ACS Pharmacology & Translational Science

In some countries, melatonin is sold without a physician prescription and dosage is unregulated. Transdermal products have become popular including those marketed for children. We measured consumer assumptions about these products among adult residents of the United States, analyzed lot-to-lot variability, and compared the pharmacokinetics of melatonin administered in oral, lotion, and bath product forms. Survey respondents (n=199) believed oral melatonin was more effective than transdermal products and that all melatonin products were relatively safe. Melatonin lotion products analyzed by HPLC displayed lot-to-lot variability as well as changes in formulation and product claims. To determine pharmacokinetics, three different treatments (oral tablets, lotion, and bath immersion) were administered to twelve undergraduate participants in a randomized, crossover design. Five additional participants completed bath product treatment only. Participants collected saliva samples up to 48 hours after administration, which were analyzed for melatonin by enzyme-linked immunosorbent assay. Oral (n=11) and lotion formulations (n=12) caused maximum salivary melatonin levels within 30 minutes after administration, but bath immersion did not cause increases in saliva melatonin (n=17). The half-life of oral melatonin was 1.17 [0.69 -- 1.65] hours versus 5.72 [3.75 -- 7.68] hours for lotion treatment (p = 0.011, effect size r = 0.770). Melatonin lotion may pose a risk to consumers who assume it is safe and less effective than oral tablets, when in fact it may be very potent and remain at high physiological levels into the following day. This study is registered on clinicaltrials.gov (NCT06382610) and was funded by the Sleep Research Society.

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

Rationale: Efficacious dose selection for anti-tuberculosis drugs has traditionally relied on achieving plasma exposures above the minimum inhibitory concentration, but this approach has not consistently aligned with clinical outcomes. Objectives: We sought to identify early pharmacokinetic-pharmacodynamic targets most predictive of clinical efficacious dose. Methods: We conducted a back-translational, pharmacokinetic-pharmacodynamic simulation-based analysis of 15 anti-tuberculosis drugs. Using pharmacokinetic data from multiple biological matrices and a range of pharmacodynamic metrics, we established candidate exposure-response targets for attainment. We systematically evaluated the predictive accuracy of each target pair against established clinical doses to formulate a decision-making framework linking key drug properties to the most predictive targets. Measurements and Main Results: Depending on the target used, projected clinical doses varied widely - both within and across compounds - highlighting the importance of target selection for dose projection and go/no-go decisions. In general, targeting cellular lesion-level drug exposures relative to in vivo preclinical potency provided an effective approach for early dose selection. However, for highly penetrating drugs, targeting site-of-action therapeutic exposures in the caseum was more predictive of clinical dose. Based on these findings, we developed a preliminary dose prediction tool that enables drug developers to estimate clinically relevant dose ranges of compounds using in vitro and early in vivo data. Conclusions: This work establishes and validates a simple, evidence-based framework to standardize early translational decision-making on dose selection of anti-tuberculosis candidates in development.

Joint modelling of longitudinal data using non-linear mixed effects models and time-to-event outcomes provides a suitable framework to account for informative censoring when estimating biomarker dynamics and quantifying event risk using covariates and longitudinal trajectories. Their usefulness in clinical research depends on data collection design, particularly to precisely estimate the association (link) parameter between longitudinal and survival processes. However, optimal design strategies have so far been addressed separately for longitudinal and survival endpoints and remain unexplored for joint models. We propose two Fisher Information Matrix (FIM) computation methods for joint models, relying on Monte-Carlo integration over observations combined with either Markov Chains Monte-Carlo or Adaptive Gaussian Quadrature to integrate random effects. Their accuracy is assessed against clinical trial simulations in an oncological example based on the HORIZON III study with a tumour-growth-survival model including discrete and continuous covariates. We apply these methods to quantify the impact of follow-up duration, sampling richness, sample size, and covariate distribution on parameter uncertainty and test power. In our example, longitudinal-parameter uncertainty is barely affected by follow-up duration or sampling richness, whereas survival-parameter uncertainty decreases substantially from 1-year to 2-year follow-up. The number of subjects needed (NSN) to achieve <15\% uncertainty on the link parameter is comparable for a 2-year rich design and a 3-year sparse design. Optimal covariate distributions are stable across designs and systematically improve test power, outperforming longer and richer but non-optimised designs. These FIM-based methods accurately predict uncertainty and test powers, enabling design evaluation and NSN computation for joint-model-based clinical studies.

Background: Psychedelics are emerging as potential management options for chronic musculoskeletal pain due to preliminary evidence of effectiveness and low addictive potential, but patients perceptions remain unknown. This study assessed patient perceptions regarding psilocybin for musculoskeletal pain. Methods: We conducted a cross-sectional survey of adults ([&ge;]19) with musculoskeletal pain attending a hospital-based orthopaedic clinic. Participants reported demographics, perceptions of psychedelics for pain management, and willingness to participate in psychedelic research. Multivariable regression explored factors associated with perceived analgesic potential, and willingness to try a full therapeutic dose of psilocybin or a microdose. Results: Among 295 participants, 73% reported moderate-to-severe pain; 75% used analgesics; of these, 41% used opioids (86/209). While 24% reported prior psychedelic use, only 3% had discussed psychedelics with a healthcare provider. Most perceived that psilocybin had moderate-to-high effectiveness for pain (76%). Most respondents endorsed a moderate-to-high willingness to try microdoses (58%) and macrodoses (53%) of psilocybin for pain. Prior non-therapeutic psychedelic use predicted a 1.05-unit increase in perceived analgesic potential on the 10-point scale (p=.013). Willingness to try a macrodose of psilocybin was most strongly associated with prior non-therapeutic (B=3.16) and therapeutic (B=2.42) psychedelic use; in contrast, pain severity had a significant but modest association, with a 0.21-point increase in willingness for every 1-unit increase in pain severity (p=.017). Similarly, willingness to try a microdose of psilocybin was predicted by non-therapeutic (B=2.82) and therapeutic (B=2.48) use, whereas the effects of pain severity (B=0.20) and younger age (B=-0.30) were significant but small. Most respondents (52%) reported moderate-to-high willingness to participate in a trial of psilocybin for pain relief, and health risks were the primary concern (33%). Conclusions: Study findings suggest a majority hold neutral-to-positive perceptions of psilocybin for pain. Addressing perceived barriers, including health effects and gaps in patient knowledge, should be considered when designing future trials.

The proliferation of gambling advertising has intensified concerns regarding its influence on vulnerable populations, yet the neural mechanisms underlying cue-reactivity to these stimuli remain underexplored in ecologically valid settings. This study protocol proposes a novel methodological framework to investigate prefrontal cortical responses to gambling advertisements in individuals with varying degrees of gambling experience. Materials and methods: This cross-sectional study will recruit 44 participants, divided into a clinical group (individuals with high-frequency gambling or gambling disorder) and a matched control group. Neural activity will be recorded using fNIRS while participants view gambling-related, neutral, violent, and sexual stimuli. Secondary measures include validated scales for gambling severity (SOGS), impulsivity, sensation seeking, and alexithymia. Data analysis will primarily utilize inter-subject correlation (ISC) to quantify neural synchronization and multiband frequency decomposition to capture dynamic affective processing. Advanced preprocessing, including short-channel regression, will be applied to ensure signal robustness. Discussion: By combining portable neuroimaging with a data-driven ISC approach, this study aims to identify objective neural markers of gambling vulnerability. The findings will provide novel insights into the idiosyncratic processing of commercial stimuli, potentially informing public health policies and the development of more effective evidence-based regulations for gambling marketing.

Background and Aims: Synthetic opioids cause tens of thousands of deaths each year in North America, and there are indications that synthetic opioids are also becoming increasingly prevalent in the European drug market. This study aimed to examine high-risk substance use in the German drug-using community with a particular focus on the synthetic opioids fentanyl and nitazenes and related awareness, concerns, overdose experiences, and harm-reduction behavior. Design: Cross-sectional, observational online survey. Setting: Open drug-use scenes, addiction clinics, and substitution practices at numerous geographic locations throughout Germany, August to September 2025. Participants: 235 individuals aged 14+ from the drug using community (mean age 43.4 years; 57.9% male), 79.6% recruited by peers in open drug-use scenes. Measurements: The primary outcome was substances used within the past 12 months. In addition, sources, forms, routes of administration, and perceived changes in availability and price of (synthetic) opioids were assessed as well as risk perceptions, fears, harm-reduction behavior, and overdose-related experiences. Findings: 227 respondents reported substance use with an average of 6.2 substances, and 73.1% (95% confidence interval [CI] = 67.0-78.5%) had used at least one opioid in the past year. Synthetic opioids were consumed in many parts of Germany and across all age and gender groups. Among participants who experienced a shortage of their primary opioid in the past year, 25% (95% CI = 15.8-37.2%) reported having used fentanyl instead. 56.5% (95% CI = 36.8-74.3%) of individuals using synthetic opioids reported having experienced an overdose in the past twelve months. Most of the respondents perceived synthetic opioids as posing a high risk, and a substantial proportion expressed fear that they could be mixed into their own substances. However, only 9.9% (95% CI = 6.6-14.7%) use drug checking, although the vast majority stated they would use it if it were available to them. Conclusions: Synthetic opioids, including fentanyl and nitazenes, have entered the German drug scene, with users reporting high rates of overdose and limited access to harm reduction measures. Germany may be in an early phase of a synthetic opioid transition, warranting urgent expansion of surveillance, naloxone distribution, and drug checking services.

Pain in pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, but whether altered pain processing carries prognostic significance is unknown. We analyzed a prospective cohort of 143 patients with PDAC who underwent pancreatic quantitative sensory testing (PQST) after diagnosis. Patients were classified as having normal pain processing (n=84), segmental hyperalgesia (n=30), or widespread hyperalgesia (n=29). Survival was measured from the date of P-QST assessment. During follow-up, 70 deaths occurred. Widespread hyperalgesia was associated with increased mortality in unadjusted Cox analysis (HR 1.96, 95% CI 1.14,3.35) and after adjustment for age, sex, tumor stage, comorbidity, opioid treatment, and body mass index (adjusted HR 2.33, 95% CI 1.30,4.15). Segmental hyperalgesia was not associated with mortality. Kaplan Meier analysis demonstrated lower survival probability in the widespread hyperalgesia group (log rank p=0.025). These findings suggest that widespread hyperalgesia, reflecting altered central pain processing, identifies a subgroup of PDAC patients at increased risk of mortality independent of conventional clinical factors.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

We present a compact pump-and-probe mid-infrared Optothermal Spectrometer (OTHES) equipped with Spatial Probing and Autocorrection (SPAC) optimized for robust intravital application in humans. SPAC-OTHES facilitates alignment stability and spectral comparability across different measurement sessions involving different skin types. Contrary to state-of-the-art, SPAC-OTHES uses camera-based beam detection and an auto-calibration mechanism that enables ca. 73% better spectral reproducibility in intravital measurements in human volunteers than non-calibrated readouts. Moreover, SPAC-OTHES has the potential to lower the glucose quantification error, as demonstrated here in artificial skin phantoms, where an improvement of 52% compared to conventional diode-based detection was observed. The compactness of OTHES, combined with reliable SPAC-readout, has the potential to accelerate commercialization and broad application of biosensors based on mid-infrared spectroscopy.

Background: Antenatal care (ANC) utilization is critical for improving maternal and neonatal health outcomes. Despite the World Health Organization recommendation of at least eight ANC contacts during pregnancy and the implementation of free maternal healthcare policies in Ghana, significant geographic and socioeconomic disparities in ANC utilization persist. This study therefore assessed the spatial distribution and geographically varying determinants of ANC utilization among women in Ghana. Methods: A cross sectional analytical study was conducted using women data from the 2022 Ghana Demographic and Health Survey. The analysis included women aged 15 to 49 years with an index child younger than five years preceding the survey. Descriptive statistics were computed using Stata version 18, while spatial analyses were conducted in QGIS version 3.44. Global Morans I was used to assess spatial autocorrelation, whereas Local Morans I and Getis Ord Gi analyses identified spatial clusters, hotspots, and coldspots of ANC utilization. Ordinary Least Squares (OLS) regression and Geographically Weighted Regression (GWR) models were fitted to assess global and local determinants of ANC utilization. Results: Overall, only 26.0% of women achieved adequate ANC utilization, while 74.0% reported inadequate ANC attendance. Adequate ANC utilization was higher among women with higher education (42.0%) and those from the richest households (41.3%) compared with women without formal education (19.1%) and those from the poorest households (17.6%). Regional disparities were observed, with Western (48.8%), Eastern (48.0%), and Greater Accra (47.3%) regions recording the highest ANC utilization, whereas Savannah (24.7%), Northern (25.8%), and North East (26.8%) regions recorded the lowest utilization levels. Global Morans I demonstrated significant positive spatial autocorrelation (Morans I = 0.457, p = 0.044), indicating geographic clustering of ANC utilization across Ghana. Getis Ord Gi analysis identified significant coldspots within Northern, Savannah, and North East regions, while Central Region demonstrated significant hotspot clustering. OLS regression showed that maternal education (B = 0.284, p = 0.003) and household wealth (B = 0.191, p = 0.011) positively influenced ANC utilization, whereas distance to health facility negatively influenced utilization (B = -0.156, p = 0.019). The GWR model demonstrated improved explanatory performance (Adjusted R-squared = 0.71), confirming substantial spatial heterogeneity in ANC determinants across Ghana. Conclusion: Adequate ANC utilization in Ghana remains low and geographically unequal. Maternal education, household wealth, and geographic accessibility significantly influence ANC utilization, with pronounced disparities concentrated within Northern Ghana. Spatially targeted maternal health interventions aimed at improving education, reducing socioeconomic inequalities, and enhancing healthcare accessibility are required to improve equitable ANC utilization across Ghana.

Wearable digital health technologies may complement traditional gait assessments in amyotrophic lateral sclerosis (ALS) by sensitively capturing real-world mobility changes. In this study, we validated six digital gait metrics derived from ankle-worn sensors in a natural history cohort of 182 individuals with ALS. Investigated metrics correspond to various aspects of gait, including volume, speed, intensity, similarity, variability, and fragmentation. Longitudinal analyses showed significant declines in step count, peak cadence, stride intensity, and stride similarity, with increasing stride duration variability and walking fragmentation over 52 weeks. Many participants exhibited greater relative change in the gait metrics than the self-reported ALS Functional Rating Scale-Revised (ALSFRS-RSE). Stratified analyses revealed that digital metrics captured significant functional decline even in participants with stable walking scores on the ALSFRS-RSE. These findings support the potential utility of these metrics for disease monitoring in ALS clinical care and trials.

Background: The rising prices of cancer medicines have intensified concerns about treatment access and health system sustainability particularly in low- and middle-income settings. Systematic facility level evidence on what medicines is actually available, at what prices, and at what cost to patients remains scarce, constraining evidence-based policy reform. Methods: Using adapted WHO/Health action international methodology, we conducted a cross-sectional survey of 52 cancer medicines across five therapeutic classes at five health facilities in Kisumu County, Kenya. Availability was measured as the proportion of facilities stocking each medicine. Affordability was assessed using days' wages required for the lowest-paid government worker to purchase standard treatment regimens, calculated per one chemotherapy cycle and maximum possible cycles. Results: Overall medicine availability was 48.1%, with marked inter-facility variation. Affordability analysis revealed severe financial barriers. The breast cancer AC regimen required 19.6-47.4 days' wages per full course; cervical cancer cisplatin, 19.8-49.2 days' wages; colorectal FOLFOX, 80.0-303.6 days' wages; and prostate docetaxel reached 437 days' wages at the highest-cost facility. The Social Health Authority's (SHA) KES 550,000 annual ceiling adequately covered cytotoxic regimens for common cancers at competitive prices but was exceeded by 24-116% for HER2-positive breast cancer requiring trastuzumab, with further strain for recurrent cervical and metastatic prostate cancers. Conclusions: Cancer medicines in Kisumu County are inconsistently available and highly variable in price resulting in inequitable access. We call for urgent retail price markup regulation, expanded pooled procurement through KEMSA, inclusion of priority targeted therapies on the Kenya Essential Medicines List, and SHA benefit packages redesigned around full-course regimen costs.

Background: RNA sequencing (RNA-seq) is increasingly recognized as a complementary tool to DNA-based sequencing for improving the diagnostic yield in Mendelian disorders. However, how the diagnostic performance of RNA-seq varies across molecularly and phenotypically distinct patient subgroups remains poorly defined. This study aimed to evaluate and compare the diagnostic utility of RNA-seq across three stratified groups of patients with non-diagnostic exome sequencing. Methods: We performed RNA-seq on whole blood samples from 90 patients with suspected Mendelian disease in whom clinical exome or whole-exome sequencing had failed to establish a molecular diagnosis. Patients were prospectively stratified into three groups of 30: (i) patients with a candidate variant of uncertain significance (VUS) with predicted splicing impact (Group 1), (ii) patients with a specific clinical pre-diagnosis but no identified pathogenic variant (Group 2), and (iii) patients without a specific pre-diagnosis or candidate variant (Group 3). Aberrant splicing, gene expression outliers, and allele-specific expression were analyzed using multiple bioinformatic tools and compared against a GTEx-derived control cohort. Results: RNA-seq contributed to a molecular diagnosis in 29 of 88 evaluable patients (32.9%). Diagnostic yield differed substantially across groups: 82.8% (24/29) in Group 1, 6.9% (2/29) in Group 2, and 10% (3/30) in Group 3. In Group 1, RNA-seq enabled reclassification of candidate VUS through direct demonstration of aberrant splicing events. In Group 2, RNA-seq identified a somatic mosaic ACTB variant missed by exome sequencing and reclassified a previously deprioritized APPL1 VUS. In Group 3, a deep intronic pseudoexon-activating variant in IGBP1 was identified in two siblings with severe microcephaly, providing evidence for a candidate X-linked microcephaly gene, and a pathogenic RNU4-2 variant was detected in a patient with ReNU syndrome, a non-protein-coding gene not captured by standard exome sequencing. Conclusions: RNA-seq has the highest diagnostic utility when applied to evaluate candidate splice variants identified by prior DNA testing but also provides independent diagnostic value in patients without candidate variants. The systematic comparison across stratified patient groups supports the integration of RNA-seq into clinical genomic workflows and highlights the need for standardized analytic frameworks.

Background and Objective: Access to real-world electronic health records (EHRs) remains limited by privacy, governance and annotation constraints, hindering the development of clinical natural language processing models. Realistic synthetic progress notes may provide EHR-like corpora that preserve clinically rigorous information on diagnoses, treatments, symptoms, imaging, laboratory findings and therapeutic trajectories without relying directly on sensitive patient records. This study evaluates whether large language models (LLMs) can generate realistic Spanish prostate cancer progress notes from published case reports, preserving clinical content, temporality and hospital-style conventions.

Objective Memory impairment is a frequent comorbidity of focal epilepsy, incompletely explained by seizure frequency or structural pathology. Ictal and postictal hippocampal dysfunction disrupt memory processes, but their cumulative impact remains poorly quantified. This study introduces cumulative hippocampal seizure-related burden metrics and examines their association with long-term memory consolidation. Methods Twenty consecutive patients undergoing stereo-EEG in Marseille (2016-2018) were prospectively included. Continuous stereo-EEG recordings between two memory assessments (30 minutes and one week post-encoding) were analysed. Hippocampal ictal involvement and durations were assessed using epileptogenicity markers and visual stereo-EEG analysis. The postictal period was quantified using permutation entropy. Cumulative hippocampal seizure-related burden metrics (ictal, postictal and combined: c-HipSZB) were computed across hippocampus-involving ictal events. Verbal and visual memory were assessed using standardized recall and recognition tasks. Associations were examined using univariate and multivariate analyses. Results Higher dominant-hemisphere hippocampal burden was associated with poorer one-week verbal memory (performance and retention), independently of most covariates. Higher c-HipSZB was associated with lower total recall performance (RT; free + cued) and RT retention ({beta} = -25.04 and -23.88; R2 = 0.57 and 0.53; p < 0.05) and accounted for the greatest variance in both outcomes (adjusted R2= 0.59 and 0.53; {beta} = -25.45 and -24.27; p < 0.01), particularly when adjusting for epilepsy duration. No robust associations were observed between non-dominant-hemisphere hippocampal seizure-related burden metrics and visual memory. Effects predominantly involved recall. Interpretation Cumulative ictal-postictal hippocampal dysfunction is a major determinant of impaired long-term verbal memory consolidation in focal epilepsy.

Background Oropouche virus (OROV) is an emerging vector-borne virus with rapidly expanding geographic range, increasing case counts, and growing evidence of severe outcomes including neuroinvasive disease and vertical transmission. Because OROV infection presents with nonspecific febrile illness that overlaps clinically with other viruses including dengue, zika, and chikungunya, accurate molecular diagnostics are essential for patient care and surveillance. Yet existing assays rely on single genomic targets and are vulnerable to detection failure as the virus evolves and reassorts. Methodology/Principal Findings To support diagnostic capacity, we developed and clinically validated a multiplexed qPCR assay targeting three regions of the OROV S segment, incorporating redundancy to preserve sensitivity across viral diversity while enabling robust clinical interpretation. The multiplex also includes an assay targeting RNaseP as an internal sample control to ensure adequate sample processing. We evaluated assay performance using both historical and contemporary OROV strains and validated the assay on contrived serum, plasma, and cerebrospinal fluid samples, assessing linearity, limit of detection (LOD), accuracy, specificity, precision, and sample stability. The assay met or exceeded all predefined acceptance criteria for clinical testing and achieved an LOD as low as 6 copies per reaction for contemporary outbreak strains. We further implemented a logic-based interpretation matrix that reduced false-positive risk while maintaining sensitivity near the analytical LOD. Conclusions/Significance Our assay sensitively and specifically detects OROV RNA in serum, plasma, and cerebrospinal fluid while incorporating safeguards against viral evolution and reassortment. The assay has been approved for use by CLIA at Nexus Medical Labs in 49 U.S. states, expanding access to timely OROV diagnostics in the United States and providing a durable framework for molecular detection of reassorting, rapidly evolving viruses as OROV continues to spread into new regions.

Background: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Abstract Aims To examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Meta's algorithms actually delivered the adverts to. Design Cross-sectional analysis of advert-level data from the Meta Ad Library. Setting Meta social media platforms (including Facebook and Instagram) in the UK. Cases A random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general). Measurements Outcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR). Findings Advertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0-8.2). Conclusions Nicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.

Background: Climate mitigation policies can lower air pollutant concentrations and deliver substantial health co-benefits. The French Ecological Transition Agency (ADEME) proposed four contrasting Transitions 2050 net-zero scenarios. We quantified mortality, morbidity, and health-economic co-benefits from projected PM2.5 and NO2 reductions across all four scenarios in continental France. Methods: Emission projections were input to the CHIMERE chemistry-transport model to estimate PM2.5 and NO2 concentrations for 2030 and 2050. Health impacts were assessed using disease-specific cessation-lag assumptions relative to 2019, covering premature mortality, morbidity, DALYs, and economic benefits across nine outcomes (hypertension, lung cancer, ischaemic heart disease, stroke, COPD, type-2 diabetes, acute lower respiratory infections, and asthma in children and adults). Findings: Population exposure is projected to decline by about 40% for PM2.5 and 70% for NO2 by 2050, with health gains remaining substantial and broadly equivalent across all four scenarios and modest differences between sufficiency-oriented and technology-driven pathways. Under delayed-impact assumptions, avoided premature deaths ranged from 21,300 to 22,100 for PM2.5 and 24,500 to 26,200 for NO2. Morbidity and disability-adjusted life year (DALY) reductions, as well as economic savings, spanned similarly; total avoided morbidity cases were 84,000-88,000, direct medical cost reductions were e1.0-1.1 billion/year, and intangible cost savings of e41-43 billion and e36-39 billion, respectively. Interpretation: Health co-benefits are substantial, consistent across contrasting scenarios, and increase markedly from 2030 to 2050. Explicitly incorporating these co-benefits into climate policy appraisals may strengthen the case for ambitious mitigation and improve decision-maker acceptability.