搜索结果：Chronic diseases and translational medicine

There were well-documented changes in health care use during the COVID-19 pandemic. Little is known about whether there were any associated decreases in claims-based comorbidity ascertainment that might have relevance to health services and policy research. To quantify differences in claims-based comorbidity assessment in Medicare beneficiaries pre- vs post-COVID-19. This cross-sectional study analyzed data from the 30 Chronic Conditions Warehouse 1- or 2-year lookback claims algorithms to ascertain each comorbidity with exact date ranges for all fee-for-service (FFS) and Medicare Advantage (MA) beneficiaries. Data were analyzed from April 2025 to April 2026. The first quarter (Q1) of 2019 and 2022 were evaluated as pre- and post-COVID-19, respectively. The main outcomes were comorbidities per beneficiary and association between each comorbidity and mortality in 2019 vs 2022. The changes in prevalence of each comorbidity between 2019 and 2022 were analyzed and fit models within disjoint population subgroups were combined via multilevel meta-analysis models to determine whether each comorbidity's association with mortality changed over time. This study included 59 514 042 beneficiaries in 2019 (32 351 732 females [54.4%]; 50 814 834 aged 65 years or older [85.4%]) and 63 202 599 beneficiaries in 2022 (34 377 560 females [54.4%]; 55 197 435 aged 65 years or older [87.3%]). The mean number of coded comorbidities per beneficiary decreased from 3.85 to 3.62 for FFS and 4.54 to 4.39 for MA (-0.15) between 2019 and 2022. In FFS, 19 comorbidities (63.3%) decreased, 2 (6.7%) were unchanged, and 9 (30%) increased. In MA, 14 comorbidities (46.7%) decreased, 7 (23.3%) were unchanged, and 9 (30%) increased. In multivariable analyses pooled across FFS and MA, 11 comorbidities (36.7%) were more positively associated with mortality, and 4 (13.3%) were more negatively associated with mortality in Q1 2022 than in Q1 2019. Coded levels of many comorbidities in Medicare were lower postpandemic than prepandemic, and the association of these codes with mortality changed. This suggests that across the COVID-19 pandemic comorbidity capture was affected by utilization changes, and the association between comorbidities and mortality changed as a result. Analyses that include immediately pre- or post-COVID-19 data and condition inferences on membership in utilization-based disease groups, or use claims-based risk adjustment, may be subject to bias.

Cardiovascular disease increases risks of chronic kidney disease (CKD) progression and mortality in type 2 diabetes. The study sought to assess semaglutide effects on kidney and survival outcomes by baseline cardiovascular status in the FLOW trial. Participants with type 2 diabetes and CKD were randomized to once-weekly subcutaneous semaglutide 1.0 mg vs placebo. Baseline subgroups included atherosclerotic cardiovascular disease (ASCVD), heart failure, and high total cardiovascular disease risk without established cardiovascular disease (10-year PREVENT [Predicting Risk of cardiovascular disease EVENTs] score &#x2265;20%). The primary outcome was &#x2265;50% estimated glomerular filtration rate (eGFR) decline, eGFR <15 mL/min/1.73 m2, dialysis, transplantation, and kidney or cardiovascular death. All-cause death was a confirmatory secondary outcome. At baseline, 1,198 (33.9%) of 3,533, 678 (19.2%) of 3,532, and 1,329 (66.5%) of 2,000 participants had ASCVD, heart failure, or high total cardiovascular disease risk in those without established cardiovascular disease, respectively. Semaglutide reduced the primary outcome risk in subgroups with (119 of 593 vs 146 of 605) or without (212 of 1,174 vs 264 of 1,161) ASCVD (HR: 0.80; 95% CI: 0.63-1.02; and HR: 0.74; 95% CI: 0.62-0.89, respectively; P for interaction = 0.62), with (67 of 342 vs 88 of 336) or without (264 of 1,424 vs 322 of 1,430) heart failure (HR: 0.67; 95% CI: 0.49-0.93; and HR: 0.79; 95% CI: 0.67-0.93, respectively; P for interaction = 0.40), and with (134 of 675 vs 168 of 654) or without (44 of 331 vs 58 of 340) high total cardiovascular disease risk (HR: 0.73; 95% CI: 0.58-0.91; and HR: 0.73; 95% CI: 0.49-1.08, respectively; P for interaction = 0.99). Numbers needed to treat to prevent 1 primary kidney outcome at 3 years were 22, 13, and 17 in the ASCVD, heart failure, and PREVENT score &#x2265;20% subgroups, respectively. Semaglutide also reduced risks of all-cause death with (99 of 593 vs 121 of 605) or without (128 of 1,174 vs 158 of 1,161) ASCVD (HR: 0.82; 95% CI: 0.63-1.07; and HR: 0.78; 95% CI: 0.62-0.99, respectively; P for interaction = 0.79), with (64 of 342 vs 79 of 336) or without (163 of 1,424 vs 200 of 1,430) heart failure (HR: 0.75; 95% CI: 0.54-1.05; and HR: 0.81; 95% CI: 0.66-0.99, respectively; P for interaction = 0.74), and with (73 of 675 vs 98 of 654) or without (23 of 331 vs 28 of 340) high total cardiovascular disease risk (HR: 0.71; 95% CI: 0.52-0.95; and HR: 0.82; 95% CI: 0.47-1.43, respectively; P for interaction = 0.63). Semaglutide improved kidney and survival outcomes in type 2 diabetes with CKD, irrespective of established ASCVD, heart failure, or high total cardiovascular disease risk. (Evaluate Renal Function with Semaglutide Once Weekly [FLOW]; NCT03819153).

Chronic diseases are the leading causes of morbidity and mortality worldwide and impose a substantial and long-lasting burden on individuals, families, communities, and healthcare systems. In Australia, more than 47% of the population had at least one chronic condition in 2018, and the prevalence rose sharply with age: approximately 80% of adults aged 65 and over lived with one or more chronic diseases. These conditions are complex and driven by multiple factors, with modifiable behavioral risks such as poor diet, physical inactivity, tobacco use, and harmful alcohol consumption playing a major role. Although notable progress has been made since the implementation of the National Strategic Framework for Chronic Conditions 8 years ago, the overall burden of chronic diseases persists at a significant level. This ongoing burden highlights the need for more targeted evidence-based public health interventions that address these modifiable risk factors to reduce the prevalence of chronic diseases and improve population health outcomes.

Glutathione (GSH), the most abundant intracellular antioxidant, plays a central role in maintaining redox homeostasis, regulating immune responses, and protecting cellular integrity. In chronic diseases such as type 2 diabetes mellitus (T2DM), GSH deficiency is a consistent hallmark, contributing to oxidative stress, mitochondrial dysfunction, inflammation, and progressive organ damage. This review critically examines the efficacy and safety of GSH supplementation and precursor strategies, synthesizing evidence across mechanistic studies, clinical trials, and translational research. In T2DM, GSH augmentation has been linked to improved insulin sensitivity, reduced oxidative damage, and better microvascular outcomes, although findings remain preliminary and heterogeneous. Safety profiles across populations are highly favorable, with gastrointestinal discomfort being the most reported adverse effect and serious toxicities rare. Importantly, both acute and chronic studies reinforce the compatibility of GSH and its precursors with standard antiretroviral and antidiabetic therapies. Despite this encouraging data, significant research gaps remain. Standardization of biomarkers, dose-response mapping, and long-term outcomes are urgently needed to move from proof-of-concept to clinical trials. Future directions include integrating mechanistic endpoints such as mitochondrial function and multi-omic profiling, exploring targeted delivery systems, and embedding implementation science to ensure real-world feasibility and equity. Collectively, the emerging evidence supports GSH-centered strategies as promising adjuncts for oxidative stress-driven chronic disease. Rigorous, well-designed trials are now required to define their definitive role in clinical care.

Chronic eosinophilic pneumonia is a rare inflammatory lung disease that typically responds to systemic glucocorticoids but is frequently complicated by relapses and treatment-related toxicity. In recent years, monoclonal antibodies targeting the interleukin-5 (IL-5) pathway have emerged as effective glucocorticoid-sparing therapies in relapsing or glucocorticoid-dependent chronic eosinophilic pneumonia. Alongside these advances, a substantial proportion of patients develops progressive fibrotic changes over time, challenging the traditional view of chronic eosinophilic pneumonia as a fully reversible condition. This narrative review summarises current clinical evidence on the use of anti-IL-5/IL-5 receptor subunit &#x3b1; biologicals in chronic eosinophilic pneumonia, examines the emerging phenotype of fibrotic chronic eosinophilic pneumonia, and discusses the mechanistic links between eosinophilic inflammation and pulmonary fibrosis. We also review experimental and clinical data implicating eosinophils, type 2 cytokines, epithelial alarmins and extracellular traps in fibroblast activation and extracellular matrix deposition, providing a biological rationale for a continuum from inflammation to irreversible lung remodelling. Available data on the use of IL-5-targeted therapies in fibrotic disease are limited, and no prospective studies have specifically addressed this patient population. Conversely, antifibrotic agents such as nintedanib have demonstrated efficacy in progressive fibrosing interstitial lung diseases but have been rarely studied in eosinophilic lung disorders. We propose a phenotype-adapted therapeutic framework in which sustained control of eosinophilic inflammation aims to prevent fibrotic progression in early disease, while antifibrotic therapy may be considered in patients with established or progressive fibrosis. Fibrotic chronic eosinophilic pneumonia thus represents a clinical entity at the crossroads between inflammation and fibrosis, requiring individualised management strategies and dedicated future studies.

Camel milk is increasingly recognized as a premium functional food, attributed to its rich nutraceutical compounds. Recent research has concentrated on the nanoscale extracellular vesicles derived from camel milk (CM-EVs), which exhibit distinctive properties. This review examines the methodologies for isolating and characterizing CM-EVs, alongside their potential health benefits in functional foods and nutraceuticals. CM-EVs have the capacity to safeguard functional proteins, noncoding RNAs, and bioactive lipids from degradation within the gastrointestinal tract, rendering them particularly suitable for incorporation into infant formulas, adult dietary supplements, and nutraceuticals targeting chronic inflammatory and metabolic disorders. Preclinical models indicate that CM-EVs can mitigate oxidative stress, enhance intestinal barrier integrity, and modulate gut microbiota, thereby contributing to the reduction in colonic injury and inflammation. Nonetheless, the majority of these findings are derived from laboratory and animal studies, highlighting a substantial deficiency in human clinical trials. Critical research gaps remain, necessitating further investigation into the elucidation of molecular mechanisms, assessment of long-term safety, evaluation of bioavailability, and compatibility with dairy processing techniques. This review underscores the significance of CM-EVs as bioactive food components and delineates research priorities, such as standardizing isolation methods, investigating food matrix integration, and providing translational evidence for their application in nutrition and preventive medicine.

Gastrointestinal symptom-specific anxiety (GSA) is increasingly recognized as an important construct in the disease experience of inflammatory bowel diseases (IBD). However, it remains unclear to what extent GSA overlaps with general anxiety in the IBD population, and whether it is associated with disability beyond general anxiety and other clinical and demographic variables. First, we examined how many patients with elevated GSA do or do not experience general anxiety, and vice versa. Second, we assessed the unique contribution of GSA to variance in IBD-related disability, keeping general anxiety, disease activity, and other variables constant. In a cross-sectional survey study, over 1000 IBD patients completed questionnaires on general anxiety (the anxiety subscale of the Hospital Anxiety and Depression Scale [HADS]), GSA (the Visceral Sensitivity Index [VSI]), IBD-related disability (the IBD Disk), and self-reported clinical disease activity (Patient-Reported Outcomes [PRO] and Manitoba IBD Index [MIBDI]) alongside a set of general demographic and clinical questions. GSA and general anxiety frequently co-occurred, but 38.0% of patients reported GSA without general anxiety. Additionally, GSA was significantly associated with IBD-related disability (P&#x2009;<&#x2009;.001) even when general anxiety, disease activity, and other variables were controlled for. Although general anxiety showed the strongest association with disability (&#x3b2;&#x2009;=&#x2009;.27), the association for GSA (&#x3b2;&#x2009;=&#x2009;0.22) was stronger than for clinical disease activity (&#x3b2;&#x2009;=&#x2009;.18) and other demographic and clinical variables. Overall, this highlights the clinical significance of GSA beyond general anxiety and disease activity in IBD.

Diabetes mellitus has been linked to cognitive impairment and Alzheimer's disease (AD). They share common pathologic pathways, including insulin resistance, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These shared mechanisms have prompted interest in repurposing antidiabetic agents as promising therapies for neurodegenerative diseases. Despite this overlap, these drugs face translational challenges, primarily due to their poor penetration across the blood-brain barrier (BBB) and, consequently, poor central nervous system (CNS) bioavailability. Nanoparticle-based drug delivery offers an alternative route to improve targeting of the CNS by increasing the drug stability and augmenting transport across the BBB. Although preclinical evidence showed promising results, the extent to which these findings translate into clinically tangible outcomes remains uncertain. This review critically evaluates the main preclinical studies on nanoparticle-mediated delivery of antidiabetic agents, with particular emphasis on AD and diabetes-associated cognitive impairment, where most available data are concentrated. We also discuss the main brain-targeting strategies, their limitations, and the translational challenges to their clinical application, particularly for conditions beyond AD, where the evidence remains sparse. Addressing these barriers is crucial for the development of nanomedicine-based approaches from bench to bedside. This review provides a critical standpoint on the field and highlights priorities for future research aimed at the effective translation of nanoparticle-enabled therapies for neurodegenerative diseases.

Abdominal aortic aneurysm (AAA) is a progressive vascular disease characterized by chronic inflammation, extracellular matrix degradation, and aortic wall remodeling, yet effective pharmacological therapies remain lacking and how macrophage state heterogeneity contributes to disease progression and defective inflammation resolution remains incompletely understood. We combined single-cell RNA sequencing of elastase-induced murine AAA with pathway, cell-cell communication, trajectory, and regulon analyses, and validated key findings in vivo by immunostaining and flow cytometry and in vitro by pharmacologic ERK inhibition, gene-expression analysis, and macrophage efferocytosis assays. Single-cell transcriptomic analysis identified four macrophage subsets in AAA, comprising Thbs1+Spp1+ inflammatory macrophages, Mrc1+Gas6+ efferocytosis-associated macrophages, Cdca8+ proliferative macrophages, and Cd36+Lpl+ lipid-handling macrophages. AAA progression was characterized by expansion of Thbs1+Spp1+ macrophages and emergence of Cdca8+ macrophages, together with relative loss of Mrc1+Gas6+ and Cd36+Lpl+ macrophages. Thbs1+Spp1+ macrophages showed inflammatory, chemotactic, oxidative stress, and metabolic remodeling signatures, whereas Mrc1+Gas6+ macrophages were enriched for efferocytosis- and homeostasis-associated features but exhibited increased apoptosis-related signals and reduced expression of Mertk, Gas6, and Igf1 during AAA progression. ERK signaling was overactivated in AAA and associated with loss of these effectors and impaired macrophage efferocytosis, whereas ERK inhibition restored Mertk, Gas6, and Igf1 expression and enhanced uptake of apoptotic cells in macrophage-line models. Trajectory and regulon analyses further suggested that inflammatory and efferocytosis-associated macrophages follow distinct state trajectories, with Maf emerging as a candidate regulator of the Mrc1+Gas6+ program. AAA is characterized by an imbalance between inflammatory and efferocytosis-associated macrophage states. ERK-associated dysfunction of Mrc1+Gas6+ macrophages may contribute to defective inflammation resolution and represents a potential therapeutic target in aneurysmal disease.

Obstructive sleep apnea (OSA) is a major public health crisis affecting nearly one billion people worldwide and is associated with significant cardiovascular and metabolic complications. The prevalence of OSA is rising steadily due to the obesity pandemic and is contributed by interacting anatomical, inflammatory, and neuro-respiratory mechanisms. Continuous positive airway pressure (CPAP) remains the gold standard for the management of OSA; however, it does not address underlying obesity or weight-independent pathophysiology. Obesity is an important modifiable risk factor for OSA, as weight loss is associated with resolution/improvement of the disease. Therefore, growing evidence now supports surgical and medical management of obesity as complementary strategies to improve both body weight and apnea-hypopnoea index (AHI), prompting a paradigm shift towards integrated, multimodal care. Bariatric interventions typically achieve 25%-35% total weight loss and yield significant but variable reductions in AHI with remission rates of 50%-75%, driven by mechanical unloading, improved ventilatory control, and favorable metabolic and anti-inflammatory effects. However, it is constrained by eligibility, cost, and perioperative risks. Alternatively, Incretin-based therapies, particularly Tirzepatide, achieve 10%-22% weight loss and reduce AHI to 12-30 events per hour, securing the first regulatory approval for OSA based on the largest trial-level AHI reductions. The recent introduction of several therapeutic agents with excellent weight loss potential has reshaped the management landscape of people with obesity and OSA. This review aims to analyze the literature across surgical, endoscopic, and pharmacological interventions and OSA while proposing an individualized treatment framework integrating weight-loss pharmacotherapy with device-based and structured lifestyle strategies and surgical interventions, tailored to disease phenotypes.

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a significant risk factor for pancreatic cancer, with both diseases sharing complex metabolic and molecular underpinnings. Insulin resistance, chronic inflammation, and aberrant activation of the KRAS-mTORC1 signaling axis collectively foster a tumor-permissive microenvironment and disrupt glucose regulation. Recent advances have highlighted disulfidptosis, a novel NADPH-depletion and disulfide-accumulation-driven cell death, as a therapeutic vulnerability in KRAS-mutated, cystine-dependent tumors. This process is linked to the metabolic interplay between glutamate/glutamine and cystine/cysteine, intersecting with mTORC1 signaling and GPX4 regulation. Key regulators, including system Xc-, GPX4, and GLUT, orchestrate the interplay between insulin resistance, redox imbalance, and oncogenic signaling in T2DM-associated pancreatic cancer. High expression of cystine/glutamate antiporters (system Xc-) promotes cystine accumulation and NADPH depletion, sensitizing tumor cells to disulfidptosis under glucose deprivation. Biomarker-guided precision medicine approaches leverage SLC7A11, GPX4, and p-mTOR expression to identify patient subsets vulnerable to dual metabolic-redox disruption. Emerging therapeutic strategies focus on restricting glucose availability or manipulating antiporters to induce disulfide stress. Integration of metabolic inhibitors with immune checkpoint inhibitors induces immunogenic cell death and overcomes the immunosuppressive pancreatic tumor microenvironment. Targeting these pathways may overcome therapy resistance and improve outcomes in KRAS- or mTOR-driven malignancies. This review synthesizes mechanistic and translational insights into the cyst(e)ine-mTORC1-GPX4 axis, glutaminolysis, biomarker-guided precision medicine, and disulfidptosis, offering a foundation for future therapeutic development in T2DM-associated pancreatic cancer.

As populations age and climate variability intensifies, seasonal migration has emerged as a strategy among older adults to reduce exposure to climatic extremes and optimise living conditions. In China, millions of older adults migrate annually between cold northern and tropical southern regions, providing a natural setting to examine the health effects of seasonal migration. The Frigid-Tropical Migratory Population Health (ftMPH) cohort was established to assess the short- and long-term health effects of this migration and the underlying biological, behavioural and social pathways. The ftMPH cohort is a prospective, dynamic cohort jointly conducted in Heilongjiang (a cold region) and Hainan (a tropical region) in China, with a planned sample size of approximately 26&#x2009;000 participants. Adults aged &#x2265;60 years are recruited and classified into four subcohorts: cold-origin seasonal migrants, cold-region residents, tropical-origin seasonal migrants and tropical-region residents. Baseline assessments include questionnaires, clinical examinations, biospecimen collection and environmental exposure measurements. Each migration cycle is assessed at predefined time points spanning the departure and return phases. Migration exposure will be updated longitudinally at each follow-up interval.The primary outcome is the incidence of major cardiovascular disease events, including non-fatal myocardial infarction, coronary revascularisation, stroke and cardiovascular mortality. Secondary outcomes include non-cardiovascular mortality, chronic disease events, healthcare utilisation and ageing-related measures. Time-to-event analyses will be performed using Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) will be used to control for baseline confounding, with stabilised weights and covariate balance assessed using standardised mean differences. Longitudinal changes in repeated measures will be analysed using mixed-effects models. Ethical approval was obtained from the Ethics Review Committee of Harbin Medical University (approval No HMUIRB2024029PRE) and the Ethics Review Committee of Hainan Medical University (approval No HYMLL-2025-102). Findings will be disseminated through peer-reviewed publications, conference presentations and policy or technical reports. The ftMPH cohort is registered with the Chinese Clinical Trial Registry (ChiCTR2500102337; registered on 13 May 2025).

Brazil's Unified Health System (Sistema &#xda;nico de Sa&#xfa;de, SUS) represents one of the world's largest universal health systems and provides a unique real-world platform for integrating prevention, diagnosis, treatment, and survivorship across the cancer continuum. While One Health frameworks have traditionally focused on infectious diseases, environmental exposures, and planetary health, their application to surgical oncology and health-system innovation remains insufficiently explored. This article proposes that the SUS offers a valuable model for operationalizing One Health and population health principles in prostate cancer care by connecting environmental, social, biological, and healthcare system determinants across the patient journey. The recent incorporation of robot-assisted radical prostatectomy (RARP) into the SUS represents a critical milestone in this evolution. Beyond the adoption of an advanced surgical technology, this initiative illustrates the capacity of a universal health system to evaluate, implement, and monitor complex innovations while balancing effectiveness, equity, sustainability, and population-level impact. The Brazilian experience highlights the emergence of a learning health system in which real-world evidence, implementation science, surgical quality assessment, and health policy interact to guide innovation at the national scale. In this context, RARP serves as a case study of how technological advances can be integrated into publicly funded healthcare while generating evidence relevant to diverse populations and healthcare settings. By bridging concepts from Surgical Public Health, population health, health-systems science, implementation science, and One Health, the SUS provides a distinctive framework for understanding how surgical innovation can contribute to resilient and equitable cancer care. As translational oncology increasingly incorporates environmental, societal, and biological determinants of disease, Brazil offers important lessons on the governance, evaluation, and dissemination of high-complexity surgical technologies within universal health systems. The insights emerging from this experience may help inform future strategies to optimize prostate cancer care and strengthen health-system resilience globally.

The EAT-Lancet diet was developed to support both human health and environmental sustainability and has been linked to multiple chronic diseases. However, its associations with metabolic profiles and circulating proteins in colorectal cancer (CRC) have not been comprehensively evaluated. This study aimed to investigate the association between adherence to the EAT-Lancet diet and CRC risk and to explore potential metabolic, inflammatory, and proteomic pathways that may mediate this relationship. We included 106,944 UK Biobank participants who completed at least two 24-h dietary recalls. Cox regression models were used to assess associations between adherence to the EAT-Lancet diet and CRC risk. Mediation analyses evaluated the potential mediating roles of body mass index, inflammation, metabolites, and circulating proteins, while enrichment and single-cell analyses explored potential underlying mechanisms. During a median follow-up of 13.54 years, 1591 CRC cases were recorded. Higher adherence to the EAT-Lancet diet was associated with a 12.2%-28.9% lower risk of CRC, with the strongest effects observed in individuals with medium genetic risk. These associations remained consistent across sensitivity and stratified analyses, and dose-response relationships were detected. The potential protective effects of the EAT-Lancet diet on CRC risk were comparable to those observed for the Mediterranean diet. Nine metabolites and nine proteins were significantly associated with all EAT-Lancet indices. Mediation analyses suggested that high body mass index (9.0%-18.0%), protein score (29.2%), and low-grade inflammation (INFLA score, 4.0%) partially mediated the relationship between dietary adherence and CRC risk. Circulating protein GGT1 was negatively associated with the diet, with lower levels linked to reduced CRC risk. Single-cell analysis showed GGT1 enrichment in immune and epithelial cells within CRC tumors. Our findings suggest that greater adherence to the EAT-Lancet diet is associated with lower CRC risk and favorable metabolic and protein profiles, supporting its potential as a sustainable and economically viable dietary strategy for CRC prevention. This study is the first to comprehensively characterize the metabolic and proteomic signatures associated with adherence to the EAT-Lancet diet and to explore their potential mediating roles in colorectal cancer (CRC) risk. By integrating multi-omics analyses with dietary assessments, we identified novel molecular pathways-particularly involving GGT1 and immune-inflammatory signaling-through which the EAT-Lancet diet may influence CRC development, providing mechanistic insights that extend beyond previous epidemiologic findings.

Myocarditis is a heterogeneous inflammatory syndrome with aetiologies ranging from viral infection and drug hypersensitivity to systemic autoimmune/autoinflammatory disease and immune checkpoint inhibitor (ICI) therapy. In response to these triggers, the innate immune response and inflammasome activation can amplify myocardial injury via IL-1, providing a mechanistic rationale for IL-1 pathway inhibition as a targeted therapeutic strategy. This review synthesizes preclinical and clinical evidence for IL-1 blockade in myocarditis and related inflammatory cardiac syndromes. The immune system plays a central role in the pathogenesis of myocarditis, both in idiopathic/viral cases and in systemic autoimmune and autoinflammatory diseases (SAAD). Interleukin-1 (IL-1) has emerged as a key mediator linking inflammation to myocardial dysfunction, supported by experimental and translational evidence implicating activation of the NLRP3 inflammasome. Clinically, the randomized trial of anakinra in acute myocarditis (ARAMIS) did not improve outcomes in a largely low-risk cohort, but accumulating case reports and small series suggest potential benefit in fulminant/hyperinflammatory myocarditis and chronic active refractory myocarditis. In contrast, IL&#x2011;1 inhibitors have robust randomized and real-world evidence in recurrent pericarditis, supporting a myo&#x2011;pericardial inflammatory continuum and validating IL&#x2011;1 pathway engagement as an actionable target in selected inflammatory cardiac phenotypes. Together, these findings support the evolving concept of cardioimmunology. Current management of myocarditis remains largely supportive, with limited disease-modifying options. Anti-IL-1 therapies, particularly anakinra, have shown promising efficacy in selected severe and refractory cases, with a favourable safety profile. However, evidence is mainly derived from case reports and small series, and robust randomized data are lacking. Key clinical questions remain unresolved, including patient selection, timing of initiation, and treatment duration. Future studies should focus on identifying inflammatory endotypes and evaluating targeted immunomodulatory strategies, including in emerging settings such as ICI-associated myocarditis in which IL&#x2011;1 blockade remains investigational.

Metastasis is a major driver of treatment failure and mortality for gastric cancer, and the detailed cellular and molecular patterns driving tumor cells from the primary tumor to metastatic lesions remain poorly characterized. We analyzed single-cell RNA sequencing data from 131 samples, including 27 normal gastric tissue (NC), 48 primary gastric tumors (PT), and 56 metastatic lesions (lymph node metastasis, LNM [sample number&#x2009;=&#x2009;2]; liver metastasis, LM [sample number&#x2009;=&#x2009;9]; ovary metastasis, OM [sample number&#x2009;=&#x2009;3]; peritoneum metastasis, PM [sample number&#x2009;=&#x2009;42]), and finally generated a high-resolution cellular atlas. Using all cells, we identified 11 major cell types and characterized remodeling of T cell or natural killer cell, myeloid, and epithelial cells across primary and metastatic lesions. The depletion of cytotoxic CD8.Teff and NK cells in LNM, concomitant with enrichment of exhausted CD4.Tex cells, were observed. CD4.Treg cells were found enriched in PT but reduced in metastatic lesions. Comparison of gene expression between primary and metastasis for epithelial cells identified NAP1L1 as a consistently upregulated gene across all four distinct metastatic sites (LNM, LM, OM, and PM). In silico knockout of NAP1L1 in epithelial cells indicated the perturbation of focal adhesion and cell-substrate junction pathways and high expression of prometastatic genes, including Jun proto-oncogene, AP-1 transcription factor subunit, JunB proto-oncogene, AP-1 transcription factor subunit, and activating transcription factor 3. Our study deciphered the immune and epithelial cell dynamics of metastasis and identified NAP1L1 as a novel regulator of epithelial cell reprogramming and metastatic progression.

Metabolic syndrome (MetS) is a chronic disorder that poses a major threat to global health. Exosomes have emerged as promising biomarkers for diagnosing and monitoring chronic diseases. However, stage-specific alterations in the exosomal metabolome during MetS development remain poorly understood. This study aimed to characterize the plasma exosomal metabolome and explore candidate exosomal biomarkers in individuals with MetS. This study included 20 patients with MetS, 23 individuals with pre-MetS, and 45 healthy controls. Plasma exosomes were isolated and analyzed using untargeted liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were defined by a dual-threshold, that is, p&#x2009;<&#x2009;0.05 from t-test and variable importance in projection >&#x2009;1 from partial least squares discriminant analysis, with fold change indicating their expression changes. Further, we employed machine learning algorithms to predict MetS status. We identified 27 differential metabolites between the pre-MetS and control groups, mainly enriched in histidine metabolism and the tricarboxylic acid cycle. Of these, 12 metabolites were upregulated, and 15 were downregulated, with 1-methylhistidine and isocitrate playing central regulatory roles. Comparison between the MetS and control groups revealed 45 differentially expressed metabolites, mainly enriched in thiamine metabolism, including 13 upregulated and 32 downregulated. In the pre-MetS group, cladribine showed the highest area under the curve (AUC) (0.743, p&#x2009;<&#x2009;0.05), whereas 3-methylxanthine yielded the largest AUC (0.714, p&#x2009;<&#x2009;0.05) in the MetS group. Our study characterized stage-dependent alterations in the plasma exosome-derived metabolome in MetS and suggests that exosomal metabolomics may provide complementary molecular information on early MetS metabolic perturbations.

Cardiometabolic diseases, including diabetes mellitus, are complicated by vascular disease, a major driver of morbidity and mortality. Although hyperglycaemia contributes to vascular dysfunction, it does not fully explain the vascular complications observed in patients. Chronic low-grade inflammation and persistent release of pro-inflammatory cytokines as interleukin-1&#x3b2; (IL-1&#x3b2;) are increasingly recognized as central mediators of diabetic vasculopathy. However, the mechanisms by which elevated glucose amplifies inflammatory signalling and vascular dysfunction, and their pharmacological modulation, remain incompletely understood. We investigated the interplay between IL-1&#x3b2; and high glucose in human aortic smooth muscle cells (HASMC) and its impact on NLRP3 inflammasome activation, cellular metabolism and small extracellular vesicles (sEV)-mediated intercellular communication. IL-1&#x3b2; induced NLRP3 inflammasome activation and a metabolic reprogramming characterized not only by a glycolytic shift, but also by activation of the pentose phosphate pathway and NADPH oxidase. IL-1&#x3b2; promoted the release of sEV enriched in inflammasome components, particularly pro-caspase-1, which propagated inflammation and senescence in recipient vascular cells. High glucose alone had no effect but potentiated IL-1&#x3b2;-induced responses. Pharmacologically, blockade of IL-1R with anakinra prevented inflammasome activation, metabolic reprogramming and sEV release. Moreover, both anakinra and the NLRP3 inhibitor MCC950 impeded, at different levels, the potentiating effect of high glucose on IL-1&#x3b2;-driven responses, reinforcing the relevance of targeting the IL-1&#x3b2;-NLRP3 autoinflammatory axis. These findings reveal that high glucose potentiates IL-1&#x3b2;-driven vascular inflammation by altering bioenergetic flexibility and sEV signalling in human vascular cells, providing novel mechanistic insight into how IL-1&#x3b2;-targeted therapies may mitigate vascular complications in cardiometabolic disorders as diabetes.

This study aimed to investigate the associations of serum sodium and potassium levels within the normal range with cardiovascular (CV) and all-cause mortality, and to further explore the potential roles of oxidative stress and inflammatory biomarkers in these associations. We analyzed NHANES 1999-2018 data from 32,837 adults with normal baseline serum sodium (135-146&#x2009;mmol/L) and potassium (3.5-5.0&#x2009;mmol/L), stratified by tertiles. Weighted Cox models assessed associations with CV and all-cause mortality, and bootstrap-based causal mediation analysis assessed nine oxidative stress and inflammatory biomarkers. The lowest tertile of serum sodium was associated with an increased risk of all-cause mortality (HR: 1.17; 95% CI: 1.03-1.32; p&#x2009;=&#x2009;0.017), while the highest tertile of serum potassium was associated with an increased risk of CV (HR: 1.26; 95% CI: 1.00-1.58; p&#x2009;=&#x2009;0.052) and all-cause mortality (HR: 1.14; 95% CI: 1.02-1.29; p&#x2009;=&#x2009;0.025). Serum sodium and potassium showed a statistically significant interaction for all-cause mortality (p&#x2009;=&#x2009;0.044), with the lowest risk at sodium 138-139&#x2009;mmol/L and potassium 3.5-3.8&#x2009;mmol/L (HR: 0.46, 95% CI: 0.31-0.68; p&#x2009;<&#x2009;0.001). Mediation analysis showed that inflammatory biomarkers accounted for 0.8% to 1.5% of the associations between serum sodium/potassium and CV or all-cause mortality. In the general population, lower normal-range serum sodium was associated with higher all-cause mortality, while higher serum potassium was linked to increased cardiovascular and all-cause mortality. Inflammatory biomarkers may partially mediate these associations. Our findings provide more evidence that the "safest" sodium and potassium interval needs to be reconsidered.