Biology and Life Sciences

Abstract: Background and Objective: The diagnosis of childhood obesity has historically relied on the Body Mass Index (BMI), which is biologically imprecise during the growth stage due to variations in adiposity rebound and the pubertal growth spurt. This study aims to validate the Tri-ponderal Mass Index (TMI), which accounts for the three-dimensional expansion of the human body, against BMI at a population level. It uses Primary Care Big Data to improve the early detection of metabolic risk. Materials and Methods: An observational, cross-sectional study was conducted using electronic health records from the Basque Country public health network (Osakidetza) for the year 2026. Following a rigorous data cleaning process, a validated cohort of 21,371 patients aged 0 to 18 years was analyzed. TMI and BMI values were grouped by exact decimal age (in 0.5-year intervals) and statistically compared against the 2011 Orbegozo Foundation population reference standards. Results: While BMI displayed the classic biphasic “J-shaped” curve, TMI demonstrated a remarkable biological plateau and robust cross-sectional stability between 6 and 14 years, consistently fluctuating between 13.0 and 14.5 kg/m³. Furthermore, the contemporary cohort exhibited significantly higher body mass (p < 0.001) compared to the historical 2011 Or-begozo standards from 9.5 years onwards. In addition, the baseline stability of TMI facilitated a clearer statistical detection of the subpopulation with extreme adiposity and high metabolic risk. Conclusions: TMI proves to be a biomechanically superior, more stable, and physiologically coherent index than BMI between the ages of 6 and 16. It is posited as the clinical tool of choice in Primary Care to identify the metabolically unhealthy obese phenotype and optimize patient referrals to Pediatric Endocrinology.

Abstract: Insulin resistance has a key role in type 2 diabetes (T2D). However, there may be differences in transcriptomic associations of these phenotypes within different studies. Here we re-analysed data from GSE27951 and GSE20950 microarrays from adipose tissue to understand the differences in differential expression, find overlaps in differentially expressed genes and understand classification performance. We retrieved pre-processed microarray data from GSE27951 and GSE20950 using Affymetrix Human Genome U133 Plus 2.0 arrays from the Gene Expression Omnibus . We performed a differential expression between T2D and NGT (n = 10 vs 11 samples) and insulin resistant vs sensitive subcutaneous adipose tissue (IR vs IS)(n = 9 vs 10 samples). 3 samples were removed from GSE27951 as they had conflicting annotations. We performed differential expression using a probe-wise welch test. We performed false discovery rate correction using the Benjamini Hochberg method. We performed a threshold on the absolute difference in expression (log2(1.5)). Logistic regression was performed with feature selection and scaling to explore classification performance. We performed additional analysis to account for sex, perform permutation tests to understand significance of classification and look at alternative annotation. No probes met the FDR threshold of < 0.05 in T2D vs NGT. 13,124 probes met the FDR threshold of < 0.05 in IR vs IS. Once adding the effect size threshold no probes met the criteria in T2D and 3,501 probes were selected. Once adjusting for sex 3,356 probes were selected in IR. Cross validated classification using feature selection in training gave AUC values of 0.818 and 1.000 in T2D vs NGT and IR vs IS respectively. However, once performing permutation tests on classification using 100 label shuffles we found empirical p-values of 0.0495 and 0.0099. Changing the 3 conflicting annotations in GSE27951 did not give any probes meeting the FDR in T2D. The two cohorts produced substantially different differential-expression results under the implemented analytical workflow. The large IR-associated signal persisted after adjustment for sex, but technical confounding and differences between cohorts remain unresolved. Although internal cross-validation produced high AUC values, particularly for IR, these findings do not establish external predictive validity or identify clinically validated biomarkers. Further independent validation is required.

Abstract: Purpose: Routine medicolegal autopsies generally do not include systematic assessment of hepatic CYP450 protein abundance, inflammatory markers, and oxidative stress markers as potential indicators of physiological vulnerability in initially unexplained sudden infant deaths. Building on the published five-domain Metabolic Vulnerability Index (MVI), this paper introduces a streamlined four-domain operational framework designed to facilitate standardized postmortem research while preserving medicolegal priorities. The immediate objective is to establish specimen-acquisition feasibility and measurement reproducibility. Longer-term objectives include calibration and validation of the proposed measurements and classification thresholds, followed by investigation of candidate mechanistic vulnerability patterns for concordance with clinical, developmental, environmental, and toxicologic contextual variables to inform subsequent hypothesis-generating studies.Methods: The operational MVI narrows the original framework to four biologically interconnected domains. Domain 1 assesses hepatic CYP450-mediated metabolic capacity indirectly through measurement of age-referenced CYP3A4, CYP2C19, and CYP2D6 protein abundance in qualified frozen liver. Domains 2 and 3 assess inflammation-associated processes through hepatic C-reactive protein (CRP) immunoreactivity and oxidative stress through 4-hydroxy-2-nonenal (4-HNE) protein-adduct immunoreactivity, respectively, using immunohistochemistry in formalin-fixed, paraffin-embedded liver tissue. Domain 4 addresses documented xenobiotic exposure through contextual interpretation of finalized routine forensic toxicology findings. The revised workflow eliminates additional research requirements for femoral venous blood and specifically oriented medulla/pons specimens. Original quantitative measurements and supporting assessment data are retained independently of their provisional Tier 0–3 classifications, preserving the underlying evidence for subsequent empirical analyses of distributions, variability, interdomain associations, and refinement of classification thresholds rather than reducing the data permanently to categorical scores. Specimen qualification, analytical evaluability, interpretive scorability, missing evidence, and scoring-rule versions are documented separately. Missing or unevaluable evidence is not assigned Tier 0 or interpreted as a normal finding.Results: The proposed framework specifies provisional Tier 0–3 classifications for each scorable domain. Complete four-domain profiles generate an unweighted composite MVI score ranging from 0 to 12 and one of 16 descriptive four-bit configurations representing candidate patterns of physiological vulnerability. The framework establishes standardized documentation requirements, scoring rules, and specimen-adaptive procedures intended to support consistent implementation across participating medicolegal investigations. These represent methodological outputs rather than empirically validated findings.Discussion: Consolidating three research measurements within hepatic tissue and incorporating existing forensic toxicology findings may reduce additional specimen demands and facilitate integration with routine autopsy procedures. This narrower approach preserves investigation of selected interconnected metabolic, inflammatory, oxidative, and exposure-related processes but excludes direct assessment of brainstem serotonergic and respiratory-autonomic vulnerabilities addressed by the original MVI. Prospective investigations must evaluate specimen acquisition, laboratory performance, reproducibility, personnel burden, potential autopsy delays, and incremental costs.Conclusions: The four-domain operational MVI provides a standardized, specimen-aware framework for investigating candidate physiological vulnerabilities in initially unexplained sudden infant deaths. Its operational feasibility, measurement reproducibility, and biological interpretability remain to be established through prospective investigation. The framework incorporates provisional, heuristically derived, literature-informed age-specific minimum-abundance thresholds for CYP450 proteins and investigator-selected immunohistochemical staining conventions. If reliable specimen acquisition and reproducible measurements can be demonstrated, subsequent adequately powered studies may empirically calibrate and validate these thresholds, characterize biological variability, and investigate candidate mechanistic vulnerability patterns and their concordance with contextual variables. The framework remains exploratory, is not a diagnostic test, and does not establish individual causation of death.

Abstract: Chronic inflammation and subfertility converge on a number of ligand-dependent transcription factors induced by chemically heterogeneous environmental exposures. Foremost among them is the aryl hydrocarbon receptor (AhR), of the basic helix-loop-helix (bHLH)–PER-ARNT-SIM (PAS) superfamily. Identified first as the receptor for dioxins and long regarded as a mediator of xenobiotic toxicity, AhR is now established as a regulator of physiological homeostasis, responding to microbial, dietary, phytochemical substances and endogenously generated metabolites. In this review, we examine AhR ligands and the transcriptional programmes they elicit, organising the evidence around one distinction: whether a ligand is a substrate for the cytochrome P450 enzymes it induces, and therefore self-limiting, or whether it persists and converts a single exposure into a chronic stimulus. We follow the receptor through the gastrointestinal tract, skin and adipose tissue; through the eye, where biallelic loss-of-function genetic variants cause foveal hypoplasia and retinitis pigmentosa and through the reproductive axis, where AhR sets ovarian aromatase expression, follicular recruitment, spermatogenesis and trophoblast invasion. Spanning the good, the bad, the ugly and the blind, we argue that therapeutic progress depends not on deciding whether to activate or inhibit AhR, but on confining modulation to a defined tissue, ligand residence time and transcriptional output.

Abstract: Type 2 diabetes (T2D) is associated with transcriptional and proteomic heterogeneity in human pancreatic islets, yet inter-individual variance is rarely treated as a phenotype in its own right. We tested whether variance captures disease-associated information missed by mean-based analysis, focusing on crinophagy, the direct lysosomal degradation of insulin secretory granules (iSGs). A 31-member crinophagy set and a 14-member macroautophagy comparator were pre-registered before analysis and evaluated in a discovery proteomics cohort of 129 organ donors and an independent RNA-seq cohort of 54 donors (18 non-diabetic, 36 T2D), with adjustment for batch, immune infiltration, and b-cell content. Global proteome dispersion did not differ between groups (centroid-distance ratio 1.05, permutation P = 0.71), and the mean crinophagy-set abundance was unchanged by glycemic status (P = 0.88). In contrast, crinophagy-set variance was greater than expected from size-matched random gene sets (median SD ratio 1.178 vs 1.078, permutation P = 0.036), with no corresponding shift in the comparator set (P = 0.71). UNC13D and STX7 ranked at the 99.38th and 99.09th percentiles of 20,255 expressed genes. UNC13D showed closely concordant SD ratios in discovery proteomics and replication RNA-seq (2.065 and 2.001), whereas RAB3A did not replicate (1.725 and 1.101). Neither UNC13D nor STX7 showed a corresponding mean-expression difference in independent single-cell b-cell data. Inter-individual variance therefore identifies molecular differences in T2D islets not captured by mean-based analysis, with UNC13D providing a reproducible variance phenotype across independent cohorts and molecular platforms.

Abstract: Background/Objectives: This study evaluated potential temporal associations between international histopathological classifications, staging updates, and the long-term divergence observed between papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) incidence trends. Applying an advanced statistical protocol comprising the recursive Supremum Chow Test, Piecewise Segmented Regression with Regime Switching (PSR-RS), and a non-linear Markov-Switching Intercept and Slope (MSIA) model, we analyzed population-level annual incidence rates (AIR) in the United States from 1975 to 2023. Methods: We implemented a two-pronged approach to identify and validate structural trend changes in incidence trends. Approach 1 tracked endogenous, data-driven incidence shifts, while Approach 2 tested the fixed calendar milestones corresponding to the official publication dates of major classifications. Crucially, this multistage analytical protocol was applied directly to the individual PTC and FTC series, as well as to the scale-independent log ratio, ln ( PTC /FTC ) and aggregate diagnostic gap timelines. Results: The results show that the incidence gap between the two cancers widened until 2014 and stabilized thereafter. AG quadrupled from 2.9 per 100,000 population in 1975 (PTC AIR = 3.6 minus FTC AIR = 0.7) to 11.6 in 2014 (PTC AIR = 12.8 minus FTC AIR = 1.2) with no further increase thereafter (AG = 11.6 in 2022 and 2023). Under Approach 1, the natural breakpoints partitioned the timelines into highly diverse behavioral segments. Specifically, the data identified five evolutionary regimes for PTC, three independent regimes for FTC, and four distinct regimes for AG. The breakpoint identified in 1987 coincided with the staging updates introduced that year and marked a clear change in the incidence trends of both histotypes. Between 1987 and 1991, PTC incidence increased, while FTC incidence declined toward its historical minimum. Despite these changes, the aggregate diagnostic gap continued along its existing trend, with no structural break detected. The 2004 WHO third edition corresponded to a systematic upward level shift (β2 = +4.1500) associated with the formal codification of microcarcinomas. Finally, both analytical approaches converged on 2014 as a significant historical turning point in the slowing of incidence growth. This phase is characterized by a significant negative slope change (Δβ = - 0.35) consistent with conservative classification updates and subsequent stabilization at a structural plateau. Conclusions: The progressively widening AIR gap between PTC and FTC does not appear to reflect a purely biological phenomenon. Instead, these population-level changes are highly consistent with systematic reporting shifts and diagnostic thresholds introduced in successive international staging and histopathological classifications.

Abstract: Zepbound (tirzepatide) is among the most effective obesity medicines for weight reduction, in both clinical trial and real-world settings. Product marketing largely centers on weight-loss magnitude, which may reinforce the expectation that larger reductions are always better. Using de-identified EHRs, we compared 1,039 Zepbound initiators (1.7%) whose first-year weight loss reached ≥30% (“excessive weight loss”) with 20,668 Zepbound initiators (34.7%) who lost 5%-15% (“moderate weight loss”). After 1:4 propensity score matching (837 versus 3,348 patients), large language model (LLM)-curation extracted 24 adverse events that physician notes explicitly attributed to weight loss. The rate of any weight loss-attributable adverse event was significantly higher with excessive weight loss, at 39.4 versus 14.4 per 100 patient-years, representing 294 (35.1%) versus 479 (14.3%) patients (rate ratio [RR]: 2.78, 95% confidence interval [CI] 2.40-3.21; P<0.001). Falls, weakness, syncope, alopecia, low blood pressure, gastro-intestinal symptoms, and muscle loss were significantly enriched in the excessive weight loss cohort after false-discovery-rate correction (all q<0.001). Hospitalization was documented in 215 patients (25.7%) with excessive weight loss versus 527 patients (15.7%) with moderate weight loss (RR: 1.63, 1.42-1.87), Intensive care admission in 44 patients (5.3%) versus 77 patients (2.3%) (RR: 2.29, 1.59-3.28) (both q<0.001), and newly recorded heart-failure diagnosis in 11 patients (1.3%) versus 16 patients (0.5%) (RR: 2.75, 1.28-5.91; q=0.028). Laboratory tests and vital measurements recorded within 30 days of the lowest achieved body weight corroborated these findings, including significant enrichments in systolic (<90 mmHg) or diastolic (<60 mmHg) hypotension (RR: 3.19, 95% CI 2.51-4.05), anemia (RR: 1.86, 1.45-2.40), hyponatremia (RR: 2.74, 1.63-4.60), hypokalemia (RR: 2.34, 1.58-3.46), hypocalcemia (RR: 3.25, 1.87-5.68), hypoalbuminemia (RR: 2.93, 1.83-4.70), and hypoproteinemia (RR: 3.89, 2.32-6.52) in excessive weight loss patients (all q<0.001). While residual confounding and documentation differences may contribute to some real-world associations, the significantly greater burden of adverse events, hospitalization rates, laboratory test anomalies, and vital-sign abnormalities among Zepbound patients with excessive weight loss warrants further investigation. These findings support moving towards individualized weight-loss goals, motivate the need for prospective studies into the risk-benefit profile of Zepbound, and call for closer scrutiny of pharmaceutical marketing to clarify that the greatest weight reduction may not translate into better health outcomes.

Abstract: Alzheimer’s disease (AD) affects women more than men, with risk increasing during and after the menopausal transition. Estrogen deficiency has long been a leading explanation for this sex difference, but emerging evidence suggests that follicle-stimulating hormone (FSH) may represent an additional, contributory endocrine factor. This narrative and mechanistic review integrates evidence on reproductive aging, AD pathobiology, and sex differences in AD, with particular emphasis on endocrine, metabolic, protein-clearance, inflammatory, and vascular mechanisms. PubMed and Google Scholar were searched for peer-reviewed human studies, animal models, and mechanistic investigations published through September 2026, prioritizing primary research and systematic reviews concerning FSH signaling, ApoE biology, and AD pathophysiology. Circulating FSH rises markedly across the menopausal transition and has been associated with cerebral amyloid burden in women, although the magnitude of this association is modest relative to established genetic risk factors such as APOE ε4 and causal directionality has not been established in humans. Preclinical studies further suggest that elevated FSH may influence pathways relevant to AD, including C/EBPβ–δ-secretase signaling, neuronal glucose metabolism, mitochondrial function, autophagic-lysosomal clearance, and apolipoprotein biology. Several steps within these proposed mechanisms, including the predominance of Gαi coupling by neuronal FSH receptors and any direct FSH action on microglia, remain incompletely established. Dysregulation across these interrelated systems may contribute to Aβ accumulation, tau pathology, impaired protein clearance, and chronic neuroinflammation, while reproductive aging is also associated with vascular and blood-brain barrier changes that may precede classical AD pathology. Taken together, current evidence supports a model in which sustained FSH elevation may act as one component of the broader biological changes accompanying reproductive aging that influence AD vulnerability. Further human and mechanistic studies are needed to determine the magnitude, cellular pathways, and therapeutic relevance of this contribution.

Abstract: This study investigates the metabolic parameters of prenatal exposure to low doses of Bisphenol A (BPA) and its analogues, BPS and BPF, and the subsequent effects of high-fat diet (HFD) challenge in offspring during adulthood. Pregnant Sprague Dawley rats received saline (control), BPA or BPS (5 µg/kg BW), or BPF (1 µg/kg BW) via oral gavage from gestation days 6–21. Offspring growth, fat deposition, glucose tolerance, insulin, corticosterone, and cholesterol levels were measured in male and female offspring. Prenatal BPA exposure reduced food intake in males and induced pronounced glucose excursions in chow-fed females, which improved over time. In males, BPA caused a rapid 30-min glucose spike and increased body weight, fat, and lean mass following HFD. BPS exposure resulted in mild postnatal growth retardation and reduced food intake in chow-fed females, while males showed increased fluid mass. BPS females exhibited sharp glucose declines after 2 weeks, and HFD led to reduced brown adipose tissue. In males, BPS increased liver and serum cholesterol following HFD. BPF exposure increased water intake and led to greater fat accumulation after HFD, along with reduced fluid mass in males. HFD increased adiposity across groups, with sex-specific differences in body composition but no major effects on glucose tolerance. These findings demonstrate that low-dose prenatal exposure to BPA analogues alters metabolic parameters in offspring, with sex- and compound-specific effects, which can be modulated by dietary challenge.

Abstract: Introduction: Perimenopause is associated with adverse body composition and strength changes, yet resistance training and creatine monohydrate (CM) remain underrepresented in this population. This study examined the effect of six-weeks of high-intensity resistance training (HIRT) with or without CM on body composition, muscle size and quality, strength, volume, and sleep in perimenopause. Methods: Fifty-one perimenopausal women (Age: 46.2±4.6 years; Body Mass Index: 25.4±4.0 kg/m2) were randomized to CM, placebo (PL), or control (CON). CM and PL completed a 5-day loading (CM: 20g/day; non-caloric PL: 14.5g/day), followed by a maintenance phase (CM 4.5g/day; PL gummies) combined with six-weeks of HIRT; CON maintained normal activity. Lean soft-tissue (LST; kg) was assessed from dual-energy x-ray absorptiometry. Muscle characteristics were determined from peripheral quantitative computed-tomography [muscle area (MuA); cm2; muscle density (MuD); mg/cm3]; and ultrasound [muscle cross-sectional area (mCSA): cm2; echo intensity (EI): a.u.]. Sleep was determined from a wrist-worn wearable. Results: CM resulted in increased LST compared to PL (mean difference±standard error: 0.380±0.431 kg, p=0.999) and CON (1.052±0.474 kg, p=0.096). Muscle size increased in CM compared to CON (MuA: 6.11±2.19 cm2; mCSA: 3.222±1.051 cm2; p=0.011-0.023), but not PL. No main treatment effects were observed for MuD or EI. Both lower (CM: 139.6±34.1 lbs; PL: 126.2±31.5 lbs; p< 0.001) and upper body (CM: 9.0±3.4 lbs; p=0.031; PL: 8.1±3.0 lbs; p=0.032) strength increased compared to CON, with no volume differences. No training by treatment interactions were observed for sleep. Conclusion: HIRT improved muscle outcomes, with CM adding 0.38 kg to LST and 148.6 lbs to strength.

Abstract: Transdermal drug delivery is an effective and, for some substances, the only feasible method. The most effective and advanced method for its implementation is the use of microneedles made of bi-odegradable polymeric materials. This study proposes a method for producing transdermal delivery patches containing microneedles on their surface. The method involves developing a 3D model of the patch master mold, 3D printing it, filling the intermediate mold with polydimethylsiloxane, and then filling the patch with a biopolymer. The biopolymers studied were PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PDLLA (poly-d,l-lactic acid). PLGA showed the best results. Two microneedle array topology variants were used. In the first case, the needles were arranged in a 34 × 34 array with a tip-to-tip spacing of 500 µm and a height of 800 µm. The base thickness was 5 mm, and the side dimensions were 20 mm. A second design variant featuring larger needles was pro-posed; this array consisted of 21 × 21 needles with a height of 1.6 mm.

Abstract: Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, which, together with associated metabolic abnormalities, contributes to progressive damage in multiple organ systems. The development of effective and safe therapeutic alternatives remains a major research priority. Phlorizin is a dihydrochalcone that inhibits sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2). 4‐ortho‐mono‐fructosyl phlorizin (4PHF) was synthesized from phlorizin by transfructosylation with a levansucrase from Paraburkholderia phymatum (KesL) using sucrose as a donor. The in vivo antidiabetic effect of 4PHF was evaluated using a murine model of experimental diabetes (high-fat diet followed by a single streptozotocin dose). Groups were treated as follows for 28 days: Non-Diabetic control group received only distilled water; a group receiving 4PHF, and a group treated with a SGLT2 inhibitor, dapagliflozin. 4PHF exhibited a tendency to reduce blood glucose levels, increased urinary glucose excretion, improved lipid profile by lowering triglycerides and total cholesterol. Histologically, 4PHF showed clear hepatoprotective and renoprotective effects. Immunohistochemistry revealed a marked decrease in SGLT2 expression and in the number of SGLT2-positive tubules in treated animals, suggesting that the treatment may modulate SGLT2 inhibition. Overall, 4PHF emerges as a promising therapeutic candidate for diabetes mellitus, as it reduces renal SGLT2 expression, improves metabolic dysfunction, and attenuates diabetes-induced hepatic and renal damage.

Abstract:

Circadian light exposure influences cardiometabolic health, yet the extent to which genetic variation modifies this relationship remains unclear. We investigated whether MTNR1B rs10830963 genotype modulates blue-light exposure (BLE) patterns and blood lipid profiles in 63 Arctic residents (35 G-carriers) measured around the winter solstice and spring equinox. Participants were stratified by genotype (CC homozygotes vs. G-allele carriers) and contributed weeklong actigraphy data undergoing time-resolved analyses, mixed-effects and cosinor modeling. Genotype-dependent seasonal changes were observed in light-hygiene indices, including the normalized amplitude of BLE (NA BLE) and the nocturnal excess index of BLE (NEI). G-allele carriers also exhibited a less favorable lipid profile, with higher morning LDL-C, TG/HDL-C ratio, and Castelli risk index I, together with lower HDL-C in both seasons. A larger NA BLE was associated with lower TG, TG/HDL-C ratio, and Castelli index, and higher HDL-C, with stronger associations in G-allele carriers. Time-resolved analyses further showed that associations between morning fasting lipid values and 24-h BLE, assessed across 30-min exposure bins within each season, were rhythmically patterned and more pronounced in G-allele carriers, with later acrophases. These findings suggest that MTNR1B rs10830963 modifies the link between seasonal light exposure and lipid metabolism in Arctic residents.

Abstract: Semax and Selank are synthetic regulatory peptides that are not FDA-approved for human use but are marketed direct-to-consumer for cognition, mood and stress resilience. The extent of the documented use of these unapproved peptides in routine clinical care remains poorly characterized and, because neither is dispensed through regulated pathways, is largely absent from structured medication data of Electronic Health Records (EHRs). Using Large Language Model (LLM) curation of de-identified clinical notes from the nference federated data network with manual adjudication of the LLM-curated insights, here we characterize the clinically documented use of each peptide and the real-world medical contexts in which their use occurs. Clinical note documentation of both Semax and Selank increased starting in 2024, with an average quarter-over-quarter growth of 14% for Semax and 16% for Selank over the past year. Among 43 and 39 patients with clinical note-mentions of Semax or Selank, use was confirmed via LLM curation in 22 (51%) and 27 (69%) patients, respectively. Physician adjudication agreed with the LLM’s use classification in 164 of 165 individual note-level assessments (99.4%) across patients with a Semax or Selank mention, including patients whose use was not confirmed. In the pooled cohort of patients with confirmed Semax or Selank use (N = 49), cognitive enhancement (28.6%) and mood/anxiety/stress support (28.6%) were the most common reasons for use provided by the patients, with less common reasons including energy or performance, sleep, musculoskeletal and gastrointestinal indications. Manual adjudication showed 86.7% agreement with the LLM-curated reasons for use. Both peptides were commonly administered intranasally (37%), and there was documentation of “stacking” with other peptides in 33 patients (67%), such as CJC-1295, ipamorelin, semaglutide, and tirzepatide. In the pooled cohort, clinical notes recorded patient-reported positive or effective responses in 16 of 49 patients (33%) and product- or administration-related safety concerns or adverse-event sentiments in 13 of 49 (27%). Manual adjudication agreed with LLM-curated self-reported-effect classifications in 94.2% of 103 reviewed records. Manual review showed isolated dyspnea, palpitations, flushing, and emergency department visits during the temporal periods overlapping with patient-reported use of Semax or Selank (n<11). This study is not designed to evaluate the effectiveness or harm of Semax or Selank. Rather, it highlights the rising use of unapproved direct-to-consumer peptides without any structured coding mechanism in EHR systems, emphasizing the need for greater awareness among healthcare practitioners.

Abstract: Background/Objectives: Oral semaglutide (Wegovy pill) and orforglipron (Foundayo) were recently approved for chronic weight management. Their safety and effectiveness have not been evaluated in real-world practice, particularly during the first few months when dose escalation, early treatment response, and tolerability may shape adherence.Methods: We retrospectively analyzed de-identified electronic health records through September 2026, including 16,220 oral Wegovy and 1,106 Foundayo recipients. Propensity matching on demographics, baseline characteristics including cardiometabolic burden, incretin history, the date of treatment initiation, and clinical visit frequency yielded 756 adult patients per drug. Clinical notes were curated with large language models (LLM), validated by physician adjudication.Results: In the unmatched cohorts, prior incretin exposure was recorded in 56.0% of oral Wegovy users versus 63.8% of Foundayo users (P<0.001). Prior injectable Wegovy use predominated among subsequent oral Wegovy users, whereas prior Zepbound use predominated among subsequent Foundayo users (both P<0.001). Dose escalation by day-90 lagged the recommended schedules for both agents. In matched cohorts, despite similar pre-treatment weight trajectories, mean weight change by 90 days after GLP-1 pill initiation was −3.1% with oral Wegovy (n=26) versus +0.4% with Foundayo (n=18), corresponding to a 3.55-percentage-point difference (95% CI, 1.02-6.08; P=0.007). Post-treatment initiation, LLM-curated clinical notes with physician adjudication confirmed weight-gain in a higher percentage of Foundayo users (5.3%) than oral Wegovy users (2.4%) (RR 2.20; P=0.016). Higher documentation of abnormal lipids was also evident from the LLM-curated notes among Foundayo users (1.7%) versus oral Wegovy users (<1.4%) (RR>5; P=0.009). Serial diagnostic lab testing showed a decrease in triglycerides during oral Wegovy use (−31.6 mg/dL; P=0.011, n=19) and a decrease in non-HDL cholesterol during Foundayo use (−30.5 mg/dL; P=0.04, n=11). Statins use did not meaningfully change upon Foundayo initiation, whereas significant statin-record frequency decrease was observed upon oral Wegovy prescribing (4.8% to 1.8%; P=0.020). Among Foundayo users, those with post-index statin co-prescriptions had numerically higher documented prevalence of abnormal lipids as expected, but also dizziness, and elevated liver enzymes than those without post-index statin co-prescriptions. Furthermore, adverse liver events and elevated liver enzymes were also numerically more frequent among Foundayo users than matched oral Wegovy users, presenting an emerging hypothesis that warrants prospective validation considering the FDA's postmarketing requirement to evaluate Foundayo liver safety and a subsequent FDA adverse-event report of hepatic failure. Conclusions: In a small subset of patients with follow-up weight measurements approximately 90 days after treatment initiation, oral Wegovy was associated with greater weight loss than Foundayo in routine care. Larger-scale and prospective follow-up analyses are warranted to more robustly compare the safety and effectiveness of these agents.

Abstract: Lipedema is a chronic, predominantly female disorder characterized by disproportionate regional expansion of subcutaneous adipose tissue, pain, tenderness and easy bruising. Although adipocyte hypertrophy, altered progenitor-cell behavior, microvascular dysfunction, extracellular-matrix remodeling, immune-cell alterations and variable lymphatic abnormalities have been reported, their causal and temporal relationships remain unresolved. Here, we propose that these findings may represent interacting manifestations of dysregulation within an adipovascular unit (AVU) rather than independent pathological processes. We define the AVU as a spatially organized regenerative niche comprising adipose stem and progenitor cells, microvascular endothelial and mural cells, immune populations, extracellular matrix and mature adipocytes, linked through reciprocal cellular, paracrine and extracellular-vesicle-mediated communication. We hypothesize that lipedema may arise when physiological, female hormone-responsive adipose remodeling encounters a regionally susceptible AVU in which regenerative activity is inadequately constrained in space, magnitude or duration. Subsequent cross-compartment remodeling could amplify and stabilize the altered tissue state, potentially linking disproportionate adipose expansion with vascular, interstitial, immune, extracellular-matrix and sensory manifestations. Current evidence is compatible with this framework but does not establish the AVU as the primary site of disease initiation or demonstrate a self-maintaining regenerative state. We therefore derive falsifiable predictions involving paired affected and spared adipose depots, context-dependent endocrine responses, functional cross-talk between AVU compartments, extracellular-vesicle transfer, spatial biological boundaries and persistence after stimulus withdrawal. Testing these predictions using spatially resolved and multicellular experimental systems should determine whether AVU dysregulation represents a causal organizing principle of lipedema biology or a descriptive consequence of disease.

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.