) consistently reflected greater contributions of positive outgroup evaluations than negative ingroup evaluations. In contrast, the outgroup biases of higher-status group members (i.e., White, straight, and younger people) reflected a more varied pattern of evaluations. We replicated this pattern of results using explicitly measured intergroup evaluations. Taking these data together, the present research demonstrates a positive-negative asymmetry effect of outgroup bias, primarily among members of lower-status groups.

The Wolffian ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here, we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting of ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes.

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

BackgroundThe incidence of systemic lupus in children with discoid lupus is unknown.ObjectiveThis study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE).MethodsMedical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of 1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P

BackgroundThe updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)-specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality.MethodsBecause complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count

AimsIn heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll-in cohort of the REBALANCE-HF trial.Methods and resultsThe open-label (roll-in) arm of REBALANCE-HF will enrol up to 30 patients, followed by the randomized, sham-controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow-up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-min walk test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll-in, open-label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4-81) years, LVEF 61.0 (56.0-63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non-serious moderate device/procedure-related adverse events were reported. At 1-month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p

OBJECTIVE: Tracking changes in hemodynamic congestion and the consequent proactive readjustment of treatment has shown efficacy in reducing hospitalizations for patients with heart failure (HF). However, the cost-prohibitive nature of these invasive sensing systems precludes their usage in the large patient population affected by HF. The objective of this research is to estimate the changes in pulmonary artery mean pressure (PAM) and pulmonary capillary wedge pressure (PCWP) following vasodilator infusion during right heart catheterization (RHC), using changes in simultaneously recorded wearable seismocardiogram (SCG) signals captured with a small wearable patch. METHODS: A total of 20 patients with HF (20% women, median age 55 (interquartile range (IQR), 44-64) years, ejection fraction 24 (IQR, 16-43)) were fitted with a wearable sensing patch and underwent RHC with vasodilator challenge. We divided the dataset randomly into a training-testing set (n = 15) and a separate validation set (n = 5). We developed globalized (population) regression models to estimate changes in PAM and PCWP from the changes in simultaneously recorded SCG. RESULTS: The regression model estimated both pressures with good accuracies: root-mean-square-error (RMSE) of 2.5 mmHg and R2 of 0.83 for estimating changes in PAM, and RMSE of 1.9 mmHg and R2 of 0.93 for estimating changes in PCWP for the training-testing set, and RMSE of 2.7 mmHg and R2 of 0.81 for estimating changes in PAM, and RMSE of 2.9 mmHg and R2 of 0.95 for estimating changes in PCWP for the validation set respectively. CONCLUSION: Changes in wearable SCG signals may be used to track acute changes in intracardiac hemodynamics in patients with HF. SIGNIFICANCE: This method holds promise in tracking longitudinal changes in hemodynamic congestion in hemodynamically-guided remote home monitoring and treatment for patients with HF.

BackgroundEpigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD.MethodsBlood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis.ResultsA total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.ConclusionsDifferential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

BackgroundDisparities in objective assessments in graduate medical education such as the In-Training Examination (ITE) that disadvantage women and those self-identifying with race/ethnicities underrepresented in medicine (URiM) are of concern.ObjectiveExamine ITE trends longitudinally across post-graduate year (PGY) with gender and race/ethnicity.DesignLongitudinal analysis of resident ITE metrics at 7 internal medicine residency programs, 2014-2019. ITE trends across PGY of women and URiM residents compared to non-URiM men assessed via ANOVA. Those with ITE scores associated with less than 90% probability of passing the American Board of Internal Medicine certification exam (ABIM-CE) were identified and odds of being identified as at-risk between groups were assessed with chi square.ParticipantsA total of 689 IM residents, including 330 women and URiM residents (48%).Main measuresITE score KEY RESULTS: There was a significant difference in ITE score across PGY for women and URiM residents compared to non-URiM men (F(2, 1321) 4.46, p=0.011). Adjusting for program, calendar year, and baseline ITE, women and URiM residents had smaller ITE score gains (adjusted mean change in score between PGY1 and PGY3 (se), non-URiM men 13.1 (0.25) vs women and URiM residents 11.4 (0.28), p

BackgroundHuman milk oligosaccharides (HMOs) are an abundant class of compounds found in human milk and have been linked to the development of the infant, and specifically the brain, immune system, and gut microbiome.ObjectivesAdvanced analytical methods were used to obtain relative quantitation of many structures in approximately 2000 samples from over 1000 mothers in urban, semirural, and rural sites across geographically diverse countries.MethodsLC-MS-based analytical methods were used to profile the compounds with broad structural coverage and quantitative information. The profiles revealed their structural heterogeneity and their potential biological roles. Comparisons of HMO compositions were made between mothers of different age groups, lactation periods, infant sexes, and residing geographical locations.ResultsA common behavior found among all sites was a decrease in HMO abundances during lactation until approximately postnatal month 6, where they remained relatively constant. The greatest variations in structural abundances were associated with the presence of α(1,2)-fucosylated species. Genomic analyses of the mothers were not performed; instead, milk was phenotyped according to the abundances of α(1,2)-fucosylated structures. Mothers from the South American sites tended to have higher proportions of phenotypic secretors [mothers with relatively high concentrations of α(1,2)-fucosylated structures] in their populations compared to the rest of the globe, with Bolivia at ∼100% secretors, Peru at ∼97%, Brazil at ∼90%, and Argentina at ∼85%. Conversely, the cohort sampled in Africa manifested the lowest proportion of secretors (South Africa ∼ 63%, the Gambia ∼ 64%, and Malawi ∼ 75%). Furthermore, we compared total abundances of HMOs in secretors compared with nonsecretors and found that nonsecretors have lower abundances of HMOs compared to secretors, regardless of geographical location. We also observed compositional differences of the 50+ most abundant HMOs between milk types and geographical locations.ConclusionsThis study represents the largest structural HMO study to date and reveals the general behavior of HMOs during lactation among different populations.

PurposeGOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL).MethodsPatients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates.ResultsParticipants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time (P < .001) for all three groups. A group by time interaction (P < .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time.ConclusionBoth WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.

PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non-cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR2) in colitis. To localize PAR2 and assess redistribution during disease, we generated knockin mice expressing PAR2 fused to monomeric ultrastable green fluorescent protein (muGFP). PAR2-muGFP signaled and trafficked normally. PAR2 messenger RNA was detected at similar levels in Par2-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR2) and Gfp probes revealed that PAR2-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR2-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR2-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR2 PAR2 agonists stimulated endocytosis of PAR2 and recruitment of Gαq, Gαi, and β-arrestin to early endosomes of T84 colon carcinoma cells. PAR2 agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR2 endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR2 endocytosis sustains protease-evoked inflammation and nociception and PAR2 in endosomes is a potential therapeutic target for colitis.

Branching morphogenesis is a fundamental process by which organs in invertebrates and vertebrates form branches to expand their surface areas. The current dogma holds that directional cell migration determines where a new branch forms and thus patterns branching. Here, we asked whether mouse Lgl1, a homolog of the Drosophila tumor suppressor Lgl, regulates epithelial polarity in the mammary gland. Surprisingly, mammary glands lacking Lgl1 have normal epithelial polarity, but they form fewer branches. Moreover, we find that Lgl1 null epithelium is unable to directionally migrate, suggesting that migration is not essential for mammary epithelial branching as expected. We show that LGL1 binds to Integrin β1 and inhibits its downstream signaling, and Integrin β1 overexpression blocks epithelial migration, thus recapitulating the Lgl1 null phenotype. Altogether, we demonstrate that Lgl1 modulation of Integrin β1 signaling is essential for directional migration and that epithelial branching in invertebrates and the mammary gland is fundamentally distinct.

BACKGROUND: COVID-19 has profoundly affected sleep, although little research has focused on high-risk populations for poor sleep health, including American Indian/Alaska Native (AI/AN) adolescents. METHODS: This is the first longitudinal study to examine changes in sleep with surveys completed before the pandemic and during the early months of COVID-19 in a sample of urban AI/AN adolescents (N = 118; mean age = 14 years at baseline; 63% female). We use a mixed-methods approach to explore how COVID-19 affected urban AI/AN adolescents sleep, daily routines, and interactions with family and culture. Quantitative analysis examined whether pandemic-related sleep changes were significant and potential moderators of COVID-19s effect on sleep, including family and community cohesion and engagement in traditional practices. RESULTS: : Findings demonstrate changes in sleep, including increases in sleep duration, delays in bedtimes and waketimes, and increases in sleep-wake disturbances (ps

PurposeTo investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women.DesignThis was a retrospective study using data from the Women's Health Initiative.MethodsPatients with glaucoma or ocular hypertension were excluded. Large CDR was defined as ≥ 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics.ResultsFinal analyses included 1,196 White women with mean age of 69.60 ± 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 ± 0.31 vs. 1.41 ± 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007).ConclusionsIndependent of the CDR GRS, women with large CDR had a lower cognitive function.

Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.