<p>Some evidence suggests that pediatric sarcomas have both shared and distinct genetic profiles; however, large-scale efforts to characterize germline genetic susceptibility across these malignancies are limited by their rarity. We evaluated the role of common and rare variants in the genetic etiology of the more frequent pediatric sarcomas: osteosarcoma (OS); Ewing sarcoma (ES); and rhabdomyosarcoma (RMS), subcategorized into embryonal (ERMS) and alveolar (ARMS).</p>

<p>Cross‐sector relationship building is an important strategy in corporate social responsibility initiatives, and communicating cross‐sector relationships on social media can help raise the visibility of collaborative relationships. A noticeable gap in the literature is how social media enables and constrains the formation patterns of cross‐sector connections. To understand how businesses communicate their relationships with government agencies and nonprofits about social issues on social media, we propose a theoretical framework that centers public attention as a critical resource and considers different sectors' interests in the COVID‐19 issue. We tested this framework with a nationally representative sample of 1,980 organizations on Twitter. The analysis reveals that the increase in public attention to the COVID‐19 issue was accompanied by a greater likelihood of cross‐sector ties. Specifically, firms severely affected by COVID‐19 were more likely to build ties with government agencies, and the increase in public attention also drove firms to build more ties with nonprofits, especially advocacy nonprofits. Our findings suggest managers of social media communication should observe the volatile public attention and design communicative strategies accordingly.</p>

<h3>Importance</h3><p>Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes.</p><h3>Objective</h3><p>To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin.</p><h3>Design, Setting, and Participants</h3><p>This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20.</p><h3>Intervention</h3><p>Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin.</p><h3>Main Outcome</h3><p>The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization.</p><h3>Results</h3><p>A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65;<i>P</i> = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54;<i>P</i> = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83;<i>P</i> = .17).</p><h3>Conclusions and Relevance</h3><p>In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding.</p><h3>Trial Registration</h3><p>ClinicalTrials.gov Identifier:NCT04491695</p>

BACKGROUND A wealth of clinically relevant information is only obtainable within unstructured clinical narratives, leading to great interest in clinical natural language processing (NLP). While a multitude of approaches to NLP exist, current algorithm development approaches have limitations that can slow the development process. These limitations are exacerbated when the task is emergent, as is the case currently for NLP extraction of signs and symptoms of COVID-19 and postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE This study aims to highlight the current limitations of existing NLP algorithm development approaches that are exacerbated by NLP tasks surrounding emergent clinical concepts and to illustrate our approach to addressing these issues through the use case of developing an NLP system for the signs and symptoms of COVID-19 and PASC. METHODS We used 2 preexisting studies on PASC as a baseline to determine a set of concepts that should be extracted by NLP. This concept list was then used in conjunction with the Unified Medical Language System to autonomously generate an expanded lexicon to weakly annotate a training set, which was then reviewed by a human expert to generate a fine-tuned NLP algorithm. The annotations from a fully human-annotated test set were then compared with NLP results from the fine-tuned algorithm. The NLP algorithm was then deployed to 10 additional sites that were also running our NLP infrastructure. Of these 10 sites, 5 were used to conduct a federated evaluation of the NLP algorithm. RESULTS An NLP algorithm consisting of 12,234 unique normalized text strings corresponding to 2366 unique concepts was developed to extract COVID-19 or PASC signs and symptoms. An unweighted mean dictionary coverage of 77.8% was found for the 5 sites. CONCLUSIONS The evolutionary and time-critical nature of the PASC NLP task significantly complicates existing approaches to NLP algorithm development. In this work, we present a hybrid approach using the Open Health Natural Language Processing Toolkit aimed at addressing these needs with a dictionary-based weak labeling step that minimizes the need for additional expert annotation while still preserving the fine-tuning capabilities of expert involvement.

The US Midwest, which is home to over 20 percent of Americans, is heavily dependent on the primary sector of the economy, especially agriculture. We look at the relationship between commodity prices-corn and soybean prices, the dominant commodities in the Midwest-and mortality in a sample of 485 Midwestern counties for the period 1980 to 2016. As outcome variables, we look at crude or age-adjusted all-cause death rates. Because commodity prices are only available at the state or global level, we interact (i) state-level or global commodity prices with (ii) how much of each commodity is grown within each county. Our treatment variable thus captures how, for each commodity, revenues from that commodity within a given county change in response to changes in commodity prices. For identification, we combine the exposure design just described with a two-way, county and year fixed effects design as well as with a number of robust panel data estimators. On average, we find that a decrease in commodity prices is associated with increased mortality across all counties: A 10-percent decrease in either corn or soybean revenues is associated with an increase in the crude death rate of about 0.2 percent, or 0.205 additional deaths per 1,000 persons in a county. This result appears driven by rural counties and by corn price shocks. For robustness, we also estimate specifications in which we instrument revenues from each commodity with measures of drought severity, and we conduct falsification tests. Finally, we show that the relationship between commodity prices and rural mortality appears driven by cardiovascular disease and by suicides.

Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (−2.44 units, 95% CI −4.42 to −0.45), though to a lesser extent than exclusive use of cigarettes (−6.01 units, 95% CI −6.01 to −4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes. Data are available on reasonable request.

<h3>Importance</h3><p>Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.</p><h3>Objective</h3><p>To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.</p><h3>Design, Setting, and Participants</h3><p>A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.</p><h3>Exposures</h3><p>LDL-C, cumulative past LDL-C, FH variant status.</p><h3>Main Outcomes and Measures</h3><p>Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.</p><h3>Results</h3><p>Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.</p><h3>Conclusions and Relevance</h3><p>In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.</p>

PURPOSETo evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.METHODSCumulative incidence of late mortality (a- 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of a- 4 chemotherapy agents.RESULTSAmong 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.CONCLUSIONWith approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

The estimation of the central space is at the core of the sufficient dimension reduction (SDR) literature. However, it is well known that the finite-sample estimation suffers from collinearity amon...

Causal mediation analysis aims to investigate how an intermediary factor, called a mediator, regulates the causal effect of a treatment on an outcome. With the increasing availability of measurements on a large number of potential mediators, methods for selecting important mediators have been proposed. However, these methods often assume the absence of unmeasured mediator-outcome confounding. We allow for such confounding in a linear structural equation model for the outcome and further propose an approach to tackle the mediator selection issue. To achieve this, we firstly identify causal parameters by constructing a pseudo proxy variable for unmeasured confounding. Leveraging this proxy variable, we propose a partially penalized method to identify mediators affecting the outcome. The resultant estimates are consistent, and the estimates of nonzero parameters are asymptotically normal. Motivated by these results, we introduce a two-step procedure to consistently select active mediation pathways, eliminating the need to test composite null hypotheses for each mediator that are commonly required by traditional methods. Simulation studies demonstrate the superior performance of our approach compared to existing methods. Finally, we apply our approach to genomic data, identifying gene expressions that potentially mediate the impact of a genetic variant on mouse obesity.

This research note investigates citation bias using probabilities of zero citations, total citations, and citations per year since publication from Web of Science, Scopus, and Google Scholar for al...

<p>Normobaric Hyperoxia (NBO) is a potentially promising stroke treatment strategy that could protect the ischemic penumbra and could be administered as an adjunct before vascular recanalization. However, the efficacy and safety of NBO have not been confirmed by randomized controlled trials.The study aims to assess the efficacy and safety of NBO for ischemic stroke due to large artery occlusion (LVO) of acute anterior circulation among patients who had endovascular treatment (EVT) and were randomized within 6h from symptom onset. Based on the data of the modified Rankin scale (mRS) score at 90 days from the normobaric hyperoxia combined with endovascular treatment for acute ischemic stroke (OPENS: NCT03620370) trial, 284 patients will be included to achieve a 90% power by using Wilcoxon-Mann-Whitney (WMW) test and the proportional odds model to calculate the sample size. The study is a prospective, multicenter, blinded, randomized controlled trial. The NBO group is administered with mask oxygen therapy of 10L/min while the sham NBO group is with that of 1L/min. The primary outcome is the modified Rankin Scale (mRS) score at 90 days. Secondary endpoints include cerebral infarct volume at 24-48 hours, functional independence (mRS≤2) at 90 days, and improvement in neurological function at 24 hours. Safety outcomes include 90-day mortality, oxygen-related adverse events, and serious adverse events. This study will indicate whether NBO combined with EVT is superior to EVT alone for acute ischemic stroke caused by LVO in subjects randomized within 6h from symptom onset, and will provide some evidence for NBO intervention as an adjunct to thrombectomy for acute stroke.</p>

<p>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy causing ischemic organ impairment. Blacks are overrepresented in iTTP cohorts in the United States but racial disparities in iTTP outcomes and response to therapy have not been studied. Using the United States Thrombotic Microangiopathy (USTMA) Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the US from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS [hazard ratio (HR) of 1.60 (95% CI 1.16-2.21)]; the addition of rituximab to corticosteroids improved RFS in White [HR 0.37 (95% CI 0.18-0.73)] but not Black patients [HR 0.96 (95% CI 0.71-1.31)]. In de novo iTTP, rituximab delayed relapse, but Blacks had shorter RFS than Whites regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression following rituximab treatment. How race, racism, and the social determinants of health contribute to the disparity in relapse risk in iTTP deserve further study.</p>

Introduction: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demio...

There is ample literature on interventions to reduce human immunodeficiency virus (HIV) stigma and discrimination and extant theory around intersectionality. However, the integration of intersectionality into the design and implementation of stigma reduction interventions is nascent. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we reviewed 23 studies from six countries to examine the state of the evidence on interventions to reduce intersectional stigma in the context of HIV. Thirteen studies made explicit reference to intersectionality, 11 of which addressed all three stigma domains: drivers, facilitators, and manifestations. Most interventions were multilevel and multistrategy, yet only five included a structural component. Thirteen studies focused on four or more intersections (e.g., HIV, race, sexual identity, gender), five on three intersections, and five on two intersections. Twenty studies (87%) reported medium ( n = 5) to high ( n = 15) community engagement. The majority of studies (19/23) assessed HIV-related (e.g., antiretroviral therapy [ART] adherence) and/or empowerment-based outcomes (e.g., self-esteem, coping), with 91% reporting some positive intervention effects. Of 13 studies that measured stigma outcomes, only seven (54%) documented some improvement in the stigma measures assessed. Our review revealed a range of sophisticated, intersectionality-informed interventions that were mostly successful at improving HIV, sexual health, and empowerment-based outcomes, but less successful at reducing the aspects of stigma measured. Future research should encompass wider geographical regions, use validated measures of intersectional stigma, and test structural interventions and approaches that challenge the systems of power and oppression that fuel stigma, inequality, and poor health outcomes among multiply marginalized populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved) (Source: journal abstract)

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction. A multi-ancestry meta-regression study analyses diverse genome-wide association studies and genome loci associated with tobacco and alcohol use.