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Influenza infection can represent a key factor for functional decline and loss of independence among older adults. In France, over 600,000 seniors live in social institutions, including nursing homes (NH). Yet, real-world data on the place of influenza hospitalization in care pathway before institutionalization are scarce in France. This study described the care pathway of older adults hospitalized for influenza-like illness (ILI) before NH admission. A retrospective observational study based on the French National Health System (SNDS) was conducted. All patients aged ≥ 65 years who were admitted to a NH between the start of the 2018-2019 epidemic season and up to eight months after were identified. Those hospitalized for ILI within six months prior to institutionalization were included and followed for six months prior to and up to three months after NH admission. Demographic and clinical characteristics of patients were described. State sequence analysis (SSA) was used to identify clusters of patients based on healthcare events (e.g. hospitalizations, rehabilitation, and deaths) during follow-up. Among 119,869 NH admissions, 1,239 (1.1%) had prior ILI hospitalization. About 70% of patients had received influenza vaccination. Median age was 88 years; 64.6% were women; over 90% had at least one comorbidity, notably hypertension (75%) and neurodegenerative disorders (31.3%). After ILI-hospitalization, 31.2% of patients were transferred to rehabilitation before NH admission, and 8.4% were admitted directly to NH. SSA identified five patient clusters differing in vaccination rates, comorbidities and healthcare utilization. Cluster 1 and Cluster 2 were generally healthier and admitted to NH immediately after discharge (median 20.5-22.5 days). Cluster 3-5 had more comorbidities and were more frequently transferred to rehabilitation after discharge and before NH admission. The total cost to the French health insurance for these patients exceeded €20 million. Rehabilitation accounted for €9.6 million, ILI hospitalizations €6.0 million, and other hospitalizations (including cardiorespiratory) €4.3 million. This study explored the place of influenza in the care pathway of French older adults admitted to NH after ILI hospitalization. Findings underscore the important place of rehabilitation care following ILI hospitalization, specifically among adults with multiple comorbidities, highlighting the need for improving vaccination coverage among frail older adults to mitigate post‑ILI care burden.

Respiratory syncytial virus (RSV) infections are a leading cause of lower respiratory tract infections (LRTI), particularly bronchiolitis and pneumonia, leading to significant hospitalizations and economic burden in infants. In Colombia, RSV is endemic with high morbidity and mortality rates, underscoring the need for effective prophylactic technologies to reduce its impact. This study aimed to analyze the health and economic impact of new RSV immunization technologies in Colombia, focusing on two interventions: nirsevimab and RSVpreF. A static cohort decision model was used to compare these interventions against the standard of care (palivizumab-SoC), estimating outcomes including hospitalizations, intensive care unit (ICU) admissions, deaths, and event-related healthcare costs. The model included outcomes such as QALYs and direct and indirect event-related costs from the third-party and societal perspectives. Acquisition costs of prophylactic interventions were not included because prices are not publicly available during ongoing negotiations. Nirsevimab was associated with a greater reduction in healthcare events and costs compared to both SoC and RSVpreF. In the base-case scenario, it prevented an additional 44,039 events and was associated with US$23.4 million lower event-related healthcare costs compared to SoC. When compared with RSVpreF, it averted 14,558 more events and was associated with US$8.4 million lower event-related costs. The greatest reduction occurred in primary care visits, with 32,744 and 10,458 fewer cases versus SoC and RSVpreF, respectively, followed by reductions in hospitalizations of 6210 and 2257 cases. Nirsevimab yielded up to 646 additional QALYs compared with RSVpreF and associated with up to US$25.3 million lower event-related costs from avoided health events in societal scenarios. Sensitivity analysis identified nirsevimab efficacy and infection distribution as the key drivers of event-related cost and QALY outcomes. Nirsevimab was associated with larger reductions in RSV-related events, greater reductions in event-related costs, and higher QALYs than SoC and RSVpreF. Its adoption in national immunization programs could significantly reduce the economic and disease burden of RSV and improve infant health.

Wildfire smoke is a major source of fine particulate matter (PM2.5) and may increase vulnerability to severe infectious outcomes such as sepsis, a condition responsible for an estimated 49 million cases and 11 million deaths annually. Despite this global burden, to our knowledge, no prior epidemiological study has specifically examined the association between wildfire-specific PM2.5 exposure and infectious disease-related sepsis. We conducted a multi-country time-series analysis across 1,024 communities in seven countries/territories (2000-2019). Daily hospitalizations for infectious disease-related sepsis were identified using ICD-10 codes, restricted to explicit sepsis diagnoses. Wildfire-specific PM2.5 was estimated using the GEOS-Chem chemical transport model combined with machine learning calibration and linked to hospitalization data. Associations between wildfire-specific PM2.5 and sepsis hospitalizations were estimated using quasi-Poisson regression with distributed lag non-linear models over lag 0-7 days. Community-specific estimates were pooled using random-effects meta-analysis. Across all communities, we identified 2.3 million infectious disease-related sepsis hospitalizations, with the highest burden among older adults and in Brazil. Each 10 &#x3bc;g/m3 increase in wildfire-specific PM2.5 was associated with a 1.5% increase in sepsis hospitalizations (Relative Risk [RR]: 1.015, 95% Confidence Interval [CI]: 1.007-1.024), nearly double the effect of non-wildfire PM2.5 (0.8%). Strongest associations were found among children aged <5 years (RR: 1.063, 95%CI: 1.029-1.097) and those aged 5-19 years (1.093, 1.050-1.138), in moderately populated communities, and in New Zealand and Brazil. Sensitivity analyses confirmed the robustness of the findings. Short-term exposure to wildfire-specific PM2.5 was associated with increased risk of hospitalization for infectious disease-related sepsis, particularly greater risks in adolescents and young children. These findings underscore the need of further research to clarify underlying mechanisms and long-term impacts.

Cancer remains a leading global cause of mortality, with approximately 20 million new cases and 9.7 million deaths reported in 2022. Traditional treatments, including chemotherapy and external beam radiotherapy, are often limited by non-specific targeting, systemic toxicity, and resistance. Targeted radionuclide therapy using iodine-131 (131I), which emits both &#x3b2;-particles for therapeutic effects and &#x3b3;-rays for imaging, offers a promising alternative. This study developed 131I-radiolabeled silver-doped indium oxide nanoparticles (131I-Ag-In2O3 NPs) as a novel nanoplatform for enhanced permeability and retention (EPR) mediated tumor accumulation for radionuclide therapy. For comparison, undoped In2O3 nanoparticles were also radiolabeled with 131I under identical conditions to evaluate the effect of silver doping on radiolabeling efficiency and biological performance. Ag-In2O3 NPs were synthesized via photodeposition, characterized by XRD, FTIR, and TEM (revealing quasi-spherical particles of 15-25&#x202f;nm), and radiolabeled with 131I using chloramine-T, achieving a radiochemical yield of 94.02&#x202f;&#xb1;&#x202f;0.21&#x202f;% under optimized conditions (200&#x202f;&#x3bc;g/ml NPs, pH 7, 50&#x202f;&#x3bc;g/ml CAT, 30&#x202f;min at room temperature). The formulation demonstrated excellent in vitro stability (94.02&#x202f;&#xb1;&#x202f;0.21&#x202f;% % up to 24&#x202f;h). Biodistribution studies in Ehrlich ascites carcinoma (EAC) bearing mice showed preferential tumor accumulation (peak 11.2&#x202f;&#xb1;&#x202f;0.8&#x202f;% ID/g at 2&#x202f;h post-injection), prolonged retention (t&#xbd;&#x202f;=&#x202f;30.41&#x202f;h), and high tumor-to-muscle ratios (up to 22.67&#x202f;&#xb1;&#x202f;0.07&#x202f;at 24&#x202f;h), mediated by the EPR effect. These findings demonstrate favorable biodistribution characteristics, tumor accumulation, and retention of 131I-Ag-In2O3 NPs in the EAC model, supporting their potential for further investigation as a radiolabeled nanoparticle platform.

For over five decades, Colombia's armed conflict has constrained rural development, especially in the Territories Most Affected by the Armed Conflict (ZOMAC). Nonetheless, the agro-industrial sector offers significant potential for energy generation from non-conventional renewable sources, particularly biomass, estimated at over 500,000 TJ per year. This study assesses the economic feasibility of valorizing swine manure through anaerobic digestion in ZOMAC territories, promoting circular economy and sustainable development. Four operational and economic scenarios of biogas plants using upflow anaerobic sludge blanket reactors were evaluated through Net Present Value (NPV) and Discounted Payback Time (DPBT). Profitability was found to depend mainly on fiscal incentives and plant scale. Scenario 3, involving biogas upgrading to biomethane, achieved a positive NPV (0.03&#xa0;million USD) and an Internal Rate of Return (IRR) of 12.7% under Colombian tax incentives (Laws 1715/2014 and 1819/2016), with a DPBT of 7.4 years. Doubling the processing capacity improved profitability (IRR&#x2009;=&#x2009;26.8%, NPV&#x2009;=&#x2009;1.1&#xa0;million USD, DPBT&#x2009;=&#x2009;4.2 years) and made electricity generation (Scenario 4) viable (IRR&#x2009;=&#x2009;13.8%, NPV&#x2009;=&#x2009;0.16&#xa0;million USD). These findings highlight that fiscal incentives and scaling-up are decisive for achieving economic feasibility, environmental sustainability, and inclusive rural development in post-conflict Colombia.

With U.S. health systems increasingly entering partnership, acquisition, and merger agreements, the usual stated goals are improvement in quality of care and patient experience, along with improved financial performance. But attainment of these goals has been inconsistent at best. After its April 2023 acquisition of Sparrow Health, Michigan Medicine and its five-hospital system, University of Michigan Health, launched a major effort to advance business, clinical, and cultural integration across the new 11-hospital enterprise. The goal was to achieve a coordinated, integrated statewide system of care that delivered improved quality and better experience, while providing academic hospital-caliber care closer to home for patients across the state. Those efforts have led to improved financial performance. The adjusted operating margin at the former Sparrow hospitals, renamed University of Michigan Health-Sparrow (UM Health-Sparrow), increased from negative US$158 million in 2022 to positive US$28 million in 2024. Employees' response to a survey question about their level of satisfaction with UM Health-Sparrow as a place to work, measured on a 1 to 5 scale, increased from 3.54 in 2022 to 3.87 in 2024. Annual turnover of registered nurses at UM Health-Sparrow dropped from 17.4% in 2022 to 7.7% in 2024. Clinical integration, driven by the development of local clinical programs, initiatives to coordinate statewide care, and innovative technology solutions, has resulted in a higher quality of care delivered closer to home. A new neurosurgical program at UM Health-Sparrow has improved local access for patients with more complex diagnoses while also delivering higher-quality care. In the Michigan Spine Surgery Improvement Collaborative, the overall quality score increased from 63% in 2022 to 91% in 2024. For cultural integration, the keys to success have been leadership alignment, a clear vision and goals, a supportive infrastructure, strong systemwide communication, and achieving and celebrating early wins. Although the journey is ongoing, progress to date demonstrates that a carefully planned and executed strategy for system integration can yield greater operational efficiency, meaningful improvements in patient care, and progressive cultural alignment.

Distance-based methods are commonly used to reconstruct phylogenies for various applications owing to their excellent speed, scalability and theoretical guarantees. However, classical de novo algorithms are hindered by cubic time and quadratic memory complexity, making them impractical for emerging datasets containing millions of sequences. Here we present DIPPER, a distance-based tool for phylogenetic reconstruction on graphics processing units (GPUs), designed to maintain high accuracy and a low memory footprint. DIPPER employs a divide-and-conquer strategy, a placement strategy and an on-the-fly distance calculator that improve runtime and memory complexity to O(N.log(N)) and O(N), respectively, with N taxa. DIPPER also maintains a low memory footprint on the GPU that is independent of the number of taxa. DIPPER outperforms existing methods in speed and memory efficiency on both simulated and real-world datasets, enabling the reconstruction of 10 million sequences in under 7&#x2009;h on a single NVIDIA RTX A6000 GPU.

Cancer is a term that evokes global concern which extends beyond a single disease entity claiming 9.7 million lives with incidence of 20 million per year. Transforming Growth Factor-&#x3b2; Regulator 4 (TBRG4), a mitochondrial regulatory protein, has recently emerged as a molecule of interest in several malignancies. Growing evidence also highlights its involvement in carcinomas such as hepatocellular carcinoma (HCC), lung cancer, breast cancer, and oral squamous cell carcinoma (OSCC), where altered expression of TBRG4 has been associated with cancer progression. Therefore, the current study aimed to systematically review the role of TBRG4 in cancer progression. PROSPERO registration preceded the strategic searching of electronic databases MEDLINE via PubMed, Cochrane Central, Embase, and Google Scholar. Upon comprehensive full-text assessment, ten articles meeting inclusion criteria were incorporated. ROBINS-E and QUIPS tools were used for quality assessment. In majority of the studies, TBRG4 expression-at both mRNA and protein levels was elevated in tumour tissues relative to adjacent normal tissues across multiple cancer types. Statistically significant correlations were, observed between TBRG4 expression and advanced clinical stages (III and IV) of OSCC, as well as with high histological grade (IV) and advanced tumour stages (T3 and T4) of HCC. This systematic review demonstrates that TBRG4 is closely associated with tumour progression, poor differentiation, therapeutic resistance, and diminished survival outcomes across various malignancies. These insights suggest the potential role of TBRG4 serving not only as a diagnostic adjunct (early lesion stratification in oral premalignant lesion such as leukoplakia), but also as a prognostic indicator (in OSCC and HCC), a predictive biomarker (for pharmacological response in Colorectal Cancer), and possibly as a therapeutic target.

Rare undiagnosed diseases impose a substantial burden on patients, families, and health systems. Collectively they affect an estimated 300-350 million people worldwide. Of these, approximately 250 million live in low- and middle-income countries (LMICs). Many rare diseases have a genetic basis and can be diagnosed using molecular testing. However, patients in LMICs often lack access to advanced diagnostics and specialist care, leading to prolonged diagnostic odysseys and significant distress. To address this gap, the Global Genomic Medicine Collaborative (G2MC) implemented a Rare Disease Pilot Project to enable clinical genomic testing at six LMIC sites (Chile, Malaysia, Mexico, Nepal, South Africa, Sri Lanka). Using trio exome sequencing for 18 selected families, supplemented by chromosomal microarray as indicated, definitive molecular diagnoses were established in 5 families (pathogenic/likely pathogenic variants explaining the phenotype). An additional 8 families had suspected molecular diagnoses with strong phenotype correlation that require functional validation, while 5 families remained undiagnosed at the end of the pilot. The integration of genomic data into clinical decision-making enabled definitive diagnoses, precise management, and genetic counseling for these patients. The pilot also strengthened local capacity building by conducting cross-site case conferences and enabling local reanalysis of sequence data at sites with bioinformatics capabilities. This study demonstrates the feasibility, effectiveness, and adaptability of implementing exome sequencing in resource-limited settings and highlights its potential to transform rare disease diagnosis and care in LMICs.

TRICARE is the primary health insurer for US military personnel, military retirees, and their families. Between October 1, 2019 (FY2020) through September 30, 2024 (FY2024), TRICARE authorized private sector reimbursement of outpatient platelet-rich plasma (PRP) injections for knee osteoarthritis and lateral epicondylitis without the need for prior authorization, despite minimal evidence of efficacy for these conditions. We sought to describe utilization and reimbursement patterns for outpatient PRP injections covered under the TRICARE Provisional Coverage Program to illustrate potential usage patterns where PRP was generally covered without regard for scientific evidence of effectiveness. (1) What was the total number of, reimbursement for, and temporal variation of PRP injections reimbursed to nonmilitary providers during the TRICARE Provisional Coverage Program? (2) What proportion of reimbursed PRP injections met authorized use criteria under the Provisional Coverage Program? (3) What was the geographic variation in utilization and cost of PRP injections under the Provisional Coverage Program? The Military Data Repository (MDR) was queried for all paid claims by TRICARE for Current Procedural Terminology code 0232T (injection of platelet-rich plasma) administered at nonmilitary clinics between October 1, 2019, and September 30, 2024 (FY 2020 through 2024); there were 13,277 such claims. To the best of our knowledge, this is the only centralized location containing data on all such claims. Claims were excluded when the injections were performed in an inpatient setting, performed in conjunction with a surgical procedure, administered in an ambulatory surgery center, or the reason for the injection could not be ascertained from the listed ICD-10 diagnosis codes; after applying those exclusions, 95% (12,613) were further considered, encompassing 13,386 injections. Claims were considered to have "met criteria" if filed with an associated ICD-10 code for knee osteoarthritis or lateral epicondylitis. Claims were considered to have "potentially met criteria" if administered for any diagnosis of the knee or elbow. All other claims were categorized as "not meeting criteria." Mean reimbursement (amount paid by TRICARE to providers) was calculated for the total cohort and for each US state individually. The number of injections increased annually, from 657 injections in FY2020 to 4140 injections in FY2024. The mean reimbursement increased 266% over the study period from FY2020 (USD 667 per injection) to FY2024 (USD 1764 per injection). Most injections (92% [12,253 of 13,386]) definitively or potentially met TRICARE criteria for reimbursement. One clinic received more than USD 7 million in reimbursement, accounting for nearly one-third of the money reimbursed nationally. During the 5 years that outpatient PRP treatment was covered by TRICARE without preauthorization, utilization showed substantial year-on-year increases, with associated increases in reimbursement to providers. The value of these treatments is questionable given the weak evidence base for its use. The program allowed for one outlier clinic to receive millions of dollars while still technically adhering to requirements. Policymakers should consider both the efficacy of treatment and the potential for exploitation when considering coverage of newer treatments and institute administrative controls to protect against outlier behaviors. Level IV, therapeutic study.

High-throughput sequencing (HTS) allows large-scale DNA barcoding of individually tagged specimens ('megabarcoding'), but deep amplicon sequencing produces a mixture of authentic mitochondrial sequences together with nuclear pseudogenes (NUMTs), environmental and cross-sample contaminants, and sequencing artefacts. Standard approaches relying on read clustering or dominant-read selection often fail to classify these types, leading to incorrect taxonomic identifications and species counts. We developed an authentication framework by integrating abundance filtering, phylogenetic placement and taxonomic congruence. The workflow was applied to 18,533 morphospecies of tropical beetles (Coleoptera) from multiple biogeographic regions, which were imaged for family-level identification, prior to individual Illumina barcoding. Sequencing yielded >&#x2009;36&#x2009;million reads and 64,544 unique ASVs, which were evaluated against a reference phylogeny of >&#x2009;13,000 mitogenomes. Authentication succeeded for 86.5% of quality-passing specimens (15,901 ASVs). Non-authentic sequences were technical artefacts (58.0%), environmental contamination including prey DNA (14.2%), intra-individual variants (NUMTs, heteroplasmy; 11.3%) and cross-sample contamination (7.5%). Authentication success and the proportions of failure categories varied markedly across trap types, sampling campaigns, taxonomic groups and sequencing runs. We identified 930 confirmed NUMTs based on consistent co-occurrence patterns and phylogenetic proximity to authenticated haplotypes. Single-specimen HTS data contain substantial biological and technical complexity not resolved by standard filtering methods. Our pipeline-agnostic, phylogenetically informed authentication framework achieves robust recovery of validated barcodes while retaining informative secondary variants, improving the accuracy of molecular ASV data to a standard sufficient for inclusion in barcode reference databases and the phylogenetically informed DNA barcoding of tropical insects.

Gonorrhea, caused by the Gram-negative bacterium Neisseria gonorrhoeae (Ng), affects millions of people globally. The absence of a vaccine and the rising antibiotic resistance complicate infection control, highlighting the urgent need for new prophylactic and therapeutic strategies. Since partial protection against gonorrhea has reportedly been linked to vaccination with the anti-meningococcal 4CMenB vaccine, we utilized Reverse Vaccinology 2.0 to identify gonococcal antigens through characterization of monoclonal antibodies (mAbs) produced by memory B cells (MBCs) following vaccination of volunteers with 4CMenB. A mAb, named mAb_4, with cross-reactivity among Ng strains was selected for deeper investigation. Genetic and biochemical approaches revealed that the cognate antigen was NGO_1985, a protein involved in outer membrane biogenesis and stability. Notably, NGO_1985 is the ortholog of the N. meningitidis (Nm) GNA_2091 protein, which is included as a fusion protein in the 4CMenB vaccine and contributes to stability and immunogenicity. The NGO_1985 epitope recognized by mAb_4 was predicted in silico and experimentally confirmed by Hydrogen Deuterium Exchange Mass Spectrometry. This study enhances our understanding of the molecular basis for the cross-reaction/protection conferred by 4CMenB and might guide future developments of antibody cocktail therapeutics, protein-based vaccines, and in vivo research.

Kidney transplantation stands as a pivotal treatment for end-stage renal disease, offering improved survival and quality of life. In Brazil, the first documented kidney transplant was performed in 1964, marking the beginning of a complex historical trajectory characterized by technical advances and persistent regional disparities. Therefore, this manuscript aimed to analyze the spatial and temporal distribution of kidney transplants in Brazil from 1964 to 2023, with particular emphasis on the association between infrastructure, logistics, and socioeconomic factors and access to care. This ecological time series study followed STROBE guidelines and used data from the National Transplant System, DATASUS, the Brazilian Association of Organ Transplants, and published literature. Descriptive and inferential statistical analyses were conducted to assess transplant trends, regional disparities, and correlations with socioeconomic indicators such as the Human Development Index. Statistical tests were performed using Jamovi, GraphPad Prism, and QGIS software. Between 1964 and 2023, 130,556 kidney transplants were performed in Brazil. The transplant rate showed a significant long-term increase (average annual percent change, 7.14%), with inflection points marking periods of expansion, plateau, and decline, particularly after 2013. Living donor transplants increased until 2006, then declined significantly. All macroregions showed rising transplant rates over time, but the Southeast and South regions accounted for 81% of all procedures during the years with available regional data (1964-1978 and 1997-2023), compared with only 1.3% in the North. The highest transplant rates per million population were concentrated in wealthier southern states. The study reveals a sustained national increase in kidney transplants over the decades but also underscores profound regional and socioeconomic inequalities.

Wastewater treatment plants (WWTPs) are pivotal in the dissemination of antibiotics, antibiotic resistance genes (ARGs), and human pathogenic bacteria (HPB); however, their fate across treatment units and the associated microbial metabolic responses remain poorly quantified, and current risk assessments based on relative abundance mask the true occurrence of contaminants due to biomass fluctuations. Here, we applied absolute quantification across the wastewater-sludge continuum of a large-scale WWTP (serving 9 million inhabitants) to unravel the divergent fates of 46 antibiotics, ARGs, and HPB, and to elucidate metabolic responses associated with biogeochemical cycling and xenobiotic biodegradation. The results revealed distinct phase-partitioning behaviors of antibiotics within the WWTP. Sulfonamides and macrolides predominated in the wastewater, whereas quinolones strongly partitioned into the sludge, enriching across gravity thickening, anaerobic digestion (AD), dewatering, and drying processes. The anoxic unit was a key hotspot for sulfonamides, quinolones, and associated ARG accumulation during wastewater treatment. Sludge AD effectively removed sulfonamides (44.42%-100%) and reduced the absolute abundances of sul1 and sul2 by 1.47 and 1.60&#x202f;log copies/g, respectively. Microbial absolute quantification analysis indicated that, although most potential HPB were significantly reduced during biological wastewater treatment and AD, Legionella-like amoebal pathogen HT99 was distinctly enriched. Functional prediction indicated that xenobiotic biodegradation and metabolism was most abundant in sludge AD, with enriched cytochrome P450 and monooxygenase encoding genes likely facilitated antibiotic co-metabolic pathways. Collectively, this study demonstrates that the anoxic zone and sludge processing are critical reservoirs requiring targeted optimization, and underscores the importance of absolute quantification for accurate antimicrobial resistance risk management.

Higher-risk medication use-including regimens with polypharmacy, drug-drug interactions (DDIs), and potentially inappropriate medications (PIMs)-has been linked to adverse outcomes in older adults. However, studies establishing associations between higher-risk medication use and mortality have lacked measures of organ function and considered types of higher-risk medication exposures in isolation, allowing potential confounding and overestimation of harm. We conducted a prospective cohort study of adults aged &#x2265;&#x2009;65&#x2009;years who took part in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016, with mortality follow-up through 2019. Our primary exposures were three types of higher-risk medication use: polypharmacy, DDIs, and PIMs. In primary analyses, these were defined, respectively, as follows: being on &#x2265;&#x2009;5 prescription medications (polypharmacy); using two medications with &#x2265;&#x2009;1 major DDI; and using &#x2265;&#x2009;1 prescription PIM. Exposures were determined by medication review during the baseline survey. The primary outcome was all-cause mortality. Multivariable Cox regression models estimated mortality risk associated with each type of higher-risk medication use, sequentially adjusting for sociodemographic factors and comorbidities, organ function and health behaviors, and patterns of higher-risk medication use. Among 7828 eligible participants (representing 26.5&#x2009;million adults), 54.3% experienced at least one type of higher-risk medication use: 40.0% had polypharmacy, 11.4% had a DDI, and 37.6% used a PIM. In fully adjusted models including all higher-risk medication exposures, only polypharmacy remained significantly associated with increased mortality (hazard ratio [HR] 1.38; 95% CI 1.26-1.51). Sensitivity and subgroup analyses by age and health status yielded generally consistent findings. When considering multiple types of higher-risk medication exposure, only polypharmacy was consistently and independently associated with increased mortality among older adults. These results highlight the harms of polypharmacy specifically and could help further target deprescribing interventions to the most high-risk patients.

Neuropsychiatric safety concerns, including depression and suicidal ideation, have emerged during the expanding clinical use of incretin-based therapies for type 2 diabetes mellitus (T2DM) and obesity. However, whether risks differ across successive generations of incretin-based therapies remains uncertain. This retrospective cohort study used the TriNetX Global Federated Network (>&#x2009;192 million patients). Adults with T2DM, obesity, or both initiating tirzepatide, semaglutide, or other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) between July 2022 and June 2025 were identified using a new-user design with a 12-month washout. Propensity score matching balanced demographic, clinical, and metabolic variables. Two comparisons were conducted: tirzepatide versus semaglutide and semaglutide versus other GLP-1 RAs. Follow-up included Year 1 (day 31-365) and Year 2 landmark analysis (day 366-730). Hazard ratios (HRs) for incident depression, anxiety, and suicidal ideation were estimated using Cox models. After matching, 85&#x2009;546 pairs were included for tirzepatide versus semaglutide and 80&#x2009;115 pairs for semaglutide versus other GLP-1 RAs. Tirzepatide and semaglutide showed similar risks for the composite psychiatric outcome (Year 1 HR 0.984 [95% CI 0.950-1.019]; Year 2 HR 1.002 [0.960-1.046]); a nominally higher anxiety hazard was observed with tirzepatide during Year 2 (HR 1.052 [1.001-1.106]), which should be interpreted cautiously given multiple comparisons. Compared with other GLP-1 RAs, semaglutide was associated with lower risks of depression (HR 0.811 [0.770-0.855]), anxiety (HR 0.915 [0.871-0.961]), suicidal ideation (HR 0.488 [0.339-0.702]), and the composite psychiatric outcome (HR 0.866 [0.832-0.901]) during Year 1. In real-world practice, tirzepatide and semaglutide demonstrated comparable neuropsychiatric risk profiles over 2&#x2009;years. Semaglutide was associated with lower psychiatric event rates compared with earlier-generation GLP-1 receptor agonists.

Panel count data occurs in a wide variety of applications, ranging from biomedical research to business, such as the number of accidents, product defects, and insurance claims. For such data under the FDA investigation, millions of reported adverse events (AEs) associated with thousands of drugs are monitored in the post-market drug safety surveillance systems worldwide. Evaluating the AEs of the associated drugs is an important public health concern and motivates our method. One statistical challenge in such systems is handling the excessive number of zero AE counts. Most existing methods utilize Poisson count models that cannot incorporate covariates nor account for the excessive zero counts adequately. This article proposes a novel semiparametric nonhomogeneous panel count model to detect AE signals by accounting for covariates, background AE occurrences, and excessive zero counts. The model is estimated using the Expectation-Maximization (EM) algorithm iteratively, where in each M-step, the maximization of the nonparametric component is reformulated as an optimization problem, as in the isotonic regression. The strong consistency and the asymptotic distributions of the estimators are formally derived. We conduct extensive simulation studies to evaluate the finite sample performance of the proposed method and to demonstrate the apparent advantage of the proposed method in signal detection with high power, high specificity, and sensitivity. We apply the method to a VigiBase dataset to detect the AE signals as an application of the proposed method.

While machine-learned interatomic potentials offer near-quantum-mechanical accuracy for atomistic simulations, many are material-specific or computationally intensive, limiting their broader use. Here we introduce NEP89, a foundation model based on neuroevolution potential architecture, delivering near-empirical-potential speed and high accuracy across 89 elements. A compact yet comprehensive training dataset covering inorganic and organic materials was curated through descriptor-space subsampling and iterative refinement across multiple datasets. NEP89 achieves competitive accuracy compared with representative foundation models while being three to four orders of magnitude more computationally efficient, enabling previously impractical large-scale atomistic simulations of inorganic and organic systems. In addition to its out-of-the-box applicability to diverse scenarios, including million-atom-scale compression of compositionally complex alloys, ion diffusion in solid-state electrolytes and water, rocksalt dissolution, methane combustion and protein-ligand dynamics, NEP89 also supports fine-tuning for rapid adaptation to user-specific applications, such as mechanical, thermal, structural and spectral properties of two-dimensional materials, metallic glasses and organic crystals.