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Preventable Differences in Recommended Outpatient COVID-19 Treatment Among Adults With COVID-19 in the United States
Full text linkThe COVID-19 pandemic exposed differences in health care outcomes, including the prescription of COVID-19 antiviral medications. This analysis aimed to describe prescribing patterns in outpatient COVID-19 treatment and assess factors that contributed to these differences. A cross-sectional analysis was conducted using electronic health record data from August 2022 through March 2024 from health care institutions participating in PCORnet,® the National Patient-Centered Clinical Research Network. Descriptive statistics were used to characterize COVID-19 outpatients eligible for treatment, and regression models were used to calculate adjusted prevalence ratios (aPR) of prescribed COVID-19 outpatient treatment. Interaction terms assessed the interactions between race and ethnicity and the combined comorbidity index (CCI), age and sex, and age and race and ethnicity. Of 1,247,420 patients eligible for COVID-19 treatment, 334,947 (26.9%) were prescribed outpatient treatment. In adjusted analyses, compared with White patients, all other racial and ethnic groups had lower aPR for treatment (aPRs:0.89–0.99), except patients who reported being multiracial (aPR:1.00; 95% CI: 0.93–1.08). Those aged 65–74 were prescribed treatment more often (aPR: 1.13; 95% CI: 1.12–1.13) compared with patients aged 20–49. Patients with a CCI of 1–3 and ≥4 were prescribed treatment less often (aPR: 0.99, 95% CI: 0.97–1.01 and aPR: 0.91, 95% CI: 0.89–0.94, respectively), compared with those with a CCI of ≤0. These differences were sustained when considering the interactions between race and age and race and CCI. We found differences in recommended outpatient treatment by several sociodemographic variables. Addressing COVID-19 prescription barriers is essential to slow preventable differences from unmet COVID-19 outpatient care
Agreement Across 10 Artificial Intelligence Models in Assessing Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Breast Cancer Whole-Slide Images
Full text linkHistorically, eligibility for receiving human epidermal growth factor receptor 2 (HER2)-targeted therapies was limited to HER2-positive tumors (immunohistochemistry 3+ or in situ hybridization amplified), but recent advances in antibody-drug conjugates have expanded these criteria to include HER2-low and HER2-ultralow expression. This evolving therapeutic landscape underscores the need for precise and reproducible HER2 assessment. Digital and computational pathology tools may help address these needs, but their measurement variability must be evaluated to inform research and clinical use. We evaluated HER2 scoring variability across 10 independently developed computational pathology artificial intelligence models applied to 1124 whole-slide images from 733 patients with breast cancer. Analyses included American Society of Clinical Oncology-College of American Pathologists categorical scores (0, 1+, 2+, and 3+), H-scores, tumor cell staining percentages, and counts of total and stained invasive carcinoma cells. Agreement among models and 3 pathologists was assessed using pairwise overall percent agreement (OPA), Cohen kappa, and hierarchical clustering. Median model pairwise OPA for categorical HER2 scores was 65.1% (kappa, 0.51). Agreement was highest for HER2 3+ vs not 3+ (OPA, 97.3%; kappa, 0.86) and lowest for HER2-low cases, reflecting existing measurement challenges. For HER2 0 (negative) vs not 0 (positive) scoring, the average negative agreement was 65.3%, compared with the average positive agreement of 91.3%, suggesting more agreement in non-HER2 0 scores. H-score and cell count analyses indicated that scoring differences were more related to staining interpretation than tumor cell detection. Pathologists showed numerically higher concordance than models, but interobserver variability persisted. In exploratory analyses, sample type, staining artifacts, and heterogeneous HER2 expression appeared to be associated with discrepancies. Artificial intelligence-based HER2 scoring demonstrated high agreement in identifying HER2 3+ cases. Variability was most pronounced in borderline HER2 categories, particularly in HER2 low, underscoring the need for continued tool refinement for handling low-intensity staining. Standardized training data sets, validation frameworks, and regulatory alignment are important to improve reproducibility. Developing reference standards and benchmarking data sets is critical to evaluate performance, support regulatory decision-making, and ensure real-world applicability
Spatial Resolution of Microbial Community Members Within Cyanobacterial Mats From Temperate Mud Flats
Full text linkBenthic cyanobacterial mats (BCMs), known for their high cyanobacterial abundances, are distributed globally across diverse aquatic and semi-aquatic habitats. The microbial composition of BCMs is determined by various environmental factors that regulate key chemical and physical conditions, leading to complex community structures that vary across space and time. Recently, temperate mats have emerged as model systems for studying community structure and nutrient cycling. Using 16S metabarcoding and stable isotope analyses, our study characterized the bacterial members present at a fine-scale resolution across vertical layers of long-standing BCMs from Shackleford Banks Island in North Carolina, USA. Spatially expansive BCMs were mainly composed of Proteobacteria, Bacteroidota, Planctomycetota, Desulfobacterota, Verrucomicrobiota, and Cyanobacteria. Mat communities did not differ along horizontal transects but differed in both the diversity and community composition between vertically stratified layers. Trends in organic matter, carbon, and nitrogen availability match changes in microbial composition and diversity across vertical strata. These findings provided the first molecular characterization of the full bacterial community from BCMs from North Carolina and provide insight into the potential biogeochemical processes within this system
User-centred prototyping solutions to solve adult critical care issues: a scoping review
Full text linkBACKGROUND: How user-centred prototyping is carried out to solve adult critical care issues depends on the unique characteristics of this context. This review aimed to characterise prototyping in the context of critical care in terms of the types of prototypes developed, activities used to generate prototypes and settings in which prototypes were generated. METHODS: Four databases (PubMed, CINAHL, SCOPUS and IEEExplore) were searched for articles published from inception to 25 September 2025, in English, that involved prototyping to address issues in adult critical care. Two reviewers independently screened the search results to identify eligible articles and reviewed retained articles. RESULTS: 22 of 860 articles met the eligibility criteria. Role, look and feel, implementation and integration prototype types which combined two or more of these prototypes were identified. Prototypes addressing both role and look and feel were most common. 10 prototyping activities were reported, namely sketching, storyboarding, interactivity simulation, digitalising and adapting paper-based forms, rank ordering, building a functional device model, survey for item selection, card sorting, adapting a predeveloped high-tech prototype to a low-tech version, and revising existing workflow. Six of 22 articles reported multiple activities. Sketching was the most often used activity, and the in-person hospital setting was the most reported. CONCLUSIONS: Overall, there was a lack of reporting on the details of the prototyping processes. Such details could help future researchers anticipate the unique challenges of prototyping to develop solutions to solve adult critical care issues, learn from prior successful experiences and better plan strategies to address these challenges
SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting
Full text linkSignificance Previous work has demonstrated that the proteome of SARS-CoV-2 can potentially be a rich source of AMP-like viral fragments, exemplars of which are associated with severe COVID-like inflammation in vitro and in vivo. Here, we demonstrate that direct proteolytic processing of SARS-CoV-2 proteins can yield xenoAMPs, and that the full heterogeneous ensemble of resultant fragments can collectively exert AMP-like pore-forming activity. We describe an unanticipated general mechanism of host cellular targeting for viral AMP-like pore forming peptides, based on local Gaussian curvatures of the host cell membrane, and show that this mechanism can selectively target and deplete specific immune cell types in a manner consistent with clinical observations for severe COVID-19 patients. Immune cell populations are dysregulated in COVID-19 for currently unknown reasons: Plasmacytoid dendritic cell (pDC) populations are reduced, thus hampering antiviral responses. CD8+ T cell populations are reduced, the level of which has emerged as an index of disease severity. Recent work has shown that the proteome of SARS-CoV-2 is a rich reservoir of antimicrobial peptide-like sequence motifs (xenoAMPs) which can chaperone and organize dsRNA for amplified Toll-Like Receptor 3 (TLR3)-mediated inflammation in vitro and in vivo. Here, we demonstrate that proteolytic digestion of the SARS-CoV-2 spike protein by host trypsin-like serine proteases directly produces xenoAMPs. Synchrotron Small Angle X-ray Scattering, mass spectrometry, and a theoretical analysis based on continuum membrane elasticity show that proteolytically generated xenoAMPs from SARS-CoV-2 proteins in vitro and machine learning-predicted high-scoring xenoAMPs all induce negative Gaussian curvature (NGC) necessary for pore formation in membranes. We find that xenoAMPs alone as well as xenoAMPs synergistically with endogenous AMP LL-37 can induce NGC in membranes. A computational analysis of immune cells with morphologically complex shapes (e.g., pDC, CD8+, and CD4+ T cells) suggests that surfaces with high local NGC can concentrate AMP-like sequences and promote selective membrane disruption. Consistent with this hypothesis, experiments with freshly isolated human peripheral blood mononuclear cells confirm that viable pDCs, DCs, and T cells are significantly depleted after xenoAMP exposure, in contrast to monocytes and neutrophils, the immune cell subsets with spheroidal morphology. Structural data from Omicron variant xenoAMP homologs indicate reduced pore formation, consistent with clinical observations of reduced T cell cytopenia in Omicron variant infections
Monitoring diversity in genome-wide association studies requires measuring and reporting on immigration-related factors
Full text linkGenome-wide association studies (GWAS) have made remarkable progress to date in deciphering the genetic foundations of complex traits, yet persistent gaps remain in how sample heterogeneity is measured and reported. Current practices typically emphasize diversity by broad ancestry categories or stratification by country of recruitment, but these dimensions alone fail to capture the immigration-related factors that contribute to the genetic or environmental origins of heterogeneity. We argue that incorporating variables, such as country of origin, in descriptions and analyses provides essential context for interpreting genetic associations, particularly in increasingly multi-population and trans-national GWAS samples. We highlight how neglected these variables are in the literature using the GWAS Catalog. We provide suggestions for reporting on these data in future studies. By advocating for a more comprehensive view of diversity in GWAS, we aim to address the under-representation of immigrants in GWAS and thereby strengthen the validity and interpretability of future genomic studies
Mental health and sexual dating violence victimization among U.S. high school students during the COVID-19 pandemic: results from 2021 national survey
Full text linkObjective Sexual dating violence victimization (SDV) is a significant public health issue among high school students, impacting short-term (physical injuries) and long-term (substance abuse). Mental health issues during the pandemic may have increased adolescents’ vulnerability to experiencing SDV by impairing coping mechanisms, reducing decision-making capacity, and limiting access to protective social support. Few studies have investigated demographic disparities in SDV and how the pandemic impacted SDV among high school students. Our aim was to examine the demographic and racialized disparities in SDV and assess the association between mental health during the pandemic and SDV among high school students. Methods We conducted a cross-sectional study using 2021 national pooled Youth Risk Behavior Surveillance surveys of 234,572 US high school students. We used complex survey-weighted multivariable logistic regression models to assess the association between mental health during the pandemic and SDV in US high school students overall and subgroups. Results We identified demographic and racialized disparities in SDV, including differences in age, sex, and race. Females were more likely to experience SDV when compared to males (AOR=3.50, p<0.001). Worse mental health during the pandemic was independently associated with SDV in high school students overall and subgroups. Compared to high school students with “never not good” mental health, those with “always not good” mental health were more likely to experience SDV (AOR=5.15, p<0.001). The association was stronger in younger students (14 years old or younger), females, 9th graders, and those of minority races compared to the overall high school student population. For example, females with “always not good” mental health were more likely to experience SDV (AOR=7.67, p<0.001) than those with “never not good” mental health. Conclusion It is imperative to implement prevention strategies to reduce SDV among high school students. Strategies should prioritize mental health support, especially for those demographic and racialized at-risk groups
Dengue therapeutics consortium 2025: a global collaboration in action
Full text linkDengue is a global health emergency, with annually increasing case numbers that overwhelm healthcare systems, an ever-expanding range of the mosquito vector, and no antiviral or host-directed treatments proven to alter the course of disease. This article reports on a meeting of the Dengue Therapeutics Consortium, which included attendees from 19 countries with backgrounds in basic science, clinical research, drug development, industry, clinical trial methodology and policy. We summarise the current state of dengue therapeutics research and highlight the necessary steps to ensure that patients have equitable access to affordable and effective treatments. We review the antiviral pipeline, including novel and repurposed antiviral candidates, and we propose both human challenge and rate of viral clearance studies as methods to rapidly screen for antiviral activity prior to larger phase 3 clinical trials. We review ongoing phase 2 and phase 3 clinical trials to evaluate repurposed host-directed therapies for patients with moderate and severe disease, and we suggest considerations for future trial design, such as factorial randomisation and the use of a core outcome set to maximise efficiency and enable evidence synthesis by meta-analysis. We consider that multisectoral collaboration will be essential to achieve our aim of effective treatments for dengue. This will include drug development aligned to target product profiles, conduct of clinical trials with endpoints acceptable to both patients and regulators and sustained commitment from the pharmaceutical industry, non-profit initiatives and policymakers to ensure that effective treatments reach those who need them the most
A Phase 1 Dose‐Escalation, Food Effect, and Drug–Drug Interaction Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MALT1 Inhibitor, SGR‐1505, in Healthy Volunteers
Full text linkSGR‐1505 is a novel small‐molecule inhibitor of MALT1, a key mediator of NF‐κB signaling implicated in the pathogenesis of B‐cell malignancies. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SGR‐1505 in healthy volunteers. In this four‐part, open‐label study, 73 participants received single or multiple oral doses of SGR‐1505 (25–225 mg). A food effect study assessed SGR‐1505 exposure with and without a high‐calorie, high‐fat meal. The CYP3A4 drug–drug interaction potential of SGR‐1505 was evaluated by co‐administration with posaconazole, a strong CYP3A4 inhibitor. SGR‐1505 was rapidly absorbed (median Tmax 2–4 h) with a dose‐proportional increase in exposure up to 100 mg. Twice daily dosing at 100 mg over 10 days resulted in a 1.6‐fold increase in both Cmax and AUC and a 2.5‐fold increase in Ctrough compared to once daily dosing at 150 mg. A high‐fat, high‐calorie meal increased SGR‐1505 Cmax 1.6‐fold and AUC 1.3‐fold compared to the fasted state. Co‐administration with posaconazole increased SGR‐1505 exposure 3‐fold. SGR‐1505 inhibited ex vivo stimulated T‐cell derived IL‐2 production in a concentration‐dependent manner. Most adverse events were mild. Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR‐1505 was well‐tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development
Cost-Effectiveness of Home-Based Self-Sampling vs Clinician Sampling for Anal Precancer Screening
Full text linkAnal cancer screening is recommended for high-risk populations, particularly sexual and gender minority (SGM) individuals. However, the cost-effectiveness of home-based self-sampling in increasing anal cancer screening uptake has not yet been evaluated in the US. To evaluate the cost-effectiveness of home-based anal self-sampling compared with clinic-based screening among SGM individuals. This economic evaluation used data from a 2-group randomized clinical trial conducted in Milwaukee, Wisconsin, from January 2020 to August 2022, enrolling SGM individuals aged 25 years or older. Participants were randomized to home-based self-sampling or clinic-based screening. Costs for home-based screening were obtained from the trial, and clinic-based costs were sourced from the Medicare reimbursement schedule. Travel and time costs were derived on the basis of participant self-reports. The analysis was performed between February and October 2025. Participants in the home-based screening group received self-sampling supplies and instructions, and those in the clinic-based screening group were instructed to visit a clinic for anal cancer screening. The primary outcome was the incremental cost-effectiveness ratio (ICER), measured as the additional cost needed to increase screening participation by one person. The 95% CIs for the ICERs were estimated using a bootstrap method with 1000 iterations. Net benefit regression and cost-effectiveness acceptability curves were used to assess the likelihood of cost-effectiveness across different willingness-to-pay (WTP) thresholds. The study included 240 SGM individuals (227 with gender identity as a man [95%]; median [IQR] age, 46 [33 to 57] years), of whom 65 (27%) had HIV. The cost per participant was 60.40 for clinic-based screening from a societal perspective, and 42.06 for clinic-based screening from a health care payer perspective. Home-based screening was associated with increased screening participation vs clinic-based screening (107 participants [89.2%] vs 89 participants [74.2%]). The ICER per additional screened participant was 27.66 to 132.36 (95% CI, 402.20) for the health care payer perspective. Home-based screening had a 49.6% probability of being cost-effective at a WTP of 100 (societal perspective), and 90.9% at a WTP of $200 (health care payer perspective). The ICERs for home-based screening compared with clinic-based screening were highly sensitive to screening participation rates. The findings of this economic analysis suggest that home-based anal cancer screening is a cost-effective approach to increasing screening participation among SGM individuals. Home-based screening may serve as a valuable and efficient tool for expanding screening rates