Obesity

Background and AimsThe glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has demonstrated efficacy for the secondary prevention of cardiovascular disease among patients with overweight/obesity without diabetes mellitus. However, the comparative effectiveness of GLP-1 RA versus other antiobesity medications (e.g. phentermine-topiramate) not been evaluated. MethodsThis was a retrospective, observational, cohort study using target trial emulation methodology using the Truveta electronic health record database of more than 120 million patients. Adult patients with a body mass index (BMI) >=27 kg/m2, a history of cardiovascular disease (prior ischemic stroke, transient ischemic attack, or myocardial infarction, or known coronary artery disease, heart failure, or peripheral artery disease) without diabetes mellitus were included in the study. The primary endpoint was time to first major adverse cardiovascular or cerebrovascular event (MACCE, defined as stroke or myocardial infarction). ResultsIn total, 35,240 were included in the bupropion-naltrexone versus GLP-1 RA comparison, and 27,051 were included in the phentermine-topiramate versus GLP-1 RA comparison. In the pre-weighting cohort, GLP-1 RA use was associated with decreased hazard of MACCE compared to bupropion-naltrexone (HR 0.50 [95% confidence interval (CI) 0.36-0.69]) and phentermine-topiramate (HR 0.43 [95% CI 0.30-0.60]). In the propensity score-overlap weighted cohort, GLP-1 RA prescription was not associated with a lower hazard of MACCE than bupropion-naltrexone (aHR 0.69 [95% CI 0.47-1.00]) but was associated with a lower hazard compared to phentermine-topiramate (aHR 0.61 [95% CI 0.41-0.91]; adjusted absolute rate difference 0.98 per 1000 person-years). ConclusionsPrescription of a GLP-1 RA was associated with a lower risk of subsequent MACCE than phentermine-topiramate.

Cushings disease is caused by the overproduction of cortisol. The effects of this disease are well known in a general population, including high blood pressure, diabetes, and weight gain. Cushings disease causes both obesity and metabolic related symptoms, and it can be difficult to discern the obesity-dependent from the obesity-independent mechanisms of Cushings disease. To identify patients with Cushings disease, we identified 476 Michigan Medicine patients between January 1st 2000-2025 along with propensity-matched control cases. We stratified our participants by obesity status and into a Cushings disease group and a control group. As expected, the Cushings group had an elevated BMI compared to the control group (34 kg/m2 vs 29 kg/m2). We found a higher proportion of females diagnosed with Cushings compared to males (287 vs 72). Cushings disease was associated with an increase in the fasting glucose levels in both non-obese and obese patients. In both the obese, and non-obese patients, there was an increase in ALT and AST levels regardless of Cushings disease status, but the increase due to Cushings disease was much greater in the patients with obesity (73.4 vs 35.1 mg/dL). Cushings disease also had a moderating effect on blood pressure, with participants a BMI under 30 kg/m2 increasing by 12.6 mmHg and participants with obesity increasing by only 7.9 mmHg. These findings highlight the need to consider obesity status when evaluating the effects of Cushings disease.

BackgroundDigital health self-monitoring tools are widely used to support weight management and metabolic health. Higher engagement with these tools is often associated with better clinical outcomes; however, real-world engagement-outcome relationships for consumer metabolic monitoring devices remain incompletely characterized, particularly in heterogeneous user populations. ObjectiveTo evaluate whether engagement with a portable breath-based metabolic device (Lumen; Metaflow Ltd.) is associated with greater weight loss and reduction in body fat among real-world glucagon-like peptide-1 receptor agonist (GLP-1RA) users. The study also explores correlations between engagement and a device-specific measure of metabolic flexibility (FLEX score). MethodsWe retrospectively analyzed 2,296 adult Lumen users who self-reported GLP-1RA use over 24 weeks. Engagement was quantified as total engagement days over a 24-week period and ordered engagement consistency groups defined by weekly use frequency thresholds. Weight and body fat percentage data were collected by a combination of connected devices and manual user input in the Lumen smartphone application. Associations with weight loss and reduction in body fat percentage were evaluated using linear regression and ANCOVA adjusted for age, baseline BMI, and sex, with HC3 robust standard errors. Body fat percentage data were available for only 490 of the 2,296 subjects. In addition, similar associations were evaluated for FLEX score. GLP-1RA exposure was self-reported at onboarding and not verified longitudinally. ResultsAt 24 weeks, low/medium/high engagement users lost 3.2%, 4.6%, and 5.2% of body weight (trend p=2.36x10-11). Engagement days were associated with percent weight change (slope -0.0214% per day; P(HC3)=7.9x10- 18). Engagement days showed modest association with body fat percentage change (n=490; slope -0.0105% per day; P(HC3)=.010). The adjusted ANCOVA trend across engagement groups was not significant (P=.19). Engagement days and consistency both showed a highly significant trend in increase in FLEX score (slope +0.0185 per day; P(HC3)=2.0x10- 36). ConclusionsIn a real-world digital health dataset, higher engagement with a breath-based metabolic monitoring device and its smartphone application was associated with greater 24-week weight loss after adjustment for age, baseline BMI, and sex. The absolute difference between low and high engagement (2.0% body weight) is modest but clinically meaningful in real-world settings after 24 weeks of tracking. Associations with body fat percentage change were smaller and not consistently significant in adjusted analyses. Associations with metabolic flexibility were highly significant, but it remains unknown whether this parameter is predictive or reflective. Prospective controlled studies are needed to test causality and determine whether device-driven biofeedback and sustained engagement independently improve outcomes because GLP-1RA use was self-reported and unverified, and the present analysis was observational. These findings should be interpreted as engagement-outcome associations and reflect behavioral motivation and adherence rather than evidence of device efficacy.

ObjectivesTo estimate potential launch prices of generic semaglutide following patent expiry from 2026 and to quantify the global obesity and type 2 diabetes (T2DM) burden in countries where generic access may become possible. MethodsWe used World Bank population data and World Obesity and Diabetes Atlas prevalence estimates to calculate obesity and T2DM burden in countries where semaglutide patents expire in 2026 or were not filed. Patent status was identified using MedsPaL and cross-checked with regional databases. We updated established cost-plus pricing methodologies using 2024-2025 Indian API shipment data to estimate production costs for oral and injectable semaglutide, incorporating formulation, packaging, taxation, and profit assumptions. ResultsTen countries with 2026 patent expiry represent 44% of the global population and 48% of the global obesity burden. No patent filings were identified in 150 additional countries. By the end of 2026, generic injectable semaglutide could be distributed in 160 countries where 69% of global T2DM and 84% of clinical obesity occurs. Estimated generic injectable costs ranged from $28-140 per person-year, while oral formulations ranged from $186-380 per person-year. Injection devices contributed disproportionately to total cost. ConclusionPatent expiry could substantially expand access to semaglutide at dramatically lower prices, particularly in high-burden settings. However, device costs, secondary patents, and health system constraints may limit equitable uptake without coordinated policy action. Study ImportanceO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISemaglutide is highly effective for obesity and cardiometabolic disease but remains unaffordable in many low- and middle-income countries due to high branded prices and patent protections. C_LIO_LIPrevious cost-plus analyses show that generic competition can substantially reduce prices of essential medicines after patent expiry. C_LI What are the new findings in your manuscript?O_LIUsing 2024-2025 API shipment data, we estimate generic injectable semaglutide could be produced for $28-140 per person-year following 2026 patent expiry. C_LIO_LIBy 2026, generic semaglutide could be available in 160 countries comprising 69% of global T2DM and 84% of clinical obesity burden. C_LI How might your results change the direction of research or the focus of clinical practice?O_LIProvides an evidence base for procurement planning and price negotiations ahead of patent expiry. C_LIO_LIHighlights the importance of addressing device costs and secondary patents to ensure equitable global access. C_LI

ObjectiveTo introduce and evaluate the clinical utility of the "adipo-B index" as a novel metric of the adipose tissue-pancreatic beta cell axis. To our knowledge, no prior clinical metric has integrated adipose tissue insulin resistance and pancreatic beta-cell function into a single index applicable across therapeutic classes. MethodsTreatment-naive subjects with T2DM received monotherapy with modified traditional diet for diabetes (MJDD, n=61), canagliflozin (n=67), pioglitazone (n=54), or sitagliptin (n=63). Correlations between the baseline and changes in adipo-IR or adipo-B and clinical parameters were analyzed. This is a prospective, non-randomized observational study. ResultsAt baseline, among all the subjects, adipo-B significantly correlated with FBG, HbA1c, non-HDL-C and BMI, while adipo-IR did not. At 3 months, across all therapeutic strategies, significant negative correlations were observed between the changes in ({Delta})adipo-B and baseline adipo-B. By contrast, in MJDD, canagliflozin and pioglitazone, significant negative correlations were seen between {Delta}adipo-IR and baseline adipo-IR, while with sitagliptin, no correlations were noted. {Delta}adipo-B, but not {Delta}adipo-IR, correlated with the improvements of glycemic (FBG, HbA1c) and lipid (non-HDL-C) parameters across all these therapies. While significant correlations were seen between {Delta}adipo-B and {Delta}adipo-IR with MJDD, pioglitazone and sitagliptin, canagliflozin uniquely "decoupled" this axis. With sitagliptin and pioglitazone, adipo-B improved despite weight gain. ConclusionThe adipo-B index is a superior indicator of systemic metabolic status and therapeutic response and could serve as a useful tool for precision therapy for diabetes.

BackgroundEvidence on how leisure-time physical activity (LTPA) improves lifetime body mass index (BMI) remains fragmented and prone to confounding. MethodsWe pooled 14,993 adults (30-90 y; 52.7% women; cohorts: REGICOR-ACRISC, ILERVAS, ARTPER) with baseline estimated LTPA (moderate-to-vigorous LTPA [MVLTPA] in REGICOR-ACRISC), genotype, and repeated BMI values from electronic health records (1990-2024, 36,157 measures). LTPA was categorized into cohort-specific quartiles; MVLTPA in 0, <100, <200, and [&ge;]200 METs-min/day. In one-sample Mendelian randomization analyses, we categorized participants in quartiles of a cardiorespiratory fitness polygenic risk score derived from a large GWAS in UK Biobank. Group-dependent BMI trajectories were modeled using spline mixed-effects models. Obesity onset (first BMI [&ge;]30 kg/m2) was analyzed with IPW-weighted Kaplan-Meier curves and Cox models. ResultsHigher LTPA was associated with slower BMI increases in ages 30-60 (Q1: +0.120 vs Q4: +0.075 kg/m2{middle dot}year), slower declines in ages 70-90 (Q1: -0.143 vs Q4: -0.123 kg/m2{middle dot}year), and lower obesity risk (Q4 vs Q1: HR 0.83, 95% CI 0.72-0.96). Similar trends were observed for MVLTPA. Higher genetically determined cardiorespiratory fitness showed parallel gradients (ages 30-60, Q1: +0.109 vs Q4: +0.101 kg/m2{middle dot}year; ages 70-90, Q1: -0.130 vs Q4: -0.102 kg/m2{middle dot}year) and lower obesity risk (Q4 vs Q1: HR 0.66, 0.56-0.78). Associations were present for women and men separately, but were stronger in men. ConclusionsHigher LTPA and MVLTPA were associated with more favorable lifelong BMI trajectories, delayed obesity risk, and convergent support from Mendelian randomization analyses, supporting a causal protective role of physical activity (in both sexes but stronger in men).

ObjectiveAs cannabis use has increased in the United States, so has cannabinoid hyperemesis syndrome (CHS), a disorder characterized by severe nausea, vomiting, and abdominal pain among heavy cannabis users. We previously showed that CHS symptoms are associated with several behavioral and psychological characteristics linked to psychosocial impairment. We examined links between CHS symptoms and suicidal thoughts, behaviors, and proximal suicide risk factors. MethodsWe used data from the National Firearms, Alcohol, Cannabis, and Suicide survey, a nationally representative survey of 7,034 US adults. Items assessed symptoms of CHS and suicidal thoughts and behaviors. Comparisons focused on: those with daily cannabis use and CHS symptoms (n = 191), those with daily cannabis use without CHS symptoms (n = 882), those with past year cannabis use but not daily use (n = 1288), and those without past year cannabis use (n = 4673). ResultsThose with CHS symptoms reported the highest prevalence of suicidal thoughts and behaviors with most lifetime rates being significantly higher than those with daily cannabis use without CHS symptoms. Those with CHS symptoms also reported higher mean-levels of thoughts and feelings associated with suicide (i.e., perceived burdensomeness, thwarted belongingness, defeat, entrapment) than all the other groups. ConclusionsThose with CHS symptoms reported especially high rates of suicidal thoughts, behaviors, and attempts even when compared to others with daily cannabis use. People with CHS symptoms appear to be at high risk of suicide, possibly related to distress from their gastrointestinal symptoms and psychiatric, substance use, and medical comorbidities.

ObjectivesTo examine associations between cardiometabolic conditions and health-related quality of life (HRQoL) and to evaluate whether condition-associated HRQoL changed from 2001 to 2022. MethodsWe analyzed nationally representative data from U.S. adults aged [&ge;]18 years in the Medical Expenditure Panel Survey, 2001-2022. Survey years without BMI data (2017, 2019, 2021) were excluded. EQ-5D utilities were mapped from SF-12 scores using a validated algorithm. For each survey year, survey-weighted multivariable regression models estimated associations of sociodemographic characteristics, BMI, and cardiometabolic conditions (diabetes, heart disease, high blood pressure, high cholesterol, obesity, stroke) with HRQoL measured by EQ-5D. Temporal changes in condition-associated HRQoL decrements were assessed using meta-regression across years. Associations in recent survey years were summarized using pooled estimates from 2015, 2016, 2018, and 2022. ResultsOverall HRQoL improved from 2001 to 2022 across age groups, with the largest improvement among older adults. In pooled analyses, stroke was associated with the largest adjusted HRQoL decrement (-0.0714), followed by heart disease (-0.0503), diabetes (-0.0427), high blood pressure (-0.0328), obesity (-0.0305), and high cholesterol (-0.0236). Additional adjustment for BMI attenuated condition-associated decrements, most notably for obesity (-0.0305 to -0.0183), diabetes (-0.0427 to -0.0414), and high blood pressure (-0.0328 to -0.0316). Over time, diabetes- and heart disease-associated decrements attenuated linearly (diabetes: - 0.0489 in 2001 to -0.0406 in 2022; heart disease: -0.0591 to -0.0493). High blood pressure (-0.0337 in 2001, -0.0415 in 2012, -0.0306 in 2022) and obesity (-0.0305 in 2001, -0.0283 in 2012, -0.0367 in 2022) showed nonlinear patterns. ConclusionsCondition-associated HRQoL decrements varied over time, and recent-year utility estimates are recommended for population health research. HRQoL decrements for diabetes and heart disease attenuated, consistent with improvements in treatment and survival. High blood pressure-associated were lowest around 2012, and obesity-associated became more negative after 2012, consistent with worsening blood pressure control and obesity severity.

Uric acid (UA) is traditionally regarded as a metabolic risk marker; however, its dynamic behavior during glucose-lowering therapy remains incompletely understood. We compared UA responses to a modified traditional Japanese diet (MJDD) and the DPP-4 inhibitor alogliptin in patients with early-stage type 2 diabetes mellitus (T2DM). In this prospective observational study, drug-naive patients received MJDD (n=58) or alogliptin (n=52) monotherapy for 3 months. Changes ({Delta}) in serum UA were analyzed in relation to glycemic control, insulin resistance, adipose tissue insulin resistance (adipo-IR), and beta-cell function. Both interventions significantly reduced fasting blood glucose and HbA1c while paradoxically increasing serum UA and HOMA-B. Baseline UA was the primary determinant of {Delta}UA in both cohorts. MJDD significantly reduced body mass index, insulin, free fatty acids, HOMA-R, and adipo-IR, with effects most pronounced in subjects with baseline BMI >25. In contrast, alogliptin selectively reduced adipo-IR in leaner subjects (BMI <25). Across both treatments, {Delta}UA correlated positively with {Delta}HOMA-B and inversely with {Delta}HbA1c. Notably, during MJDD, {Delta}UA showed a paradoxical negative correlation with {Delta}BMI and {Delta}FBG, and a positive correlation with {Delta}FFA. Patients exhibiting the greatest UA increases demonstrated the most marked improvements in beta-cell function and, with MJDD, the greatest weight loss. These findings indicate that MJDD and alogliptin exert distinct metabolic effects in early T2DM, yet both link rising UA to enhanced beta-cell function, suggesting that UA may serve as a dynamic pharmacometabolic biomarker reflecting therapy-specific metabolic adaptation rather than metabolic deterioration.

Background and AimsAvoidance of symptom-related situations is common in chronic gastrointestinal (GI) conditions, contributing to greater symptom severity, psychological distress, and reduced quality of life. However, no validated measure exists to comprehensively assess GI-specific avoidance. We developed and validated the GI-specific Avoidance Scale (GIAS), a self-report instrument measuring behavioral and cognitive avoidance specific to GI symptoms. MethodsFollowing literature review and multidisciplinary input, an initial pool of 58 items was generated and refined through expert and patient ratings, yielding 37 items. A sample of 102 adults (mean age 40.8 years) with medically diagnosed GI conditions completed the GIAS and validated measures of avoidance, psychological flexibility, illness shame, GI symptoms, distress, and quality of life. Exploratory factor analysis was used to determine factor structure. Internal consistency, convergent validity, incremental validity, and mediation analyses were conducted. ResultsFactor analysis supported a 20-item, three-factor solution: General Avoidance, Food Avoidance, and Intimacy/Body Exposure Avoidance. Internal consistency was excellent for the total scale ( = .94) and good-to-excellent for subscales ( = .82-.94). GIAS scores correlated positively with illness shame, GI symptoms, and distress, and negatively with psychological flexibility, self-compassion, and quality of life. GIAS showed incremental validity over a general illness avoidance measure (IBAS) in predicting GI symptoms and anxiety. Moreover, mediation models suggested that GI-specific avoidance partially mediates bidirectional associations between GI symptoms and psychological distress. ConclusionsThe GIAS is a novel, psychometrically robust, and multidimensional self-report questionnaire of GI-specific avoidance. It holds potential for clinical assessment, treatment planning, and evaluation of intervention mechanisms in GI populations.

BackgroundCannabinoid hyperemesis syndrome (CHS) is characterized by episodes of severe nausea, vomiting, and abdominal pain among those with heavy cannabis use. We estimated differences between those reporting CHS symptoms and other daily and less frequent cannabis users on drug use, psychiatric problems, other health problems, antisocial behavior, and personality. MethodsThe National Firearms, Alcohol, Cannabis, and Suicide survey was administered to 7034 US adults in 2025. Survey items assessed substance use, common psychiatric symptoms, personality traits, and symptoms of CHS. ResultsThose with CHS symptoms reported the highest rates and greatest variety of drug use compared to others who used cannabis. Those with CHS symptoms reported higher rates of other drug use than those who used cannabis daily without CHS symptoms across a variety of drug classes, including opioids, hallucinogens, and sedatives, higher rates of drug overdoses, and greater use of all drug classes than those with less-than-daily cannabis use. Those with CHS symptoms also reported more depression, anxiety, sleep problems, chronic pain, antisocial behavior, intimate partner violence, and disinhibited personality traits than those who used daily (mean d = 0.58) and less frequently (mean d = 0.69) and those with no cannabis use in the past 12 months (mean d = 0.99). ConclusionsThose with CHS symptoms exhibit a variety of psychological and behavioral problems including higher rates of other drug use, psychiatric symptoms, antisocial behavior, and dysfunctional personality traits. Results highlight the importance of understanding and addressing the broader psychosocial challenges faced by people experiencing CHS symptoms. Highlights O_LICHS symptoms are linked to greater polysubstance use and overdose risk C_LIO_LICHS symptoms are associated with depression, anxiety, sleep, and pain problems C_LIO_LICHS tied to antisocial behavior and intimate partner violence C_LIO_LICHS shows disinhibited personality traits and low well-being C_LIO_LINational survey identifies high-risk psychosocial CHS profile C_LI

Many Asian American (AA) subgroups experience disproportionate rates of cardiometabolic (CMB) conditions, yet the contextual drivers of these disparities remain unclear. Little is known about the role of Asian residential segregation, often conceptualized as Asian enclaves, with limited prior work largely ignoring region of origin and nativity. Using six years of population-based survey data from New York City (N>6,000 AAs) linked with multiple sources of community data, we examine how residence in ethnicity-specific enclaves relates to CMB risks (obesity, hypertension, and diabetes), whether these associations differ by nativity, and the extent to which neighborhood socioeconomic conditions, the built environment, social cohesion, and institutional support account for observed associations. Our combined concentration-based and spatial clustering analysis identified five East Asian enclaves and six South Asian enclaves, with no geographic overlap between the two. Logistic regression analyses show that residence in an East Asian enclave was associated with lower odds of obesity (OR=0.63), while residence in a South Asian enclave was linked to higher odds of diabetes (OR=1.42) and hypertension (OR=1.46). These associations were present only among foreign-born individuals. After adjusting for neighborhood characteristics, the lower obesity risk in East Asian enclaves persisted, while elevated risks in South Asian enclaves were partly reduced. Both suggest a role for unmeasured enclave factors, including cultural and food environments. Our findings challenge the view that Asian enclaves are monolithically health-promoting and redirects scholarly attention toward disaggregated approaches to investigating AA health disparities.

BACKGROUNDVisceral adipose tissue (VAT) has been associated with cardiovascular disease (CVD) mortality. However, the comparative performance of VAT-related clinical surrogates remains poorly characterized. OBJECTIVESTo evaluate the performance of seven VAT-related clinical surrogates for predicting CVD and cause-specific CVD mortality. METHODSWe analyzed data from the Mexico City Prospective Cohort, a population-based prospective cohort study, with baseline recruitmetn between 1998 - 2004 and ongoing mortality follow-up. CVD mortality included deaths from cardiac, stroke-related, and other vascular causes. Seven VAT-related surrogates (METS-VF, CVAI, EVA, DAAT, LAAP, VAI, and DAI) were estimated using clinical, biochemical, and anthropometric data at baseline. Associations with outcomes were evaluated using Cox regression models to estimate adjusted hazard ratios (aHRs). Discrimination was assessed with Harrells C-statistic (Cs) and fixed-point at 10-years receiver operating characteristic (ROC) curves, and calibration with slope plots. RESULTSIn a subsample of 102,385 participants (median age: 47 years; 67% female), 4,068 (3.97%) died from any CVD causes. METS-VF (Cs: 0.722; aHR: 1.17, 95% CI: 1.12-1.23), EVA (Cs: 0.72; 1.14, 1.12-1.23), CVAI (Cs: 0.70; 1.13, 1.09-1.18), and DAAT (Cs: 0.626; 1.13, 1.09- 1.18) were positively associated with CVD mortality and showed the highest predictive capacity among the surrogates. Adding METS-VF to a CVD risk score among individuals classified as intermediate risk improved discrimination for CVD mortality. CONCLUSIONSIn this large cohort of Mexican adults, four VAT-related clinical surrogates, particularly METS-VF, demonstrated good discriminatory performance for long-term CVD mortality. These indices could help to identify individuals with high VAT accumulation and high CVD risk in resource-limited settings.

BackgroundPhysical activity is a key modifiable determinant of health, yet current guidelines primarily emphasize moderate-to-vigorous physical activity and provide limited guidance on other actionable dimensions such as daily step count and sedentary time. The growing availability of wearables enables high-resolution measurement of these metrics and assessment of their associations with clinical outcomes. MethodsMinute-level wearable data from adult participants of All of Us between 2015-2023 were used to calculate step count and sedentary time. Patterns of step count and sedentary behavior were assessed across temporal scales, U.S. states, and sociodemographic groups. Phenome-wide association (PheWAS) and dose-response analyses were conducted to evaluate associations with incident disease. ResultsAmong 50,300 participants (68% female, 71% White, median age 55 years), 19,845,612 person-days of wearable monitoring over a median follow-up of 13 months were included in this analysis. Step counts peaked at midday with weekly highs on Saturdays and seasonal highs in May, while sedentary time was highest in midafternoon and winter. Higher step counts and lower sedentary time were observed among males, individuals with higher income and education, and residents of the Northeast, upper Midwest, and West Coast. In PheWAS (n=31,446), higher step count and lower sedentary time were associated with lower risk of multiple diseases, including obesity, cardiometabolic risk factors, and mood and anxiety disorders. Dose response analyses demonstrated heterogeneous relationships across disease groups, with cardiovascular benefits plateauing beyond 9,000-10,000 steps/day and below 600-640 minutes/day of sedentary time. ConclusionsIn this nationwide cohort of U.S. adults, wearable-derived physical activity and sedentary behavior showed distinct temporal and geographic patterns with significant disease-specific associations with clinical outcomes. These findings support the use of longitudinal high-resolution wearable data for advancing personalized guidelines of physical activity and sedentary behavior.

IntroductionMechanistic research has shown that prior obesity induces durable transcriptomic and epigenetic reprogramming in adipose tissue that persists after weight loss and predisposes individuals to weight regain. This phenomenon, termed obesogenic memory (OM), is currently conceptualized primarily as a molecular process. We propose extending OM beyond adipose tissue biology to include interacting biological and sociocultural processes through which past exposures shape present physiological regulation and health-related behavior. MethodsIn-depth qualitative interviews were conducted with individuals living with obesity (n=31) and with healthcare professionals (n=18). The data were analyzed abductively to examine participants lived experiences of obesogenesis. ResultsWe developed a three-phase model of OM comprising memorizing, remembering, and rescribing. The memorizing phase describes the initial acquisition and encoding of biological and sociocultural obesogenic influences. The remembering phase captures the persistence of these influences, contributing to long-term obesity maintenance. The rescribing phase refers to processes through which obesogenic influences may be attenuated or reversed, creating conditions for sustainable health behavior change. ConclusionExtending OM to include sociocultural dimensions provides a more comprehensive understanding of obesity persistence. This integrative framework identifies multilevel targets for obesity prevention and treatment that acknowledge past exposures while supporting resilience and long-term weight management.

BackgroundGLP-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited. ObjectivesTo compare the cardiovascular effectiveness of individual GLP-1RAs and SGLT2Is. MethodsWe conducted a multi-national, retrospective, new-user active-comparator cohort study using 10 US and non-US administrative claims and electronic health record databases. The study included 1,245,211 adults with T2DM receiving metformin who initiated second-line therapy with one of six GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or one of four SGLT2Is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin). Empagliflozin (393,499; 31.6%), semaglutide (235,585; 18.9%), dapagliflozin (208,666; 16.8%), and dulaglutide (207,348; 16.8%) were most commonly used. A secondary subgroup analysis included 316,242 patients with established cardiovascular diseases (CVD). Primary outcomes were 3-point major adverse cardiovascular events (MACE: acute myocardial infarction, stroke, sudden cardiac death) and 4-point MACE (adding hospitalization/ER visit with heart failure). Secondary outcomes included the individual components. Hazard ratios (HRs) were estimated for pairwise agent comparisons while on-treatment (per-protocol) and over total follow-up using Cox proportional hazards models, with propensity score adjustments, negative control calibration, and pre-specified study diagnostics to guard against potential confounding. Random-effects meta-analysis produced summary HR estimates across data sources that passed diagnostics. ResultsAcross the study cohort, individual GLP-1RAs and SGLT2Is demonstrated broadly similar cardiovascular effectiveness, both within and across drug classes. For example, semaglutide and empagliflozin showed comparable risks for 3-point MACE (meta-analytic HR 1.05; 95% CI 0.79-1.39) and 4-point MACE (meta-analytic HR 0.95; 95% CI 0.81-1.12), with consistent findings in the CVD subgroup. Study diagnostics confirmed adequate equipoise, covariate balance and statistical power to detect similarity in HRs between 0.8 and 1.2 for commonly used agents. ConclusionsIn this large-scale real-world study, individual GLP-1RAs and SGLT2Is exhibited largely comparable cardiovascular benefits, including in patients with established CVD. These findings align with network meta-analytic estimates from major cardiovascular outcome trials and broadly support current treatment guidelines. Clinical choices should be guided by relevant factors such as safety, adherence, tolerability, cost, and patient preference, where further work is needed.

Objective To test the effectiveness of a postpartum behavioural intervention delivered by automated text messaging in reducing weight. Design Two parallel group, multicentre, randomised controlled trial. Setting Recruitment from five areas across the United Kingdom (Belfast, Bradford, Stirling, London and Cardiff) through healthcare and community pathways, including social media. Participants A diverse sample of 892 women between 6 weeks and 24 months postpartum, aged 18 years or more and with a body mass index of 25 kg/m2 or more, enrolled between May 2022 and May 2023: 445 were randomised to the intervention and 447 to an active control (comparator). Interventions Twelve months of fully automated text messages with embedded behaviour change techniques and two-way messaging components to support weight loss and maintenance of weight loss in the postpartum period by targeting dietary, physical activity and weight management behaviours. The comparator group received 12 months of text messages on child health and development tailored to child age. Main outcome measures Primary outcome: weight in kilograms at 12 months (end of intervention). Secondary outcomes recorded at 6 and 12 months were changes in weight (at 6 months), body mass index, proportions of women with weight gain or loss of 5 kg or more, waist circumference, self-reported dietary intake, physical activity and infant feeding practices. Results 674 (75.6%) participants were included in the primary analysis. There was no statistically significant difference found in the adjusted mean weight change between the intervention and active control groups (-0.1 kg (95% confidence interval -1.0 to 0.8, P= 0.84). Sensitivity analyses did not change these results. There was a small statistically significant improvement in Fat and Fibre Barometer scores at 12 months in the intervention compared with control group (adjusted mean difference 0.09, 95% CI: 0.04 to 0.14; P <0.001) and a statistically significant increase in physical activity scores (International Physical Activity Questionnaire Short Form) at 12 months in the intervention group compared with the control group (adjusted mean difference 405.3 total MET minutes/week, 95% CI: 141.3 to 669.3; P= 0.003). Conclusions A 12 month automated, interactive behavioural weight management intervention delivered by text message did not support weight loss for postpartum women but did have a positive impact on diet and physical activity behaviours.

ObjectivesTo characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohns disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. DesignProspective cohort study. SettingTwo large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. ParticipantsUK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Main outcome measuresPrimary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. ResultsA UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman {rho}: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HRper SD=2.65, 95% CI 1.57-4.48). WGCNA revealed a cluster enriched in fatty acids. Within this cluster, docosahexaenoic acid (DHA) emerged as the strongest, which mediated 17.1% of the UPF-CD association. External validation in ONE-IBD supported DHA as the strongest associated metabolite with UPF and CD. Mendelian randomization supported a causal protective effect of DHA on CD (OR=0.72, 95% CI 0.61- 0.83; P<0.001), with colocalization implicating rs174546 in the FADS1 gene. ConclusionThe adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention.

ContextPolycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with reproductive dysfunction and long-term cardiometabolic risk. Traditional phenotype classifications based on diagnostic criteria may not fully capture the multidimensional biological variability underlying endocrine and metabolic risk profiles, particularly in young women. ObjectiveTo identify data-driven endocrine-metabolic phenotypes in young women with PCOS and evaluate their association with established cardiometabolic risk markers. Design and SettingCross-sectional study conducted at a tertiary Gynecological Endocrinology Clinic in Poland between January 2018 and May 2025. ParticipantsA total of 1300 young women diagnosed with PCOS according to Rotterdam criteria were included. The primary analytic cohort comprised 1032 participants aged 16-25 years with complete endocrine-metabolic biomarker data. Main Outcome MeasuresEndocrine-metabolic phenotypes were derived using principal component analysis followed by Gaussian mixture model clustering. Cardiometabolic risk endpoints included impaired glucose tolerance (2-hour plasma glucose during an oral glucose tolerance test [&ge;]140 mg/dL), an atherogenic lipid profile (triglycerides (TG)/high-density lipoproteins (HDL-C) ratio >3.50), elevated non-HDL cholesterol ([&ge;]130 mg/dL), and a composite outcome of any abnormality. ResultsPrincipal component analysis retained 10 components explaining 81.9% of total variance. Unsupervised clustering identified two stable phenotypes (silhouette = 0.392; ARI = 0.842). Cluster 0 (n=954; 92.4%) represented a mixed endocrine-metabolic profile, whereas cluster 1 (n=78; 7.6%) was enriched for thyroid/autoimmune features, with higher anti-thyroid peroxidase antibody levels and higher thyroid-stimulating hormone. Cluster 1 showed a higher prevalence of an atherogenic lipid profile compared with cluster 0, while differences in glucose intolerance and non-HDL cholesterol were modest. Logistic regression analyses suggested phenotype-specific variation in cardiometabolic risk markers. ConclusionsIn a large cohort of young women with PCOS, data-driven analysis identified two reproducible endocrine-metabolic phenotypes, including a distinct thyroid/autoimmune-enriched subgroup. These findings highlight clinically relevant heterogeneity beyond traditional diagnostic phenotypes and support the potential value of integrated endocrine-metabolic profiling for early risk stratification in PCOS.

BackgroundEndoscopic resection is the standard treatment for rectal neuroendocrine tumors (r-NETs) [&le;]10 mm, yet the optimal technique remains controversial. Modified endoscopic mucosal resection (m-EMR) has emerged as a potential alternative compared to endoscopic submucosal dissection (ESD), but existing evidence is largely retrospective and the results of recent randomized controlled trials (RCTs) are inconclusive. AimsTo compare the efficacy and safety of m-EMR versus ESD for r-NETs [&le;]10 mm. MethodsWe systematically searched CENTRAL, PubMed, Embase, and WanFang from January 1st, 1970 to December 23, 2025 for RCTs comparing m-EMR with ESD in r-NETs [&le;]10 mm. The GRADE framework assessed evidence certainty, while trial sequential analysis (TSA) controlled random errors and evaluated conclusion validity. ResultsSix RCTs involving 440 patients were analyzed. No significant difference between m-EMR and ESD was found in histologic complete resection (RR = 1.00, 95% CI 0.97-1.03; I2 = 0%), en bloc resection rates (P = 0.75) and procedure-related complications (P = 0.94). And m-EMR was associated with a significantly shorter procedure time (P<0.00001) and lower hospitalization cost (P<0.00001). The evidence was of moderate certainty; TSA confirmed its reliability, and both cumulative and sensitivity analyses supported the robustness. ConclusionsModerate-certainty evidence indicates m-EMR achieves oncologic outcomes comparable to ESD while offering clear advantages in procedural efficiency and cost for r-NETs [&le;]10 mm, supporting m-EMR possibly as a preferred endoscopic strategy in clinical practice.