Canadian Medical Association Journal

BackgroundMultimorbidity is common among U.S. skilled nursing facilities (SNFs) residents and complicates pharmacologic management, yet real-world evidence on treatment patterns in this population remains limited. This study evaluated medication order rates and identified resident- and facility-level factors among SNF residents with multimorbidity. MethodsRetrospective, observational study using electronic health record (EHR) data from PointClickCares Life Sciences database. Participants were 728,222 residents active in a U.S. SNF on April 30, 2025 with at least one documented diagnosis of hypertension, hyperlipidaemia, type 2 diabetes (T2D), depression, or Alzheimers disease and related dementias (ADRD). The outcome was presence of guideline-recommended medication order for each condition, modelled with modified Poisson regression to estimate adjusted prevalence risk ratios (RRs) and 95% confidence intervals. ResultsMedication order rates were 79% for ADRD, 79.1% for T2D, 87.7% for hypertension, 83.3% for hyperlipidaemia, and 90.8% for depression. Rates varied across comorbidity combinations: ADRD was associated with lower medication order prevalence, while cardiometabolic multimorbidity profiles associated with higher prevalence. Black/African American identity had the lowest likelihoods of a medication order for 3 of 5 conditions (RRs of 0.93 to 0.92), while having hypertension or hyperlipidaemia medication order was associated with higher likelihood of having orders for 3 of remaining 4 conditions (RRs of 1.02 to 1.19). ConclusionsMost SNF residents with multimorbidity had a medication order for common chronic conditions, although important variability and disparities remain. Differences by comorbidity profile and social context underscore the need for targeted strategies supporting equitable, integrated prescribing and person-centred care in SNFs.

Background. Coronary CT angiography (CCTA) and calcium scoring detect subclinical coronary atherosclerosis, but the results of community based screening in asymptomatic adults with cardiovascular risk factors are poorly described. Objective. To describe the results of the first phase of a county-funded CT screening program and their variation by demographics, health system, time, and ZIP code. Methods. Retrospective analysis of aggregate reports from the Broward County Florida Heart Project (May 2023 to September 2025). Eligible residents were those with insurance coverage, age 45 to 70 years (limited exceptions), free of known cardiovascular disease and symptoms, with at least one risk factor. Examinations at six hospitals in four health systems were classified by the program team as normal (Category 1), abnormal (Category 2), or very abnormal (Category 3), with a separate flag for other non coronary abnormality. We used Wilson confidence intervals and chi square, trend, and Mantel Haenszel tests. Results. Among 7,135 participants (58.3% men; 79.0% White, 8.0% Black, 17.2% Hispanic), 43.2% had Category 1, 45.4% Category 2, and 11.4% Category 3 results; 56.8% (95% CI, 55.7% to 58.0%) had abnormal or very abnormal results. The proportion rose from 39.3% at 45 to 55 years to 78.5% at 71 or older (trend P<0.001) and was higher in men than women (68.9% vs 39.8%; odds ratio [OR], 3.36; 95% CI, 3.05 to 3.71). Rates were lower in Black than White participants (38.9% vs 58.6%; hospital adjusted OR, 0.45; 95% CI, 0.38 to 0.54) and in Hispanic than non Hispanic participants (51.0% vs 57.8%). Abnormal results ranged from 39.5% to 60.3% across health systems (P<0.001). Variation across the 50 highest volume ZIP codes did not exceed chance (P=0.53). Conclusions. More than half of insured, asymptomatic adults with risk factors screened in this community program had abnormal results, with steep age and sex gradients and unexplained variation across health systems. Black, Hispanic, and female residents were under-represented relative to the county

We develop an age- and immunity-structured COVID-19 model with setting-specific contacts, calibrated to Ontario incidence and hospital admissions before Omicron. We simulate counterfactual vaccination strategies and contact restrictions in schools, workplaces, and other community settings, evaluating projected severe-case demand against an illustrative healthcare-capacity benchmark. Vaccination combined with workplace and community contact restrictions keeps simulated demand within capacity. In contrast, relaxing restrictions in either setting produces large surges and repeated capacity threats, even when school restrictions remain. School-only changes produce smaller effects on severe disease. These findings highlight the value of vaccination and setting-specific contact restrictions that prioritize workplace and community settings for pathogens with adult-concentrated severe outcomes.

This paper examines the impact of Cancer Care Ontario's regionalization of lung cancer surgery on blood transfusion use for thoracic surgery at The Ottawa Hospital. Using aggregate data scraped from the paper ''Changing trends in blood transfusion: an analysis of 244,013 hospitalizations'' by Shehata et al. (2014) we estimated the effect regionalization on the log mean number of blood transfusions among thoracic surgeons (who treat lung cancer), utilizing other surgical specialties as controls. We found that the average number of blood transfusions increased significantly among thoracic surgeons following the opening of a new cancer care centre at the hospital in December 2009, while control specialties showed no parallel change. Contextualizing these results in a modified ''population level'' treatment threshold model, it is argued that the main driver of this increase in blood transfusions among thoracic surgeons was due to the influx of less skilled thoracic surgeons to The Ottawa Hospital, and the closing of thoracic surgery units at smaller hospitals which was part of the broader regionalization process.

Background Under-five mortality remains a major public health challenge in Zambia despite substantial reductions over recent decades. Demographic and Health Survey (DHS) data are commonly analysed using Cox proportional hazards models; however, violations of the proportional hazards assumption and unobserved cluster-level heterogeneity may compromise inference. This study compared advanced survival modelling approaches to determine the most appropriate framework for analysing under-five mortality using pooled Zambia DHS data. Methods We conducted a pooled secondary analysis of the 2018 and 2024 Zambia Demographic and Health Survey child recode datasets. The analysis included 9,982 children, among whom 266 died before their fifth birthday. A survey-weighted Cox proportional hazards model was fitted as the reference model and assessed using Schoenfeld residual diagnostics. To address identified methodological limitations, an extended Cox model, a shared-frailty model, and a Bayesian survival model were subsequently fitted. Model performance, assumptions, and the consistency of adjusted hazard ratio estimates were compared across modelling approaches. Results The global Schoenfeld test indicated violation of the proportional hazards assumption ({chi}2=51.26, p=0.002). In the adjusted extended Cox model, male children had higher mortality risk than females (aHR 1.95, 95% CI 1.40-2.73), while children with gestation [&ge;]9 months had lower mortality risk than those with shorter gestation (aHR 0.21, 95% CI 0.14-0.32). Average and large birth size were associated with lower mortality compared with small birth size (aHR 0.47, 95% CI 0.34-0.66 and aHR 0.57, 95% CI 0.39-0.84, respectively). Newborn health checks before discharge were associated with lower mortality (aHR 0.50, 95% CI 0.38-0.66), as was any antenatal care (aHR 0.25, 95% CI 0.09-0.75). A high-risk fertility pattern involving fourth or higher births with an interval [&ge;]24 months was also associated with lower mortality (aHR 0.57, 95% CI 0.41-0.80). The shared-frailty model produced similar estimates, including increased mortality among male children (aHR 1.39, 95% CI 1.08-1.78) and twins or multiple births (aHR 2.74, 95% CI 1.36-5.53). Bayesian estimates were broadly consistent with the extended Cox model. Conclusions Advanced survival models provided a more robust analytical framework than the conventional Cox model for evaluating under-five mortality in nationally representative DHS data. While the extended Cox model accommodated time-varying effects, the shared-frailty model captured unobserved cluster-level heterogeneity, and the Bayesian model confirmed the stability of parameter estimates. Incorporating these complementary approaches can improve the validity of survival analyses and strengthen evidence for child survival research and policy in low- and middle-income settings.

Background/Objectives: Older adults are at high risk of influenza-related severe disease and complications. HD-IIV, currently recommended for adults [&ge;]65 years, is egg-based and may be subject to egg-adapted mutations. An mRNA-based vaccine for influenza, mRNA-1010, has been approved by the Food and Drug Administration. Given the clinical benefits observed in mRNA-1010 clinical trials and potential to avoid egg-adapted mutations, this analysis explores the clinical impact of mRNA-1010 compared to HD-IIV in those [&ge;]65 years in the United States. Methods: This study used a decision-analytic model of influenza infection and downstream outcomes to project influenza burden with each vaccine over a one-year timeframe. Vaccine coverage, HD-IIV vaccine effectiveness (VE) and influenza epidemiology was estimated based upon Centers for Disease Control and Prevention data. The relative VE (rVE) for mRNA-1010 vs. HD-IIV was modelled based on data from the clinical trial and published literature on the impact of egg adaptation. Results: The base-case analysis suggests mRNA-1010 may prevent an additional 232,200 symptomatic influenza infections, 130,000 outpatient cases, 21,100 influenza-related hospitalizations, and 2,200 influenza-related deaths compared to HD-IIV. The number needed to vaccination to prevent one hospitalization was 514 or mRNA-1010 vs no vaccine and 404 for HD-IIV versus no vaccine, for an incremental NNV of 110. Scenario and deterministic sensitivity analyses results indicate that clinical outcomes prevented by mRNA-1010 are most sensitive to influenza incidence and VE. Conclusions: mRNA-1010 may improve protection against influenza in US adults aged [&ge;]65 years, leading to meaningful reductions in the clinical influenza-related disease burden in older adults.

Background: Care home research often fails to address issues that matter most to residents, families, and staff. Priority-setting exercises can help reduce this lack of inclusivity, but few have received significant resident responses. Objectives: To identify research priorities of UK care home stakeholders (including residents; relatives; care staff, managers and owners; healthcare professionals; policymakers and researchers), and to assess whether these priorities can be addressed using existing research datasets. Methods: PREACH was an 18-month research priority-setting study involving 1063 stakeholders, across 50 care homes, including 381 residents. Participants submitted ideas of what care home research should focus on through 1) care home activity sessions or 2) an online survey. Responses underwent content analysis to identify themes, and these themes were mapped against a national repository of care home trial data. Results: Fifty-one themes were identified. The most frequent priority across all stakeholder groups was access to meaningful activities for residents (22%). Relatives and residents emphasised social connection and day-to-day experience, whereas staff more often highlighted system pressures. No stakeholder-prioritised topics were directly addressable using existing secondary datasets. Conclusions: Collaboration with care home teams to reach large numbers of residents offers a practical route to producing more relevant and timely care home research. Care home stakeholders consistently prioritise quality of life, meaningful activity and staffing over disease-specific or health-focused research. Existing research datasets measure relatively few of the priorities identified by residents, highlighting the need for resident-centred outcome measures and data collection.

Background: The relationship between recent viral infection and subsequent susceptibility to, or protection against, other viruses remains unclear, particularly across ages and symptom status. Methods: A prospective cohort study enrolled participants aged 6 months to 49 years in Washington and Oregon, USA, 2022-2024. Weekly nasal swabs were tested for SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A/B; additional swabs were collected during symptomatic illness and were also tested for parainfluenza (PIV) 1-4, endemic human coronaviruses (hCOV), adenovirus, human metapneumovirus, human rhinovirus (hRV), and enteroviruses. Proportional hazards regression models were used to characterize associations between incident symptomatic infection (illness) and history of recent illness due to other viruses (within 1-7, 8-14, 15-30, 31-60, 61-90, 91-180 days), adjusted for geographic region, age, sex, daycare/school/work attendance, household size, and number of children in the household. For SARS-CoV-2, influenza, and RSV, these analyses were repeated to study incidence of infection (including asymptomatic cases). Findings: Of 3,560 participants, 2,969 (83%) had [&ge;]1 illness over 4,299 person-years. Adjusted hazard ratios (aHRs) in the short term ([&le;]2 weeks) after an illness were predominantly below 1, indicating that recent viral illness was often associated with lower risk of subsequent illness with other viruses. Across age groups, recent hRV illness was associated with lower risk of hCOV, PIV, and RSV illness (aHRs 0.07-0.27). SARS-CoV-2 illness was associated with a higher short-term risk of adenovirus and PIV illness (aHRs 3.20-3.33). In children aged 6 months-4 years, recent influenza illness was associated with higher short-term risk of SARS-CoV-2 illness. Including asymptomatic infections generally attenuated these associations. Interpretation: Some viral illnesses may alter short-term susceptibility to subsequent viral illnesses. Interactions may differ by age and symptom status. Funding: US Centers for Disease Control and Prevention; Washington State Department of Health.

Coal-fired power plants remain a major source of fine particulate matter (PM2.5) exposure and mortality in the United States. Announced retirement dates mark when those burdens are expected to end, but rising electricity demand, partly from data centers supporting cloud computing and artificial intelligence, has led utilities and regulators to revisit them. Of 50 coal plants scheduled in January 2024 to retire before 2035, 20 had later or removed dates by January 2026. Projecting coal PM2.5 and mortality among Medicare beneficiaries from the 20 plants for 2026-2035, we estimate the revised schedule would result in 1,256 additional deaths (1,136 to 1,376), raising mortality to 3.1 times the original burden. Eighteen plants operate in balancing authorities with hyperscale data-center demand, and federal orders and utility filings supporting several plants' operation cited data-center growth. Retirement schedules are revised faster than health consequences are assessed, and those delays carry a measurable mortality cost.

Abstract Background: Heart failure (HF) is a major public health challenge in ageing populations and a leading cause of unplanned hospital readmissions. Biological, social, and economic factors contribute to recurrent hospitalisation, but gaps remain in understanding how these factors interact and patterns of healthcare use following hospitalisation. Methods: We conducted an explanatory sequential mixed-methods study of patients aged ?60 years with an HF hospital admission between 2016 and 2020 who completed the Sax Institute?s 45 and Up Study baseline questionnaire. Data were linked to Admitted Patient Data Collection, Medicare Benefits Schedule, and Pharmaceutical Benefits Scheme data. HF readmission within 30 days of the index admission was the outcome. Cox proportional hazards models estimated crude and adjusted hazard ratios (HRs and adjHRs) with 95% confidence intervals (CIs). Kaplan-Meier curves and log-rank tests compared survival between groups. Time-series plots mapped healthcare interactions over 1 year following the index admission. Results: Among 4,252 patients with HF, 409 were readmitted within 30 days. Significant predictors included age ?80 years (adjHR, 1.30; 95%CI, 1.01?1.67), 1 chronic condition (adjHR, 2.49; 95%CI, 1.41?4.40), ?2 chronic conditions (adjHR, 1.75; 95%CI, 1.04?2.95), and alcohol consumption above national guidelines (adjHR, 1.45; 95%CI, 1.06?1.98). Time-series analysis indicated that participants with readmission had more frequent out-of-hospital health service contact following their initial HF admission than those without readmission. Conclusions: Older age, chronic conditions, and high alcohol intake increased 30-day HF readmission risk. Differences in healthcare use after admission highlight opportunities for targeted and coordinated post-discharge care.

Importance. Observational studies dominate evidence in cardiovascular outcomes research, yet no widely adopted reporting standard requires authors to disclose how much of an observed association is attributable to systematic error. The negative-control calibration framework of the Observational Health Data Sciences and Informatics consortium returns a binary answer: a calibrated P-value either crosses 0.05 or it does not. That answer conflates "is there a signal" with "is the signal credible." Objective. To define the Bias Attribution Fraction (BAF), a continuous estimator in [0, 1] that quantifies the fraction of an observed log relative risk that is attributable to systematic bias, together with its 95% credible interval, and to evaluate whether reporting calibrated P-value plus BAF plus interval width produces more defensible decisions than reporting the calibrated P-value alone. Design. Three-part study: (i) metric definition and interval construction; (ii) Monte Carlo simulation across 1920 conditions by 1000 repetitions = 1,920,000 simulated target estimates (a primary grid plus a sign-flipped companion grid of identical size, pooled for all analyses), with truth known by construction; (iii) two-arm beta-blocker target trial emulation in MIMIC IV, adhering to the TARGET guideline, with targeted maximum likelihood estimation (TMLE) and 12 negative-control outcomes. Setting. MIMIC IV (critical care) and MIMIC IV ECG, 2008 to 2019. Participants. Adults with a first intensive care unit stay and a recorded 12-lead ECG. Exposures. Two clinical questions are evaluated: (1) reaching at least 50% of guideline-recommended target dose of an index beta-blocker within 7 days of admission, sustained to 12 months, versus lower or no exposure; (2) receiving guideline-directed medical therapy (GDMT) with at least two of three foundational drug classes at adequate dose for 12 months versus fewer. Main Outcomes and Measures. One-year all-cause mortality. Primary analytic outputs: (i) the calibrated P-value from a negative-control empirical null distribution with 12 outcomes; (ii) BAF-hat with a Markov chain Monte Carlo 95% credible interval; (iii) a verdict drawn from a truth-calibrated lookup table mapping the BAF-hat by interval-width cell to a probability of being bias-dominated. Results. Across 1,920,000 simulated repetitions, the calibrated P-value alone yielded a misuse rate (declared usable while truth was bias-dominated) of 36.02%. Adding the BAF point estimate reduced misuse to 16.48%, and requiring the whole credible interval of BAF to lie below 0.5, clear of the bias-dominated zone, reduced misuse to 10.16%. Requiring in addition a calibrated probability of bias dominance below 15% reduced misuse to 3.02% at the cost of declaring 22.1% of estimates usable (versus 61.8% for the calibrated P-value alone). Read from the bias-dominated view, meaning that withholding a repetition is a positive call and being truly bias-dominated is a positive truth, the BAF estimator achieved an area under the receiver operating characteristic curve of 0.922, compared with 0.787 for the calibrated P-value. In MIMIC IV, question 1 produced a calibrated P-value of 0.894 and BAF-hat = 0.875 (95% credible interval 0.385 to 0.992); the apparent one-year mortality reduction of 16.9% was entirely attributable to systematic bias and the association was not usable as effect evidence. Question 2 also failed layer 1, with a calibrated P-value of 0.1026, and BAF-hat = 0.460 placed it in the "competitive, no verdict" zone. Conclusions and Relevance. Pairing the calibrated P-value with BAF and its 95% credible interval turns a binary credibility judgement into a three-channel report (signal existence, effect size, and bias fraction). Despite TARGET-adherent design, doubly robust TMLE, and 12 negative controls, both clinical questions in this study still failed to qualify as effect evidence, with question 1 demonstrating complete bias domination and BAF quantifying the systematic error that remained. The reporting standard proposed here can be applied to any observational study that includes negative controls, without requiring additional data.

TrialCalibre1 is an agentic system that connects clinical evidence, study design, and executable analyses. It supports reference-trial replication, direct target-trial emulation, and BenchExCal, which combines benchmarking, extension, and cal ibration sensitivity analysis. We evaluated an ASCET-based benchmark and an extension comparing clopidogrel with aspirin among adults aged 81-90 years us ing synthetic PCORnet-style claims. Two reviewers assessed benchmark extrac tion, protocol decisions, and implementation. After discussion, 53/62 and 50/62 assessable SQL checks were rated met; both reviewers rated 12/13 assessable R checks met. Protocol and proxy disagreements remained. A separate ten-question routing development set yielded 10/10 route matches and 7/7 applicable reference trial matches. The agent benchmark and extension included 6,069 and 1,602 pa tients. The extension risk ratio was 0.848 (95% CI 0.569-1.184), with a calibrated sensitivity estimate of 1.274 (0.439-3.700). The human implementation provided descriptive comparisons, not same-data validation. Dose proxies, unpopulated co variates, residual imbalance, implementation deviations, and ignored cross-cohort covariance limited interpretation. This case demonstrates a connected workflow whose protocols, code, and results can be reviewed.

Aims. It is unknown whether large language models (LLMs) can predict a trial's result at the design stage, from the information available when it is registered. We tested three LLMs prospectively on the Late-Breaking Science programme of the European Society of Cardiology (ESC) Congress 2026. Methods and results. Of 139 trials, 50 were selected by pre-specified criteria, and predictions were locked and registered on the Open Science Framework before the congress. Claude Fable 5, GPT-5.5 and Gemini 3.5 Flash, without web access, received each title and an investigator-compiled summary of the registered design. They gave the probability that the primary endpoint would be met, and a point estimate with an 80% prediction interval for a locked effect measure. Results were adjudicated from publications (19) or presenters' slides (31). Of 48 scorable trials, 28 (58%) were positive. The area under the receiver operating characteristic curve was 0.80 (95% CI 0.66-0.92) for Claude, 0.79 (0.66-0.91) for GPT and 0.74 (0.59-0.87) for Gemini, with accuracies of 73%, 71% and 67%. Among 26 trials whose effect was reported exactly as locked, the direction was correct in 88% of predictions and the median multiplicative error of ratio estimates was about 15%. The 80% prediction intervals contained the observed effect in 73.1% (Claude), 84.6% (GPT) and 57.7% (Gemini). Conclusion. From the registered design alone, LLMs showed statistically significant discrimination between positive and negative trials and usually predicted the direction and approximate size of the effect. Such predictions might help trial design, and further studies are needed.

Background: Cardiovascular (CV) screening is critical for personnel deploying to Antarctica, where geographic isolation and limited medical care make the management of acute cardiovascular events challenging. The utility of contemporary risk prediction tools such as the AHA PREVENT equations in this unique population remains uncertain. Methods: We retrospectively analyzed 154 individuals referred for enhanced CV evaluation before deployment to the U.S. Antarctic Program (USAP). Participants were evaluated across three temporal cohorts (2018-2020, 2021-2023, and 2024-2026). Demographics, CV risk factors, cardiac testing, and deployment clearance outcomes were collected. Risk was estimated using the Framingham Risk Score (FRS), AHA/ACC Pooled Cohort Equations (PCE), and AHA PREVENT risk models. Results: The cohort was predominantly male (79.9%; mean age 44.6 {+/-} 14.6 years), and abnormal ECG was the most common referral trigger (70.8%). Median 10-year risk was low by PREVENT and FRS and borderline elevated by PCE (PREVENT 2.7% [IQR 1.1-6.6], FRS 2.3% [IQR 0.5-7.1], and PCE 6.1% [IQR 2.4-9.2]). Among 72 participants with all scores, 51% were classified discordantly; PREVENT ASCVD agreed closely with FRS (=0.77) but poorly with PCE (=0.24-0.35), which consistently estimated higher risk. PCE was calculable in 52.6% versus 70.8% for PREVENT. Overall, 132 participants (85.7%) were cleared for deployment, while 8 (5.2%) were not physically qualified (NPQ); 6 of these NPQs were due to cardiovascular causes. Of 22 cardiac medical evacuations during the study period, 21 involved individuals without prior advanced cardiovascular screening. One screened individual was evacuated for symptoms subsequently found to have no cardiac cause. Conclusions: Risk calculators disagree substantially in the fitness-selected population. We recommend PREVENT as the primary risk-stratification tool as it is the most contemporary derivation, incorporates renal function, is race-agnostic, extends to heart failure, applies from age 30, and agrees closely with FRS, easing transition. Targeted imaging, including coronary artery calcium scoring, may supplement intermediate-risk candidates.

BackgroundSevere community-acquired pneumonia (CAP) remains a leading cause of mortality in children under five. The PediCAP trial evaluated oral step-down therapy using dispersible amoxicillin or amoxicillin/clavulanate tablets in African children hospitalised with severe CAP. Dispersible tablet formulations are preferred in children; however, pharmacokinetic data for oral amoxicillin/clavulanate in paediatric populations remain limited. We characterised the pharmacokinetics of 4:1, 7:1, and 14:1 dispersible amoxicillin/clavulanate tablets in children enrolled in the PediCAP trial and predicted target attainment under different dosing schemes. MethodsChildren were randomised within 24 hours of starting intravenous antibiotics to oral step-down therapy with weight-banded dosing of twice-daily amoxicillin/clavulanate (4:1, 7:1, or 14:1). Plasma concentrations were quantified following intensive sampling and analysed using nonlinear mixed-effects modelling with allometric scaling and postmenstrual age-dependent clearance maturation. Pharmacodynamic indices included %fT>MIC for amoxicillin and %fT>Ct for clavulanate. ResultsA total of 157 children (median [range] age, 12 [2-70] months; weight, 8.4 [4.0-22.0] kg) contributed 707 paired concentrations. Amoxicillin was described by a two-compartment model and clavulanate by a one-compartment model, both with sequential zero-and first-order absorption. Typical clearance for an 8-kg individual at full maturation was 11.8L/h for amoxicillin and 6.1L/h for clavulanate. Pharmacokinetics were similar between the formulation ratios. Weight-banded dosing achieved balanced exposures across weight groups. Amoxicillin achieved 40%fT>MIC for MICs[&le;]2mg/L. A proposed clavulanate target of 20%fT>0.5mg/L was achieved in most children even at the lowest amoxicillin/clavulanate ratio. ConclusionWeight-banded dosing using dispersible amoxicillin/clavulanate tablets provide consistent exposure profiles in African children with severe CAP. SUMMARYPopulation pharmacokinetic modelling of dispersible amoxicillin/clavulanate tablets (4:1, 7:1, 14:1) in 157 African children with severe pneumonia showed weight-banded dosing achieved consistent and adequate amoxicillin and clavulanate exposures across formulations.

Background: Localized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component. Objective: To evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period. Methods: We conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety. Results: No patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [&ge;]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion. Conclusions: Sirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.

Background: Multiple performance measures are used to assess the management of common cardiovascular conditions, such as coronary artery disease (CAD), heart failure with reduced ejection fraction (HFrEF), and atrial fibrillation (AF). These measures are sometimes used to assess individual clinicians, despite lack of evidence of reliability and accuracy. We used national Veteran Affairs (VA) data to test medication-based performance measures for assessment of clinician performance in outpatient cardiology care. Methods: This retrospective study examined VA cardiology clinician/Veteran dyads from 2017-2023 to evaluate 10 medication-based performance measures for CAD, HFrEF, or AF with elevated stroke risk. Achievement of each performance measure was defined as an active prescription of an indicated medication for each eligible patient encounter, summarized at the clinician level. Reliability was calculated using the beta-binomial method. A Bayesian causal model was used to assess the impact of case complexity on performance measure achievement. Finally, we performed peer review of a subset of cases (n=952) to assess the accuracy of three representative performance measures. Results: Of 456,071 unique cardiology encounters, 312,331 included CAD, 224,599 included HFrEF, and 178,678 included AF. These patients were treated by 1,043 cardiology clinicians. Median performance measure achievement ranged from 0.23 (SGLT2i for HFrEF) to 0.99 (beta blocker for HFrEF). Measure reliability varied from 0.63 to 0.90. Case complexity did not significantly affect performance measure achievement. Using peer review as the gold standard, accuracy was poor to moderate (balanced accuracy 0.51-0.73), and measures underestimated performance relative to peer review. Conclusions: Ten medication-based performance measures for CAD, HFrEF, and AF can be efficiently measured using electronic health record data, and most have sufficient reliability to support clinician benchmarking and the identification of potential care gaps. However, suboptimal accuracy compared with a peer review indicates that these measures may be insufficient as a standalone assessment of clinician quality.

Background Emerging evidence has linked frailty to individual chronic diseases, but whether it predicts a broad disease spectrum and accelerates multimorbidity accumulation over time remains unknown. This study aimed to systematically evaluate the associations of physical frailty with the burden of incident disease across a wide range of chronic conditions, and with the long-term rates of multimorbidity accumulation. Methods In this prospective cohort study of 466,864 UK Biobank participants , frailty status was assessed using the Fried frailty phenotype and categorized as robust, pre-frailty, or frailty. Chronic diseases were defined based on International Classification of Diseases (ICD)-10 codes, and disease patterns were identified using network analysis. Cox proportional hazards models were used to examine the associations of frailty status with incident chronic diseases, and linear mixed models were used to assess the annual rate of chronic disease accumulation. Results During a median follow-up of 13.8 years (IQR: 13.1-14.5), 536 incident chronic diseases across multiple systems were recorded. Physical frailty was associated with a significantly increased risk of 458 incident diseases (Bonferroni-corrected P < 0.05/536). In the overall cohort, compared with robust participants, those with pre-frailty ({beta} = 0.266, 95% confidence interval [CI]: 0.264-0.267) and frailty ({beta} = 0.941, 95% CI: 0.936-0.946) exhibited significantly faster rates of multimorbidity accumulation. This accelerated multimorbidity accumulation was consistently observed across strata of baseline disease burden, including participant with 0 ({beta} = 0.644, 95% CI: 0.635-0.653), 1 ({beta} =0.748, 95% CI: 0.727-0.768), [&ge;] 2 ({beta} =0.940, 95% CI: 0.933-0.947) chronic conditions at baseline. Similar associations were also found across distinct disease patterns, including neurodegenerative, metabolic, and psychiatric patterns. Conclusions Physical frailty predicts a broad range of incident diseases and is associated with accelerated multimorbidity accumulation. Incorporating frailty assessment into prevention strategies may help mitigate the growing burden of multimorbidity.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.

Background: Genomic reassessment may reveal clinically relevant diagnoses in patients with young-onset kidney failure despite established clinical diagnostic labels. We evaluated this approach after excluding clinically apparent polycystic kidney disease (PKD). Methods: Among 1,139 patients receiving maintenance dialysis at participating Japanese facilities, 355 had initiated dialysis at age [&le;]50 years. After excluding 17 patients with clinically apparent PKD, 108 of 338 eligible patients underwent whole-genome sequencing through voluntary, nonrandom enrollment. Analysis included 465 nuclear candidate genes, mitochondrial DNA, and copy-number/structural variants. Clinically concordant diagnoses were adjudicated using integrated clinical and genetic evidence, with a separate pathogenic/likely pathogenic (P/LP)-supported subset. Results: Diagnoses were identified in 10/108 participants (9.3%; 95% confidence interval, 5.1-16.2), comprising seven renal and three systemic/metabolic diagnoses. Nine diagnoses were P/LP-supported (8.3%; 95% confidence interval, 4.4-15.1). The remaining diagnosis was phenotype-based clinical Dent disease associated with a CLCN5 variant of uncertain significance. Diagnoses occurred across diabetic kidney disease, nephrosclerosis, chronic glomerulonephritis, unknown-cause, and other clinical categories. In a post hoc analysis excluding three participants with low target coverage, the integrated and P/LP-supported proportions were 9/105 (8.6%) and 8/105 (7.6%). Six exploratory findings were excluded from both diagnostic numerators. Gitelman syndrome was included as a clinically manifest renal disorder, although its contribution to kidney failure remained uncertain. Conclusions: Integrated genomic assessment can uncover renal and systemic/metabolic diagnoses across conventional labels in young-onset kidney failure after exclusion of clinically apparent PKD. Nonrandom enrollment and variable sequencing coverage limit generalizability and interpretation of negative results.