We aimed to investigate associations between newborn metabolite concentrations and the development of early-life wheezing and asthma. Our goal was to advance understanding of pathways involved in childhood asthma pathogenesis and identify potential targets for disease prevention. Our study populations included children enrolled in two Environmental influences on Child Health Outcomes (ECHO) cohorts (INSPIRE, discovery; Healthy Start, replication) with linked newborn screening metabolic and outcome data (4-year recurrent wheeze and 5-year current asthma). We used elastic net penalized regression, followed by multivariable logistic regression, to determine metabolite-wheeze and metabolite-asthma associations. We secondarily assessed whether metabolite-asthma associations differed by asthma phenotype in the discovery cohort. Among 1554 INSPIRE children, the prevalence of recurrent wheeze and current asthma is 11% and 18%, respectively. Newborn concentrations of butyrylcarnitine + isobutyrylcarnitine (C4) and decenoylcarnitine (C10:1) are associated with recurrent wheeze (C4: aOR 0.75 [95% CI 0.59, 0.95]; C10:1: aOR 1.42 [95% CI 1.13, 1.78]), while linoleoylcarnitine (C18:2) and citrulline (CIT) are associated with current asthma (C18:2: aOR 1.20 [95% CI 1.02, 1.41]; CIT: aOR 0.74 [95% CI 0.58, 0.93]). The effect size and directionality of the association between C18:2 and childhood asthma is similar in Healthy Start (n = 518), although the relationship is not statistically significant. C18:2 is additionally associated with increased odds of non-allergic asthma compared to no asthma in INSPIRE. These findings suggest biologic pathways that may be involved in childhood asthma pathogenesis and support investigation of the mechanisms underlying these relationships given the potential for targeted prevention strategies.

Whether oxaliplatin should be given sequentially or upfront in metastatic colorectal cancer remains clinically relevant, especially for older patients often underrepresented in trials. We report updated overall survival and prespecified quality-of-life outcomes from the open-label, randomized, multicenter phase 3 C-cubed trial in Japan. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry UMIN000015405 (October 14, 2014) and UMIN000036690 (May 10, 2019). The primary endpoint was reported previously. Of 311 randomized patients with previously untreated metastatic colorectal cancer, 300 were included in the full analysis set. Patients received fluoropyrimidine plus bevacizumab, with oxaliplatin added at progression, or received fluoropyrimidine, oxaliplatin, and bevacizumab from the start. Overall survival was analyzed using Cox regression and time-restricted survival methods. Quality of life was assessed prospectively using patient-reported questionnaires. Here we show that overall survival is similar between strategies. Median overall survival is 27.2 months with sequential treatment and 27.4 months with upfront treatment (hazard ratio, 1.00; 95% confidence interval, 0.76-1.33; p = 0.98). Additional time-restricted and milestone analyses show no between-group differences. There is no evidence that age modifies the relative treatment effect. Patient-reported outcomes indicate a lower early treatment burden with sequential treatment, including smaller early declines in physical functioning and less sensory neuropathy. Updated overall survival is comparable between sequential and upfront oxaliplatin-based strategies, while sequential treatment is associated with lower early treatment burden. These findings support individualized selection of first-line treatment based on age, vulnerability, and treatment goals.

Ambulatory blood pressure monitoring (ABPM) plays an irreplaceable role in the diagnosis and management of hypertension. However, more than 100 million of the 1.4 billion people with hypertension worldwide cannot tolerate nighttime ABPM due to noise and arm compression. Previous prediction methods relying on demographic factors and home blood pressure measurements are time-consuming and burdensome while exhibiting limited accuracy for nocturnal hypertension. There is a need for a more accurate, low-burden approach to identify high-risk patients intolerant to nighttime ABPM monitoring. We collected 2,874 ABPM records at a regional medical center to conduct a retrospective cohort study. Kernel density estimation based preprocessing was applied to stabilize data fluctuations. A variational autoencoder based deep learning model was developed using daytime blood pressure and heart rate combined with full-day activity and posture states to predict nocturnal hypertension. Here we show that the ABPM-VAE model achieves an AUC of 0.82 (95% CI 0.77-0.88) on the test set, outperforming the ablation model (AUC 0.67; 95% CI 0.61-0.74; p<0.001) and prior methods based on demographic and home blood pressure data (AUC 0.69). For nocturnal hypertension prediction, the model yields a PPV of 92.12%, NPV of 55.20%, sensitivity of 0.73, and specificity of 0.84. The entropy reduction preprocessing-enhanced deep learning model predicts nocturnal hypertension risk from ABPM without adding burden to patients or physicians. It serves as an effective screening tool to identify high-risk individuals intolerant to nighttime monitoring, serving as a valuable complement to conventional ABPM.

Implementing population-wide risk-stratified breast screening (RSBS) requires coordinated planning across diverse stakeholders and adaptation within complex healthcare systems. We convened a multi-stakeholder workshop with 34 policymakers, breast screening program leaders and healthcare professionals across Canada. Participants co-envisioned an RSBS program and focused on defining care pathways, the implementation roadmap, stakeholder engagement, and workforce training. A national, flexible RSBS strategy was proposed with multiple entry points and timings for risk assessment, interoperable information technology systems, phased roll-out, and an embedded learning healthcare system. The resulting actionable plans support RSBS implementation in Canada and offer transferable insights for planning RSBS in varied international settings.

Developmental plasticity refers to biological adaptations, most often prenatally, to environmental cues. These can help organisms adapt to similar postnatal environments, with health benefits if prenatal and postnatal conditions match. While associations between various prenatal exposures and adverse offspring health have been documented, the interaction between prenatal and postnatal conditions remains less understood. We address this gap by examining whether pre- and postnatal drought exposures interact in their impact on cognitive performance, as early-life nutrition is a critical factor for cognitive development. Standardized math and reading scores from 11-16 year-olds in rural India (N = 2,032,917) from the 2007-2018 Annual Status of Education Report (a cross-sectional cognitive assessment household survey) were combined with University of Delaware Terrestrial Precipitation data. Given the high reliance on rainfed agriculture in the setting, rainfall levels below the 20th percentile of the district-specific long-term mean served as a proxy for nutritional adversities in a quasi-experimental study setup. We show that early-life droughts adversely impact cognitive function. We find positive interaction terms between prenatal and postnatal drought exposures, suggesting that children already exposed to droughts prenatally are better equipped for postnatal droughts. The findings of this study align with the predictions around phenotypic plasticity, i.e., that prenatal conditions prepare organisms for similar postnatal challenges. However, given the increasing unpredictability of the climate, such alignments cannot be planned or anticipated, implying frequent mismatches between prenatal and postnatal conditions.

Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults; however, older adults remain significantly at risk for severe influenza-related illness. Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo immune assays with human samples to investigate B cell, CD4+ T cell, and myeloid cell responses to influenza vaccine antigens at the serologic and single-cell level. We found that older adults mounted antibody titers equivalent to those of younger adults but had fewer influenza-reactive CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets. These data suggest that with aging, transcriptional programming alterations in myeloid and T cells contribute to reduced antiviral responses, and formulating vaccines tailored to cellular immune responses is necessary to improve outcomes in older adults.

Among pharmaceuticals currently in clinical use, few drugs directly target bacterial toxins. Clostridium perfringens α-toxin, a phospholipase C (PLC), is a major virulence factor responsible for gas gangrene caused by C. perfringens type A. There is a clinical need for small-molecule compounds that inhibit such bacterial toxins. A library of 764 FDA-approved drugs was screened to identify compounds that inhibit the PLC activity of C. perfringens α-toxin. Identified hits were further evaluated for their ability to inhibit α-toxin-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs). Additional in vitro assays were conducted to assess changes in neutrophil activation and cytokine production. In vivo efficacy was evaluated in female C57BL/6J mice (n = 21 or 18 per group) challenged with purified α-toxin or infected with C. perfringens type A. The initial screen identifies 21 compounds that inhibit the PLC activity. Among them, micafungin, an antifungal agent, is the only compound that suppresses α-toxin-induced cell death in HUVECs. Micafungin also reduces α-toxin-induced CD11b expression in neutrophils and cytokine release in HUVECs. Caspofungin, another antifungal with similar properties, also inhibits α-toxin-induced cell death and cytokine production. In mouse models, caspofungin, but not micafungin, significantly reduces lethality caused by α-toxin. Caspofungin also improves survival and mitigates muscle damage in mice infected with C. perfringens type A. Caspofungin demonstrates promising therapeutic potential as a life-saving treatment for gas gangrene caused by C. perfringens type A, likely through its inhibitory action on α-toxin activity. These findings support the development of new classes of small-molecule therapeutics that directly target bacterial toxins.

Accurate diagnosis of hematologic malignancies from peripheral blood smears (PBSs) requires integrating cellular morphology and composition across numerous white blood cells. Existing computational approaches predominantly automate single-cell classifications and do not provide holistic, slide-level diagnostic predictions. We present a framework that employs a high-performance cell-based encoder (DeepHeme) for feature extraction, integrated with our weakly supervised, attention-based multiple instance learning (MIL) model, termed CAREMIL (Cell AggRegation, Explainable, Multiple Instance Learning). Through comprehensive evaluations of leading image encoders and MIL architectures, the combination of DeepHeme and CAREMIL demonstrated superior performance on disease classification tasks. CAREMIL functions as a robust aggregation mechanism, consistently outperforming established slide-level MIL methods (gated MIL and Dual-stream MIL Network) across multiple encoder types. The most pronounced performance gains were observed with out-of-domain encoders, including ImageNet-pretrained and open-source pathology foundation models (UNI2 and Virchow2). CAREMIL combined with DeepHeme achieves the highest diagnostic accuracy across acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and hairy cell leukemia (HCL), with AUROCs of 0.999, 0.891, and 0.945, respectively, and successfully identifies AML even in cases with minimal or absent circulating blasts. Attention values assigned by CAREMIL highlight diagnostically relevant cells and reveal disease-specific morphometric patterns, enabling biological interpretability and case-level insights. The framework remains resilient to individual cell misclassifications and does not require explicit cell-level supervision. These findings establish CAREMIL as an effective and interpretable MIL framework for hematologic slide diagnosis, extendable to bone marrow aspirates, cytology, and other liquid biopsy specimens, supporting a shift toward quantitative, morphology-informed hematologic diagnostics.

Suboptimal dialysis initiation is associated with adverse patient outcomes. Whether it is also associated with access to downstream transplant care is unknown. Adults initiating dialysis treatment for kidney failure in the Southeast U.S., from 1/1/2015 to 12/31/2019 were identified from the United States Renal Data System, linked to the Early Steps to Transplant Access Registry, and followed through 12/31/2021. The primary exposure was pre-dialysis care and categorized as highly, moderately, minimally, or non-optimal based on presence of nephrology care, dialysis type (in-center or home hemodialysis, peritoneal dialysis), and vascular access vs. catheter. Primary outcomes were referral to a transplant center within 12-months of dialysis initiation and evaluation start at a transplant center within 6 months of first referral. Multivariable competing risk models quantified the association between pre-dialysis care context and referral and evaluation. Among 49,057 patients initiating dialysis, 28.8%, 15.5%, 31.0%, and 24.8% are highly, moderately, minimally, and non-optimal start, respectively. Patients initiating dialysis in moderately, minimally, and non-optimal ways are 28% (adjusted hazard ratio: 0.72, [95% CI: 0.69 - 0.72], 31% (0.69, [0.66 - 0.71], and 57% (0.43, [0.41 - 0.44]) less likely to be referred as compared with highly optimal starters. Those who had a non-optimal start are also 37% less likely to start the evaluation after being referred (0.63, [0.59 - 0.66]) as compared with highly optimal dialysis starters, while all other groups have a similar likelihood. More than half of U.S. adults with kidney failure initiate dialysis in a minimal or non-optimal way leading to reduced likelihood of transplant referral and evaluation.

Bempedoic acid is an oral cholesterol-lowering medication used to reduce low-density lipoprotein cholesterol (LDL-C), particularly in patients who require additional lipid lowering. Clinical trials have shown that bempedoic acid increases serum uric acid levels, but the implications of this effect in real-world clinical practice, including the need for anti-gout treatment, are not well defined. We conducted a retrospective cohort study using a large, multi-institutional U.S. electronic health record database. Adult patients with hyperlipidemia who have newly initiated bempedoic acid were compared with those initiating ezetimibe. Propensity score matching was used to balance baseline characteristics, yielding 7676 patients in each group. The primary outcome was incident hyperuricemia, defined as serum uric acid >7.0 mg/dL. A secondary outcome was initiation of anti-gout therapy. During 12 months of follow-up, hyperuricemia occurs more frequently in patients treated with bempedoic acid than in those receiving ezetimibe (hazard ratio [HR] 1.94; 95% confidence interval [CI] 1.58-2.37; p = 0.008). In contrast, initiation of anti-gout therapy does not differ between groups (HR 1.06; 95% CI 0.86-1.29; p = 0.59). Longitudinal changes in lipid parameters, inflammatory markers, and glycemic measures are generally similar between groups. In real-world clinical practice, bempedoic acid use is associated with a higher incidence of laboratory-defined hyperuricemia compared with ezetimibe, but this increase does not translate into greater use of anti-gout medications. These findings support the continued use of bempedoic acid for additional LDL-C lowering, with awareness of its effect on serum uric acid.