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.
Ceramides have garnered considerable attention as pro-aging bioactive lipids implicated in both metabolic dysfunction and musculoskeletal decline. Among these, C18:0 and C24:1 ceramides may play a role in the pathophysiology of sarcopenia, a key manifestation of age-related deterioration. However, their specific contributions to muscle degeneration remain poorly defined. C2C12 myoblasts and primary myoblasts were treated with C18:0 or C24:1 ceramides during differentiation to assess myotube formation, migration and intracellular reactive oxygen species (ROS) levels. Three-month-old C57BL/6 mice received daily intraperitoneal injections of C18:0 or C24:1 ceramides for 4 weeks to evaluate muscle morphology and function. In a human cohort of 165 community-dwelling older adults (≥ 65 years), serum ceramide levels were measured via LC-MS/MS and analysed in relation to sarcopenia parameters. Both C18:0 and C24:1 ceramides significantly impaired myogenic differentiation in vitro, as evidenced by reduced myotube number, total myotube area, average area per myotube, nuclei count per myotube and fusion index, through ROS-mediated mechanisms (with up to an 8.6-fold increase in ROS production). Consistently, C18:0 and C24:1 ceramides markedly downregulated key myogenic markers and inhibited ITGB1-FAK-AKT signalling while promoting nuclear activation of FoxO-associated catabolic pathways. These deleterious effects were attenuated by treatment with the antioxidant N-acetylcysteine. In mice, systemic administration of either ceramide resulted in reduced muscle fibre cross-sectional area in the tibialis anterior (by 20.5% and 20.9% for C18:0 and C24:1, respectively) and soleus muscles (by 18.1% and 16.1%), accompanied by decreased grip strength, shorter grid hanging times and reduced latency to fall in the rotarod test. Clinically, in a cohort of 165 older adults (80.6% female; mean age 75.2 ± 5.2 years in controls and 79.7 ± 4.8 years in the sarcopenia group), serum levels of C18:0 and C24:1 ceramides were 27% and 14% higher, respectively, in individuals with sarcopenia compared to controls (p = 0.001 and 0.018). Furthermore, each standard deviation increase in serum C18:0 and C24:1 ceramide levels was associated with a 2.0- and 1.6-fold increased risk of sarcopenia, respectively (p = 0.003 and 0.040). Our findings reveal that circulating C18:0 and C24:1 ceramides are significantly associated with sarcopenia in older adults, while experimental models demonstrate they promote muscle atrophy through oxidative stress-induced impairment of myogenesis and muscle function. These ceramides may serve as minimally invasive biomarkers and potential therapeutic targets for age-related muscle decline. Interventions aimed at modulating ceramide metabolism could offer new avenues for sarcopenia prevention and treatment in aging populations.
The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population. This double-blind, parallel-group, phase 3a trial (REDEFINE 5) was conducted across 21 sites (community, hospital) in Japan and one site in Taiwan. We included participants aged at least 18 years with a BMI of at least 27 kg/m2 and at least two obesity-related complications, or with a BMI of at least 35 kg/m2 and at least one obesity-related complication (per the Japan Society for the Study of Obesity guidelines), with or without type 2 diabetes. Participants were randomly assigned (1:1) to once-weekly subcutaneous injections of cagrilintide-semaglutide or semaglutide (both escalated to 2·4 mg), plus lifestyle intervention, for 68 weeks. Randomisation was done centrally using an interactive web response system and stratified according to planned CT scan, BMI of at least 35 kg/m2, and type 2 diabetes status. Participants, site staff, investigators, and study funder were all masked to active study treatments. The primary endpoint was relative change in bodyweight from baseline to week 68. Efficacy analyses were done in all participants who underwent randomisation, using the trial product estimand (ie, assuming the treatment was taken as intended, regardless of dose) as the primary estimand. Missing data at week 68 were imputed. Safety analyses were done in all participants who underwent randomisation and received at least one dose of trial product. This trial is registered with ClinicalTrials.gov (NCT05813925) and is complete. Between April 3, 2023, and Sept 15, 2023, we screened 355 individuals; 331 were randomly assigned to cagrilintide-semaglutide (n=164) or semaglutide (n=167). 226 (68%) participants were male and 105 (32%) were female; 80 (24%) had type 2 diabetes. 17 (10%) participants discontinued cagrilintide-semaglutide and ten (6%) discontinued semaglutide. The estimated mean change in bodyweight from baseline to week 68 was -18·4% (SE 0·7) in the cagrilintide-semaglutide group versus -11·9% (0·7) in the semaglutide group (estimated treatment difference [ETD] -6·5 percentage points [95% CI -8·4 to -4·6]; p<0·0001). Adverse events were reported by 143 (87%) of 164 participants in the cagrilintide-semaglutide group and 141 (84%) of 167 in the semaglutide group, the most common of which were gastrointestinal disorders (87 [53%] of 164 participants in the cagrilintide-semaglutide group vs 85 [51%] of 167 in the semaglutide group). One death was reported in the semaglutide 2·4 mg group, which was not judged to be treatment related by the investigator. These findings support the efficacy and safety of cagrilintide-semaglutide for weight management in individuals from east Asia with overweight or obesity, with or without type 2 diabetes. Novo Nordisk. For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.
Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. None.
Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder characterized by hyperandrogenism, anovulation, and polycystic ovaries, and it is frequently associated with low-grade inflammation and microbiota dysbiosis. Secoisolariciresinol diglucoside (SDG), a flax-derived polyphenol, exhibits estrogenic and anti-inflammatory properties. This study explored the therapeutic potential of dietary SDG in a rat model of PCOS. Female Sprague-Dawley rats were divided into four groups: control, model, SDG-treated control, and SDG-treated model. After 3 weeks of PCOS modeling, dietary SDG was administered for 8 weeks. Samples were collected after the intervention for subsequent analyses. SDG improved estrous cyclicity, ovulation, ovarian morphology, and sex hormone balance. It reduced obesity, dyslipidemia, insulin resistance, and oxidative stress. Inflammation was alleviated through reductions in interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α, along with an elevation in IL-10. SDG increased splenic regulatory T cells and intestinal γδT cells while reducing ovarian and peritoneal macrophages. Gut microbiota composition was reshaped, with increased abundances of Bifidobacterium, Butyrivibrio, and Ruminiclostridium, and decreased abundances of Bacteroides and Parasutterella. Vaginal microbiota composition improved, as indicated by increased Lactobacillus and decreased Enterobacteriaceae. Plasma lipopolysaccharide levels decreased, whereas short-chain fatty acids increased. Metabolomic analysis highlighted alterations in histidine metabolism. SDG ameliorates PCOS by suppressing inflammation and modulating gut and vaginal microbiota.
The burden of diabetes mellitus (DM) in Asia has been increasing; however, systematic assessments of long-term incidence trends, subtype-specific differences, and modifiable risk factors remain limited. Using Global Burden of Disease Study 2021 data, we evaluated incidence trends in DM and its subtypes (type 1 diabetes mellitus [T1DM] and type 2 diabetes mellitus [T2DM]) in Asia from 1990 to 2021 and quantified the risk-attributable burden. We analyzed the number of cases, age-standardized incidence rate (ASIR), estimated annual percentage change (EAPC), and risk-attributable age-standardized disability-adjusted life year rate (ASDR) for DM and its subtypes. Decomposition analysis was also performed to quantify the contributions of population growth, aging, and epidemiological changes to increases in case numbers. From 1990 to 2021, DM and T2DM incidence in Asia increased, with T2DM showing the most pronounced rise (ASIR increased by 65.03%, EAPC=1.53; T1DM: 27.04%, EAPC=0.80). Substantial heterogeneity was observed across sex, region, and age group. Decomposition analysis indicated that the increase in T2DM cases was primarily driven by epidemiological changes (contributing 99.03%) and population growth (97.84%). Environmental particulate matter pollution, alcohol consumption, and high sugar-sweetened beverage intake were the fastest-rising risk factors, with ASDR increases of 219.61%, 202.01%, and 182.94%, respectively. Over three decades, Asia's DM burden has increased, with T2DM as the primary growth source driven by epidemiological changes. Future prevention and control efforts should focus on environmental and behavioral risk factors and implement tiered intervention strategies tailored to population characteristics.
Hypertension and dyslipidemia are major risk factors for cardiovascular disease, and effective management of these conditions is essential for reducing long-term morbidity. Mobile health (mHealth) education has emerged as a widely used strategy to enhance disease awareness and encourage lifestyle modification. This study evaluated the impact of an mHealth-based education on cardiovascular risk factors and disease awareness among individuals with hypertension. This single-arm retrospective cohort study analyzed health screening data collected in 2022 (baseline), 2023 (Phase I), and 2024 (Phase II). Participants received a series of mobile-delivered educational materials focused on hypertension and dyslipidemia, emphasizing lifestyle modification, self-management, and improved understanding of chronic disease risks. Primary outcomes were changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Secondary outcomes included changes in triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and fasting blood sugar (FBS). Annual prevalence rates of hypertension and dyslipidemia were also assessed. A total of 408 participants were included in the final analysis. SBP declined from 131 mmHg (IQR: 125-138) at baseline to 130 mmHg (IQR: 124-136) in 2023 and 128 mmHg (IQR: 120-136) in 2024 (P < 0.001). DBP decreased from 84 mmHg (IQR: 81-89) to 84 mmHg (IQR: 80-89) in 2023 and 82 mmHg (IQR: 75-89) in 2024 (P < 0.001). Hypertension prevalence decreased from 27% to 23.5% and 23%, though changes were not statistically significant. TG levels significantly decreased from 141 mg/dL (IQR: 96-206) to 138 mg/dL (IQR: 91-193) and 127 mg/dL (IQR: 92-185) (P < 0.001). LDL showed a statistically significant but small reduction (127 → 128 → 126 mg/dL; P = 0.003), while HDL remained unchanged. FBS increased slightly but significantly across the study period (98 → 99 → 99 mg/dL; P = 0.01). Dyslipidemia prevalence declined modestly (45.1% → 43.6% → 43.4%) without statistical significance. This study supports the feasibility of mobile health education as a low-cost strategy for improving blood pressure and lipid control. Strengthening education program content and enhancing participant engagement may further amplify its impact on population cardiovascular health.
17α-Hydroxylase/17,20-lyase deficiency (17OHD) is a rare congenital adrenal hyperplasia with cortisol and sex steroid deficiency and mineralocorticoid excess. We aimed to describe the phenotypic spectrum and clinical course of Korean patients with 17OHD in a multicenter cohort. This retrospective study included 17 patients with genetically confirmed 17OHD from six tertiary centers in Korea. Demographic, biochemical, and genetic data were reviewed to evaluate clinical variability and long-term outcomes. Of the 17 patients, seven had a 46,XX karyotype and 10 had a 46,XY karyotype; all had female external genitalia and were raised as females. Primary amenorrhea predominated in 46,XX patients; 46,XY patients presented variably (hypertension and hyperpigmentation). The median age at diagnosis was 16.4 years. Higher follicle-stimulating hormone levels (54.2 mIU/mL vs. 18.2 mIU/mL, P=0.003) and less frequent hypokalemia (40.0% vs. 85.7%, P=0.038) were observed in 46,XY patients compared with 46,XX. The most frequent genotype was c.1118A>T (55.9%). At diagnosis, 58.8% of the patients exhibited hypokalemia, resolved with treatment. During a median follow-up of 8.1 years, 82.4% had hypertension, and 57.1% achieved normal blood pressure with glucocorticoids and/or antihypertensives. Low bone mineral density was found in 46.2% of the patients, and improvement with sex hormone replacement was observed. Gonadectomy was performed in nine XY patients (90.0%), with no malignancies identified. Patients with 17OHD commonly present with hypergonadotropic hypogonadism, hypertension, and hypokalemia; however, phenotypic variability exists. Clinicians should consider 17OHD in adolescents with delayed puberty and hypertension, even without classical biochemical findings, to ensure timely diagnosis and management.
Although pregabalin is a first-line therapy for painful diabetic polyneuropathy (PDPN), its optimal dose-response relationship remains unclear. We conducted a network meta-analysis to evaluate the efficacy and safety of fixed pregabalin dosages in PDPN patients. We systematically searched major databases through October 2025 comparing various doses of pregabalin (75, 150, 300, and 600 mg/day) with placebo in adults with PDPN. The outcomes were short- and long-term changes in the average daily pain score, patient/clinician global impression of change, and adverse events (AEs) including dizziness, somnolence, headache, and peripheral oedema. Twelve RCTs were eligible. In the short term, pregabalin 300 (Standardised Mean Difference [SMD], 1.09; 95% CI, 0.69-1.50) and pregabalin 600 mg/day (SMD, 0.90; 95% CI, 0.24-1.55) produced significant pain reduction compared with placebo. In the long term, both pregabalin 300 (SMD, 0.12; 95% CI, 0.06-0.17) and 600 mg/day (SMD, 0.31; 95% CI, 0.23-0.38) remained effective, whereas pregabalin 75 and 150 mg/day did not demonstrate superiority over placebo. Regarding safety, both pregabalin 300 and 600 mg/day were associated with greater risks of dizziness, somnolence, and peripheral oedema compared with pregabalin 75 mg/day, pregabalin 150 mg/day, and placebo. Pregabalin doses ≤ 150 mg/day demonstrated no clinical benefit over placebo. Conversely, both pregabalin 300 and 600 mg/day showed a pain reduction effect at short- and long-term follow-up. Given that pregabalin 600 mg/day was associated with a higher incidence of AEs, pregabalin 300 mg/day appears to offer a more favourable balance, aligning potent efficacy with a manageable safety profile.
Thyroid cancer (TC) is a common endocrine malignancy with a rising global incidence. This study examined trends in TC incidence and mortality in the United States over the past two decades. TC mortality data from 1999-2023 and incidence data from 1999-2022 were obtained from Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research. Age-adjusted incidence rates (AAIRs) and age-adjusted mortality rates (AAMRs) per 100,000 person-years were standardized to the 2000 United States standard population. Temporal trends were analyzed using the Joinpoint Regression Program to calculate annual percent changes (APCs) and average annual percent changes (AAPCs) with 95% confidence intervals. Analyses were stratified by sex, age, race, and census region. A sensitivity analysis restricted to 1999-2019 was also conducted. Overall, 933,521 TC cases and 43,071 TC-related deaths were identified, with an AAIR of 12.12 and an AAMR of 0.49. Incidence rose markedly from 1999 to 2009 (APC=7.25%), stabilized during 2009-2014, and declined from 2014 to 2022 (APC=-2.42%), especially among females. In males, incidence increased until 2011 and then declined slightly. Mortality increased modestly overall (AAPC=0.30%), mainly among males and adults aged ≥75 years. The Northeast had the highest AAIR (15.73), whereas the West had the highest AAMR (0.55). Non-Hispanic Whites had increasing mortality, while non-Hispanic Blacks had the lowest incidence. In the United States, TC incidence shifted from increase to decline, coinciding with growing awareness of potential overdiagnosis. In contrast, mortality continued to show a modest upward trend, underscoring the importance of ongoing surveillance and focused attention to high-risk populations.
The incidence of thyroid cancer in Korea increased rapidly for decades and started declining around the mid-2010s. However, the mortality rate is stable without significant changes. This study evaluated the long-term trends in the standardized incidence rate/standardized mortality rate (SIR/SMR) of thyroid cancer in Korea. Cancer-specific incidence data from 1999 to 2021 and mortality data from 1985 to 2023 were obtained from Statistics Korea. SIR and SMR were calculated using the 2000 and 2005 Korean mid-year resident registration populations, respectively, as the standard populations. Trends in incidence and mortality were further analyzed using joinpoint regression analysis. The SIR was 7.41 per 100,000 in 1999, which peaked at 75.06 in 2012. It then decreased to 42.50 by 2015, but subsequently increased to 60.13 in 2021. SIR patterns tend to vary by age and sex. Stage-specific analyses revealed a renewed increase in both localized and distant stage cancers from 2015 onwards. Histologically, the incidence of papillary carcinoma decreased after 2010, whereas that of follicular carcinoma and medullary carcinoma showed recent upward trends. The SMR increased until the early 2000s but has since steadily declined, with the trend most evident among those aged ≥55 years. The incidence of thyroid cancer in Korea peaked in 2012, decreased until 2015, and has since modestly increased, particularly among men, younger adults, and patients with follicular, localized, or distant-stage disease. Thyroid cancer mortality has continually declined since the early 2000s. Continuous long-term monitoring is required to assess the effects of changes in clinical and diagnostic practices.
In patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and sulfonylurea, evidence directly comparing glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors as add-on therapy is limited; therefore, we compared dulaglutide and empagliflozin in this setting. This 12-week, single-center, randomized, open-label, parallel-group pilot study included a 24-week observational extension. Patients with HbA1c≥7.0% receiving stable doses of metformin and glimepiride were randomized to dulaglutide 0.75 mg/week or empagliflozin 10 mg/day. Doses were uptitrated at week 4 if tolerated and maintained for 12 weeks, with follow-up until week 36. The primary endpoint was the change in HbA1c at week 12. Secondary endpoints included changes in glycemic and obesity-related parameters. Exploratory analyses were performed to assess plasma metabolite profiles using liquid chromatography-mass spectrometry, and gut microbiota using 16S rRNA gene sequencing. Twenty-four patients completed the 12-week study (dulaglutide, n=13; empagliflozin, n=11). Both treatments significantly reduced HbA1c at week 12, with no significant between-group difference. Empagliflozin significantly reduced HOMA-IR, whereas dulaglutide significantly increased HOMA-β. At week 12, empagliflozin was associated with greater reductions in body weight and body fat compared with dulaglutide, whereas these differences were attenuated at week 36. Exploratory analyses suggested potential, modest treatment-related differences in plasma metabolite profiles and microbiome-metabolic associations, without marked alterations in overall microbial diversity. As add-on therapy to metformin and sulfonylurea, both dulaglutide and empagliflozin improved glycemic control, with no significant between-group difference observed in this exploratory pilot study. Empagliflozin induced earlier weight loss, whereas dulaglutide showed more gradual weight reduction over time, accompanied by exploratory findings suggesting possible differences in plasma and microbiome-related metabolic signatures.
The dietary index for gut microbiota (DI-GM) and its associations with mortality risk, as well as the underlying mechanisms, remain underexplored. We aimed to investigate the associations among DI-GM, a corresponding metabolic signature, and all-cause and cardiovascular disease (CVD) mortality. We analysed two cohort studies including 170,575 participants from the United Kingdom (UK) Biobank and 26,651 participants from the United States (US) National Health and Nutrition Examination Survey. We calculated DI-GM using 24-hour dietary recall questionnaire data and derived a corresponding metabolic signature using an elastic net regression model. Associations were assessed using Cox proportional hazards regression. Participants in the highest DI-GM group had a lower risk of all-cause mortality (hazard ratio [HR], 0.86, P<0.001 in the UK cohort; HR, 0.79, P<0.001 in the US cohort) and CVD mortality (HR, 0.79, P=0.013 in the UK cohort; HR, 0.68, P=0.007 in the US cohort) than those in the lowest group. Both overall DI-GM and foods beneficial for gut microbiota were inversely associated with mortality risk in a dose-response manner. We identified a DI-GM metabolic signature comprising 124 metabolites in the UK cohort (r=0.25, P<2.2×10-16); this signature was associated with the risk of all-cause mortality (HR, 0.68, P<0.001) and CVD mortality (HR, 0.65, P=0.003) and explained 52.60% of the association between DI-GM and all-cause mortality. We identified a close connection between DI-GM, its metabolic signature, and mortality outcomes, highlighting the potential benefits of dietary patterns that support gut microbiota health for longevity.
Subdural hematoma (SDH) represents a growing hemorrhagic concern among ischemic stroke survivors receiving long-term antithrombotic therapy. Although aging, multimorbidity, and antithrombotic exposure are all contributors to SDH, there is limited evidence on subtype-specific risk factors in stroke populations, and existing studies have often overlook competing mortality. Practical tools to guide individualized antithrombotic stewardship remain absent from contemporary guidelines. A nationwide retrospective cohort study was conducted using Korean National Health Insurance Service data from 2010 to 2023. Adults with incident ischemic stroke were followed for traumatic and non-traumatic SDH using Fine-Gray competing risk regression and cause-specific hazard models. Variables were selected using the Akaike information criterion to develop integer-based prediction scores. Internal validation used cross-validation, and external validation applied the models to an independent ischemic stroke cohort from the UK Biobank. A web-based calculator was employed to facilitate clinical use. Among 506,746 ischemic stroke survivors (median follow-up 57.9 months), 7,425 developed traumatic SDH and 1,705 developed non-traumatic SDH. The 10-year cumulative incidences were 1.94% for traumatic and 0.43% for non-traumatic SDH. Older age, multimorbidity, and antithrombotic exposure were independently associated with increased risk. Traumatic SDH demonstrated stronger associations with antiplatelet therapy and diabetes, whereas non-traumatic SDH was most strongly linked to warfarin use. Warfarin emerged as the only modifiable risk factor. Prediction models showed clear risk-gradient separation for both subtypes and maintained stratification performance in the UK Biobank cohort. A web-enabled platform provided individualized 10-year cumulative incidence estimates using routinely available clinical variables. This nationwide competing-risk analysis identified subtype-specific associations of aging, comorbidities, and antithrombotic exposure with SDH risk among ischemic stroke survivors. Because the models predict SDH specifically rather than overall intracranial hemorrhage, they are intended to support risk-stratified surveillance, monitoring, and patient counseling rather than to guide antithrombotic cessation in isolation, as such decisions require balancing ischemic recurrence against the full spectrum of major bleeding risk.
Background/Objectives: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a significant cause of severe visual impairment. Intermittent fasting (IF) has demonstrated metabolic benefits. We investigated the association between IF and DR risk in individuals with prediabetes and diabetes. Methods: This retrospective cohort study included participants of the Korean National Health and Nutrition Examination Survey 2017-2018 aged ≥40 years who were diagnosed with diabetes or prediabetes who had fundus photography and dietary pattern data. Participants were allocated to the IF (fasting for 24 h or skipping breakfast or dinner) and regular diet groups. Demographic, dietary pattern and clinical data, including DR prevalence, were compared between the groups. Multiple logistic regression assessed the association between IF and DR risk. Results: Of 922 participants, 831 followed a regular diet while 91 practiced IF. The participants in the IF group were significantly younger and more obese, had higher fat intake, and showed a lower prevalence of DR than those in the regular diet group (8.8% vs. 20.6%, p = 0.010). After adjusting for multiple covariates, including demographics, comorbidities, health behaviors, biochemical parameters, and nutritional intake profiles, IF was associated with a 70% reduced risk of DR (OR 0.30, 95% CI 0.12-0.65, p = 0.005). This association did not differ across subgroups (all p for interaction > 0.05). Conclusions: IF was significantly associated with reduced DR risk in this study. Further studies are needed to validate the effectiveness of IF as a dietary intervention for DR.
This study sought to assess the utility of the inflammatory burden index (IBI) in differentiating subacute thyroiditis (SAT) from Graves' disease (GD) and to investigate its association with recovery time, hepatic function impairment, recurrence, and permanent hypothyroidism in patients with SAT. Clinical and laboratory data from 357 adult patients with SAT, 412 patients with GD, and 633 healthy controls were retrospectively analyzed. Determinants influencing recovery time, hepatic function impairment, recurrence, and permanent hypothyroidism in patients with SAT were systematically evaluated. The IBI in the SAT cohort was markedly higher than that observed in both patients with GD and healthy controls. Receiver operating characteristic curve analysis indicated that the optimal IBI cutoff value for distinguishing SAT from GD was 9.13, yielding a diagnostic sensitivity of 90.76%, a specificity of 88.35%, and an area under the curve (AUC) of 0.944 (95% confidence interval, 0.927 to 0.961). The AUC for IBI was markedly superior to those for erythrocyte sedimentation rate (ESR), C-reactive protein, systemic immune-inflammation index, and other complete blood count-derived indices. Among patients with painless SAT, the IBI was markedly elevated compared with that in thyroid-stimulating hormone receptor antibody (TRAb)-negative GD patients. Stepwise multiple logistic regression identified ESR, IBI, free thyroxine, and thyroid-stimulating hormone as independent predictive factors for SAT. IBI was not associated with recovery time in patients with SAT. However, higher IBI values were observed in patients requiring glucocorticoid therapy due to an insufficient response to non-steroidal anti-inflammatory drugs. Furthermore, no significant associations were identified between IBI and hepatic function impairment, recurrence, or permanent hypothyroidism in patients with SAT. IBI, as a simple and practical inflammatory biomarker, could potentially serve as a valuable diagnostic tool for differentiating SAT, particularly in diagnostically challenging cases. Moreover, it may have clinical relevance in guiding therapeutic decision- making for patients with SAT.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that can be fatal if not diagnosed early or adequately managed. This study investigated the risk of all-cause mortality and secondary malignancies in patients with PPGL compared to age- and sex-matched controls without PPGL. This nationwide population-based cohort study included 1,672 patients with PPGL and 16,790 controls with a median follow-up of approximately 7.1 years. A Cox proportional hazard model was used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI). The mean age was 46.5 years and 50.5% were male. All-cause mortality was identified in 118 patients with PPGL (7.06%) and 749 controls (4.46%) during the follow-up period. The incidence of all-cause mortality in patients with PPGL was significantly higher than that in controls (9.92 per 1,000 person-years vs. 6.49 per 1,000 person-years, P=0.0003). The risk of all-cause mortality was significantly higher in patients with PPGL than in the controls (HR, 1.372; 95% CI, 1.124 to 1.675). The risk of secondary malignancies was significantly higher in patients with PPGL than in controls (HR, 1.612; 95% CI, 1.33 to 1.954) after adjusting. Among the various cancer subtypes, thyroid and prostate cancers were observed more frequently in PPGL patients, and these findings should be interpreted as descriptive trends. Patients with PPGL exhibited significantly increased risks of all-cause mortality and secondary malignancies compared with controls, highlighting the importance of appropriate assessment and follow-up.
Although type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) are associated with an increased risk of ischemic stroke, the extent to which steatotic liver disease (SLD) subtypes and advanced liver fibrosis confer additional risk in individuals with T2DM remains unclear. We aimed to investigate the association of SLD categories and/or advanced liver fibrosis with ischemic stroke risk among patients with T2DM. A total of 2,220,249 patients with T2DM were classified into five groups: no steatosis, MASLD, MASLD with other combined disease, metabolic dysfunction and alcohol-related steatotic liver disease (MetALD), and alcohol-related liver disease (ALD) with metabolic dysfunction (MD). SLD was defined using a fatty liver index (FLI) of ≥30, and advanced fibrosis was defined by a BARD score of ≥2. Over a median follow-up of 11 years, 135,482 ischemic strokes (6.10%) occurred. Compared with no steatosis, adjusted hazard ratios (aHRs) for stroke were higher in MASLD (aHR, 1.10; 95% confidence interval [CI], 1.08 to 1.11), MASLD with combined disease (aHR, 1.14; 95% CI, 1.12 to 1.17), MetALD (aHR, 1.13; 95% CI, 1.11 to 1.16), and ALD with MD (aHR, 1.32; 95% CI, 1.27 to 1.37). Advanced fibrosis progressively increased stroke risk compared with non-SLD and non-fibrotic SLD. Compared with the FLI <30 group, those with FLI 30-60 and ≥60 showed increased aHRs for stroke. Very heavy drinking was associated with a further increase in risk compared with non-drinking. In patients with T2DM, all SLD categories and advanced liver fibrosis were associated with an increased risk of ischemic stroke. Very heavy alcohol consumption was generally associated with a higher stroke risk across FLI categories.
The pharmacological management of type 2 diabetes mellitus has changed markedly over the past decade, largely in response to evidence generated by cardiovascular and renal outcome trials. Although contemporary guidelines are informed by a broadly shared evidence base, they differ in how they organize treatment concepts and translate evidence into clinical algorithms. This review compares major diabetes guidelines from the American Diabetes Association (ADA), the National Institute for Health and Care Excellence (NICE), the Japan Diabetes Society (JDS), and the Korean Diabetes Association (KDA), with particular attention to pharmacological algorithms, comorbidity-driven treatment strategies, and the conceptual principles underlying each framework. The ADA guideline uses a person-centered, risk-based approach that prioritizes sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists for patients with cardiorenal disease. The NICE guideline applies a more structured strategy, recommending early dual or triple therapy within a cost-effectiveness framework. The JDS guideline emphasizes pathophysiology-based treatment selection tailored to East Asian populations. The KDA guideline retains a glycemia-centered treatment structure while incorporating comorbidity-based decision-making and allowing early, flexible combination therapy. Thus, despite substantial convergence in the evidence base, these guidelines differ in how cardiovascular risk, glycemic control, and pathophysiological heterogeneity are incorporated into treatment decisions. The KDA framework can be viewed as a pragmatic hybrid model that integrates these dimensions and is further extended by recent consensus efforts addressing disease severity and pathophysiology.
We investigated tumor volume doubling time (TVDT) during active surveillance of papillary thyroid microcarcinoma (PTMC) and reviewed clinical factors including BRAF mutation associated with tumor progression. Patients with PTMC who deferred surgery for more than 1 year after diagnosis between 2014 and 2021 and were followed until 2023 were enrolled. Inclusion criteria were papillary thyroid carcinoma confirmed by fine needle aspiration cytology (Bethesda categories V-VI), maximal tumor diameter ≤1 cm, and available BRAF mutation testing. A total of 85 patients were included. The median age was 49 years, and 63 patients (74%) were female. The positivity rate for BRAF mutation was 51% in the study cohort, and 16 patients (19%) showed rapid-growing disease, defined by a TVDT of less than 5 years. The median follow-up duration was 4.4 years, and 23 patients (27%) underwent surgery after a median of 3.2 years. When TVDT groups were analyzed using logistic regression, sonographic features with microcalcification were associated with tumor growth in binary regression (odds ratio for the group combining slowly and rapid-growing disease was 4.34; 95% confidence interval [CI], 1.41 to 13.35; P=0.010), and BRAF mutation was associated with rapid-growing disease in multinomial regression (odds ratio for rapid-growing disease was 4.48; 95% CI, 1.08 to 18.51; P=0.038). BRAF mutation is presumed to be associated with tumor progression and may predict growth of PTMC. Genetic testing including BRAF testing may help distinguishing rapid-growing thyroid cancer.