Journal of Clinical Endocrinology & Metabolism最新文献

{"title":"Investigation of Fibrillar Aggregates Formed by Pathogenic Pre-pro-vasopressin Mutants that Cause ADNDI.","authors":"Refika Dilara Vaizoglu, Beril Erdem, Mehmet Gul, Ceren Acar, Huseyin Ozgur Ozdemirel, Emel Saglar Ozer, Hatice Mergen","doi":"10.1210/clinem/dgae749","DOIUrl":"10.1210/clinem/dgae749","url":null,"abstract":"<p><strong>Context: </strong>Aggregations of unfolded or misfolded proteins, both inside and outside cells, are implicated in numerous diseases, collectively known as amyloidosis. Particularly, autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare disease caused by mutations in the AVP-NPII gene, leading to the inability to secrete arginine vasopressin. These misfolded proteins accumulate within the endoplasmic reticulum (ER), causing cellular dysfunction.</p><p><strong>Objective: </strong>This study aimed to investigate the formation of amyloid-like aggregates within the cell resulting from misfolded mutant precursor proteins, which induce disulfide-linked oligomers due to the G45C, 207_209delGGC, G88V, C98X, C104F, E108D-1, E108D-2 and R122H mutations identified by our group in the AVP-NPII gene of ADNDI patients.</p><p><strong>Methods: </strong>Deglycosylation studies were performed to analyze the glycosylation patterns of mutant protein precursors. The involvement of these precursors in the ER-related degradation pathway was studied by conducting protease inhibition experiments. Disulfide-linked oligomer analysis determined the oligomerization status of the mutant precursors. Immunofluorescence and electron microscopy studies provided evidence of aggregate structures in the ER lumen. In vitro studies involved bacterial expression and fibril formation in Escherichia coli (E. coli).</p><p><strong>Results: </strong>Our findings demonstrated that the N-glycan structure of mutant precursors remains intact within the ER. Protease inhibition experiments indicated the involvement of these precursors in the ER-related degradation pathway. Disulfide-linked oligomer analysis revealed homo-oligomer structures in mutations. Immunofluorescence and electron microscopy studies confirmed the presence of aggregate structures in the ER lumen. In vitro studies showed that mutant precursors could form fibril structures in E. coli.</p><p><strong>Conclusion: </strong>Our study may support the idea that ADNDI belongs to the group of neurodegenerative diseases due to the formation of fibrillar amyloid aggregates in the cell.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1577-1586"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycystic Ovary Syndrome Underdiagnosis Patterns by Individual-level and Spatial Social Vulnerability Measures.","authors":"Emily L Silva, Kevin J Lane, Jay Jojo Cheng, Zachary Popp, Breanna D van Loenen, Brent Coull, Jaime E Hart, Tamarra James-Todd, Shruthi Mahalingaiah","doi":"10.1210/clinem/dgae705","DOIUrl":"10.1210/clinem/dgae705","url":null,"abstract":"<p><strong>Objective: </strong>To use electronic health records (EHR) data at Boston Medical Center (BMC) to identify individual-level and spatial predictors of missed diagnosis, among those who meet diagnostic criteria for polycystic ovary syndrome (PCOS).</p><p><strong>Methods: </strong>The BMC Clinical Data Warehouse was used to source patients who presented between October 1, 2003, and September 30, 2015, for any of the following: androgen blood tests, hirsutism, evaluation of menstrual regularity, pelvic ultrasound for any reason, or PCOS. Algorithm PCOS cases were identified as those with International Classification of Diseases (ICD) codes for irregular menstruation and either an ICD code for hirsutism, elevated testosterone lab, or polycystic ovarian morphology as identified using natural language processing on pelvic ultrasounds. Logistic regression models were used to estimate odds ratios (ORs) of missed PCOS diagnosis by age, race/ethnicity, education, primary language, body mass index, insurance type, and social vulnerability index (SVI) score.</p><p><strong>Results: </strong>In the 2003-2015 BMC-EHR PCOS at-risk cohort (n = 23 786), there were 1199 physician-diagnosed PCOS cases and 730 algorithm PCOS cases. In logistic regression models controlling for age, year, education, and SVI scores, Black/African American patients were more likely to have missed a PCOS diagnosis (OR = 1.69 [95% CI, 1.28, 2.24]) compared to non-Hispanic White patients, and relying on Medicaid or charity for insurance was associated with an increased odds of missed diagnosis when compared to private insurance (OR = 1.90 [95% CI, 1.47, 2.46], OR = 1.90 [95% CI, 1.41, 2.56], respectively). Higher SVI scores were associated with increased odds of missed diagnosis in univariate models.</p><p><strong>Conclusion: </strong>We observed individual-level and spatial disparities within the PCOS diagnosis. Further research should explore drivers of disparities for earlier intervention.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1657-1666"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Atrial Fibrillation Screening According to Thyroid Function: Post Hoc Analysis of the Randomized LOOP Study.","authors":"Daniel Camillo Spona, Diana My Frodi, Lucas Yixi Xing, Emilie Katrine Kongebro, Ketil Jørgen Haugan, Claus Graff, Søren Højberg, Derk Krieger, Axel Brandes, Lars Køber, Morten S Olesen, Andreas Andersen, Sofie Hædersdal, Ruth Frikke-Schmidt, Jesper Hastrup Svendsen, Søren Zöga Diederichsen","doi":"10.1210/clinem/dgae610","DOIUrl":"10.1210/clinem/dgae610","url":null,"abstract":"<p><strong>Context: </strong>Subclinical thyroid dysfunction is a marker for atrial fibrillation (AF) and stroke risk.</p><p><strong>Objective: </strong>This study explored the effects of AF screening according to thyroid-stimulating hormone (TSH) levels.</p><p><strong>Methods: </strong>An AF screening trial (the LOOP study) was analyzed post hoc according to baseline TSH. The primary outcome was stroke or systemic embolism (SE). Secondary outcomes included major bleeding, all-cause death, and the combination of stroke, SE, and cardiovascular death.</p><p><strong>Results: </strong>TSH measurements were available in 6003 of 6004 trial participants, 1500 randomized to implantable loop recorder (ILR) screening for AF and anticoagulation upon detection vs 4503 to usual care; mean age was 74.7 ± 4.1 years and 2836 (47%) were women. AF detection was approximately triple for ILR vs usual care across TSH tertiles (adjusted P interaction = 0.44). In the first tertile, screening was associated with decreased risk of the primary outcome (hazard ratio [HR] 0.52, 95% CI 0.30-0.90; P = .02) and stroke, SE, or cardiovascular death (HR 0.54, 95% CI 0.34-0.84; P = .006) compared with usual care, while no effect was observed among participants with higher TSH (adjusted P interaction .03 and .01, respectively). There was no effect on other outcomes. Analyses of continuous TSH or excluding those with abnormal TSH or thyroid medication showed similar results.</p><p><strong>Conclusion: </strong>AF screening and subsequent treatment was associated with decreased stroke risk among participants with low TSH, though the yield of screening was similar across TSH levels. TSH may be useful as a marker to indicate benefit from AF screening vs overdiagnosis and overtreatment. These findings should be considered exploratory and warrant further study.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1975-e1984"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Growth, and Development After Dapagliflozin or Saxagliptin in Children With Type 2 Diabetes (T2NOW Follow-Up).","authors":"Naim Shehadeh, Pietro Galassetti, Nayyar Iqbal, Cecilia Karlsson, John Monyak, Jennifer Ostridge, Marie Bolin, Timothy Barrett","doi":"10.1210/clinem/dgae723","DOIUrl":"10.1210/clinem/dgae723","url":null,"abstract":"<p><strong>Context: </strong>The T2NOW trial of dapagliflozin or saxagliptin vs placebo in pediatric patients with type 2 diabetes (T2D) demonstrated promising efficacy data for dapagliflozin and did not raise any safety concerns over 52 weeks.</p><p><strong>Objective: </strong>This work aimed to assess long-term effects of prior dapagliflozin/saxagliptin administration on safety, growth, and development.</p><p><strong>Methods: </strong>A multicenter, randomized, double-blind phase 3 trial (T2NOW) was conducted among 210 children with T2D aged 10 to 17 years, followed for up to 1 year after treatment. Participants were previously treated with once-daily dapagliflozin (5, 10 mg), saxagliptin (2.5, 5 mg), or placebo as an add-on to diet, exercise, metformin, and/or insulin for 52 weeks, plus a 52-week nontreatment follow-up period. Main outcome measures included change in height, weight, body mass index (BMI), Tanner staging, growth and maturation markers, bone biomarkers, and adverse events (AEs) from baseline to week 104.</p><p><strong>Results: </strong>As expected in a pediatric population, mean height and weight slightly increased from baseline to week 104. BMI remained generally stable; changes were similar across treatment groups. Sexual maturation progressed normally to week 104, with similar shifts between Tanner stages and changes in growth and maturation markers and bone biomarkers across groups. The proportion of patients reporting 1 or more AEs during the nontreatment follow-up period was similar across groups previously treated with dapagliflozin (18.5%) or saxagliptin (15.9%) compared to placebo (21.1%). No deaths occurred.</p><p><strong>Conclusion: </strong>Prior treatment with dapagliflozin or saxagliptin for 52 weeks did not raise any safety concerns relating to height, weight, BMI, Tanner staging, growth and maturation markers, bone biomarkers, or AEs for up to 52 weeks following treatment discontinuation in pediatric patients with T2D.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1587-1595"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Pregnancy Plasma Per- and Polyfluoroalkyl Substances (PFAS) and Maternal Midlife Adiposity.","authors":"Jordan A Burdeau, Briana J K Stephenson, Jorge E Chavarro, Shruthi Mahalingaiah, Emma V Preston, Marie-France Hivert, Emily Oken, Antonia M Calafat, Sheryl L Rifas-Shiman, Ami R Zota, Tamarra James-Todd","doi":"10.1210/clinem/dgae542","DOIUrl":"10.1210/clinem/dgae542","url":null,"abstract":"<p><strong>Context: </strong>Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases the risk of developing cardiometabolic disease risk factors. Limited research has evaluated associations between PFAS, assessed during pregnancy, a sensitive window for maternal endocrine effects, and long-term maternal adiposity.</p><p><strong>Objective: </strong>Estimate associations of early pregnancy measures of individual PFAS, and PFAS mixtures, with maternal adiposity in midlife.</p><p><strong>Methods: </strong>We studied 547 Project Viva participants with measures of early pregnancy (mean gestation 10.0 weeks; mean age 32.5 years) plasma concentrations of 6 PFAS and midlife adiposity outcomes (mean follow-up 17.7 years; mean age 50.7 years), including weight, waist circumference (WC), trunk fat mass (TFM), and total body fat mass (TBFM). We used linear regression and Bayesian Kernel Machine Regression (BKMR).</p><p><strong>Results: </strong>Linear regression estimated higher midlife weight per doubling of perfluorooctane sulfonate (PFOS) (3.8 kg [95% CI: 1.6, 5.9]) and 2-(N-ethyl-perfluorooctane sulfonamido) acetate (2.3 kg [95% CI: 0.9, 3.7]). BKMR analyses of single PFAS plasma concentrations (comparing the 25th percentile concentration to the 75th percentile) showed a positive association between PFOS and midlife adiposity (weight: 7.7 kg [95% CI: 4.0, 11.5]; TFM: 1.2 kg [95% CI: 0.0, 2.3]; TBFM: 3.0 kg [95% CI: 0.8, 5.2]), but inverse associations with perfluorononanoate (weight: -6.0 kg [95% CI: -8.5, -3.5]; WC: -1.8 cm [95% CI: -3.2, -0.3]; TFM: -0.8 kg [95% CI: -1.5, -0.1]; TBFM: -1.4 kg [95% CI: -2.7, -0.3]) and perfluorohexane sulfonate (TFM: -0.8 kg [95% CI: -1.5, -0.1]; TBFM: -1.4 kg [95% CI: -2.6, -0.2]). No associations were observed with the overall PFAS mixture.</p><p><strong>Conclusion: </strong>Select PFAS, assessed in pregnancy, may differentially affect maternal midlife adiposity, influencing later-life maternal cardiometabolic health.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1966-e1974"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum DLK1 During Minipuberty and Pubertal Transition in Healthy Girls and in Girls With Precocious Puberty.","authors":"Lea Vilmann, Kaspar Sørensen, Alexander S Busch, Marie L Ljubicic, Emmie N Upners, Margit B Fischer, Trine H Johannsen, Stine A Holmboe, Anders Juul, Casper P Hagen","doi":"10.1210/clinem/dgae762","DOIUrl":"10.1210/clinem/dgae762","url":null,"abstract":"<p><strong>Context: </strong>Delta-like non-canonical notch ligand 1 (DLK1) is negatively associated with bodyweight. DLK1 pathogenic variants cause central precocious puberty (CPP) and obesity, suggesting that DLK1 links the well-established association between higher body mass index and earlier pubertal onset. However, little is known about the trajectories of circulating DKL1 in healthy girls as well as in girls with precocious puberty.</p><p><strong>Objective: </strong>To evaluate longitudinal changes in circulating DLK1 concentrations in (1) full-term, singleton healthy infant girls, (2) healthy girls during pubertal transition, and (3) girls with CPP during treatment with gonadotropin-releasing hormone agonist (GnRHa).</p><p><strong>Methods: </strong>Three longitudinal studies of (1) healthy infant girls (n = 85), (2) healthy peripubertal girls (n = 15), and (3) girls with CPP before and after GnRHa treatment (n = 15). Body fat percentage calculated using the Slaughter equation, and serum concentrations of DLK1 using enzyme-linked immunosorbent assay.</p><p><strong>Results: </strong>Serum concentration of DLK1 in healthy infant girls declined significantly through the first year of life (17.6 to 9.9 ng/mL, P = .020). DLK1 was inversely correlated with birth weight and BF%: r = -0.220, P = .044, and r = -0.503, P < .001, respectively. DLK1 declined from 1 year prior to pubertal onset to time of first examination after pubertal onset (10.4  to 9.2 ng/mL, P = .004), as well as to time at the last pubertal evaluation (10.4 to 9.8 ng/mL, P = .006). DLK1 levels were not affected by GnRHa treatment.</p><p><strong>Conclusion: </strong>Circulating DLK1 levels declined steeply during infancy and were less pronounced through pubertal development. Due to considerable interindividual variation, DLK1 is not useful as a diagnostic marker of pubertal onset. Importantly, DLK1 was negatively associated with birth weight and body fat percentage.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1570-1576"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Profiles of Pregnancy With Polycystic Ovary Syndrome: Insights into Maternal-Fetal Metabolic Communication.","authors":"Huisheng Ge, Dongni Huang, Lunbo Tan, Dan Luo, Liu Zhou, Hong Liu, Yilan Zhang, Dandan Liu, Xixi Wu, Lulu Wang, Liling Xiong, Yang Yang, Ting-Li Han, Chengjin He, Hongbo Qi","doi":"10.1210/clinem/dgaf057","DOIUrl":"10.1210/clinem/dgaf057","url":null,"abstract":"<p><strong>Context: </strong>Polycystic ovary syndrome (PCOS) pregnancies are linked to metabolic disorders affecting maternal and fetal outcomes, with maternal metabolites differing from those in normal pregnancies.</p><p><strong>Objective: </strong>To investigate the metabolic communication at the maternal-fetal interface in PCOS pregnancies.</p><p><strong>Design: </strong>Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry. In-depth analysis was performed with clinical characteristics.</p><p><strong>Setting: </strong>Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry, alongside clinical characteristics.</p><p><strong>Participants: </strong>Forty-five uncomplicated PCOS pregnancies and 50 normal pregnancies.</p><p><strong>Intervention(s): </strong>None.</p><p><strong>Main outcome measure(s): </strong>The metabolic characteristics at the maternal-fetal interface in PCOS pregnancies and the underlying mechanisms.</p><p><strong>Results: </strong>A total of 79 metabolites in the placenta and 25 in umbilical cord serum showed significant differences between PCOS and normal pregnancies. The 10 most significant placental metabolites were identified through receiver operating characteristic analysis, 9 of which correlated significantly with maternal serum testosterone levels. Lasso regression analysis identified 4 key placental metabolite combinations: gamma-aminobutyric acid, proline, glycine, and isoleucine, achieving an area under the curve of 93.24%. In umbilical cord serum, 6 metabolites differed significantly between PCOS and normal pregnancies, with the highest area under the curve reaching 76.07%; 5 of these metabolites showed significant correlations with maternal serum testosterone levels. Nine differential metabolites were shared between the placenta and umbilical cord serum, which also shared metabolic pathways, including ABC transporters and aminoacyl-tRNA biosynthesis, potentially influencing maternal-fetal interactions.</p><p><strong>Conclusion: </strong>This study identifies the metabolomic profile and key pathways in maternal-fetal communication during PCOS pregnancies.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1524-1536"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Greater Urinary Calcium Excretion Is Associated With Diminished Bone Accrual in Youth With Type 1 Diabetes.","authors":"David R Weber, Kimberly O O'Brien, Lance Ballester, Noya Rackovsky, Bethany Graulich, George J Schwartz","doi":"10.1210/clinem/dgae660","DOIUrl":"10.1210/clinem/dgae660","url":null,"abstract":"<p><strong>Context: </strong>The adverse skeletal effects of type 1 diabetes (T1D) include deficient bone accrual and lifelong increased fracture risk. The contributors to impaired bone accrual in people with T1D are incompletely understood.</p><p><strong>Objective: </strong>To determine if urinary calcium excretion is associated with impaired bone accrual in youth with T1D and to characterize the contribution of glycemic control and markers of bone mineral metabolism to urinary calcium excretion.</p><p><strong>Design: </strong>Observational study.</p><p><strong>Participants: </strong>Fifty participants with T1D aged 6 to 20 years completed a 12-month longitudinal study of bone accrual. A second cohort of 99 similarly aged participants with T1D completed cross-sectional 24-hour urine and blood collections.</p><p><strong>Main outcome measure: </strong>Whole body less head bone mineral content (WBLH BMC) velocity Z-score and fractional excretion of calcium (FeCa).</p><p><strong>Results: </strong>Participants in the bone accrual cohort had lower WBLH BMC velocity compared to a healthy reference dataset (Z-score -0.3 ± 1.0, P = .03). FeCa was negatively associated with WBLH BMC velocity Z-score, ρ = -0.47, P = .001. In the urinary calcium excretion cohort, intact PTH (β = -0.4, P = .01), beta c-telopeptide (β = 0.35, P = .007), and either hemoglobin A1c (β = 0.08, P = .03) or urine fractional glucose excretion (β = 0.07, P = .03) were associated with FeCa in multivariable regression models that included known determinants of urinary calcium excretion.</p><p><strong>Conclusion: </strong>Urinary calcium excretion was negatively associated with bone accrual in this cohort of youth with T1D. Mechanistic studies are needed to determine if interventions to reduce urinary calcium excretion could increase bone accrual and reduce skeletal fragility in people with T1D.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1802-e1810"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 1 Diabetes Genetics Consortium.","authors":"Suna Onengut-Gumuscu, Patrick Concannon, Beena Akolkar, Henry A Erlich, Cécile Julier, Grant Morahan, Concepcion R Nierras, Flemming Pociot, John A Todd, Stephen S Rich","doi":"10.1210/clinem/dgaf181","DOIUrl":"10.1210/clinem/dgaf181","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β cells. Genetic factors account for approximately 50% of the risk for T1D but, by the late 1990s, the genetic basis was limited. The Type 1 Diabetes Genetics Consortium (T1DGC) was formed in 2002 to accelerate discovery of genes contributing to T1D risk through a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to assemble existing data and samples from affected sib-pair families and to establish new collections. In recognition of the 75th anniversary of the NIDDK, this manuscript highlights the contributions made by the T1DGC to understanding the genetic basis of T1D using both family (for linkage) and case-control (for genome-wide association) designs. The T1DGC conducted large-scale genetic research and used fine mapping to define risk regions. The T1DGC data, results, and samples have been made available to the scientific community, leading to the discovery of more than 100 loci associated with T1D risk, many with small effects and relevant to autoimmune pathways. The T1DGC not only expanded the list of genes contributing to disease risk but also identified noncoding genetic variation in disease-relevant cell types that contribute to the etiology of T1D. The success of the T1DGC and the NIDDK investment in the global consortium is highlighted in its continuing effect on mapping genetic variants to their function and identifying pathways that provide new targets for the prediction, prevention, and treatment of T1D.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1505-1513"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prognostic Impact of Tumor Size and BRAF Mutational Status in Middle Eastern Differentiated Thyroid Cancer.","authors":"Sandeep Kumar Parvathareddy, Abdul K Siraj, Zeeshan Qadri, Nabil Siraj, Maha Al-Rasheed, Wael Haqawi, Saif S Al-Sobhi, Fouad Al-Dayel, Khawla S Al-Kuraya","doi":"10.1210/clinem/dgae740","DOIUrl":"10.1210/clinem/dgae740","url":null,"abstract":"<p><strong>Context: </strong>Tumor size at diagnosis has been widely used as a major mortality risk factor in risk stratification of differentiated thyroid cancer (DTC).</p><p><strong>Objective: </strong>The current study was designed to analyze whether tumor size at diagnosis is a major prognostic factor in Middle Eastern DTC.</p><p><strong>Methods: </strong>We conducted a comparative study of the relationship between tumor size at diagnosis and event-free survival (EFS) with respect to BRAF status in 1709 consecutive patients treated surgically for DTC. Patients were divided into 4 groups according to the size of tumor and BRAF mutation status: Group 1 (≤4 cm without BRAF mutation), Group 2 (≤4 cm with BRAF mutation), Group 3 (>4 cm without BRAF mutation), and Group 4 (>4 cm with BRAF mutation). Predictors of EFS were compared using the log-rank test and Cox proportional hazards models.</p><p><strong>Results: </strong>Tumor size >4 cm was associated with clinicopathologic characteristics, such as older age, male gender, bilateral tumors, extrathyroidal extension, lymphovascular invasion, advanced tumor stage, and persistent/recurrent disease. Tumor size was also inversely associated with BRAF mutation. Both tumor size (>4 cm) and BRAF mutation were associated with EFS on univariate analysis. On subgroup analysis, larger tumor size was an independent predictor of EFS (Group 3 vs Group 1), irrespective of BRAF mutation status. Also, within the BRAF mutant tumors, larger tumor size was still an independent predictor of EFS (Group 4 vs Group 2).</p><p><strong>Conclusion: </strong>Tumor size is an independent predictor of EFS in Middle Eastern patients with DTC, regardless of BRAF mutational status.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1617-1623"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}