Large language models (LLMs) show potential to support antimicrobial prescribing but require simulation-based, institution-specific safety evaluation prior to any consideration of clinical use. In Australia, antimicrobial prescribing represents a high-risk domain for digital decision-support systems due to patient safety and antimicrobial resistance implications. To characterise prescribing accuracy, error phenotypes and antimicrobial stewardship risk associated with a LLM that was provided with publicly available surgical prophylaxis guidelines during inference (without fine-tuning or model modification) across 20 simulated surgical scenarios. Twenty simulated surgical scenarios were tested using a LLM that was prompt-conditioned with publicly available guideline text during inference, without any fine-tuning or modification of model weights. For each case, the model generated recommendations for agent, dose, timing, re-dosing and guideline citation. Outputs were independently assessed by two local clinicians familiar with the guideline, with accuracy scored across five domains and harm classified using a modified National Coordinating Council for Medical Error Reporting and Prevention (NCC MERP) Index. Clinically significant antimicrobial prescribing risk was identified in 10% of simulated scenarios (2/20), recognising wide confidence intervals due to the small sample size. These included omission of required anaerobic coverage and failure to redose prophylaxis in prolonged procedures. Overall guideline concordance was 4/5, with perfect dose accuracy but lower performance for timing (70%) and guideline citation (45%). This study demonstrates the feasibility of constructing institutionally governed, guideline-based AI systems while identifying stewardship-relevant safety risks that currently preclude clinical use without further validation.
The Western Himalayan states of India (J&K, Himachal Pradesh, and Uttarakhand) possess substantial renewable energy resources, yet deployment remains far below potential due to region-specific barriers. This Trend Editorial critically synthesizes government data and peer-reviewed literature (2000-2025) to evaluate five renewable energy technologies (solar, hydro, wind, biomass, and geothermal) across three analytical dimensions: resource availability, deployment feasibility, and climate resilience. Our findings reveal three key insights. First, solar energy has the highest untapped potential (111 GW in J&K alone) but utilization is negligible (0.06% in J&K) except in Uttarakhand (3.42%), highlighting state-level policy disparities. Second, hydropower remains the dominant renewable source (10.5 GW installed in Himachal Pradesh) but faces growing climate risks from glacier melt and hydrological variability, favoring small-scale and run-of-river projects over large dams. Third, biomass and wind energy play niche roles, while geothermal remains largely unexplored despite promising sites (e.g., Puga Valley). Major barriers include terrain-blind subsidy mechanisms, capacity-based (rather than performance-based) policy metrics, weak institutional coordination, and the absence of an off-grid-specific framework for remote Himalayan villages. Based on this analysis, we offer a few actionable policy recommendations including terrain-adjusted subsidies, performance-based metrics, single-window clearances, a dedicated Himalayan Off-grid Renewable Mission, climate-resilient design standards, and state-specific renewable energy targets. The Western Himalayan region can transition from a clean energy frontier to a clean energy leader, but only through targeted, region-sensitive, and climate-informed policy reforms.
Highly efficient Si-O bond-forming macrocyclization has recently emerged as a powerful platform for the selective construction of structurally precise macrocycles. Here, we demonstrate that modification of the diol linker structure completely alters the preferred reaction outcome. Whereas the previously reported Ar-O-Si-O-Ar system exclusively afforded cyclic tetramers, introduction of methylene spacers into the linker overturns this inherent selectivity to achieve the selective formation of cyclic trimers in high yields. A series of silyl ether macrocycles were synthesized with outstanding efficiencies even at high concentrations. These results show that the outcome of Si-O-based macrocyclization can be effectively tuned by rational linker design.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects the upper and lower motor neurons and leads to progressive paralysis. More than 40 genes have been implicated in familial ALS, which represents about 10% of ALS cases. Some genes, including C9orf72, SOD1, FUS and TARDBP are undoubtedly considered causative, but many others have uncertain pathogenicity and low penetrance. Here, we described the cases of two siblings affected by ALS and carrying both an ATXN2 heterozygous 32 CAG trinucleotide repeat expansion and a novel NEK1 heterozygous c.1674_1677dup. The segregation of both variants in this large family with thirteen siblings may support a role for these variants as susceptibility alleles within an oligogenic model. Our review of the literature suggests that NEK1 variants are frequently found in combination with other variants and repeats expansion in the ATXN2 gene appears to be more associated with monogenic ALS, but also frequently combined with C9orf72 repeat expansion.
This Perspective discusses female biology and resilience regarding Alzheimer disease despite pathologic risk.
Ebola virus disease (EVD) causes multiorgan damage and is highly fatal. EVD's neurological impact among survivors remains poorly characterized due to limited neurological assessment capabilities in the remote regions where most outbreaks occur. To characterize neurological sequelae in EVD survivors over more than 7 years' longitudinal follow-up. Under the Ebola Natural History Study (PREVAIL III; PIII), the Neurology Study of PIII was a prospective longitudinal cohort study in Liberia of adult Ebola survivors and control individuals conducted from September 2015 to March 2023 at the Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) site at John F. Kennedy Medical Center in Monrovia, Liberia. Data were analyzed from April 2023 to September 2025. Neurological evaluations were performed by trained neurologists biannually. Questionnaire and neurological examination data were collected on case report forms. Neurological symptom prevalence and neurological examination scores were compared to those of control individuals. Tests for differences between survivors and control individuals were conducted using generalized linear mixed-effects models controlling for age and sex. Overdispersed Poisson models were used to test for computed neurological examination score differences. Neurological examination scores were developed for this study, representing the cumulative abnormalities on neurological examinations, denoted on standardized case report forms, with the general neurological examination score representing all examination abnormalities and the central nervous system score representing the central nervous system-specific abnormalities on examination. Analysis after serologic testing included 148 Ebola antibody-positive survivors (mean [SD] age, 34.8 [10.5] years; 74 [50%] female) and 81 antibody-negative contacts (mean [SD] age, 35.8 [12.6] years; 41 [51%] female). During acute infection, survivors reported headaches, altered mental status, and strokelike symptoms or meningoencephalitis (rarely). Survivors had significant neurological sequelae involving the entire neuraxis: cognitive dysfunction (83 [56.1%]), persistent headaches (98 [66.2%]), sleep abnormalities (40 [27.0%]), depression (73 [49.3%]), sexual dysfunction (48 [32.4%]), tremor (18 [20.3%]), fatigue (71 [51.1%]), cranial nerve abnormalities (60 [40.5%]), and sensory abnormalities (45 [30.4%]). Over 7 years' follow-up, most survivors demonstrated improvement in neurological status. The final visit included 115 survivors (77.7%) and 61 close contacts (75.3%). Persistent symptoms at final evaluation in survivors compared to contacts were memory loss (66 [57.4%] vs 16 [26.2%], respectively; P < .001), irritability (42 [36.5%] vs 9 [14.8%], respectively; P = .006), and trouble concentrating (34 [29.6%] vs 6 [9.8%], respectively; P = .002). The findings indicate that Ebola virus infection is associated with neurological complications in survivors, with increased health care burden and socioeconomic consequences. These neurological issues generally improved with time, but some persisted long-term. Close neurological follow-up of EVD survivors may be warranted.
A novel, eco-friendly synthesis method for producing dithiocarbamates and rhodanines is presented, offering a greener alternative to conventional methods. This one-pot, three-component reaction involves the reaction of simple cyclic and acyclic aliphatic amines, carbon disulfide, and N-substituted maleimides under mild, ambient conditions. Importantly, the method proceeds without metal catalysts, bases, or additional additives, helping to minimize waste and reduce environmental impact. It delivers excellent efficiency, rapidly producing biologically relevant dithiocarbamate and rhodanine derivatives in high yields and with much shorter reaction times. Using commercially available starting materials further enhances accessibility and lowers costs, making this approach highly suitable for both research and industrial applications. This study highlights how green chemistry principles can enable sustainable and convenient routes for synthesizing important dithiocarbamate and rhodanine derivatives.
Patients with cancer are routinely prescribed extended-spectrum antibiotics despite overall low multidrug-resistant organism (MDRO) prevalence. Evidence for effective strategies to reduce antibiotic overuse in this population is limited. To evaluate the association of computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates with empiric extended-spectrum antibiotic use in patients with cancer. This secondary analysis of the 4 Intelligent Stewardship Prompts to Improve Real-Time Empiric Antibiotic Selection (INSPIRE) cluster randomized clinical trials identified non-critically ill hospitalized adults (aged ≥18 years) with discharge diagnosis codes for hematologic or solid organ malignant tumors in the INSPIRE pneumonia, urinary tract infection (UTI), abdominal, and skin and soft tissue infection (SSTI) trials. Each trial evaluated the effect of CPOE prompts that used real-time patient-specific electronic health record data to estimate MDRO infection risk for patients prescribed extended-spectrum antibiotics during the first 3 hospital days; the prompt recommended standard-spectrum antibiotics when the risk of antibiotic-resistant infection was less than 10%. Extended-spectrum antibiotic days of therapy were evaluated using as-randomized, adjusted difference-in-difference analyses with generalized linear mixed-effects models and clustering by patient, hospital, and period. Days to intensive care unit transfer, hospital length of stay, hospital readmissions, and in-hospital mortality were also assessed. In all trials, 36 861 patients (mean [SD] age, 69.0 [13.6] years; 19 076 [52%] female), including 18 272 baseline and 18 589 intervention patients, had cancer. Extended-spectrum antibiotic days of therapy decreased by 27% (rate ratio [RR], 0.73; 95% CI, 0.67-0.80; P < .001) in the pneumonia trial, 24% (RR, 0.76; 95% CI, 0.68-0.84; P < .001) in the UTI trial, 17% (RR, 0.83; 95% CI, 0.74-0.92; P < .001) in the SSTI trial, and 24% (RR, 0.76; 95% CI, 0.69-0.84; P < .001) in the abdominal infection trial. Pre-post changes in hospital length of stay, intensive care unit transfers, readmissions, and in-hospital mortality were similar in the 2 groups. In this secondary analysis of randomized clinical trials, an antibiotic stewardship bundle that included CPOE prompts recommending standard-spectrum antibiotics for patients at low risk for antimicrobial-resistant infections was associated with reduced extended-spectrum antibiotic use in non-critically ill patients with cancer who were hospitalized with community-acquired pneumonia, UTI, SSTI, or abdominal infection, without observed differences in safety outcomes. The findings support scalable, low-burden strategies to improve antimicrobial use in patients with cancer, a population with limited evidence to guide stewardship. ClinicalTrials.gov Identifiers: NCT05423756, NCT05423743, NCT03697070, NCT03697096.
This article is an ethnography of the Hitnü, a nomadic Indigenous people who, due to killings and threats, sought refuge in the city of Arauca, on the border with Venezuela (northeastern Colombia). It examines the urban experience of poverty and exclusion in a context of Indigenous rights and differentiated policies offered to the displaced and Indigenous peoples and demonstrates how different forms of violence affect their health and limit effective responses to illness. A four-month ethnographic study (2023-2024) was carried out, during which one of the authors lived with 68 members (12 families) of the El Alcaraván settlement in Arauca, Colombia. The data provide insight into the settlement's living conditions, the experience of illness in the urban context, the search for medical care, and the manifestations of violence. Respiratory infections and diarrhea are common among the Hitnü, and cases of tuberculosis and Chagas disease were also identified. So-called "mild illnesses" are managed through family-based self-care and treatment provided by the cacique, whereas "difficult illnesses" require biomedical intervention. Structural violence shapes both the burden of disease and the ways the Hitnü treat their ailments, particularly due to food insecurity, lack of drinking water, and inadequate sanitation. Venezuelan migrants, despite being foreigners, receive greater humanitarian assistance, generating tensions with the Hitnü. Physicians' practices tend to be hegemonic, highly medicalized, and revictimizing. Health services must be grounded in the actual needs of the Hitnü and guided by an intercultural approach based on the findings of this study. Ensuring a safe territory would prevent the reproduction of direct, structural, and symbolic violence, and reduce health inequities.
Renal fibrosis is the final common pathological outcome of chronic kidney disease and is characterized not only by excessive extracellular matrix (ECM) deposition but also by profound and persistent alterations in tissue mechanics. Among emerging mechanosensors, the mechanosensitive ion channel Piezo1 has gained attention as a direct transducer of mechanical forces into intracellular calcium signaling. This review reframes renal fibrosis as a self-reinforcing mechanobiological process driven by an ECM-Piezo1 feedback loop, rather than a purely biochemical cascade. In the kidney, pathological mechanical cues including matrix stiffening, tissue stretch, and blood pressure activate Piezo1 in tubular epithelial cells, mesangial cells, fibroblasts, and immune cells. Piezo1-mediated Ca2⁺ influx interfaces with integrin-based adhesion complexes, cytoskeletal tension systems, and canonical profibrotic signaling pathways, thereby amplifying extracellular matrix synthesis, epithelial-mesenchymal transition, inflammatory activation, and metabolic dysregulation. These interactions establish a self-reinforcing mechanobiological loop in which ECM stiffening enhances Piezo1 activation, further promoting matrix remodeling and tissue rigidity. This review summarizes current knowledge of ECM composition and mechanical remodeling in the kidney, delineates the molecular mechanisms underlying Piezo1-dependent mechanotransduction, and discusses the compartment-specific roles of the ECM-Piezo1 axis in glomerular, tubular, and immune cell populations. We further highlight emerging therapeutic strategies targeting this axis, including pharmacologic modulation of Piezo1 activity, gene- and cell-based approaches, and biomaterial-guided mechanical reprogramming. Here, we provide a kidney-centered, compartment-specific synthesis of ECM-Piezo1 mechanotransduction, highlighting how progressive matrix stiffening perpetuates compartment-specific pathological signaling and revealing precision intervention points beyond global Piezo1 blockade.
Cancer diagnoses impact adherence to antidiabetic medications, but limited research has focused on patients with prostate cancer and type 2 diabetes (T2DM). We investigated adherence trajectories to oral antidiabetic medications one year before and after a prostate cancer diagnosis and identified risk factors. This retrospective cohort study used the 2011-2021 MarketScan Commercial and Medicare Supplemental databases. We included newly diagnosed prostate cancer patients with T2DM with continuous insurance enrollment. We applied group-based trajectory modeling with a beta distribution to evaluate adherence patterns before and after prostate cancer diagnosis. Model covariates included age, total number of medications, number of antidiabetic medications, the Charlson Comorbidity Index (CCI), cost, insurance type, and complicated diabetes from the year before diagnosis. Metastasis and cancer treatments were included in the model after diagnosis. The study included 7864 patients (mean age = 74.5 ± 7.1). Three adherence trajectories were identified before diagnosis: consistently high adherence, steady decliners, and consistently low adherence. After diagnosis, a fourth trajectory revealing a moderate decline emerged. Over half (61.2%) changed adherence patterns after diagnosis. Among those with consistently high adherence before diagnosis, 57.8% transitioned to a lower adherence trajectory. In contrast, 58.5% of steady decliners and 57.6% of consistently low adherents transitioned to a higher adherence trajectory after diagnosis. Predictors of high adherence included older age, fewer antidiabetic medications, lower CCI, and complicated diabetes before diagnosis. After diagnosis, fewer antidiabetic medications and complicated diabetes remained predictive of high adherence. Patterns of adherence to oral antidiabetic medications undergo substantial changes after a prostate cancer diagnosis. Targeted interventions are needed to support and facilitate effective diabetes management in this population.
Non-small cell lung cancer (NSCLC) is a particularly aggressive subtype of lung cancer characterized by early metastasis and poor prognosis. Lung adenocarcinoma (LUAD) represents the most prevalent histological subtype within NSCLC. The development of brain metastases in LUAD is frequently associated with a severely unfavorable outcome. While extrachromosomal circular DNA (eccDNA) has been implicated in various tumors, its specific role in brain metastasis related to LUAD remains largely unexplored. EccDNA associated with brain metastasis in LUAD profiles was collected through sequencing 20 cerebrospinal fluid (CSF) samples from both control subjects and LUAD patients with brain metastases, focusing on those with Epidermal Growth Factor Receptor (EGFR) mutations, rare mutations, or no mutations at all. The genomic characteristics of the eccDNAs were examined across groups utilizing a circular map. Differentially expressed eccDNAs were subjected to analysis and functional annotation by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), employing eccDNA-related genes. The distribution of eccDNAs within the genome is intricately associated with gene density. We compared the genomic features of eccDNAs between the subtypes of control and brain metastatic LUAD. Differentially expressed eccDNAs in CSF were identified, and subsequent GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated their functional relevance in each group. Our findings offer initial insights into the features of CSF-enriched eccDNAs across LUAD subtypes with varying pathogenic mechanisms, emphasizing their potential as diagnostic and prognostic indicators for LUAD.
A rapid method for quantifying the niacin metabolite 1-methylnicotinamide (1-MNA) in human blood is required to address the limitations of existing low-throughput techniques such as mass spectrometry. In previous studies, we demonstrated that supramolecular pillar[6]arenes (P6As) bearing either carboxylate groups (P6AC) or sulfonate groups (P6AS) functioned as "turn-off" fluorescent sensors for 1-MNA detection in urine by photoinduced electron transfer (PET). However, because the concentration of 1-MNA in blood is very low, PET-based detection in aqueous solutions was insufficient for reliable quantification on its own. Here, we report that phosphonate-functionalized P6A (P6AP) in 90% acetonitrile formed aggregates with columnar morphology, which was associated with markedly enhanced detection sensitivity for 1-MNA. Under these conditions, aggregation-induced emission (AIE) resulted in increases in the fluorescence intensity, photoluminescence quantum yield, and photoluminescence lifetime. The addition of 1-MNA suppressed the formation of columnar aggregates of P6AP, and this was accompanied by decreases in the fluorescence intensity, photoluminescence quantum yield, and photoluminescence lifetime. This solvation-dependent fluorescence response substantially improved the detection sensitivity for 1-MNA, enabling its detection in human blood. By contrast, in 80% acetonitrile, P6AP showed AIE but did not exhibit similar columnar aggregates or increase the sensitivity. Overall, the aggregation-state-associated enhancement of the fluorescence response provides a functional framework that enhances fluorescence-based detection and represents a promising platform for extension to a broad range of biologically relevant analytes.
Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.
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The development of hybrid metal nanoparticles (NPs) for use as computed tomography (CT) contrast agents is a promising area of research. Achieving optimal in vivo performance of imaging for NPs is challenging and depends on their geometry, materials properties, bioreactivity, and biocompatibility. In this study, we designed and developed a novel CT contrast agent composed of gold nanoparticles (AuNPs) coordinated on the surface of bismuth sulfide-core nanorods (Au@Bi2S3 NRs) utilizing a solvothermal synthesis approach. We conducted solid-state characterization of Au@Bi2S3 NRs, demonstrating their structural configuration, excellent stability, uniformity, and high crystallinity. We also tested their biocompatibility with mesenchymal stem cells and found that they were well tolerated at lower tested concentrations, with reduced viability observed at higher concentrations. To evaluate the imaging potential of Au@Bi2S3 NRs, we tested them in small animals using CT imaging. Our results showed contrast enhancement in soft tissues, indicating the retention of the particles at these locations with no local inflammatory responses. Taken together, our study provides a proof-of-concept for the robust synthesis and use of Au@Bi2S3 NRs as effective CT imaging contrast agents. Future work will explore the potential to functionalize Au@Bi2S3 NRs with therapeutic molecules for theranostic applications.
Short-chain fatty acids (SCFAs) are immunometabolites produced by the gut microbiome. In animal models, SCFAs affect traumatic brain injury (TBI) severity by modulating the immune response and serving as an energy source. The goal of this study was to assess whether SCFAs are associated with functional outcome in adult patients with moderate-to-severe TBI (msTBI). Prospective cohort study. Urban Trauma Center. Adults (age ≥ 15 yr) who had TBI with Glasgow Coma Scale 3-12, intracranial hemorrhage on head CT scan, and at least one reactive pupil. Blood samples had to be collected within 3 hours of trauma. None. Univariate and multivariate analyses demonstrated that plasma SCFAs were associated with better functional outcomes at discharge and 6 months, an association driven primarily by differences in plasma acetate and propionate. K-means clustering of acetate and propionate levels identified two patient clusters with distinct discharge and 6-month functional outcomes but similar clinical, biomarker, and radiographic injury severity. Cluster 1 (n = 47) had higher SCFA levels compared with cluster 2 (n = 76) and cluster 1 had more favorable outcomes at discharge (Glasgow Outcome Scale 4-5: 83% vs. 55%; p = 0.003) and 6 months (Extended Glasgow Outcome Scale 4-8: 78% vs. 45%; p = 0.005). Multivariable logistic regression adjusting for the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)lab model identified an independent association between the SCFA cluster and functional outcome at discharge (p = 0.001) and 6 months (p = 0.03). Adding the SCFA cluster to the IMPACTlab model improved the area under the receiver operating characteristic curve for the prediction model for a favorable outcome. Our study suggests that SCFA levels are associated with functional outcome after msTBI. Future studies will focus on identifying mechanisms through which SCFAs may improve msTBI outcomes and what drives interpatient variation in their levels, which could position SCFAs as prognostic biomarkers and therapeutic targets in TBI.
Programmed death-ligand 1 (PD-L1) expression assessed by the combined positive score (CPS) is required for eligibility to first-line pembrolizumab-based therapy in metastatic triple-negative breast cancer (mTNBC). However, the predictive value of CPS beyond treatment eligibility, particularly for disease control, response kinetics and response durability in real-world practice, remains uncertain. This study evaluated the association between CPS analyzed as a continuous variable and clinical outcomes in a Polish real-world mTNBC population. This multicenter retrospective study included patients with PD-L1-positive (CPS ≥ 10) mTNBC treated with first-line pembrolizumab plus chemotherapy across 13 oncology centers in Poland (2022-2025). CPS was assessed locally and primarily analyzed as a continuous variable with exploratory categorical analyses performed for descriptive and visualization purposes. Primary endpoints included objective response rate (ORR), disease control rate (DCR), and progression as best response. Secondary endpoints were time to best response (TTBR) and duration of response (DoR). Seventy-two patients were eligible for analysis. Median age was 57 years (IQR 48-67) and median CPS was 20 (IQR 15-50). After a median follow-up of 11.6 months, ORR was 48.6% and DCR was 88.9%. CPS did not differ between patients achieving ORR versus no ORR (p = 0.58) or DCR versus no DCR (p = 0.56), nor was it associated with progression as best response. CPS showed no correlation with TTBR (ρ = 0.02, p = 0.9) or DoR (ρ = -0.33, p = 0.05). In univariable analysis, CPS was not associated with PFS. However, in multivariable Cox regression, CPS showed a statistically significant association with PFS, although the effect size was minimal (HR 1.01 per CPS unit). In real-world PD-L1-positive mTNBC, CPS was not significantly associated with response outcomes. Although statistically linked to PFS, the effect was minimal and likely not clinically meaningful, supporting its role as a threshold-based rather than quantitative biomarker.
Prognosis of marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains poor, even after R0 resection. JCOG0405 established preoperative cisplatin plus S-1 as a provisional standard of care in Japanese guidelines, based on a favorable 3-year overall survival (OS) of 58.8%. We report the 3-year survival outcomes of JCOG1704, a phase II trial evaluating preoperative docetaxel, oxaliplatin, and S-1 (DOS) for marginally resectable gastric cancer with ELM, following promising short-term outcomes. Patients with histologically confirmed HER2-negative gastric adenocarcinoma and bulky nodal (BN) involvement and/or para-aortic node (PAN) metastasis were eligible. Patients received three cycles of DOS (docetaxel 40 mg/m2, day 1; oxaliplatin 100 mg/m2, day 1; S-1 80-120 mg/m2, days 1-14) every 3 weeks, followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year. Between December 2018 and March 2022, 47 patients (BN only, 20; PAN only, 17; both, 10) were enrolled. At the data cutoff date (May 2025), the 3-year OS and progression-free survival (PFS) were 86.7% (95% CI 72.7-93.8%) and 75.6% (95% CI 60.2-85.6%), respectively, among 46 eligible patients. Among 42 patients who underwent R0 resection, the 3-year relapse-free survival (RFS) was 78.6% (95% CI 62.9-88.2%). In subgroup analyses, the 3-year OS/PFS/RFS were 85.0%/75.0%/77.8% in BN only, 93.8%/81.3%/86.7% in PAN only, and 77.8%/66.7%/66.7% in both. Preoperative DOS for gastric cancer with ELM yielded unprecedentedly favorable 3-year survival outcomes and was considered a provisional standard of care without a phase III trial within our JCOG community.
Older adults are an important group affected by both non-communicable diseases (NCDs) and ambient fine particulate matter pollution (ambient PM2.5). This study aimed to estimate the disease burden of NCDs attributable to ambient PM2.5 among adults aged 65 years and older from 1990 to 2021 globally, and forecast to 2031. The data were extracted from Global Burden of Disease Study (GBD) 2021 project. The estimated annual percentage change (EAPC) was used to measure the temporal trend. The Bayesian APC model was employed to predict the disease burden. In 2021, there were an estimated 3.32 million NCDs deaths and 56.30 million disability-adjusted life years (DALYs) attributable to ambient PM2.5 among older adults, globally, with cardiovascular diseases (CVDs) being the leading cause. From 1990 to 2021, the age-standardized mortality rate (ASMR) and age-standardized DALYs rate (ASDR) showed a downward trend, with EAPC of -0.33 (95% CI: -0.45-0.21) and -0.17 (95% CI: -0.2-0.15). But the numbers of deaths and DALYs increased by125.56% and 127.05%, respectively. Males, elderly and the middle the Socio-demographic Index (SDI) region had a greater burden. Finally, only despite a slight increase in both ASMR and ASDR in the next decade, the numbers of deaths and DALYs would increase by over 50%. The numbers of deaths and DALYs for NCDs attributable to ambient PM2.5 among older adults showed an upward trend globally in the past 31 years, and projected to increase in the next decade. Therefore, it is necessary to introduce targeted policies.