Biology and Life Sciences

Abstract: Background: The vitamin D (VD)-hyperuricemia (HUA) association in postmenopausal women (PMW) remains unclear. Our study examined the serum 25(OH)D-HUA association in this high-risk population. Methods: Our study included 7,203 PMW from six NHANES cycles (2007-2018). HUA was defined as serum uric acid (SUA) ≥360 µmol/L, and missing covariates were multiply imputed. Survey-weighted logistic regression (LR), restricted cubic spline (RCS) regression, and stratified analyses were carried out. Results: The weighted HUA prevalence was 22.5%. RCS analysis demonstrated a marked nonlinear, U-shaped association (P for overall=0.005; P for nonlinear=0.002), with the lowest odds at approximately 71 nmol/L and elevated odds at both extremes. In comparison to Q1 (< 56.5 nmol/L), fully adjusted odds ratios (ORs) were 0.79 (95% CI: 0.65-0.97) for Q2 (56.5-78.0 nmol/L) and 0.75 (0.59-0.95) for Q3 (78.0-99.1 nmol/L). The inverse association was confined to women with body mass index (BMI) ≥25 kg/m² and absent in the population with BMI < 25 kg/m² (P for interaction=0.70). Conclusions: In PMW, serum 25(OH)D displayed a U-shaped association with HUA, with the lowest odds at approximately 71 nmol/L; the inverse association was confined to overweight or obese women. Maintaining mid-range rather than high 25(OH)D concentrations may aid HUA prevention. Randomized trials are warranted.

Abstract: Background/Objectives: Papillary thyroid carcinoma (PTC) shows a striking sex disparity: women are diagnosed roughly three times more often than men, yet male sex is an independent risk factor for recurrence, disease progression, and disease-specific mortality once PTC is established. This “female incidence–male mortality paradox” has hormonal, genetic, immunological, and clinical explanations, none individually sufficient, and clinical risk-stratification has only recently begun incorporating sex-relevant molecular variables. We synthesized this evidence and evaluated an underexplored regulatory layer, non-coding RNA, as a candidate mechanistic bridge across the pathways implicated. Methods: We conducted a structured narrative synthesis of epidemiological, hormonal, genetic, immunological, and clinical literature on sex differences in PTC (over 100 candidate papers), integrated with institutional pilot data (native-classification reanalysis of tumor-only clinical exome sequencing; 18 patients, 13 female, 5 male), an independent validation query of The Cancer Genome Atlas (TCGA) thyroid carcinoma (THCA) cohort (n = 564) for two immune- and stroma-related transcripts, and a targeted review of non-coding RNA literature intersecting the mechanisms identified. Results: Global age-standardized incidence in 2022 was 13.60 per 100,000 in women versus 4.60 per 100,000 in men, while mortality rates were far closer (0.53 vs. 0.35 per 100,000); this gap narrows toward parity for small, subclinical tumors, consistent with detection and surveillance bias. Independent of detection bias, male sex remained an adjusted predictor of mortality (HR 1.46–1.63), with the female survival advantage confined to age under 55 years and a marked sex-by-BRAF/TERT genotype interaction (HR 0.70 in BRAF-wild-type disease versus 2.74–3.51 in BRAF V600E-positive disease; HR 37.77 with BRAF/TERT co-alteration). Institutional and TCGA data were consistent with a more immunosuppressive, PD-L1-low, α-SMA-high male tumor phenotype. Literature review identified the lncRNA XIST, X-linked microRNAs, and an androgen receptor–miR-146b axis as mechanistically plausible, PTC-relevant non-coding RNA regulators of these same sex-differential pathways that have not yet been analyzed with patient sex as a stratifying variable. Conclusions: The paradox reflects superimposed detection bias and multiple converging, incompletely consistent biological mechanisms that disadvantage male patients once PTC is established. Non-coding RNA regulation of these pathways is mechanistically plausible but remains untested by sex, and represents a concrete, near-term research priority for sex-stratified PTC investigation.

Abstract: Early weight-loss responses to oral glucagon-like peptide-1 (GLP-1) receptor agonists vary substantially, yet the longitudinal clinical characteristics associated with super-response remain incompletely understood. Here using de-identified electronic health records, we studied 9,287 GLP-1 receptor agonist (GLP-1 RA) treatment-naive patients with a prescription for oral Wegovy. Of 8,381 patients with an index weight, 3,011 had a follow-up weight recorded between 30 and 180 days (early clinical observation period) and were classified by their best percent weight change as non-responders (no loss), responders (>0–5% loss), strong responders (>5–10%), or super-responders (>10%). Body weight was traced back five years, and HbA1c, blood pressure, comorbidities, dose escalation, and phenotypes extracted from clinical notes using AI-augmented curation were compared across these treatment response groups. At treatment initiation, super-responders weighed less than non-responders (94.1 versus 101.7 kg; P<0.001). Five years before treatment, super-responders weighed 7.6% less than at the index date, compared with 0.8% less among non-responders (P<0.001 across groups). Super-responders subsequently lost 7.2% by day 60 and 11.4% by day 90, returning on average to their weight from five years earlier within two months. Age, sex, type 2 diabetes, HbA1c, and blood pressure did not differ across groups at treatment initiation, and neither HbA1c nor blood pressure differed one, two, or five years earlier. Super-responders more often reached significantly higher doses early in treatment than non-responders: approximately 37% versus 24% were prescribed >1.5 mg at day 30 (P=0.001), 16% versus 9% were prescribed >4 mg at day 60 (P=0.056), and 6% versus 2% were prescribed >9 mg at day 90 (P=0.022; Fisher's exact test). Systolic blood pressure at day 90 fell by 10.2 mmHg in super-responders versus 3.3 mmHg in non-responders (P=0.006 across groups; P=0.003 for trend). Among 1,978 phenotypes AI-curated from unstructured clinical notes, before the first prescription, severe obesity was documented in 19.4% of super-responders versus 36.1% of non-responders (P<0.001; q=0.003). Super-responders had more pretreatment documentation of disordered eating (7.9% versus 3.1%) and less sleep-disordered breathing (35.2% versus 48.1%) and impaired fasting glucose (3.0% versus 7.5%) than non-responders, although differences were not significant after multiple-testing adjustment (all q≥0.26). Among GLP-1 RA-naive patients initiating oral Wegovy, greater early weight-loss response was associated with a more strongly rising weight trajectory over the preceding five years rather than with baseline glycemic or hemodynamic characteristics. In this observational study, pre-treatment weight trajectory and dosage emerged as associates of early oral semaglutide response, but the outcome-defined groups and short follow-up make these findings hypothesis-generating and warrant prospective validation.

Abstract: Background/Objectives: High-fat diet (HFD) feeding disrupts systemic metabolism and hypothalamic mechanisms that coordinate energy balance. Whether quercetin modifies the coordinated transcriptional systems linking m6A-related regulation with leptin-insulin and melanocortin biology remains unclear. We examined the metabolic and hypothalamic transcriptional response to quercetin during chronic HFD exposure. Methods: Male Wistar rats were studied for 16 weeks in a 2 × 2 factorial design: Control (n = 8), Control + quercetin (n = 5), HFD (n = 5), and HFD + quercetin (n = 6). Quercetin was administered orally at 100 mg/kg/day. Body weight, fasting glucose, oral glucose tolerance, visceral adiposity, serum lipids, and terminal tissue measures were evaluated. Hypothalamic expression of 21 transcripts spanning m6A regulation, leptin-insulin signaling, melanocortin-associated genes, and oxidative response was quantified by RT-qPCR. Gene-level inference was complemented by principal component analysis, PERMANOVA, module-level analyses, bootstrap resampling, leave-one-sample-out sensitivity testing, and treatment-adjusted gene-gene covariance. Results: At week 16, HFD + quercetin reduced glucose AUC relative to HFD by 2415 mg·min/dL (q = 0.0029), visceral fat by 5.16 g (q = 0.004), and triglycerides by 47.03 mg/dL (q < 0.001), without a corresponding difference in final body weight. Sixteen of 21 transcripts met the predefined robustness criteria for the HFD + quercetin versus HFD contrast. PC1 and PC2 captured 73.5% of transcriptional variance, and the four groups differed in global molecular structure (PERMANOVA R² = 0.628, p = 0.0001). All three predefined transcriptional modules showed robust HFD + quercetin versus HFD differences. Conclusions: Quercetin attenuated major metabolic consequences of HFD feeding and was accompanied by coordinated hypothalamic transcriptional remodeling across m6A-regulatory, leptin-insulin, and melanocortin-associated domains. These data identify a transcriptional network for mechanistic follow-up without implying direct measurement of m6A activity or pathway activation.

Abstract: Nitric oxide (NO) is a central regulator of cardiovascular function, influencing vascular tone, platelet activity, and inflammatory signaling. Despite decades of work defining its molecular pathways, translation into consistent clinical application has remained uneven, with findings across experimental, biomarker, and therapeutic studies often appearing inconsistent.Part of this variability reflects how NO behaves under different biological conditions. Its effects are shaped by where it is produced, how much is generated, and the biochemical environment in which it operates. Under some conditions, NO supports vascular homeostasis, while in others it contributes to oxidative and nitrosative stress, a pattern we refer to as the nitric oxide paradox.This review revisits commonly used NO-related biomarkers, including nitrate/nitrite (NOx), asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine, and considers why their clinical interpretation remains inconsistent. It also examines the limitations of NO-based therapies, where short half-life, systemic exposure, and limited control over delivery continue to constrain outcomes.Rather than viewing these findings as conflicting, this article considers them as reflections of how NO signaling shifts across different physiological contexts. We organize NO signaling according to four interacting determinants: enzymatic source, magnitude and duration of production, cellular compartment, and the surrounding redox environment. Framing NO biology in this way may help explain variability in both diagnostic and therapeutic settings and clarify where current approaches remain limited.

Abstract: Metabolic Syndrome (MetS) is a complex cluster of metabolic disorders that significantly increases the risk for cardiovascular disease and Type 2 Diabetes Mellitus. This study aimed to elucidate the molecular architecture and systemic burden of MetS by integrating high-resolution plasma proteomics, metabolomics, and lipidomics. A cohort of 60 adult volunteers (n=37 controls; n=23 MetS) from Brazil underwent comprehensive clinical evaluation and multi-omics profiling. Clinical analysis identified HOMA-IR and triglycerides as primary predictors of MetS. Untargeted proteomics identified 589 proteins, with 26 showing significant dysregulation, including the upregulation of Intercellular Adhesion Molecule-1 (ICAM-1) and Vanin-1 and the depletion of protective Apolipoprotein D (ApoD). Metabolomic analysis identified 410 metabolites, with 27 distinct features, revealing an accumulation of branched-chain and aromatic amino acids, alongside a significant reduction in the signaling molecule 3-hydroxybutyrate. Lipidomic profiling identified 1,241 lipids, with 41 abundantly different, highlighting a profound remodeling characterized by the increase of Phosphatidylinositol (PI 40:5) and Phosphatidylcholine (PC) classes and the depletion of Sphingomyelins (SM). Integrative analysis demonstrated that MetS comprises a synchronized and multisystemic molecular disruption rather than a collection of independent risk factors. The homeostatic breakdown is characterized by the depletion of the body's antioxidant and anti-inflammatory defense, and the elevation of pro-inflammatory mediators like ICAM-1 and Vanin-1, the accumulation of lipotoxic drivers and a significant disruption in amino acid catabolism (BCAA) that overactivates the mTORC1 pathway. These findings provide a multifactorial map of metabolic dysregulation, offering a robust molecular signature for early diagnosis and the development of personalized therapeutic strategies to mitigate the systemic burden of metabolic disease.

Abstract: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) marketed as Ozempic and Wegovy, is now among the most widely prescribed medications for type 2 diabetes and obesity. Rodent carcinogenicity studies demonstrated dose- and duration-dependent thyroid C-cell tumors, prompting a boxed warning for medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2), but whether this concern extends to papillary thyroid carcinoma (PTC), a follicular-cell-derived malignancy with distinct biology, remains uncertain. This narrative review evaluates current evidence on semaglutide and PTC, examining incidence, progression in patients with existing disease, receptor expression and mechanistic data, pharmacovigilance signals, sex-based patterns, and case reports published through August 2026. A pooled analysis of 93 trials (101,732 participants) and several national cohort studies found no statistically significant increase in thyroid cancer risk, and a matched cohort of 1072 patients with existing differentiated thyroid cancer found no association between GLP-1RA exposure and structural progression over a median of 69 months. A French case-control study and two FAERS disproportionality analyses reported elevated risk signals subject to detection bias and confounding by obesity. Receptor expression and functional studies were inconsistent but did not generally support a proliferative effect of GLP-1R agonism on PTC cells. Taken together, current evidence does not support semaglutide as a driver of PTC incidence or progression, though this remains an area warranting further prospective, subtype-specific study.

Abstract: Obesity is increasingly recognized as a disorder of bidirectional communication among the gut microbiota, immune system, and neural circuits controlling energy balance and feeding behavior. This review examines how obesity-associated dysbiosis promotes chronic low-grade inflammation and disrupts appetite regulation through interconnected peripheral and central mechanisms. We discuss how impaired intestinal barrier integrity and microbial translocation drive metabolic endotoxemia, adipose and hepatic inflammation, and the release of circulating inflammatory mediators that reach the brain. Within the central nervous system, these signals promote microglial and astrocytic activation, impair leptin and insulin signaling, and disrupt hypothalamic POMC and AgRP/NPY neuronal networks. We also examine how microbial metabolites and structural components influence appetite through enteroendocrine hormones, vagal afferents, blood–brain barrier integrity, and direct actions on neural and glial cells. Particular emphasis is placed on short-chain fatty acids, tryptophan-derived metabolites, bile acids, and lipopolysaccharide, as well as their effects on GLP-1, PYY, serotonergic signaling, and mesolimbic reward pathways. Together, these mechanisms create a self-reinforcing cycle in which obesogenic diets alter the microbiota, dysbiosis amplifies inflammation, and neuroimmune dysfunction promotes hyperphagia and preference for energy-dense foods. Clarifying these microbiota–immune–brain interactions may identify new targets for restoring appetite control and interrupting obesity progression.

Abstract: Understanding organ-specific effects of multi-agonist metabolic therapies beyond weight loss remains challenging, particularly while randomized clinical trials are ongoing and treatment allocation remains blinded. Here, we evaluated whether real-world longitudinal biomarker trajectories can provide early hypothesis-generating signals associated with masked trial-medication exposure. Using propensity-matched, de-identified electronic health records from a large federated health network, we compared changes in laboratory and physiologic biomarkers across receptor-defined metabolic therapies. Semaglutide, tirzepatide, and pramlintide served as reference therapies representing GLP-1 receptor, dual GIPR-GLP1R, and amylin-pathway pharmacology, respectively. Individuals with documented participation in a blinded CagriSema/placebo clinical trial were analyzed as a single masked exposure group because active treatment assignment could not be determined from routine-care records. Twenty-five CagriSema/placebo participants were propensity matched 1:5 to tirzepatide (n=125) and empagliflozin (n=125). At 6 months, the masked CagriSema/placebo cohort showed similar changes in weight and HbA1c compared with matched tirzepatide-treated patients (weight, -7.7% vs -10.2%, P=0.27; HbA1c, -2.8% vs -5.1%, P=0.69), but larger increases in estimated glomerular filtration rate (+26.4% vs +6.5%, BH P=0.028). Compared with matched empagliflozin-treated patients, the masked cohort demonstrated larger reductions in weight (-7.7% vs -3.5%, P=0.048), mean arterial pressure (-12.0% vs -1.0%, BH P<0.001), creatinine (-17.4% vs -2.4%, BH P=0.020), and greater increases in eGFR (+26.4% vs +6.4%, BH P=0.030). To provide pharmacologic context, patients with type 2 diabetes receiving basal insulin who initiated pramlintide were independently matched to tirzepatide (652 pairs) and semaglutide (761 pairs). Tirzepatide and semaglutide were associated with larger HbA1c reductions than pramlintide at 6 months (-9.0% vs -3.0%, BH P<0.001; -10.1% vs -3.5%, BH P<0.001). However, after normalization for weight loss, pramlintide demonstrated greater blood pressure reduction per kilogram of weight lost than tirzepatide for both systolic (-4.9 vs -3.4% per kg, BH P=0.046) and diastolic blood pressure (-5.7 vs -3.4% per kg, BH P=0.029), whereas tirzepatide and semaglutide showed similar weight-normalized laboratory responses. Medication-transition analyses did not support co-intervention confounding, and single-cell transcriptomic analyses demonstrated substantially broader expression of amylin receptor components (CALCR, RAMP1/2/3) than GIPR or GLP1R in the kidney (9.8-14.7-fold). These findings illustrate how real-world longitudinal biomarker analyses can complement ongoing blinded clinical trials by identifying early, hypothesis-generating physiologic signals associated with masked trial-medication exposure. The observed renal and blood-pressure patterns, together with receptor-expression analyses, motivate prospective evaluation after trial unblinding to determine whether they reflect amylin-pathway biology or other treatment-associated effects.

Abstract: Deuterium is a natural heavy isotope of hydrogen, containing a neutron as well as a proton, making it twice as heavy. Mitochondrial ATP synthase nanomotors are highly sensitive to deuterium, causing them to release reactive oxygen species (ROS) and reducing ATP synthesis. Metabolic processes have evolved to devise ways to reduce the deuterium load in the mitochondria, primarily, we argue, by exploiting several small hydrogen-containing molecular gases. When a gas is produced, deuterium, due to its extra weight, tends to stay behind in the aqueous phase, so the gas becomes deuterium-depleted (deupleted). Furthermore, many of the enzymes that synthesize these small gas molecules are designed to exclude deuterium by exploiting proton tunneling. The gut microbes play a crucial role in producing deupleted gas molecules, such as hydrogen gas (H₂), methane (CH₄), ammonia (NH₃), and hydrogen sulfide (H₂S). During inflammatory bowel disease (IBD), activated immune cells upregulate NADPH oxidase (NOX) to produce superoxide, which is converted to hydrogen peroxide (H₂O₂) by superoxide dismutase. Some microbes can convert H2O2 into two molecules of (likely deupleted) water through anaerobic respiration. H₂O₂ readily crosses the mitochondrial membrane, and human mitochondrial glutathione peroxidase can also convert H₂O₂ to water. The glutamate-glutamine exchange that takes place between astrocytes and neurons plausibly capitalizes on NH3 to safely deliver deupleted protons to neuronal mitochondria. In this paper, we investigate how small molecular hydrogen-containing gases are handled in metabolism, from a perspective that considers the roles that deuterium might play in metabolic policy.

Abstract: Introduction: Cantú syndrome, or hypertrichotic osteochondrodysplasia, is a rare genetic disorder characterized by generalized hypertrichosis, macrosomia, cardiomegaly, and distinctive coarse facial features. What is unique about this case is the clinical challenge of distinguishing syndromic hypertrichosis from premature pubarche in early childhood, emphasizing the necessity for multidisciplinary and targeted endocrine monitoring in these patients and contributing to the sparse literature on its long-term management. Main concerns and clinical findings: An 8-year-old girl with Cantú syndrome presented for a growth assessment and evaluation of early body hair development. She exhibited striking generalized hypertrichosis on her legs, back, and face, alongside a complex cardiovascular history and chronic kidney disease. Primary diagnoses, interventions, and outcomes: A thorough physical and endocrinological evaluation revealed normal baseline androgens and elevated SHBG, effectively differentiating her syndromic hypertrichosis from a reversible endocrine imbalance (e.g., premature adrenarche or pubarche). Interventions have been largely observational for her hypertrichosis due to the lack of targeted treatments and complicating comorbidities, while her cardiovascular and renal conditions continue to be managed multidisciplinarily. Conclusion: Cantú syndrome requires a highly individualized approach. Clinicians must remain vigilant for evolving endocrine dysfunctions, particularly regarding growth and pubertal development, while supporting the profound psychosocial burden caused by the currently untreatable hypertrichosis.

Abstract: Semaglutide and tirzepatide are increasingly used for obesity and diabetes, producing substantial changes in appetite, dietary intake, body weight, glycemic control, and gastrointestinal physiology that could plausibly influence oral health. Reports of xerostomia and dental complications have emerged, but population-scale risk of new-onset oral disease remains unclear. Using de-identified electronic health records from a federated system of 29 million patients, we evaluated 15 oral and dental conditions over a 12-month follow-up period in 184,582 semaglutide or tirzepatide users after excluding patients with substantial pre-existing oral-health burden. GLP-1 receptor agonist users were propensity-score matched to patients initiating other anti-diabetic therapies (42,093 pairs) and undergoing bariatric surgery (15,793 pairs) and comparisons were performed based on structured diagnosis codes and natural language processing-derived phenotypes from clinical notes. During follow-up, 8.69% of GLP-1 users developed at least one newly documented oral-health condition, with dry mouth most frequent (5.29%). Compared with matched users of other anti-diabetic therapies, GLP-1 users had lower incidence of any oral-health condition (RR 0.74, 95% CI 0.71–0.77), dental caries (RR 0.47, 0.40–0.56), and periodontitis (RR 0.50, 0.40–0.61). Dental plaque/calculus was the only condition with higher incidence (RR 1.27, 1.02–1.56). Similar trends were observed versus bariatric surgery (any oral-health condition: RR 0.80, 0.75–0.86). Dry-mouth incidence increased with greater treatment-associated weight loss (P<0.001). Overall, semaglutide or tirzepatide initiation was not associated with broadly increased oral-health risk, although dry mouth may represent a weight-loss-associated phenotype warranting further study.

Abstract: For patients treated with semaglutide or tirzepatide, weight-loss plateau followed by regain is a major concern, yet rebound occurring while treatment continues to be documented remains underappreciated and its biological correlates are poorly understood. Using a federated de-identified electronic health record (EHR) system across over 29 million de-identified U.S. patients, we analyzed adults initiating semaglutide or tirzepatide between 2021 and 2024. Among 58,618 patients who achieved ≥5% weight loss with evaluable 1-year weight trajectories, 8,389 (14.3%) regained ≥5 percentage points from their lowest observed bodyweight ("nadir"). Post-nadir treatment was ascertained from structured prescription orders together with positive mentions of medication received from clinical notes via AI-augmented curation. Among patients with at least of 90 days follow-up post-nadir, 45.8% of weight-regain patients were documented on treatment for at least half of their follow-up at a dose maintained at or above their pre-nadir maximum dose, compared with 51.6% of sustained responders (P < 0.001). Measured at the nadir relative to treatment initiation, weight-regain patients had a greater increase in neutrophil-to-lymphocyte ratio (+0.73 vs. +0.29) and neutrophils (+0.48 vs. +0.12 ×10⁹/L), with corresponding changes in albumin (−0.12 vs. −0.03 g/dL) and HDL (−0.65 vs. +1.03 mg/dL) (all P<0.001). These differences remained significant for the 45.8% of weight-regain patients with documented evidence of maintained treatment throughout their follow-up, indicating that the nadir-centred inflammatory, acute-phase, and lipoprotein changes may not be confined to patients whose treatment documentation lapsed. Gastrointestinal diagnoses and infections also peaked in weight-regain patients during the 3 months preceding the nadir (3.23% vs. 1.26% and 2.84% vs. 1.43%, both P<0.001). When weight status was reassessed longitudinally, event rates during regained time exceeded those during maintained-loss time (all q<0.001), including nonfatal MACE (12.9 vs. 9.6 per 1,000 person-years; adjusted RR: 1.43, 95% CI 1.22–1.67), heart failure (20.1 vs. 13.6; RR: 1.66, 1.45–1.89), and cardiac arrest (1.8 vs. 0.9; RR: 2.11, 1.37–3.26). Our findings identify the weight nadir as an underappreciated transition point that may help recognize patients entering rebound while treatment continues, motivating prospective study of whether weight-loss durability can be preserved and whether doing so alters cardiovascular risk.

Abstract: Retatrutide, an investigational GIP/GLP-1/glucagon receptor agonist delivered up to 28.3% mean weight reduction in the Phase 3 TRIUMPH programs, but it has not yet received FDA approval. Using a federated U.S. EHR network of 29 million patients, we identified rapidly increasing use of non-trial products purported to contain retatrutide. LLM-aided adjudication of de-identified EHRs shows 983 patients whose clinical notes mention retatrutide, with confirmed exposure in 652 patients (66.3%), and documented supply route tracing in 531 patients (54%). Of these 531 users, 378 (71.2%) obtained purported retatrutide outside of trial participation, mostly through online or telehealth vendors (57.4%) and compounding pharmacies (29.4%). Retatrutide usage grew 1.8-fold per quarter from October 2023 through March 2026, reaching 137 new users from October–December 2025, and 228 new users from January-March 2026. Next, we conducted an analysis anchored on the retatrutide/placebo trial participants (n=89), who were nearest-neighbor matched 1:3:10:10 with compounded retatrutide (n=243), semaglutide (n=890), and tirzepatide (n=890) initiators, with matching covariates of age, race, sex, baseline BMI, diabetes status, prior incretin therapy exposure, and time since the most recent exposure. The observed weight loss among retatrutide trial participants in this routine care setting was 15.5% at 6–12 months, closely approaching the observed 16.9% mean weight loss across the retatrutide and placebo arms at 80 weeks after treatment initiation in TRIUMPH-1-4 (weighted average). Users of compounded retatrutide lost 7.2% body weight at 6-12 months, considerably less than the 15.5% observed in the retatrutide trial cohort (P=0.004) and comparable to the weight-loss achieved among matched tirzepatide users (7.7%; P=0.79). A significant increase in heart-rate was observed at 3 months for both the retatrutide trial cohort (+4.3 beats per minute [bpm], P=0.028) and the compounded retatrutide cohort (+2.5 bpm, P=0.011), which was not observed in the matched semaglutide or tirzepatide cohorts (P>0.9). The retatrutide trial cohort showed numerically higher, but not statistically significant, rates of 3-point MACE versus matched tirzepatide users (RR 1.77, 95% CI 0.19–7.94; P=0.34) and semaglutide users (RR 1.02, 95% CI 0.12–4.17; P=1.00), with similar findings for expanded MACE versus tirzepatide (RR 2.03, 95% CI 0.38–7.09; P=0.21) and semaglutide (RR 1.25, 95% CI 0.24–4.07; P=0.73). Furthermore, new-onset symptom burden was significantly elevated for the pooled retatrutide cohort (trial and compounded users combined) compared to both semaglutide and tirzepatide comparators, including higher-risk of cardiovascular symptoms (RR 1.56 [1.26-1.92], q<0.001) and neuropsychiatric symptoms (RR 1.95 [1.61-2.36], q<0.001). Taken together, accelerating gray-market retatrutide use is associated with less than half the trial-level weight loss while retaining retatrutide’s characteristic heart-rate rise and elevated cardiovascular symptom burden, underscoring the need for heightened clinical awareness and real-time real-world evidence to identify emerging risks before regulatory approval.

Abstract: Background/Objectives: Female soccer players differ from males in body composition, muscular strength, and hormonal fluctuations, which may influence performance, fatigue, recovery, and injury risk. This study aimed to characterize metabolic changes following a winter training season (WTS) and estimate an appropriate recovery period using urinary metabolomics. Methods: Urinary metabolites in female soccer players were analyzed before, and after 1 and 7 days of WTS using nuclear magnetic resonance (NMR) spectroscopy combined with multivariate analysis. Results: A total of 84 metabolites were identified in urine samples, and distinct group separation was observed by partial least squares discriminant analysis (PLS-DA) in targeted profiling. Among these, 13 metabolites, including adenine, alanine, citrate, creatine, creatine phosphate (PCr), formate, glutamine, glycine, malonate, mannitol, taurine, trimethylamine N-oxide (TMAO), and urea, showed significant changes relative to pre-WTS. Conclusions: Of the identified metabolites, seven metabolites showed significant alterations at 1 day post-WTS and tended to recover toward baseline levels by day 7. Alanine, PCr, formate, glutamine, glycine, and malonate showed decreased levels, whereas taurine exhibited the opposite trend. Although these metabolites tended to recover toward baseline by day 7, complete metabolic recovery was not observed, suggesting that recovery following WTS may require longer than 7 days.

Abstract: Background/Objectives: Type 1 diabetes mellitus (T1DM) has historically been associated with impaired linear growth and delayed pubertal development due to chronic insulin deficiency. Advances in intensive insulin therapy and glucose monitoring may have substantially reduced these effects. This study evaluated growth and pubertal development in children with T1DM treated with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) compared with healthy controls and investigated whether metabolic control was associated with anthropometric outcomes. Methods: This retrospective observational study included 177 children aged 3–18 years: 102 with T1DM (60 treated with MDI and 42 with CSII) and 75 healthy controls. Height SDS, BMI SDS, Tanner stage, biochemical parameters, and diabetes-related variables were analyzed. Comparisons, correlations and multiple linear regression analyses were performed to evaluate associations between metabolic control and anthropometric parameters. Results: No significant differences were observed between children with T1DM and healthy controls regarding height SDS, BMI SDS, or pubertal development. Likewise, no anthropometric differences were identified between the MDI and CSII groups. Fasting plasma glucose was significantly lower in the CSII group (p<0.001), whereas HbA1c was comparable between treatment modalities. Neither HbA1c nor other routinely assessed metabolic parameters showed significant associations with height SDS or BMI SDS in correlation or multivariable regression analyses. Conclusions: Children and adolescents with T1DM achieved growth and pubertal development comparable to healthy peers, regardless of insulin treatment modality. Routine markers of metabolic control were not independently associated with anthropometric outcomes, suggesting that contemporary intensive diabetes management is sufficient to preserve normal growth in most pediatric patients with T1DM.

Abstract: In type 2 diabetes, adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal insulin can improve glycemic control and reduce insulin requirements while counteracting insulin-associated weight gain. However, the extent to which incretin therapies enable patients to stop or meaningfully reduce insulin, and whether they differ in this respect from other oral antidiabetic agents, remains uncertain. Here we analyzed de-identified electronic health records from a federated U.S. clinical network, comparing patients with type 2 diabetes receiving basal insulin who initiated semaglutide, tirzepatide, or an SGLT2-inhibitor (SGLT2-i). Three comparisons were evaluated using 1:1 propensity-score matching: two incretin-versus-SGLT2-i comparisons, semaglutide versus SGLT2-i (n=1,029) and tirzepatide versus SGLT2-i (n=254), and a head-to-head incretin comparison of tirzepatide versus semaglutide (n=272). Cumulative incidence of basal insulin discontinuation and of ≥20% basal-dose reduction was estimated over 24 months. At 24 months, patients who initiated semaglutide discontinued basal insulin at a significantly higher rate than those who initiated SGLT2-i (27.8% vs 22.2%; subdistribution hazard ratio [sHR] 1.26, 95% CI 1.05–1.52; Gray P=0.013), whereas tirzepatide initiators discontinued more often than SGLT2-i initiators without reaching significance (38.4% vs 31.5%; sHR 1.22, 95% CI 0.86–1.71; P=0.263). In the head-to-head incretin comparison, tirzepatide initiators discontinued basal insulin more often than semaglutide initiators, though this difference did not reach significance (38.0% vs 28.5%; sHR 1.35, 95% CI 0.97–1.89; P=0.080). Reduction of basal insulin dose by ≥20% was significantly higher with each incretin than with SGLT2-i (semaglutide sHR 1.15, P=0.045; tirzepatide sHR 1.40, P=0.015), and, in the head-to-head incretin comparison, significantly higher with tirzepatide than semaglutide (sHR 1.29, P=0.045). These reductions in insulin use were accompanied by improved glycemic control. At 6 months HbA1c dropped 1.16 versus 0.92 percentage points for semaglutide versus SGLT2-i (P=0.013), and tirzepatide lowered HbA1c more than SGLT2-i (1.79 vs 1.44 percentage points), though not significantly (P=0.18); in the head-to-head incretin comparison, tirzepatide lowered HbA1c more than semaglutide (1.85 vs 1.30 percentage points; P=0.008). In summary, in a real-world type 2 diabetes population receiving basal insulin, incretin therapies were associated with higher rates of basal-insulin dose reduction than SGLT2-i—and semaglutide with higher rates of discontinuation—while tirzepatide produced greater dose reduction and glycemic improvement than semaglutide, motivating prospective evaluation of incretin-based insulin de-escalation strategies.

Abstract: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for type 2 diabetes and obesity, but emerging evidence from randomized trials and real-world anecdotes suggest that neurosensory adverse events merit systematic investigation. We analyzed 670,422 initiators of semaglutide or tirzepatide across a large-scale federated EHR network and ascertained 14 new-onset neurosensory phenotypes over 12 months using AI-assisted clinical-note curation harmonized with ICD-10-CM codes. Among 128,377 at-risk GLP-1RA initiators — new users with at least two prescriptions within 12 months and complete 12-month follow-up, free of any studied phenotype at baseline — 29,519 (23.0%) had at least one newly documented phenotype, most commonly hypoesthesia/numbness in 16,143 patients (12.6%) and paresthesia in 15,415 patients (12.0%). Outcome ascertainment was validated by physician-led curation, with the review of 223 AI-identified events yielding a positive predictive value of 88.8% (95% CI, 84.0–92.3). In propensity-score–matched analyses, GLP-1RA initiators were associated with a 23% lower risk than initiators of the antidiabetic medications metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, or sodium-glucose co-transporter-2 (SGLT2) inhibitors (19.7% versus 25.6%; RR, 0.77; 95% CI, 0.75–0.79; q<0.001), with significantly lower risks of hypoesthesia, paresthesia, radiculopathy or sciatica, polyneuropathy, mononeuropathy and painful dysesthesia. GLP-1RA initiators also had a 22% lower associated risk than bariatric-surgery recipients who were additionally matched on achieved weight loss (21.1% versus 27.0%; RR, 0.78; 95% CI, 0.75–0.82; q<0.001). Within GLP-1RA initiators, neurosensory event incidence increased (P for trend<0.001) from 19.3% at a normal HbA1c baseline (<5.7%) to 32.0% for severe hyperglycemics at HbA1c >12%, but showed no ordered association with achieved weight loss (P=0.867), baseline body-mass index (BMI, P=0.784) or BMI reduction (P=0.740). Maximum attained semaglutide/tirzepatide dose was also not enriched among neurosensory event developers in the matched cohort. Taken together, this observational study suggests the hallmark of neurosensory risk after GLP-1RA initiation may be glycemic burden, not the magnitude of achieved weight loss, and emphasizes that population-level neurosensory risk after GLP-1RA initiation was consistently lower than among matched antidiabetic-medication and bariatric-surgery recipients.

Abstract: Polyendocrine metabolic ovarian syndrome (PMOS), previously referred to as polycystic ovary syndrome, is conventionally diagnosed through reproductive manifestations, although its metabolic evolution before diagnosis remains poorly defined. Here we conducted an observational study of de-identified electronic health records from a large federated US network to characterize the prediagnostic evolution of PMOS through four complementary analyses. First, across a reference landscape of 1,929 clinical conditions spanning 15,087,821 people, PMOS combined high body weight at diagnosis of 94.3 kg with marked five-year prediagnostic weight gain of 10.0 kg, corresponding to 15.6%, positioning it alongside insulin resistance, metabolic syndrome and obesity rather than reproductive disorders. This condition-wide pattern placed PMOS within the metabolic disease landscape and raised the question of when the anthropometric divergence begins. Second, among 104,003 women receiving their first recorded PMOS diagnosis at a mean age of 30.9 years (s.d. 9.5) and matched controls, BMI was already higher at the earliest 15-year lookback during adolescence, averaging 23 kg m⁻² versus 20 kg m⁻², respectively (P < 0.001). During the final five years before diagnosis, mean weight increased from 85.9 kg to 94.0 kg, an 8.1 kg gain corresponding to 9.4%, and was 17.9 kg higher than in matched controls at diagnosis (94.0 kg vs 76.1 kg, P < 0.001). This established that the PMOS-associated weight gap was present during adolescence rather than emerging only near reproductive-age diagnosis. Third, among 809,719 women with BMI recorded between 5 and 20 years of age, 19,681 subsequently received a PMOS diagnosis. Ten-year cumulative PMOS incidence increased progressively from 3.3% with healthy BMI to 17.9% with obesity class III, corresponding to an RR of 5.4 (P < 0.001). Black women constituted 11.1% of the healthy-BMI group and 26.5% of the obesity class III group, a 2.4-fold difference across increasing adiposity bands (each band versus healthy BMI, P < 0.001). Thus, early-life adiposity not only preceded PMOS diagnosis but stratified subsequent incidence across a pronounced dose gradient. Fourth, among 1,416 matched case–control pairs with AI-extracted serial body-composition measurements, women with PMOS had 9.8 kg greater fat mass at diagnosis than controls (55.4 kg vs 45.6 kg, P < 0.001). Despite greater absolute lean mass, their lean-mass proportion was 3.8 percentage points lower (52.0% vs 55.8%, P < 0.001). Approximately 72% of the 14.1 kg excess total weight near diagnosis was non-lean mass, revealing that the prediagnostic weight excess was predominantly adipose. Together, these analyses trace an adiposity-linked prediagnostic continuum that begins during pediatric and adolescent years, stratifies more than fivefold variation in subsequent PMOS incidence and culminates in predominantly adipose weight excess before reproductive-age diagnosis.

Abstract: Gonadotropin-releasing hormone agonists are used to treat central precocious puberty and are increasingly prescribed in gender-affirming care. Despite well-established reproductive effects, their broader physiological effects during puberty remain poorly understood. Male and female Wistar rats received a depot triptorelin injection at pubertal onset. Body mass, food intake, and locomotor activity were monitored. After 28 days, reproductive function was assessed, and pituitary and hypothalamic gene expression was analyzed. Changes in gonadal weight, estrous cycle, folliculogenesis, seminiferous tubules’ morphology, and sperm count confirmed the suppression of pubertal maturation. Triptorelin downregulated Gnrhr and Lhb, demonstrating suppression of gonadotrope function. Despite comparable reproductive suppression, metabolic responses to triptorelin were strongly sex-dependent. Females exhibited increased body weight gain accompanied by delayed hyperphagia, whereas males showed reduced body weight gain, unchanged food intake, and increased mean locomotor speed. Female-specific transcriptional remodeling was observed in the hypothalamus, characterized by downregulation of Lepr and Npy and upregulation of Sst and Kiss1 expression. Collectively, these findings demonstrate that pubertal triptorelin treatment induces profound reproductive suppression in both sexes while eliciting sex-specific hypothalamic adaptations in pathways regulating energy homeostasis. This suggests that puberty blockers exert broader neuroendocrine effects beyond the suppression of reproductive maturation.