PURPOSE:IgA nephropathy with crescents (c-IgAN) is frequently underrepresented in randomized trials. We assessed whether rituximab (RTX) plus corticosteroids (CS) improves outcomes compared with a histology-matched cohort receiving standard high-dose CS (Pozzi protocol). METHODS:We conducted a single-center retrospective comparative study in adults with biopsy-proven c-IgAN diagnosed between January 2017 and December 2024. Outcomes of 16 patients treated with RTX (1 g × 2, 14 days apart) plus CS (three 500 mg pulses followed by 1 mg/kg tapered over 4 months) were compared with eight patients treated with Pozzi's protocol. Primary endpoints were changes in 24-h proteinuria, estimated glomerular filtration rate (eGFR), and microscopic hematuria at 6, 12, and 24 months, and annual eGFR slope. Secondary endpoints included remission rates, relapse risk, and adverse events (AEs). Longitudinal analyses were performed using mixed-effects models. FINDINGS:At baseline, median age was 35.5 years, eGFR was 69 mL/min/1.73 m² with a recent eGFR decline of -15.8 mL/min/1.73 m² over 3 months, median proteinuria was 1.8 g/day, all patients had microscopic hematuria. Proteinuria reduction was greater in RTX group than Pozzi's protocol (P = 0.0065), with an -85.6% between-group difference at 24 months (P = 0.0049). eGFR changes were similar (P = 0.27), although annual slope favored RTX (+5.10 vs -8.01 mL/min/1.73 m²/year). Microscopic hematuria improved in both groups. RTX was associated with lower relapse risk (odds ratio 0.14; 95% CI 0.01-1.00; P = 0.06). AEs were comparable. IMPLICATIONS:In this real-life cohort of c-IgAN, RTX and CS combination was associated with greater proteinuria reduction and sustained proteinuria control and fewer relapses compared with high-dose CS regimen, without difference in renal function or safety. The retrospective design and limited sample size warrant confirmation in prospective studies.
PURPOSE:Plantar fasciopathy is the most common cause of heel pain in adults and is estimated to affect about 10% of people over their lifetime. The National Institute for Health and Care Excellence notes that extracorporeal shockwave therapy (ESWT) for refractory plantar fasciitis raises no major safety concerns but has inconsistent efficacy evidence and should be used with special governance/audit arrangements; further research with validated outcomes and ≥1‑year follow-up is encouraged. METHODS:This prospective, single-arm clinical series followed consecutive patients treated for refractory plantar fasciopathy in a publicly funded UK musculoskeletal service. Participants received a standardized program of 3 weekly radial ESWT (rESWT) sessions (2500 impulses; 10 Hz; 2-4 bar according to tolerance; no local anesthetic). The primary outcome was participant-level Foot Function Index (FFI) total score at baseline, 6 and 12 months. FINDINGS:Of 50 patients (71 heels) with plantar fasciopathy underwent the treatment protocol. Mean (SD) FFI improved from 60.3 (20.9) at baseline to 37.3 (23.0) at 6 months and remained improved at 39.5 (24.6) at 12 months. Improvements from baseline to 6 months (mean difference 23.0, P < 0.001) and baseline to 12 months (mean difference 20.8, P < 0.001) were statistically significant. There was no significant change between 6 and 12 months (P = 0.451). IMPLICATIONS:In this real-world NHS cohort with refractory plantar fasciopathy, rESWT was associated with substantial improvement in FFI by 6 months, sustained through to 12 months. As the study had no comparator, causality cannot be confirmed in this the single-arm study. However, these findings support further controlled trials and provide useful data to confirm their design and sample size.
PURPOSE:There is a pressing clinical need for readily accessible markers to predict the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer treatment. In this study, we aimed to evaluate the prognostic value of common pre-treatment nutrition/inflammation-based indicators in lung cancer patients receiving programmed death-ligand 1/programmed death-1 inhibitors in Northeast China. METHODS:We retrospectively evaluated 226 patients with advanced lung cancer who received ICIs between January 2019 and February 2024. Three nutrition/inflammation-based indicators were included. Researchers collected baseline clinical data from patients including body mass index (BMI), C-reactive protein (CRP), albumin, and platelet, lymphocyte, and neutrophil counts. The chi-square test was used to compare differences in the objective response rate (ORR) and disease control rate (DCR) between the high and low value subgroups defined by the optimal cut-offs of advanced lung cancer inflammation index (ALI), lymphocyte-to-CRP ratio (LCR), and neutrophil-to-lymphocyte ratio (NLR). Survival curves were plotted using the Kaplan-Meier method. Independent factors associated with overall survival (OS) and progression-free survival (PFS) were analyzed using the Cox proportional hazards regression model. The predictive ability of different indicators was assessed by calculating the C-index. FINDINGS:The overall ORR and DCR were 35.5% and 62.2%, respectively. Patients with low ALI, low LCR, or high NLR demonstrated markedly inferior responses to ICI therapy. The median PFS and OS for the entire cohort were 7.4 and 14.5 months, respectively. Low ALI, low LCR, and high NLR were significantly associated with reduced PFS and OS. Multivariate analysis further confirmed that ALI, LCR, and NLR were independent prognostic factors for both OS (all P < 0.001) and PFS (all P < 0.001). Low ALI was associated with an increased risk of adverse outcomes in lung cancer (hazard ratio [HR] for PFS: 1.526, 95% confidence interval [CI] 1.352-1.943; HR for OS: 1.532, 95% CI 1.314-1.886). C-index analysis indicated that ALI demonstrated the best predictive ability for PFS (0.626 [95% CI, 0.604-0.642]) and OS (0.639 [95% CI, 0.618-0.651]). IMPLICATIONS:ALI, LCR, and NLR are associated with treatment efficacy and prognosis in patients with advanced cancer treated with ICIs. ALI demonstrated a higher predictive ability than LCR and NLR.
PURPOSE:Bone stress injuries (BSIs) are common in athletes, carry substantial time-loss and recurrence risk, and are increasingly managed with bone-active drugs despite a limited evidence base. This narrative review appraises the evidence for pharmacologic adjuncts in BSI, distinguishes the separate clinical indications for which they are proposed, and defines where current evidence does and does not support their use. METHODS:This is a narrative review; therefore ethical approval was not required. PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception to June 2026 combining terms for BSI, stress fracture and athletes. Evidence is summarized in an evidence table that states whether each source is directly applicable to BSI in athletes or extrapolated from osteoporosis, traumatic fracture, spinal surgery, military, or animal studies. Greatest weight is given to controlled studies conducted in patients with BSI. Contemporary practice is illustrated by a previously published survey of 126 clinicians working in professional football and by the 2025 international Delphi consensus. FINDINGS:The evidence base for treatment options in BSI varies substantially based on the clinical context. Correction of a documented abnormality of energy availability, calcium or protein intake, vitamin D status is a key initial step, but there is no clear evidence that supplementation of replete athletes accelerates healing of an established injury. Evidence for bisphosphonates in BSI is limited to small uncontrolled case series and may even impair bone healing or risk reinjury. Teriparatide data derive predominantly from osteoporotic, fragility fracture, and spinal fusion populations, with a single randomized controlled trial in stress fracture in progress. Newer agents, abaloparatide and romosozumab have no direct evidence in BSI, likely because of their novelty. Across all agents, apparent benefit may represent analgesia and earlier controlled loading rather than accelerated biological healing, given that return-to-play timing is determined by numerous clinical, occupational, and organizational factors. IMPLICATIONS:There is currently insufficient evidence to recommend routine use of bisphosphonates or osteoanabolic agents as treatment for an uncomplicated acute BSI in an otherwise healthy athlete. Assessment and correction of nutritional, and metabolic abnormalities, together with load management and rehabilitation, remain the foundation of care. Off-label treatment adjuncts discussed should be considered in recurrent, high-risk or delayed-healing BSI, with shared decision-making focus. Prospective outcome collection is likely to be the most pragmatic way to advance available evidence.
PURPOSE:Drug safety is typically assessed through clinical outcomes: adverse events, dose-response relationships, and postmarketing surveillance. This commentary argues that this framing, while appropriate, can obscure manufacturing's role in determining what patients actually receive. Its purpose is to examine drug safety from a Chemistry, Manufacturing, and Controls (CMC) perspective and to make the case for integrating manufacturing considerations more explicitly into safety assessment across the product lifecycle. METHODS:The analysis draws on engineering and CMC experience, established regulatory guidance, and published examples of manufacturing-related safety events, rather than on clinical trial data or pharmacovigilance analysis. It examines how manufacturing complexity, contamination and impurity risk, and process scale-up introduce safety-relevant uncertainty that evolves throughout the product lifecycle, and how existing regulatory and quality tools address it. FINDINGS:Manufacturing complexity creates latent safety risks through operational variability and system design. Contamination and impurities function as system-level hazards rather than isolated quality failures. Scale-up constitutes a critical inflection point at which assumptions about process robustness are stress-tested under real-world constraints. These risks are difficult to detect through clinical frameworks because they are often low frequency, system driven, and surfaced through quality investigations rather than adverse event reporting. Existing tools, including continuous manufacturing, process analytical technology, real-time release testing, quality by design, and lifecycle-management guidance, mitigate but do not eliminate this uncertainty. IMPLICATIONS:Recognizing manufacturing as part of the drug safety system, and coordinating CMC and pharmacovigilance functions during process changes and scale-up would strengthen patient protection by addressing risks that originate upstream of clinical use but manifest as patient exposure over time.
PURPOSE:Artificial intelligence (AI)-enabled software as a medical device (SaMD) is increasingly used across clinical specialties, but its governance remains difficult because adaptive systems raise ongoing concerns about version control, subgroup performance reporting, and postmarket performance drift. This scoping review examined the ethical and regulatory issues surrounding AI-enabled SaMD across jurisdictions and across the product lifecycle, drawing together peer-reviewed literature, standards, and official guidance. METHODS:A scoping review was conducted using the Joanna Briggs Institute framework and reported in accordance with PRISMA-ScR. Sources published between 2015 and 2025 were identified from PubMed, PubMed Central, Google Scholar, medRxiv/bioRxiv, and the Cochrane Library. Included records were charted by lifecycle stage, jurisdiction, and six prespecified themes: transparency, equity, privacy and security, accountability, lifecycle oversight and change control, and convergence versus fragmentation. Coding was refined iteratively during reviewer calibration. FINDINGS:Of 21,672 records identified, 369 met the inclusion criteria. Most sources were published from 2019 onward and were concentrated in United States and European Union regulatory settings, with additional contributions from international bodies such as International Medical Device Regulators Forum, WHO, and ISO, as well as from emerging economies including China and India. Postmarket oversight emerged as the most strongly emphasized lifecycle stage, especially in relation to real-world monitoring, drift management, and prespecified change control. Common gaps included limited subgroup reporting, inconsistent expectations for drift thresholds and rollback criteria, and poor alignment between horizontal AI rules and device-specific regulatory frameworks. IMPLICATIONS:The evidence base shows meaningful progress in the governance of AI-enabled SaMD, but implementation remains uneven across jurisdictions and lifecycle stages. Priority areas include standardized equity reporting, clearer minimum expectations for drift management, and more explicit integration between horizontal AI governance frameworks and SaMD-specific regulatory requirements. These findings support stronger accountability through improved reporting standards, clearer postmarket controls, and better alignment of quality-management processes across the AI-SaMD lifecycle.
PURPOSE:There is an abundance of data to support the use of methicillin-resistant Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR) swabs in pneumonia and to guide therapeutic decisions. Conversely, there are few studies evaluating its utility in extrapulmonary infections. The purpose of this study was to assess the utility of this testing in extrapulmonary infections and to determine whether MRSA nasal PCRs can be used as a stewardship tool to guide antimicrobial therapy and treatment via negative predictive values (NPVs) and positive predictive values (PPVs). METHODS:This was a retrospective, multicenter, cohort study at a New Jersey health system of patients receiving treatment between March 1, 2023, and July 31, 2023. Data from patients with MRSA nares screening were obtained from electronic medical records. Subsequent clinical cultures collected 7 days before or after the nares swab were evaluated. Sensitivity, specificity, PPVs, and NPVs were assessed for the entire cohort and for subgroups for specific culture sites. FINDINGS:This cohort yielded a total of 742 patients and 1260 clinical cultures from various anatomic sites. Of the patients evaluated, 627 patients had a negative MRSA PCR, and of those with a negative MRSA PCR, 611 patients did not have cultures with MRSA growth. Blood, urine, and wound cultures were the most frequently ordered clinical cultures within our institution, whereas bone/tissue and stool cultures were limited in number. The NPV for blood cultures was 98.7%, urine cultures 100%, wound cultures 92.7%, body fluid/drainage cultures 100%, tissue/bone cultures 100%, and stool cultures 100%. The PPV for blood cultures was 11.1%, urine cultures 1.5%, wound cultures 69.8%, body fluid/drainage cultures 14.3%, tissue/bone cultures 100%, and stool cultures 0%. IMPLICATIONS:Based on the results of this study, the data suggest that a negative MRSA nares PCR obtained within 7 days of a culture has a high NPV for MRSA infections in wound, blood, urine, and body fluid/drainage samples and may be useful to aid in de-escalation of care or discontinuation of antibiotic therapy for certain extrapulmonary infections limited to these sites. Determining predictive values for screening tests is important to establish an antibiotic stewardship tool to guide treatment decisions based on the results. Protocols incorporating MRSA nares PCR could be developed to aid in antimicrobial stewardship and therapeutic management of extrapulmonary infections.
PURPOSE:Clopidogrel is a cornerstone of antiplatelet therapy after lower-limb endovascular intervention in patients with peripheral arterial disease (PAD), yet interindividual variability in treatment response may influence clinical outcomes. To our knowledge, this is the first systematic review and meta-analysis to combine an updated quantitative synthesis of functional clopidogrel resistance with a dedicated qualitative appraisal of CYP2C19 genetic determinants, while explicitly separating analyses based on raw event data from exploratory analyses using published effect estimates and applying conservative small-sample sensitivity methods. We evaluated the association between functional clopidogrel resistance and clinically relevant limb outcomes-target lesion/target vessel revascularization (TLR/TVR) and major adverse limb events (MALE)-with all-cause mortality as a secondary exploratory outcome. METHODS:The review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD42026129845). MEDLINE (PubMed), EMBASE, Web of Science, and Google Scholar were searched from inception to May 17, 2026. Functional resistance was defined as high on-treatment platelet reactivity (HTPR) assessed by platelet function testing, and genetic determinants as CYP2C19 loss-of-function alleles or metabolizer status associated with impaired clopidogrel response. Random-effects meta-analyses using restricted maximum likelihood (REML) were performed, with Hartung-Knapp-Sidik-Jonkman (HKSJ) sensitivity analyses and prediction intervals to quantify statistical uncertainty in sparse data. Genetic studies were synthesized qualitatively. FINDINGS:Ten studies met the inclusion criteria; 6 functional studies contributed to the quantitative analyses. In the primary analysis based on 3 studies with raw event data, HTPR was associated with an approximately 3.7-fold increase in TLR/TVR risk (odd ratios [OR] 3.68; 95% confidence interval [CI] 1.56-8.68; P = 0.003; I² = 59%). An exploratory analysis of 5 studies with published effect estimates was directionally consistent (OR 4.46; 95% CI 1.09-18.31; I² = 87%). HKSJ sensitivity analyses preserved the direction of effect but produced substantially wider confidence intervals crossing the null, indicating increased statistical uncertainty. HTPR was not significantly associated with all-cause mortality (OR 1.49; 95% CI 0.92-2.42). IMPLICATIONS:Functional clopidogrel resistance may be associated with an approximately 3- to 4-fold higher risk of repeat revascularization after lower-limb endovascular intervention; however, the small number of studies, substantial heterogeneity, and conservative sensitivity analyses warrant cautious interpretation. Larger prospective studies and randomized trials are needed before platelet-function-guided or genotype-guided antiplatelet strategies can be recommended. PROSPERO REGISTRATION:CRD42026129845.
PURPOSE:Middle-aged adults with hypertension and no prior cardiovascular disease are commonly seen in clinical practice, yet limited research exists on optimal antihypertensive therapy for this group. This study evaluated whether cardiovascular outcomes vary by antihypertensive drug classes in this population. METHODS:Using the Korean National Health Insurance Service database, we analyzed individuals aged <60 years without cardiovascular disease who were prescribed antihypertensive drugs between 2013 and 2014. Patients on monotherapy were grouped by drug class; those on ≥2 drug classes or uncommon agents (eg, alpha-blockers, hydralazine, or mineralocorticoid receptor antagonists) were categorized as "Others." A subgroup analysis compared outcomes between different angiotensin receptor blockers (ARBs). The primary outcome was a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, and hospitalization for heart failure. FINDINGS:A total of 217,617 participants were included; ARBs were the most common monotherapy (n = 59,906, 27.5%). During follow-up, 3.3% (n = 7080) experienced the primary outcome. The highest incidence of the primary outcome, all-cause death, and cardiovascular death occurred in the diuretic group, and the lowest observed rates were in the ARB group (P < 0.001). In multivariable analysis, beta-blockers (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.48-2.22, P < 0.001) and diuretics (HR = 2.09, 95% CI = 1.70-2.57, P < 0.001) were associated with higher event rates compared with the angiotensin-converting enzyme inhibitor reference group. No statistically significant differences were detected among the individual ARBs evaluated. IMPLICATIONS:Among middle-aged adults with hypertension and no prior cardiovascular disease, ARB users had the lowest observed cardiovascular event rates in this cohort. The higher event rates observed with beta-blockers and diuretics likely reflect confounding by indication. These hypothesis-generating findings require confirmation in prospective studies.
PURPOSE:Medication nonadherence can offset the benefits of pharmacogenomic (PGx)-guided pharmacotherapy. Integrated assessment of demographic, prescribing, and PGx determinants of medication adherence in real-world, PGx-integrated primary care populations remains insufficiently characterized. METHODS:This cross-sectional study assessed medication adherence among 1066 adult patients within the "MedeA" PGx implementation initiative across three primary care centers of the Public Health Service of Extremadura (SES) in Spain. Prescriptions were identified from electronic health records and verified for medication-by-medication adherence through structured patient interviews. Multivariable logistic regression models were applied at the patient level, and generalized estimating equation models were applied at the medication level, stratified by exposure to PGx Level 1A versus non-PGx Level 1A medications, to identify independent demographic, prescribing, and PGx determinants of medication adherence. FINDINGS:One in four primary care patients was nonadherent to the prescribed medications. At the patient level, polypharmacy was the strongest independent determinant of lower medication adherence across both PGx Level 1A and non-PGx Level 1A strata. Female sex was independently associated with lower odds of medication adherence among patients prescribed PGx Level 1A medications. At the medication level, the CYP2D6 genotype-predicted poor metabolizer phenotype was independently associated with lower odds of medication adherence only for PGx Level 1A medications. IMPLICATIONS:Implementing strategies to optimize medication burden, alongside PGx-informed, medication-level adherence assessment, may help enhance the potential clinical impact of precision prescribing in primary care; however, all PGx-related findings from this study should be considered exploratory and hypothesis-generating, requiring further confirmation via prospective studies.
PURPOSE:Comparative post-marketing safety evidence across commonly used antiglaucoma drug classes remains limited. We conducted a real-world pharmacovigilance study to compare adverse event reporting patterns associated with 6 major classes of glaucoma medications using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS:FAERS reports from 2004 to 2024 were analyzed for 6 antiglaucoma drug classes. Baseline characteristics were summarized descriptively. Safety signals were identified using 4 disproportionality methods: reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson Shrinker. Time-to-onset was compared across drug classes. FINDINGS:A total of 13,703 prostaglandin analog, 7,108 adrenergic agonist, 3,149 carbonic anhydrase inhibitor, 399 β-blocker, 149 cholinergic agonist, and 424 fixed-combination cases were identified. Ocular events were most frequently reported, but each class showed distinct safety signals. Prostaglandin analogs showed prominent signals for madarosis and eyelid pigmentation; adrenergic agonists for flushing, skin burning sensation, and rash macular; carbonic anhydrase inhibitors for eye allergy, ocular irritation-related events, hypoacusis, dysgeusia, and a systemic signal of interest for metabolic acidosis; β-blockers for bradycardia, arrhythmia, and atrioventricular block; and cholinergic agonists for vitreous detachment, vitreous opacity, and retinal detachment. Compound preparations showed signals including punctate keratitis, cataract, retinal detachment, eye pain, and visual acuity reduced. Among date-complete reports, time-to-onset differed across drug classes, with cholinergic agonists showing the shortest mean onset time and β-blockers the longest. IMPLICATIONS:This FAERS-based study compared post-marketing adverse event reporting patterns across 6 major antiglaucoma medication classes. Most signals were ocular, periocular, or visual-function related, with selected nonocular signals also observed. These findings are hypothesis-generating and warrant further clinical validation.
Purpose Prader–Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. The oxytocinergic system represents one of the key neural circuits that is dysfunctional in PWS, making it an attractive therapeutic target. The oxytocin analog carbetocin has a longer half-life and greater receptor selectivity than oxytocin and showed therapeutic potential in the phase 3 CARE-PWS study (ClinicalTrials.gov NCT03649477) based on nominally significant improvements in hyperphagia and anxiousness with the 3 times daily (TID) 3.2-mg dose of intranasal carbetocin over placebo. The phase 3 placebo-controlled COMPASS PWS study was conducted to confirm the potential benefit observed with carbetocin in the CARE-PWS study. Methods In the 12-week COMPASS PWS study (ClinicalTrials.gov NCT06173531), 175 participants were randomized 1:1 to carbetocin 3.2 mg TID nasal spray (n = 85) and placebo (n = 90). The primary efficacy endpoint was the change from baseline at week 12 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Secondary efficacy endpoints were the change in the Clinical Global Impression-Severity (CGI-S) score for PWS, and in the CGI-S for hyperphagia in PWS score from baseline at week 12, the CGI-Change for PWS score at week 12, and the percentage of participants with a treatment response (defined as improvement from baseline ≥8 points) based on the HQ-CT at week 12. Exploratory efficacy endpoints included the change from baseline at week 12 in scores for the PWS Anxiousness and Distress Behaviors Questionnaire. Findings The least squares mean (standard error) change from baseline at week 12 in the HQ-CT was −4.8 (0.8) and −5.1 (0.8) in the carbetocin and placebo groups, respectively; the treatment difference of 0.3 (95% confidence interval: −1.8, 2.4; P = 0.79) was not statistically significant. There was no separation between carbetocin and placebo for any secondary or exploratory endpoint. The most frequently reported treatment-emergent adverse events in the carbetocin-treated participants were headache (n = 6 [7.2%]) and pyrexia (n = 5 [6.0%]). Implications Carbetocin nasal spray did not demonstrate efficacy compared with placebo for hyperphagia in PWS in the 12-week COMPASS PWS study.
PURPOSE:This meta-analysis sought to evaluate whether the addition of exercise to nutritional support (NS) improves physical function compared with NS alone in older adults diagnosed with malnutrition retrospectively verified as compatible with the updated Global Leadership Initiative on Malnutrition (GLIM) 2025 phenotypic-etiologic framework. METHODS:A comprehensive search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify randomized controlled trials (RCTs) comparing combined exercise and NS versus NS alone in malnourished older adults. Studies were included if participants met GLIM-defined malnutrition criteria and the trial reported relevant physical function or nutritional outcomes. Predefining upper and lower limb strength as distinct endpoints, data were analyzed using a random-effects model, with results expressed as standardized mean differences (SMDs) and 95% confidence intervals (CIs). To facilitate interpretation, a positive SMD denotes an effect favoring the combined intervention, except for TUG, where a negative value is favorable. FINDINGS:Seventeen RCTs were included. Compared with NS alone, the combined intervention improved lower limb strength (SMD 0.35; 95% CI, 0.18-0.52; P < 0.0001) but did not improve upper limb strength (handgrip) (SMD 0.15; 95% CI, -0.01 to 0.30; P = 0.07). Muscle mass (SMD 0.65; 95% CI, -0.23 to 1.54; P = 0.15) and lean body mass (LBM) (SMD 0.27; 95% CI, -0.12 to 0.66; P = 0.18) were not significantly different. A small standardized improvement in usual walking speed (UWS) was detected with the combined intervention (SMD 0.38; 95% CI, 0.10-0.66; P = 0.008). When expressed in absolute units, the pooled UWS improvement was 0.07 m/s (95% CI, 0.03-0.12; P = 0.001). Timed Up and Go (TUG) performance favored exercise plus NS but did not reach significance (SMD -0.33; 95% CI, -0.74 to 0.08; P = 0.11). Serum 25(OH)D did not differ between groups. Accordingly, GRADE certainty was moderate for lower limb strength, but low for upper limb strength and UWS, and very low for muscle mass and TUG, indicating that confidence is highest for the lower-limb strength benefit, while effects on mobility and body composition remain more uncertain. IMPLICATIONS:Adding exercise to nutritional support was associated with small but statistically significant improvements in lower limb strength and UWS in malnourished older adults. While this combined approach optimizes specific functional outcomes, current evidence does not demonstrate added benefits for overall body composition or upper limb strength.
PURPOSE:This study aimed to investigate the sex-associated adverse events (AEs) reporting differences of phosphatidylinositol 3-kinase (PI3K) inhibitors from the US Food and Drug Administration Adverse Event Reporting System (FAERS), thereby providing a more solid foundation for evidence-based clinical practice. METHODS:All PI3K inhibitors were searched as primary and secondary suspected drugs from FAERS data (January 2004 to July 2025). We performed disproportionality analyses using reporting odds ratios (ROR) to evaluate the associations between PI3K inhibitors and adverse events. FINDINGS:Among the 6,209 AE reports associated with PI3K inhibitors, alpelisib exhibited a female predominance (82.7%), accompanied by a stronger hyperglycaemia signal in females (reporting odds ratio [ROR] 187.6 vs 79.3). Following false discovery rate (FDR) correction, significant sex differences at the preferred term (PT) level persisted for alpelisib (female predominance in hyperglycaemia, rash, and diarrhoea), yet no significant differences at the system organ class (SOC) level remained. Idelalisib demonstrated a male predominance (54.9%), with comparable diarrhoea signals between the sexes. Regarding copanlisib and duvelisib, the limited number of cases precluded reliable sex-specific comparisons. IMPLICATIONS:This research identifies sex-specific AE patterns for PI3K inhibitors. Subsequent to FDR correction, significant PT level sex differences were detected for alpelisib, yet not for idelalisib. Moreover, no differences at the standard of care SOC level persisted for either drug. The findings regarding copanlisib and duvelisib remain indeterminate. These results provide clinically relevant signals for sex-tailored AE surveillance and necessitate prospective validation.
PURPOSE:Congenital cytomegalovirus (cCMV) is the most common congenital infection worldwide and involves manifestations at birth ranging from asymptomatic to life-threatening. This study aimed to describe trends in the administrative birth prevalence of cCMV among infants and the use of antiviral treatments in the US from 2007 to 2024. METHODS:Outpatient data from Optum's de-identified ClinformaticsⓇ Data Mart database from January 1, 2007, through August 31, 2024, were analyzed to identify commercially-insured infants with cCMV infection or cCMV disease within 45 days of birth via ICD-9/10 diagnosis codes. Outpatient prescription data were also analyzed to examine antiviral treatment among infants with diagnosed cCMV. FINDINGS:The overall administrative birth prevalence of cCMV was 3.4 per 10,000 live births. A nonlinear pattern of cCMV diagnoses was observed, with a rapid increase from 3.8 to 8.4 per 10,000 live births from 2021 to 2024. Antiviral treatment was prescribed to 18.4% of infants with diagnosed cCMV during the study period, and varied year-over-year. Among 107 infants prescribed antiviral treatment, 73 were moderately-to-severely symptomatic cCMV, 2 were mildly symptomatic, 13 were asymptomatic cCMV with isolated hearing loss, and 19 were asymptomatic cCMV without isolated hearing loss. The proportion of infants prescribed antiviral treatment increased with the number of signs or symptoms present at birth and with increased severity of symptoms. IMPLICATIONS:Research is needed to monitor short- and long-term outcomes of antiviral treatment in infants with cCMV, especially asymptomatic infants (with or without hearing loss), as detection of asymptomatic infants increases with the introduction of systematic newborn screening programs.
