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Abstract Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.

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Abstract Thediagnosis of Cushing syndrome can be challenging, particularly when bilateral inferior petrosal sinus sampling (BIPSS) is required to differentiate ectopic tumors from pituitary adrenocorticotropic hormone (ACTH)-releasing tumors. When corticotropin-releasing hormone (CRH) is used as a stimulus, a state of hypercortisolism is required to suppress CRH receptors in pituitary corticotrophs, preventing the release of ACTH by normal pituitary tissue. By contrast, desmopressin acts through vasopressin receptors that are preferentially expressed in ACTH-secreting pituitary tumors, suggesting potentially different physiological behaviors during stimulation. We present the case of a 26-year-old woman with ACTH-dependent Cushing’s syndrome who underwent desmopressin-stimulated BIPSS. Hormone levels on the day of catheterization indicated eucortisolism; however, ACTH levels in the petrosal sinus confirmed the diagnosis of Cushing disease. Following transsphenoidal surgery, immunohistochemical analysis confirmed a corticotroph adenoma with positive Tpit and ACTH staining. We hypothesize that desmopressin stimulation during BIPSS may provide diagnostic information even in the absence of biochemical confirmation of hypercortisolism at the time of the procedure, because vasopressin receptors are expressed in pituitary corticotroph adenomas rather than in normal corticotroph cells. Further studies are needed to evaluate and confirm this hypothesis.

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Abstract Pheochromocytomasand paragangliomas (PPGLs) are rare catecholamine-secreting tumors that can affect systemic physiology, including bone metabolism. Although they are typically associated with genetic syndromes such as MEN2 and von Hippel-Lindau disease, PPGLs are not commonly linked to primary bone tumors. However, recent findings suggest a novel cancer syndrome involving both PPGLs and giant cell tumor of bone (GCTB) through H3F3A mutations. We report a rare case of a 53-year-old woman with multicentric GCTB, initially diagnosed at age 24, who subsequently developed bilateral pheochromocytomas. Following multiple recurrences of skeletal tumors and eventual leg amputation, imaging and biochemical evaluation revealed bilateral adrenal tumors with markedly elevated catecholamine levels. Genetic analysis identified mosaicism for a pathogenic H3F3A (G35W) variant in both adrenal and bone tumors. Surgical resection of both adrenal glands normalized catecholamine levels and resolved hypertension. The patient has remained tumor-free and normotensive for five years following adrenalectomy. This case supports the existence of a shared pathogenic mechanism linking PPGLs and GCTBs, likely mediated by postzygotic H3F3A mutations. Recognition of this association is crucial for early diagnosis, genetic counseling, and management of similar cases.

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Abstract Objective: To assess the relationship between night work, metabolic syndrome (MS) prevalence, and dietary patterns in healthcare workers at a large hospital in southern Brazil. Subjects and methods: A cross-sectional study was conducted with 156 healthcare workers (90 day-shift and 66 night-shift) from July 2023 to March 2024. Sociodemographic and occupational, sleep, dietary patterns, meal timing, anthropometric data, blood pressure, and lab test data were collected. Results: Night-shift workers had higher blood pressure, lower HDL cholesterol, and 135% greater likelihood of developing MS than those who worked during the day. They consumed more fats and less fiber. Chrononutrition analysis showed night workers had later last meals (p < 0.001), longer intervals between first and last meals (p < 0.001), and shorter night fasting (p < 0.001). Ultra-processed food consumption was similar across shifts. A shorter interval between the first and last meal in night workers was linked to a 7% lower risk of MS. Findings suggest an association between night work and higher MS prevalence, with hypertension, abdominal obesity, unfavorable lipid profile, and disrupted eating timing. Circadian rhythm disruption and misaligned eating patterns, particularly prolonged eating windows and reduced nocturnal fasting, may contribute to the increased metabolic risk. Conclusion: Interventions targeting diet and chrononutrition are essential. Occupational health programs should address the specific challenges of night work.

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Abstract Objective: To investigate the impact of dietary intake profile on body composition, physical performance, and muscle strength in patients with acromegaly. Subjects and methods: Observational, cross-sectional study involving patients with acromegaly compared with age and sex-matched controls. Body composition, including total lean mass (TLM) and appendicular lean mass (ALM), was assessed using dual-energy X-ray absorptiometry (DXA). All participants completed a Food Frequency Questionnaire (FFQ) and underwent strength and performance testing. Results: A total of 82 patients were included, 41 in the acromegaly group (AG) and 41 in the control group (CG). The AG comprised 23 women and 18 men, mean age 55.9 ± 11.8 years and mean BMI 31.1 ± 5.2 kg/m2. Muscle mass was increased in the AG, but strength and physical performance were worse compared to CG. AG exhibited a higher intake of carbohydrates, trans fats, and certain micronutrients, as omega-3, vitamin B9, and beta-carotene, compared to the CG. Niacin (R = -0.316, p = 0.004) and vitamin B6 (R = -0.320, p = 0.042) were associated with performance on the sit to stand test. Beta-carotene (R=-0.429, p=0.005), vitamin E (R = -0.321, p=0.041), and flavone (R = -0.313, p = 0.046) were associated with better time to get up and go (TUG) test performance, whereas caffeine intake (R = 0.344, p = 0.028) was associated with worse time. Additionally, niacin (R = 0.341, p = 0.029) and selenium (R = 0.317, p = 0.046) had a positive impact on the short physical performance battery (SPPB) test. Hand grip strength was positively correlated with monounsaturated fats (R = 0.387, p = 0.012) and selenium (R = 0.316, p = 0.044). Selenium, zinc, omega-6 fatty acids, calcium, and iron, were all positively associated with TLM, while caffeine and isoflavones showed a negative association. Conclusion: Patients with acromegaly exhibited increased muscle mass, but their functional capacity were compromised, potentially due to alterations in muscle composition. The intake of nutrients such as selenium, β-carotene, flavonoids, vitamin E and niacin, may improve physical performance and muscle strength.

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Abstract Objective: To analyze the impact of nicotinamide nucleotide transidrogenase (NNT) enzyme impairment on cortisol production, reactive oxygen species (ROS) formation, mitochondrial activity, and mitogen-activated protein kinase 8 (MAPK8) expression in the adrenocortical cell line. Materials and methods: siRNA NNT knockdown was performed in H295R adrenocortical cells to evaluate the effects on cortisol secretion (RIA) and reactive oxygen species (ROS) intracellular production (DCFDA) in basal conditions and after stimulation with 10 uM forskolin. MAPK8 mRNA relative expression and protein localization were evaluated using quantitative PCR (qPCR) and immunofluorescence, respectively. Results: NNT knockdown in the H295R adrenal cells specifically reduced NNT RNA and protein levels. Under basal conditions, no changes in ROS intracellular production or cortisol secretion were seen in NNT-depleted H295R cells. However, under forskolin (10 μM), a potent steroidogenesis agent, we observed a marked reduction in cortisol production (p < 0.0001) at the expense of normal ROS intracellular production and increased MAPK8 expression (p = 0.008). Conclusion: NNT-deficient adrenocortical cells can maintain mitochondrial homeostasis and cortisol secretion in basal conditions. However, under stress, these cells seem to maintain the redox balance at the expense of impaired steroidogenesis. MAPK8 pathway activation appears to compensate for NNT deficiency.

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Abstract Objective: To investigate somatic pathogenic variants (PVs) in the TERT promoter region and variants in the ATRX gene, both related to telomere maintenance in cancer, in a Brazilian cohort of adrenal and extra-adrenal paragangliomas (PPGLs), and to correlate these with metastatic disease as well as with clinical, radiological, and pathological characteristics. Materials and methods: The TERT promoter was analyzed by automated Sanger sequencing or whole-exome somatic sequencing in a cohort of 79 patients with PPGLs (53 non-metastatic and 26 metastatic), encompassing a total of 81 tumors. ATRX was assessed through whole-exome somatic sequencing in 26 patients from this cohort. Results: Germline PVs in Cluster 1A genes were identified in 28 of 79 patients (35.4%), including 20 patients harboring PVs in the Succinate Dehydrogenase Complex Iron Sulfur Subunit B gene (SDHB) (25.3%) and 8 patients (10.1%) with PVs in other Cluster 1A genes. Somatic PVs in the TERT promoter (c.-124C>T/C228T) were detected in two metastatic PPGLs (2.5% of the total cohort). Three PPGLs (two metastatic), among the 26 patients studied, harbored somatic ATRX variants classified as likely benign (11.5%). Somatic PVs in the TERT promoter were identified in patients with germline SDHB PVs. Among metastatic patients with germline SDHB PVs, the frequency of somatic PVs in the TERT promoter was 16.7%. Conclusion: This study expands the understanding of telomere maintenance mechanisms in PPGLs in a Brazilian cohort enriched for SDHB alterations. Somatic variants in the TERT promoter were associated with aggressive tumor features, such as extra-adrenal location, germline SDHB PVs, and metastatic disease.

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Abstract Objective: Research on the use of portable fundus cameras utilizing artificial intelligence (AI) for diabetic retinopathy (DR) screening in primary care remains limited. We aimed to evaluate the accuracy and reliability of DR screening in primary care using a smartphone-based, AI-assisted device in a small municipality in southern Brazil. Materials and methods: The reference standard was classification of fundus images by a retina specialist. Patients with diabetes enrolled in the Brazilian Family Health Program were recruited for the study. A general ophthalmologist obtained fundus images from 134 patients, and a retina specialist validated the DR diagnosis by AI. Results: The sample was predominantly female, with most patients having type 2 diabetes mellitus (T2DM). The age ranged from 17 to 81 years. Blood pressure was controlled in 34.9% of the sample. HbA1c levels ranged from 5.4% to 13.9%, and 35.3% of participants had levels below 7.0%. After excluding eight participants due to low image quality, the DR prevalence was 24.6%. The AI-based screening test for DR in primary care demonstrated a sensitivity of 100% (95% CI 88.8-100) and a specificity of 66.3% (95% CI 55.9-75.7). The negative predictive value (NPV) was 100% (95% CI 94.3-100), and the positive predictive value (PPV) was 49.2% (95% CI 36.4-62.1). Conclusion: The smartphone-based, AI-assisted device showed good accuracy and excellent performance for DR screening in primary care. It can avoid unnecessary medical referrals and help prioritize patients with advanced disease who require early treatment to prevent severe complications.

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Abstract Objective: To describe Brazilian national and regional trends in type 2 diabetes mellitus (T2DM) prevalence, incidence, burden, and exposure to T2DM risk factors. Materials and methods: We sourced the Global Burden of Diseases Study (GBD) 2021 to obtain estimates and trends of T2DM deaths, incidence, prevalence, Years of Life Lost (YLLs), Years Lived with Disability (YLDs), and Disability Adjusted Life Year (DALYs) in Brazil and its regions. We present crude and age-standardized metrics, as well as the exposure to T2DM risk factors between 1990 and 2021. Results: The national age-standardized prevalence of T2DM increased by 37.4% (95% UI 32.7 to 42.6) and the incidence by 32.3% (95% UI 27.6 to 37.7) from 1990 to 2021. Age-standardized deaths by T2DM decreased by 18.0% (95% UI -21.4 to -15.3), and the accompanying YLLs by 22.8% (95% UI -25.8 to -20.2). YLDs increased by 35.4% (95% UI 29.1 to 41.3), while DALYs’ rates reduced by 3.1% (95% UI -8.2 to 1.7) since 1990. The Northeast region showed higher age-standardized prevalence, incidence, YLLs, and YLDs in 2021, while the North region had the most pronounced increases. T2DM prevalence increased consistently, alongside rises in exposure to sugar-sweetened beverage consumption and high BMI. While smoking exposure declined in all regions, low physical activity and diets high in red and processed meat increased over time. Conclusion: T2DM burden in Brazil is growing due to the increasing exposure to T2DM risk factors. Greater emphasis on prevention and public policies focusing on reducing risk factors and inequalities can reduce T2DM burden in Brazil.

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Abstract Objective: This study investigated the prevalence and factors associated with diabetic peripheral neuropathy (DPN) among adults with type 2 diabetes mellitus (T2DM) attending a referral center in Midwest Brazil. Subjects and methods: This cross-sectional study included 276 patients with T2DM, categorized into DPN and non-DPN groups. DPN was assessed using the Neuropathy Disability Score. Sociodemographic and lifestyle data were collected via structured interviews, whereas clinical and laboratory data were obtained from medical records. Results: DPN prevalence was 64.5% (95% CI: 58.9%–70.1%). Among those affected, most were female (59.0%), aged over 67 years old (37.7%), living with diabetes for more than 10 years (52.3%). Poor glycemic control and a sedentary lifestyle were observed in 78.9% and 85.4% of participants, respectively. In multivariable analysis, male sex (PR = 1.32; 95% CI: 1.12–1.56), retirement/inactivity (PR = 1.43; 95% CI: 1.11–1.85), T2DM duration >10 years (PR = 1.22; 95% CI: 1.03–1.44), sedentary lifestyle (PR = 1.34; 95% CI: 1.02–1.76), peripheral arterial disease (PR = 1.25; 95% CI: 1.08–1.46), and prior acute myocardial infarction (PR = 1.21; 95% CI: 1.01–1.45) were independently associated with higher DPN prevalence. Conclusion: DPN was highly prevalent among patients with T2DM. Particular attention should be directed toward men, older adults, individuals with long-standing diabetes, and those with cardiovascular comorbidities. Promoting regular physical activity and comprehensive management of cardiovascular risk factors may help prevent disease progression and related complications.

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Abstract Objective: This study aimed to determine the prevalence of hyperglycemia using different diagnostic criteria for gestational diabetes mellitus. Subjects and methods: This cross-sectional study evaluated parturients attending a hospital complex from January to December 2017. Data were obtained retrospectively from medical records. Fasting glucose and 75-g oral glucose tolerance test results were used to assess the prevalence of hyperglycemia during pregnancy. The diagnostic criteria evaluated were: 1998 World Health Organization (WHO98), 2003 American Diabetes Association (ADA03), 2015 National Institute for Health and Care Excellence (NICE15), and 2015 International Federation of Gynecology and Obstetrics (FIGO15). The overall kappa coefficient was used to analyze agreement among the four sets of diagnostic criteria. All analyses were performed using SAS 9.2, and a significance level of 5% was adopted for all tests. Results: Data from 2,262 women were analyzed. The prevalence of hyperglycemia differed depending on the diagnostic criteria: 10.3% (FIGO15), 7.34% (NICE15), 3.1% (ADA03), and 5.7% (WHO98). The overall kappa coefficient of agreement was 0.61. Individual analysis of each set of diagnostic criteria showed a kappa coefficient indicating moderate agreement, with FIGO15 used as the gold standard. Conclusion: In this population of pregnant women, the prevalence of hyperglycemia varied according to the diagnostic criteria used, with the prevalence of the disease being lower as the criteria became stricter. Lastly, the criteria showed moderate agreement when compared collectively and individually to FIGO15.

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Abstract Objective: To investigate the involvement of regulators of pluripotency and self-renewal of embryonic stem cells in adrenocortical tumors (ACT). Subjects and methods: Clinicopathological data and tissues from 114 ACT patients (96 pediatric-pACT; 18 adults) were analyzed. Normal fetal (n = 33) and postnatal adrenals (n = 26) were used as controls. STAT3, NANOG, SOX2, and OCT4 expression was evaluated by qPCR and IHC. We evaluated intracellular NANOG localization by immunofluorescence and its interaction with beta-catenin after inhibiting the Wnt pathway in a beta-catenin-mutated ACT cell line (NCI-H295). Results: IHC showed NANOG, OCT4, SOX2, and STAT3 expression in fetal adrenals until mid-pregnancy, disappearing thereafter. Positive OCT4 nuclear staining was found in 32% of pACT samples and was associated with metastasis (OR = 2.28; 95% CI:1.13-4.59; P < 0.05). ACTs presented lower SOX2 mRNA expression (P < 0.01). STAT3 mRNA levels were higher in cortisol-secreting ACT (P = 0.01) and in adult adenomas (P < 0.01). NANOG mRNA was higher in p.S45P CTNNB1 mutated ACT (P < 0.01). NCI-H295 cells exhibit nuclear NANOG expression, which was decreased by inhibiting the Wnt/beta-catenin pathway (P < 0.01). Conclusion: Markers of pluripotency and self-renewal of embryonic stem cells are expressed until mid-pregnancy, contributing to the adult adrenal stem cell niche. They are absent postnatally but are expressed in a subset of ACT. Specifically, pS45P beta-catenin-mutated ACTs express more NANOG. Increased OCT4 expression in pACT is associated with worse prognosis, and inhibiting the Wnt/beta-catenin pathway in these cells impairs NANOG expression.

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Abstract Objective: To examine the associations of handgrip strength and CT-derived muscle and visceral fat indices with insulin resistance in middle-aged women with prediabetes and newly diagnosed type 2 diabetes. Subjects and methods: This cross-sectional study included 44 women aged 40-60 years attending a tertiary endocrinology clinic. Participants were classified according to the American Diabetes Association (ADA, 2022) criteria as having prediabetes (n = 29) or newly diagnosed type 2 diabetes (n = 15). All participants underwent anthropometric assessment, biochemical testing, L3-level CT imaging for visceral adipose tissue (VAT) and psoas muscle measurements, and handgrip strength evaluation using a digital dynamometer. Insulin resistance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Multivariable linear regression analysis was performed to identify independent factors associated with HOMA-IR. Results: Dominant-hand grip strength demonstrated an inverse association with HOMA-IR (β = -0.297, p = 0.033). VAT volume and BMI were not significantly associated with HOMA-IR after adjustment (p > 0.75). The overall model explained 28% of the variance in HOMA-IR (R2 = 0.28; adjusted R2 = 0.14). Psoas muscle thickness showed a borderline inverse relationship with HOMA-IR (p = 0.079). Conclusion: In this cohort of women with early glucose dysregulation, handgrip strength was independently associated with insulin resistance, whereas visceral adiposity was not. These findings suggest that muscle performance may represent a clinically relevant correlation of early metabolic impairment. Longitudinal studies are needed to clarify the temporal relationships.

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Abstract Objective: To investigate the impact of smoking on serum selenium levels, autoimmune activity, and macular microvascular density in patients with clinically inactive thyroid-associated orbitopathy (TAO), using optical coherence tomography angiography (OCTA). Subjects and methods: This retrospective cross-sectional study included 44 patients with inactive TAO (24 smokers, 20 non-smokers) and 32 ageand sex-matched healthy controls. All participants underwent ophthalmologic evaluation and laboratory testing for thyroid hormones, selenium, and thyroid-stimulating immunoglobulin (TSI). Macular vessel density was measured using spectral-domain OCTA at the superficial capillary plexus, deep capillary plexus, outer retinal layer, and choriocapillaris. Clinical activity score (CAS) was used to assess disease activity. The collected data were analyzed statistically. Results: Smokers with TAO exhibited significantly higher CAS (p = 0.016) and TSI levels (p = 0.027), and lower serum selenium concentrations (p = 0.042) compared to non-smokers. Central superficial and deep capillary plexus densities were significantly reduced in smokers versus healthy controls (p = 0.029 and p = 0.017, respectively). No significant differences were observed between smokers and non-smokers within the TAO group, or in the outer retinal layer and choriocapillaris layers among all groups. Conclusion: Smoking status was associated with lower selenium levels, higher TSI levels, and increased CAS. Furthermore, retinal microvascular attenuation detected by OCTA, even in the absence of clinical activity in TAO, may serve as a significant indicator of persistent vascular deterioration.

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Abstract Objective: The objective of this study is to compare the miRNA expression profiles of primary tumors and matched metastatic lesions from patients who died due to progression of metastatic PTC. Subjects and methods: We conducted an exploratory study of patients with PTC who died from disease progression and had tissue samples available from both primary tumors and distant metastases. Total RNA was extracted and analyzed to assess the expression of 64 preselected miRNAs. Expression data were normalized using endogenous controls (let-7g-5p and miR-181a-5p), and differential expression was calculated using the 2-∆Ct method. Those miRNAs detected in < 70% of samples or with cycle threshold (Ct) > 36 were excluded. Univariate analyses were performed using paired tests, and multivariate results were adjusted for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR) method. Results: Out of 3,555 patients treated for PTC between 1986 and 2015, eight patients were included. Univariate analysis identified five miRNAs differentially expressed in metastatic lesions: let-7e-5p, miR-10b-5p, miR-30e-3p, miR-423-5p, and miR-483-3p. After multivariate adjustment, miR-10b-5p and miR-30e-3p remained independently overexpressed in metastatic tissues. Conclusion: This study is one of the first to demonstrate distinct miRNA expression profiles in metastatic versus primary tumors in fatal PTC cases. The identified miRNAs are known to regulate processes such as cell migration, invasion, and apoptosis in other cancers, suggesting their potential contribution to PTC metastasis.

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Abstract Objective Insulin resistance (IR) is central to cardiometabolic risk in obesity, but the clinical utility of IR indices may vary by age. We compared homeostasis model assessment for insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR) across age groups in obese adults and examined comorbidity burden and discriminatory performance for type 2 diabetes mellitus (T2DM) and hypertension (HT). Subjects and methods: This retrospective, single-center study included adults with a BMI ≥ 30 kg/m2 (n = 481) across four age strata (18-40, 40-65, 65-75, and ≥75 years). Spearman correlation assessed the association between HOMA-IR and METS-IR. Comorbidity burden (0-3 chronic conditions) was modeled using ordinal logistic regression per 1-SD increase in z-scores, adjusted for age, sex, and BMI. Receiver operating characteristic analysis and multivariable logistic regression assessed T2DM and HT. Results: HOMA-IR and METS-IR were moderately correlated (ρ = 0.342 and p < 0.001, respectively). METS-IR was associated with comorbidity burden (adjusted odds ratio [OR] 1.84; 95% confidence interval [CI] 1.26-2.69; p < 0.01), whereas HOMA-IR was not (OR 1.12; 95% CI 0.92-1.36; p = 0.256). Discriminatory performance was limited for T2DM (area under curve [AUC] 0.500 vs. 0.537) and HT (AUC 0.471 vs. 0.519). METS-IR remained associated with T2DM (OR 2.51; 95% CI 1.60-3.93; p < 0.001) and HT (OR 1.81; 95% CI 1.13-2.91; p < 0.05). Conclusion: In obese adults, METS-IR demonstrated a stronger association with comorbidity burden than HOMA-IR. However, because both indices showed limited discriminatory performance for T2DM and HT, they should not be used as standalone tools for treatment guidance or diagnostic classification. Rather, they should be interpreted alongside age, clinical, and biochemical findings, as isolated use may be misleading and fail to identify disease in specific patient subgroups.

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Abstract Objective: To explore the associations between peripheral blood whole-genome DNA methylation and obesity in young Chinese males. Subjects and methods: Four young Chinese males aged 18-25 years with obesity (body mass index [BMI] ≥ 30 kg/m2) from Liuzhou Peoples Hospital Health Management Center and 3 age-matched healthy controls with average weights were included. Methylation sequencing was conducted using whole-blood DNA extraction and an Illumina 850K methylation chip, followed by gene functional annotation, pathway enrichment analysis, and differential analysis using bioinformatics tools. Results: MethylTarget technology was utilized for the methylation sequencing of 35 patients with obesity and 34 healthy controls, revealing 15 differential sites, two differential regions, and three differential genes. The differential regions included cg08667244 (site region 1stExon) and cg13928759 (site region TSS200, p < 0.05), with the differential genes being cg08667244 (corresponding to iodothyronine deiodinase 3, DIO3), cg13928759 (corresponding to leucine-rich glioma inactivated 1, LGI1), and cg18770216 (corresponding to integrin beta 5, ITGB5, p < 0.05). Further analysis revealed a negative correlation between cg13928759 methylation (LGI1 gene) and body mass index (R = -0.25; P = 0.04). Conclusion: This study revealed 15 differential sites, two differential regions, and three differential genes between young individuals with obesity and healthy controls, among which cg13928759 methylation (LGI1 gene) was negatively correlated with body mass index. These findings suggest that DNA methylation may contribute to obesity development, with LGI1 methylation serving as a potential biomarker.

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Abstract Objective: The global increase in metabolic syndrome (MetS) highlights the need for effective lifestyle interventions to reduce cardiovascular disease (CVD) risk. This study aimed to identify factors associated with lifestyle behaviors for preventing CVD complications among adults aware of MetS. Subjects and methods: A cross-sectional online survey was conducted from January to February 2023 among 1,000 South Korean adults aged 20-69 years. After excluding 212 participants unaware of MetS, 788 respondents were included, of whom 710 engaged in at least three of nine recommended lifestyle behaviors: smoking cessation, alcohol abstinence, body weight monitoring, waist circumference measurement, blood pressure monitoring, regular hospital visits, adequate sleep, adherence to a low-salt diet, and regular physical activity. Participants were categorized into those with one or more MetS risk factors (META) and those without (Non-META). Results: participants with MetS risk factors were predominantly male and aged 50-69 years, while those without were more likely female and aged 20-39 years. Abdominal obesity was the most common risk factor, whereas waist circumference monitoring was the least practiced behavior. The META group showed higher rates of blood pressure monitoring and hospital visits, while the Non-META group reported more frequent smoking cessation and alcohol abstinence. Conclusion: Engagement in healthy lifestyle behaviors was positively associated with female sex, older age, and higher awareness of MetS-related complications. The limited practice of waist circumference monitoring underscores the need for targeted education and personalized preventive strategies to enhance CVD risk reduction among individual aware of MetS.

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Abstract Objective: Epidemiological studies have revealed that glucose variability (GV) is a predictor of stroke, cognitive impairment, and dementia in patients with type 2 diabetes mellitus (T2DM). However, evidence on the associations of GV with white matter hyperintensity (WMH) and cerebrovascular abnormalities remains scarce. This study aimed to explore the relationships of GV with WMH and cerebrovascular abnormalities using epidemiological and Mendelian randomization (MR) approaches. The MR approach was used to assess the effects of genetic proxies for GV on MRI outcomes. Subjects and methods: This cross-sectional study was conducted at a medical center where patients with T2DM were recruited. The measures for fasting plasma glucose (FPG) and HbA1c variability included the standard deviation, coefficient of variation, average real variability (ARV), and variability independent of the mean (VIM). Brain magnetic resonance images were analyzed to assess WMHs and cerebrovascular abnormalities. For MR, instrumental variables were used to assess the causal relationships between glycemic variability and outcome based on two-stage regression analysis. Results: This study included 2,247 subjects, of whom 1,122 had WMH and 957 had cerebrovascular abnormalities. We found 80 independent single-nucleotide polymorphisms associated with GV but not with WMH or cerebrovascular abnormalities, which were subsequently used as genetic instruments. Genetically increased, unweighted FPG-VIM was linked with WMH (odds ratio 1.17 [95% CI 1.08, 1.27] per standard deviation). All genetically increased, unweighted and weighted GV measures were associated with cerebrovascular abnormalities, except FPG-ARV. Conclusion: Our study provided evidence that genetically predicted GV was associated with WMH and cerebrovascular abnormalities, supporting a potential causal link under MR assumptions.

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Abstract Objective: This study evaluated the safety and efficacy of the Android Artificial Pancreas System (AAPS) in Brazilians with type 1 diabetes mellitus (T1D). Subjects and methods: A total of 371 participants were surveyed, including 62 AAPS users and 309 non-users. AAPS configurations included continuous glucose monitoring (CGM ), Bluetooth transmitter (MiaoMiao), and a non-automated insulin pump. Results: AAPS users had a mean Time in Range (TIR) of 78.5% ± 16.6, with HbA1c levels decreasing from 7.3% ± 1.03 to 6.5% ± 0.7 (p < 0.001). Compared to non-AAPS users, AAPS users demonstrated better glycemic control, fewer severe hypoglycemic events (p = 0.006), and improved quality of life (p < 0.0001). However, 23.08% of AAPS users had a TIR below 70%, and time in level-2 hypoglycemia exceeded recommendations. Conclusion: These findings highlight AAPS as a low-cost alternative to commercial systems, with potential to expand access to automated therapy globally, particularly in resource-limited settings.

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Abstract Idiopathicshort stature (ISS) has been used for more than five decades to label children whose height is below -2 SDS without an identified underlying cause. Although originally conceived as a pragmatic diagnosis of exclusion, ISS has gradually been reified as a disease entity and is now embedded in clinical guidelines, regulatory frameworks and indications for recombinant human growth hormone therapy. In parallel, advances in genomic technologies have uncovered a growing spectrum of monogenic and chromosomal variants among children previously classified as ISS, and highlighted the continuous, polygenic architecture of height in the remainder. These developments render the idiopathic construct increasingly misleading and unstable, as every new etiological discovery shrinks - and conceptually undermines - the ISS category. In this article, we review the historical evolution and current use of ISS, summarize the impact of modern genetic testing on the classification of short stature, and argue that most children currently labeled as having ISS are better described as having “Healthy Short Stature”. We define Healthy Short Stature as short stature in otherwise healthy children without systemic, syndromic or endocrine disease, in whom short stature represents the lower extreme of normal growth variation. We discuss how adopting Healthy Short Stature can reduce stigma, remain compatible with ongoing genetic investigation, and provide a more robust framework for aligning clinical practice, research and health policy with contemporary knowledge of human growth biology.