The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Background: Migration from low- and middle-income to high-income settings is often accompanied by dietary and lifestyle changes that may increase long-term risk of non-communicable diseases. African migrants represent a growing but under-studied population in Australia, with limited evidence on post-migration nutrition transitions and associated chronic disease risk. This study examined changes in diet and lifestyle among Nigerian-born adults before and after migration to Australia and explored any association with chronic diseases. Methods: A pilot cross-sectional study was conducted among adults who migrated from Nigeria to New South Wales, Australia, between 1992 and 2019. Data were collected via a culturally adapted, self-administered online questionnaire assessing socio-demographic characteristics, dietary intake, lifestyle behaviours, and self-reported chronic conditions in the 12 months immediately before and after migration. Descriptive statistics (frequencies and proportions) and inferential analyses (Chi-square tests, McNemar test, and the Bowker test) were used to compare pre- and post-migration behaviours and examine associations with chronic disease outcomes. Results: Ninety-three participants completed the survey (mean age 37.0 ± 7.2 years; 50.5% male). Post-migration, regular breakfast consumption declined (-24.3%), while irregular eating (low and moderate) patterns increased (+7.6% and +16.7%). Regular vegetable intake improved (+5.4%), whereas fruit intake remained low (13.0%). Regular consumption of Nigerian local foods decreased markedly (-53.7%), while regular intake of meat (+18.5%), dairy foods, fats (+14.3%), and non-alcoholic beverages increased (+22.8%). Salt use shifted away from the highest-risk category (-22.2%), and smoking and alcohol consumption remained low and stable. Self-reported chronic conditions were uncommon; hypertension (6.5%) and obesity (5.4%) were the most frequently reported. Conclusions: Nigerian migrants in Australia experience substantial post-migration dietary and lifestyle transitions that may elevate long-term chronic disease risk despite a currently low reported disease burden. Early, culturally responsive nutrition and lifestyle interventions are needed to support healthy adaptation and prevent the progression of cardiometabolic conditions in this growing migrant population.
Chronic airway diseases (CAD) including chronic obstructive pulmonary disease (COPD), persistent asthma (≥2weekly episodes) and bronchiectasis, exhibit overlapping extrapulmonary manifestations potentially affecting health-related quality-of-life (HRQOL). The study objective was to quantify HRQOL of CAD patients and identify impact of associated pulmonary and extrapulmonary manifestations. Total 101 established CAD patients were recruited cross-sectionally (COPD, n = 61, persistent asthma, n = 30 and bronchiectasis, n = 10). Patients completed spirometry, body composition (Dual-energy X-ray Absorptiometry), muscle function (isometric and isokinetic dynamometry), exercise capacity (6-min walking distance, 6MWD) and patient reported outcomes, including physical activity, sleep and hospital anxiety and depression scale. HRQOL was assessed using EuroQol quality-of-life questionnaire and utility score (EQ-5D index) was stratified into tertiles to compare patient characteristics. Mean age of participants was 60.9 ± 12.8y, and 25.7% were female. Mean EQ-5D index was 0.658 (95%CI: 0.596, 0.721), significantly lower than population norms and other chronic diseases including diabetes, cardiovascular diseases and rheumatoid heart disease (p < 0.01). Participants in lowest EQ-5D tertile were older, had higher depression, lower 6MWD, lower handgrip and quadriceps muscle strength than other two tertiles, whereas anxiety was higher in both lowest and intermediate tertile compared to highest tertile (p < 0.01). In the adjusted regression model, age (AOR:1.187) depression (AOR:1.438), anxiety (AOR:1.266), and body fat (AOR:1.114) showed increased odds for poor EQ-5D index while in intermediate vs highest EQ-5D tertile, only age (AOR: 1.125) and anxiety (AOR:1.403) showed a significant association. HRQOL is significantly lower in CAD compared to other chronic non-communicable diseases and significantly associated with extrapulmonary manifestations. Interventions targeting modifiable risk factors may aid in improving HRQOL in CAD.
Understanding how multimorbidity affects activities of daily living (ADL) and instrumental activities of daily living (IADL) disability in older Irish adults is essential for planning responsive health and social care systems that can support quality of daily life. This study examines how chronic noncommunicable diseases multimorbidity affects older adults' ability to live independently in Ireland. It focuses on the relationship between multimorbidity and limitations in ADL and IADL. A cross-sectional 2019 Irish Health Survey data set was used. The study analyzed data from 2114 individuals aged 65 years and older in Ireland. Descriptive, bivariate, and multivariable logistic regression analyses were used to examine the effect of multimorbidity on functional disability. Difficulties in ADL and IADL were significantly higher among older adults with multimorbidity (25% and 62%) compared with single morbidity (10% and 38%; p < 0.001). Adjusted logistic regression results also revealed that multimorbidity significantly increased the odds of ADL (adjusted odds ratio [AOR] = 2.52; 95% CI: 1.80, 3.55) and IADL (AOR = 2.60; 95% CI: 2.02, 3.35) limitations. Depression and older age were strong predictors of disability, while moderate alcohol use was linked to lower ADL impairment. Gender and regional disparities were also observed. IADL impairments were more common, suggesting early signs of functional decline. Multimorbidity threatens older adults' independence in Ireland. Early detection of IADL limitations and integrated, person-centered care are essential. These findings support policy efforts like Sláintecare to promote aging in place.
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, idiopathic, chronic cholestatic liver diseases that respond differently to limited medical therapies and often lead to liver transplantation. We examined the compositional and functional differences in the gut microbiome, mycobiome, and metabolome of these diseases to better understand their impact on pathogenesis and outcomes. Stool sample metagenomes and metabolomes from patients with PSC (n = 245), PBC (n = 280) and matched controls (n = 245 and n = 278, respectively) were analyzed by shotgun sequencing and ultrahigh-resolution mass spectrometry. Comparisons were conducted with covariate-adjusted linear models. The gut microbiomes of patients with PSC and PBC were characterized by reduced diversity and increased abundance of pathobionts and virulence factors, coupled with altered microbial metabolism, including a reduction of short-chain fatty acids and B-vitamins. Untargeted stool metabolomics supported these results. Patients were stratified into groups using their microbial signatures, and each group had distinct patterns of microbiome-related changes. Cox regression analysis revealed that pathogenic microbial species were predictive of hepatic decompensation, whereas beneficial species had a protective effect. Based on previous groundwork and our new results, microbiome-based interventions such as probiotics, short-chain fatty acid supplementation, and phage therapy represent promising therapeutic options for cholestatic liver diseases. The gut microbiome of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) exhibited extensive dysbiosis with compositional and metabolic alterations, which were further supported by untargeted metabolomics.Association of oral Streptococci and virulence factors with increased risk of hepatic decompensation in PSC supports the relevance and potential importance of the oral–gut–liver axis.Several patient subgroups were identified in both diseases, with distinct features and significant alterations in gut microbial virulence and metabolic potential.These findings generate hypotheses that microbiome-targeted interventions, including enhancing butyrate availability or targeting the levels of specific microbes, warrant evaluation in future mechanistic and mechanistic studies as they may be beneficial for cholestatic liver diseases.
Environmental diseases include a wide spectrum of pathologies whose development is influenced by physical, chemical and biological factors external to the individual. Recent WHO estimates show that 24% of global deaths are due to environmental factors as air pollution, climate change, toxic chemicals and poor hygiene. The Province of Alessandria, Piedmont, Italy, has been subjected to contamination due to industrial plants where hazardous materials have been used. To investigate the level of awareness of the population about environmental pathologies, the Research and Innovation Department of the Azienda Ospedaliero-Universitaria of Alessandria and ASL AL distributed a survey to secondary school students and citizens of Alessandria and Casale Monferrato, in two phases between 2022 and 2023. The sample comprises 230 participants equally divided by gender and with different levels of education. The survey explores knowledge of environmental causes of diseases and their impact on mortality and possible preventive measures. The majority of the sample associate environmental diseases with human pathologies (89.1%), with a higher awareness among students (91% compared to 86.6% of citizens). The main causes identified are air pollution (70.4%) and toxic substances in the air and water (64.8%). 84.8% identify cancer and 69.6% COPD as associated diseases. 56.4% estimate an impact of environmental factors between 10 and 15% on global mortality. The main preventive measures include the use of cleaner fuels (83.9%), improved hygiene measures (70%) and the promotion of sustainable mobility (70%). This survey reveals a fair degree of awareness of environmental diseases, but also an underestimation of associated mortality. Therefore, it is necessary to improve education and communication on environmental risks through targeted campaigns and educational interventions. Future studies should broaden the sample and analyze percentage differences between subgroups to optimize educational and preventive actions.
The bone marrow niche (BMN) plays a central role in regulating hematopoietic stem-cell (HSC) maintenance, lineage commitment, and immune homeostasis, while also supporting osteogenesis and maintaining skeletal integrity. Once considered static, the BMN is now recognized as a dynamic and responsive microenvironment that integrates local signals and systemic cues to meet physiological demands and respond to stress. Aging causes profound and progressive changes to this niche, leading to functional decline across both hematopoietic and stromal compartments. Recent advances in high-resolution imaging, single-cell and spatial transcriptomics, and in vivo lineage tracing have revealed remarkable heterogeneity and plasticity within the vascular and mesenchymal elements of this niche. Yet, key questions remain unresolved, including the identity and hierarchy of mesenchymal and osteolineage cells, the specialization of subsets of endothelial cells, the integration of systemic regulation, and whether the aging bone marrow acts as a driver or a passenger in malignancy and chronic inflammation. This review revisits current models of the BMN, with a focus on the reciprocal interactions between osteogenic cells and specialized vasculature, and how their disruption during aging impairs hematopoietic output and skeletal remodeling. We also examine how systemic factors such as neural input, metabolic status, and inflammatory signaling influence the aging of the BMN. Finally, we highlight emerging translational platforms, including iPSC-derived bone marrow organoids, engineered niches/hydrogels, and vascularized organ-on-chip systems, that enable mechanistic testing of rejuvenation strategies. Together, these insights have the potential to pave the way toward targeted interventions that restore the function of the BMN and promote healthy aging of the bone and blood systems.
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 ≥20%). The primary outcome was ≥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 ≥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).
The treatment of complex orthopedic diseases such as osteomyelitis, rheumatoid arthritis, and osteosarcoma is often hindered by the limitations of systemic drug administration, including poor bioavailability, severe side effects, and an inability to address localized pathologies. Liposomes, with their exceptional biocompatibility, structural versatility, and ability to encapsulate diverse therapeutics, have emerged as a cornerstone of nanomedicine. This review provides a function-centric analysis of how liposomes are engineered as intelligent, multi-functional platforms to tackle the specific challenges of the bone microenvironment. We move beyond a simple catalog of applications to critically examine the design strategies that enable liposomes to: (1) penetrate biofilm barriers and eradicate intracellular pathogens in infectious bone diseases; (2) actively target and reprogram inflammatory cells to resolve chronic inflammation in arthritis; (3) provide spatiotemporal control over growth factor and gene delivery for enhanced bone and cartilage regeneration; and (4) enable combinatorial chemo-gene therapies and novel cytotoxic mechanisms for osteosarcoma. By comparing and contrasting these strategies, this review identifies key technological advancements-such as stimuli-responsive release, biomimetic camouflage, and stem-cell fate engineering-that are driving the field forward. We conclude by discussing the persistent challenges for clinical translation and outlining future directions for the next generation of "smart" liposomes that promise to transform the paradigm of orthopedic treatment from symptomatic management to pathology-modifying and regenerative intervention.
Despite the success of long-term antiretroviral therapy (ART), immune dysfunction-including incomplete T helper cell recovery, immune activation, and inflammation-persists and may affect the benefits of analytical ART treatment interruption (ATI) trials among people living with human immunodeficiency virus (HIV) (PLHIV) in sub-Saharan Africa (SSA). This narrative review summarizes evidence of incomplete immune function recovery among PLHIV on long-term ART and potential interventions to enhance their ability to participate in ATI trials with immunotherapies in the quest for an HIV cure in SSA. A PubMed search query was used "([Immunity, Innate{MeSH Terms}] OR [Adaptive Immunity{MeSH Terms}] AND [HIV{MeSH Terms}] AND [Anti-HIV Agents{MeSH Terms}] AND [function{Title/Abstract} OR dysfunction{Title/Abstract} OR recovery{Title/Abstract} OR restoration{Title/Abstract} OR reconstitution{Title/Abstract} OR regeneration{Title/Abstract}])", which retrieved 165 articles. These articles were filtered using an English-language filter, resulting in 160 papers. This query was translated to Web of Science and Google Scholar. In addition, we conducted a specific literature search on documented "cured" HIV cases globally to understand innate and adaptive immune functions relevant to supporting post-ART immunological viral control. Persistent dysfunction of host innate and adaptive immunity during suppressive ART is reported in SSA HIV treatment cohorts. Natural killer (NK) cells, dendritic cells, and monocyte dysfunction potentially limit post-ART viral control. In addition, persistently impaired CD4 and CD8 T-cell proliferation capacity, immune activation, and exhaustion during ART may limit host HIV-specific responses during ATI trials with broadly neutralizing antibodies (bNAbs) and therapeutic vaccines, thereby increasing the risk of post-ART viral rebound. Similarly, adjunct therapies with TLR7 agonists, such as vesatolimod, could potentially increase cytotoxic capabilities of dendritic and natural killer cells to improve HIV latency reversal and viral clearance during ART. Innovative combination immunotherapies to avert persistent immune dysfunction, such as therapeutic vaccines, combination bNabs, enhancer of zeste homolog 2 (EZH2) inhibitors to boost CD8+ T-cell function and augment post-ART viral control, and latency reversal agents to increase cytotoxicity potential of dendritic cell and natural killer cells, among others, could potentially optimize HIV-specific CD8 T-cell cytotoxicity and viral clearance, and delay viral rebound during ATI trials in SSA.
Background: The Mediterranean diet (MedDiet) has been associated with anti-inflammatory effects and potential benefits in several chronic conditions. However, adherence to the MedDiet and its relationship with lifestyle factors and disease severity across different rheumatological diseases remain poorly characterized. Objectives: This study aimed to evaluate differences in MedDiet adherence among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and fibromyalgia (FM), and to explore its association with cardiovascular comorbidities, bowel habits, and disease-related outcomes. Methods: In this monocentric cross-sectional study, adherence to the MedDiet was assessed using the 14-item PREDIMED questionnaire. Self-reported data on sociodemographic characteristics, cardiovascular comorbidities, bowel habits, and dietary behaviors were collected through questionnaires. Disease activity and severity were assessed using validated disease-specific measures. Differences in MedDiet adherence across diagnostic groups were evaluated using non-parametric tests. Multivariable models were performed to examine associations between MedDiet adherence and cardiovascular comorbidities or disease outcomes, adjusting for potential confounders including age, sex, BMI, smoking status, and educational level. Results: A total of 422 participants were included (RA n = 165, PsA n = 85, FM n = 172). Significant differences in MedDiet adherence were observed across diagnostic groups (p < 0.001), with the highest adherence in RA, intermediate values in PsA, and the lowest in FM. Compared with the other groups, a higher proportion of FM participants reported food intolerances (46.5%) and restrictive diets, including lactose-free (34.9%) and gluten-free (15.1%) diets. In the FM group, high adherence to the MedDiet was significantly associated with lower FIQR scores (β = -16.9; 95% CI -32.1 to -1.7; p = 0.01) and lower PDS scores (β = -4.34; 95% CI -7.81 to -0.86; p = 0.01). Sensitivity analyses using the continuous PREDIMED score confirmed these associations. Conclusions: Adherence to the MedDiet differs across rheumatological diseases, with the lowest adherence observed in FM. Higher adherence was associated with lower disease severity and impact in FM. These findings highlight the potential relevance of nutritional counselling in rheumatological diseases and support the need for longitudinal and interventional studies evaluating the role of the MedDiet within multidisciplinary disease management.
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.
The Chronic Respiratory Disease Questionnaire (CRQ) was developed to measure health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD), with a minimum clinically important difference (MCID) of 0.5 points per item. It has been used in clinical trials of patients with interstitial lung disease (ILD), however its validity and MCID in this population is unknown. Is the CRQ a valid measure of HRQoL in people with ILD and what is the MCID in this population? Data from a multicentre randomised controlled trial of pulmonary rehabilitation (PR) in 142 patients with ILD were analysed. Concurrent validity with the St George's Respiratory Questionnaire for IPF (SGRQ-I), known groups validity between patients of varying TLCO and GAP Index, and responsiveness to change after PR were assessed. MCID was calculated using anchor- and distribution-based methods. Analyses were repeated for the idiopathic pulmonary fibrosis (IPF) subgroup. There was a strong association between CRQ and SGRQ-I scores (r = -0.786, p < 0.05). CRQ scores differed significantly between patients in the highest and lowest TLCO quartile (effect sizes -0.49 to -0.64) and between GAP Index groups (p < 0.05), except for the emotional function domain. The CRQ was responsive to PR (effect size -0.53). The MCID ranged from 0.45 to 0.65 points per item. Results were similar in the IPF subgroup. The CRQ is a valid and responsive measure of HRQoL in patients with ILD, including those with IPF, with an MCID of around 0.5 points per item. These findings support the use of the CRQ in ILD.
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 26 000 participants. Adults aged ≥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).
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 = 2]; liver metastasis, LM [sample number = 9]; ovary metastasis, OM [sample number = 3]; peritoneum metastasis, PM [sample number = 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.
To investigate the landscape of targetable genomic alterations and programmed cell death ligand 1 (PD-L1) expression in pulmonary ground-glass opacities (GGOs) and their association with age. A total of 2509 patients with GGOs were retrospectively analyzed. Tumor characteristics, PD-L1 expression, and prevalence of targetable alterations were compared across age groups. In GGOs, the mutation rates of EGFR (61.5%) and ERBB2 (12.0%) were relatively high, whereas those of KRAS (8.2%) and ALK rearrangements (2.3%) were relatively low. The patients exhibited a low tumor mutational burden (TMB), and PD-L1 expression was negative in 86.7% of cases. TMB, PD-L1 expression, and the mutation rates of EGFR, KRAS, and MET increased significantly with age, whereas the rates of ERBB2 mutations, ALK rearrangements, and RET rearrangements decreased significantly with age. Age was identified as an independent predictor for the above eight variables. The optimal age cutoff was determined to be 53 years. Compared with the younger age group (< 53 years), the older age group (≥ 53 years) showed a 31.6%, 130.4%, and 800.0% higher likelihood of harboring EGFR, KRAS, and MET mutations, respectively. Conversely, compared with the older age group, the younger age group showed a 289.1%, 94.1%, and 108.7% higher likelihood of harboring ERBB2 mutations, ALK rearrangements, and RET rearrangements, respectively. GGOs exhibit a distinct genomic and PD-L1 profile with significant age-related heterogeneity, providing insights for age-stratified therapeutic strategies.
The liver is increasingly recognized as a major regulator of systemic cardio-renal-metabolic health. Evidence is mounting that sex-chromosome dosage per se itself, independent of gonadal sex hormones, modulates hepatic physiology and liver disease risk. Turner syndrome (TS; monosomy X) and Klinefelter syndrome (KS; 47, XXY and variants) are the two most common sex-chromosome aneuploidies and carry a clinically relevant, yet often under-appreciated, burden of liver disease. Population studies show that individuals with TS have 2- to sixfold higher odds of raised liver enzymes, steatotic liver disease, advanced fibrosis, and even hepatocellular malignancy compared with to sex- and age-matched controls. In KS, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) reaches approximately 45%, with testosterone deficiency, visceral adiposity, and systemic inflammation acting as key drivers. Pathogenetic mechanisms converge on vascular dysgenesis and estrogen deficiency in TS, and on hypogonadism-related metabolic derangements in KS, together accelerating steatosis, inflammation, and fibrogenesis. This concise review/Comprehensive perspective reviews discusses historical background, epidemiology, hepatic phenotypes, pathophysiology, and current diagnostic and management recommendations. It also highlights critical knowledge gaps, including the need for prospective cohorts, optimized hormone-replacement protocols, and trials of emerging pharmacological approaches anti-MASH agents. Raising awareness among all stakeholders, endocrinologists, hepatologists, and primary-care physicians is essential for early detection, multidisciplinary management, and improved hepatic and extra-hepatic outcomes in these vulnerable patient populations.
Inflammation-associated skin lesions, including psoriasis (PsO) and diabetic foot ulcers (DFU), greatly impair patients' quality of life. Gentiopicroside (GPS), a key iridoid glycoside from Gentiana species, exhibits anti-inflammatory, antioxidant, and wound-healing properties, but its clinical application is limited by low oral bioavailability and poor skin permeability. Nanodelivery strategies have been actively explored to overcome these limitations. The objective of this review was to critically analyze recent breakthroughs in GPS-loaded nanodelivery approaches for the treatment of inflammation-associated skin lesions, especially PsO and DFU, including the impact of these approaches on GPS bioavailability, efficacy, and safety profile. Oral bioavailability of GPS can be improved by poly (lactic-co-glycolic acid) (PLGA) nanospheres and phospholipid-complex self-nanoemulsifying drug delivery systems (PC-SNEDDS), while skin-targeted delivery and sustained release can be enhanced by chitosan (CHI) nanoparticles, electrospun nanofibers, ZIF-8 metal-organic frameworks, and nanoscale hydrogels. These nanodelivery technologies improve the translational potential of GPS for chronic inflammatory skin diseases. Although GPS-loaded systems have not yet entered clinical trials, analogous nanotechnologies have demonstrated enhanced drug stability, bioavailability, safety, and patient tolerability in treatments of other skin diseases, highlighting their strong potential for clinical translation. Future efforts toward clinical translation may focus on establishing common evaluation criteria, conducting full-scale toxicological and biodistribution tests, and implementing Good Manufacturing Practice (GMP)-scale-up projects with multicenter preclinical trials.
Ulcerative colitis (UC) exhibits substantial heterogeneity in inflammatory pathways and therapeutic response. The organic cation transporter OCTN1 (SLC22A4) and its rs1050152 missense variant (L503F) have been implicated in innate immune activation and disease susceptibility. We investigated whether OCTN1 variants modulate monocyte inflammatory responses and predict clinical outcomes in UC patients treated with anti-tumor necrosis factor α (TNFα) agents. We combined preclinical and clinical approaches. In THP-1 cells engineered for OCTN1 knockdown or variant-specific overexpression, and in primary monocytes isolated from genotyped donors and UC patients, we assessed by enzyme-linked immunosorbent assay and Western blot interleukin (IL)-1β production following bacterial stimulation (peptidoglycan, Fusobacterium nucleatum, Escherichia coli, Salmonella). In the clinical study, UC patients initiating anti-TNFα therapy were genotyped and evaluated for 1-year therapy persistence, steroid-free clinical remission, and endoscopic response. Logistic regression models were used to identify predictors of outcomes. An exploratory machine learning analysis (regularized logistic regression and neural networks) was performed to rank the variables contributing to each endpoint. OCTN1-deficient THP-1 cells showed markedly reduced interleukin-1β secretion, whereas the same cell line or primary monocytes carrying the 503F variant exhibited significantly enhanced cytokine release upon microbial stimulation. On the clinical side, 105 patients with UC were enrolled. The homozygous 503F genotype (TT) was strongly associated with higher rates of steroid-free remission, endoscopic response, and therapy persistence. Heterozygous carriers displayed intermediate outcomes. Machine learning models demonstrated moderate predictive performance (area under the curve 0.60-0.72), consistently ranking OCTN1 among relevant, though not dominant, determinants of therapeutic success. The OCTN1 503F variant enhances interleukin-1β-mediated innate immune activation and is associated with improved long-term response to anti-TNFα therapy in UC. These findings support OCTN1 genotyping as a promising component of future precision medicine strategies in inflammatory bowel disease and warrant confirmation in larger prospective multicenter cohorts. The inflammatory bowel disease–associated 503F variant of the organic cation transporter OCTN1 promotes interleukin-1β production from leukocytes and predicts a better response to anti-tumor necrosis factor α therapy in patients with ulcerative colitis. Machine learning confirms this finding.
The relationship between environmental factors and early chronic kidney disease (CKD) in young adults remains unclear, particularly regarding the joint effects and climatic modifying factors. Here, by analyzing data from the Tianshan Cohort of 2,517,928 adults (aged 18-40 years) linked with satellite-derived ozone (O3) and the Normalized Difference Vegetation Index (NDVI), and using Cox models, we quantified their associations with incident early CKD (eGFR ≥60 mL/min/1.73 m2 with proteinuria). Over a median follow-up period of 4.53 years, 264,195 incident cases were identified. Higher O3 exposure increased the risk of early CKD (HR for Q4 vs. Q1 = 1.60, 95% CI: 1.58-1.63), while higher residential greenness (NDVI) decreased the risk (HR for Q4 vs. Q1 = 0.95, 95% CI: 0.93-0.96). Notably, the exposure-response relationships were nonlinear. The risk of early CKD increased sharply when O3 levels exceeded 100.94 μg/m3, whereas a marked protective effect of NDVI emerged once its value surpassed 0.27. Mediation analysis indicated that 57.57% of NDVI's protective effect was mediated by reduced O3 exposure. Stratified analyses revealed that high temperature (HR for O3≥Q4 = 1.62, 95% CI: 1.59-1.64) and low precipitation (HR for O3≥Q4 = 1.73, 95% CI: 1.70-1.77) exacerbated O3-associated risk. Furthermore, the protective effect of NDVI was enhanced under low temperature (HR for NDVI ≥ Q4 = 0.91, 95% CI: 0.89-0.92) and high precipitation (HR for NDVI ≥ Q4 = 0.75, 95% CI: 0.73-0.76). Thus, O3 exposure is associated with an increased risk of early CKD, whereas residential greenness exerts a protective effect partly mediated by reducing O3; these nonlinear associations are intensified by high temperature and low precipitation. Integrated strategies for air quality improvement, urban greening, and climate adaptation may help mitigate CKD incidence in young adults.