Osteogenesis imperfecta (OI) is a genetic connective tissue disorder caused by abnormalities in type I collagen, which is abundant in skin. Yet, data on dermatologic manifestations and their impact on quality-of-life (QOL) are limited. This study evaluated the prevalence of skin symptoms in adults with OI compared with adults without OI and assessed their effect on QOL. In this cross-sectional, survey-based study, adults with OI were recruited via US and European OI foundations, and comparators were recruited from an Oregon Health & Science University research registry. Participants completed a 20-item skin symptom questionnaire; those reporting bothersome or itchy skin also completed validated QOL instruments (Skindex-29 and ItchyQoL). Group and severity-stratified comparisons were analyzed using t-tests, chi-square tests, and analysis of variance (P < .05). A total of 821 surveys were analyzed (547 OI). Adults with OI reported significantly more skin symptoms than comparators, most commonly easy bruising (78%), dry skin (72%), and excessive sweating (66%). Women with OI reported more symptoms than men. Queries about QOL revealed that over half of OI participants reported bothersome skin, with higher Skindex-29 and ItchyQoL scores than comparators. Symptom prevalence also varied by OI severity: severe OI was associated with pruritus and rashes, while mild OI was associated with bruising and fragile nails. Skin symptoms are a common and clinically meaningful extra-skeletal manifestation of OI. Differences in skin symptoms may be influenced by sex, age, and OI subtype, highlighting the need for further studies as recognition of these dermatologic manifestations may guide targeted management.
Background:Colorectal neuroendocrine neoplasms (NEN) are a rare entity lacking effective pharmacologic therapies. We aimed to address the paucity of preclinical models for colorectal NEN that facilitate the exploration of novel therapeutic strategies. Methods:We used 3-dimensional culture techniques to establish colorectal NEN organoids. These organoids were subjected to pathological examination and sequence analyses to verify their neuroendocrine nature. Subsequently, the organoids were subcutaneously implanted into mice to create patient-derived organoid xenograft (PDOX) models. In vitro and in vivo experiments were conducted to identify potential antitumor strategies. Results:We established 3 colorectal NEN organoids, one of which exhibited a BRAF mutation. These organoids closely recapitulated the original tumors in terms of synaptophysin, chromogranin, CD56, somatostatin receptor 2, and Ki-67 expression. DNA- and RNA-sequence analyses confirmed that the organoids preserved the genetic characteristics of their source tumors. In vitro pharmacological assays demonstrated that BRAF inhibitors (IC50: dabrafenib = 3.766 μM; encorafenib = 5.454 μM) and MEK inhibitors (IC50: trametinib = 6.602 nM; binimetinib = 0.749 μM) effectively inhibited the proliferation of organoids harboring the BRAF mutation. The combination of BRAF and MEK inhibitors (IC50: dabrafenib = 0.505 μM, trametinib = 6.395 nM; encorafenib = 1.467 μM, binimetinib = 0.210 μM) exhibited significant enhanced anticancer effects. PDOX experiments revealed that continuous oral administration of dabrafenib and trametinib resulted in a tumor growth inhibition of 66.27%. Conclusion:Organoids represent reliable preclinical models for drug screening in colorectal NENs, and BRAF mutations may constitute a promising therapeutic target for patients with colorectal NENs.
Abstract Context Accurate assessment of excess body fat and its cardiometabolic risk is essential in clinical and epidemiologic research. Body mass index (BMI), although widely used, does not capture visceral or ectopic fat. Objective To evaluate how anthropometric measures—BMI, percent body fat, waist circumference (WC), and waist-to-hip ratio (WHR)—relate to MRI-measured visceral adipose tissue (VAT) and hepatic fat fraction (HFF), overall and by sex. Design Cross-sectional analysis within the Canadian Alliance for Healthy Heart and Minds (CAHHM) cohort. Setting Community-based, pan-Canadian prospective study. Patients or Other Participants 6,683 apparently healthy adults (mean age 57±9 years; 3,665 females) with baseline anthropometric and MRI measures; analyses adjusted for study center. Intervention(s) Not applicable. Main Outcome Measure(s) MRI-derived VAT and HFF. Associations were estimated using linear regression and mixed models, stratified by sex, ethnicity, age, and BMI category. Results . Mean BMI was 26.7 kg/m2, WC 88.3 cm, VAT 71 mL, and HFF 5.7%. Females had lower VAT and HFF than males. Correlations with VAT ranged from 0.35–0.77 and with HFF from 0.26–0.47. Each 10-cm higher WC was associated with 21.0 mL higher VAT and 2.1% higher HFF; each 5-kg/m2 higher BMI predicted 24.7 mL and 2.8% higher values. When modeled jointly, WC remained strongly predictive, while BMI contributed modestly. Associations were smaller in females. VAT and HFF increased across WC tertiles within BMI categories. Conclusions . WC is a robust surrogate for visceral and hepatic fat across BMI categories, supporting its use when MRI is not feasible.
Historically, low testosterone (T) has been linked to increased atrial fibrillation (AF) risk in men, yet recent evidence suggests that elevated T levels and testosterone replacement therapy (TRT) may also confer risk. This review synthesizes emerging literature to characterize the evolving T-AF relationship and inform clinical practice. A structured literature search of MEDLINE/PubMed and Embase, supplemented by hand-searching reference lists of relevant publications, was performed, using terms including "testosterone," "testosterone replacement therapy," and "atrial fibrillation." Findings were heterogeneous. The 2023 TRAVERSE trial reported a higher AF incidence with TRT, contrasting with earlier VA data from Sharma et al. (2017) showing reduced AF risk when T normalized after treatment. A 2024 meta-analysis by Corona et al of 106 randomized placebo-controlled trials found no significant pooled AF signal. Real-world data remained mixed: a TriNetX-based replication did not confirm elevated AF risk, whereas a 5-year cohort study reported a hazard ratio of 1.27 in cisgender hypogonadal men receiving TRT. Population-level studies by Xu et al (2024) and post-hoc ASPREE analyses by Tran et al (2024) demonstrated a nonlinear association in which both low and high T levels increased AF risk. Updated mechanistic data support a U-shaped model: low T disrupts calcium handling, whereas high T alters potassium currents and promotes reentry. Converging evidence thus supports a U-shaped T-AF relationship. Until definitive data emerge, clinicians should prioritize risk-stratified TRT use, mid-physiologic T targets, stable formulations, and structured monitoring.
Introduction:Pancreatic neuroendocrine tumors (pNETs) are a recognized feature of tuberous sclerosis complex (TSC). The current evidence suggests that pNETs occurring in TSC may exhibit a different clinical course from sporadic cases, but their natural history remains poorly characterized. Objective:This study aimed to characterize the demographics, clinical presentation, management, and long-term outcomes of TSC-associated-pNETs and to propose possible guidelines for surveillance and management. Materials and Methods:We conducted a multicenter retrospective review of TSC-pNET patients from 6 UK TSC specialist clinics and from 3 NET referral centers, from 2008 to 2024. Data on demographics, tumor characteristics, management, and outcomes, were collected. A systematic review of the literature from 2009 to 2026 on TSC-pNETs was also performed. Results:We identified a total of 26 consecutive cases with the TSC-pNET-association in our cohort: 21 cases of pNETs from TSC specialist clinics (1.1% of the population), and 5 cases of TSC-pNETs from the NET referral centers (0.25% of the population). An additional 80 cases were identified from the published literature. We observed a wide spectrum of clinical phenotypes, with the majority being nonfunctioning pNETs (n = 24; 92%), whereas 2 patients were diagnosed with glucagonomas. Surgical intervention was the mainstay initial treatment, the indication being either functional pNETs, or large or symptomatic nonfunctioning pNETs. Conclusion:TSC-pNETs are rare and mostly nonfunctioning tumors with variable clinical behavior. Due to their uncertain malignant potential, we suggest that baseline pancreatic imaging should be incorporated into TSC surveillance, and we emphasize the need for heightened pNET surveillance and updated management recommendations.
Context:Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery characterized by severe postprandial hypoglycemia for which there is no approved therapy. Objective:To evaluate efficacy and safety of mizagliflozin, a sodium glucose cotransporter 1 inhibitor, for treatment of PBH. Methods:This was a phase 2, open-label, randomized, single-dose, crossover study. Nine participants with PBH were randomized to receive a baseline mixed meal tolerance test (MMTT), and single doses of mizagliflozin before each of 2 additional MMTTs. Doses included a 2.5-mg liquid formulation, and 2.5-, 5-, and 10-mg capsules. The primary outcome was change from baseline in glucose nadir, and the main secondary outcomes were change from baseline peak glucose and peak insulin. Results:Compared to baseline, all individual doses of mizagliflozin raised the glucose nadir: 6.2 mg/dL (2.5-mg capsule), 17.5 md/dL (2.5-mg liquid), 4.0 mg/dL (5-mg capsule) and 31.5 mg/dL (10-mg capsule). In a post hoc analysis of participants that exhibited hypoglycemia (<70 mg/dL) during the baseline MMTT, mizagliflozin (all capsule doses combined) raised the glucose nadir by 38% (P = .03). Treatment with mizagliflozin also lowered both peak glucose by 21% (P = .03) and peak insulin by 53% (P = .016). Glucose-dependent insulinotropic peptide area under the curve0-3h was reduced by 45% from baseline (P = .048). Conclusion:Mizagliflozin resulted in improved glucose nadir, reduction in both postprandial peak glucose and peak insulin, and reduction in postprandial glucose-dependent insulinotropic polypeptide. The results from this proof-of-concept study suggest mizagliflozin represents a promising novel oral treatment for PBH that warrants further clinical development.
Context:The American Board of Internal Medicine (ABIM) started offering the Longitudinal Knowledge Assessment (LKA) to endocrinologists as a 10-year Maintenance of Certification alternative in 2022. Participants answer 30 open-book online questions quarterly, receive real-time question-specific feedback and overall feedback via progress reports starting in year 2, and are assessed for competency every 5 years. Objective:To examine whether the LKA encouraged learning, motivated further study, and/or changed patient care. Design:We surveyed endocrinologists in 2024 who started LKA in 2022-2024 about their learning, study motivated by progress report feedback, patient care changes, and changes in the use of information resources. Results were weighted for nonresponse. Setting:Mid-career endocrinologists. Intervention:ABIM's LKA. Main outcomes:Reports of learning, motivated study, and patient care changes. Results:We surveyed 1649 endocrinologists, of whom 1015 responded to the survey (62% response). Overall, 95% of respondents reported learning while answering questions. Of those viewing their progress reports, 68% reported that they were motivated to study by the feedback. Motivated study was 17 percentage points greater for physicians with bottom vs top quartile first progress report preliminary scores. Additionally, 53% of physicians reported that LKA participation resulted in changes or planned changes to patient care. These reports were about 30 percentage points greater among physicians reporting that participation led to changes in the use of information resources, learning broader than question level, learning from question references, and study motivated by progress report feedback. Conclusion:Endocrinologists' LKA participation resulted in self-reports of patient care changes, broad learning, and motivated study.
Objective:This post hoc analysis aimed to assess the predictive value of glycemia-based criteria for development of type 2 diabetes (T2D) among adults with obesity and prediabetes in the 3-year SURMOUNT-1 study. Methods:We evaluated the sensitivity, specificity, and positive and negative predictive value of each of the following exploratory criteria for their ability to correctly identify incident T2D cases in the placebo group: oral glucose tolerance test (OGTT) 1-h glucose ≥155 mg/dL (≥8.6 mmol/L), fasting serum glucose (FSG) ≥ 110 mg/dL (≥6.1 mmol/L), and hemoglobin A1c (HbA1c) ≥ 6% (≥42.1 mmol/mol). Results:The OGTT 1-h glucose, FSG, and HbA1c based criteria, respectively, had a sensitivity of 0.83, 0.50, and 0.47; specificity of 0.25, 0.87, and 0.69; positive predictive value of 0.15, 0.37, and 0.19; and negative predictive value of 0.91, 0.92, and 0.90. Tirzepatide treatment was associated with a 90% to 99% reduction in new-onset T2D in the high-risk groups, vs 68% to 91% in the standard risk groups using the 3 different criteria. Conclusion:In this post hoc analysis, we found that OGTT 1-h glucose ≥155 mg/dL (≥8.6 mmol/L) may be a useful criterion to better identify those at high risk of incident T2D. Tirzepatide treatment was highly effective in T2D prevention compared with placebo, regardless of the high-risk criteria used. These findings may guide in the identification of people in whom intensive therapies could be considered to prevent new-onset T2D.
Prostate cancer is the second most common cause of cancer in men worldwide, and first-line therapies for metastatic disease include androgen deprivation therapy and androgen receptor pathway inhibitors, in addition to chemotherapy for selected patients. Although these strategies improve patient prognosis, progression to castration-resistant prostate cancer and therapeutic resistance remain clinically significant. In this review, we will explore published and new evidence of the expression and function of estrogen receptors (ERs) ERα and ERβ, as well as their variants, and the G protein-coupled estrogen receptor (GPER) in normal prostate gland, during development and adulthood and in prostate cancer cell lines. Consistent with these findings, studies from the literature have demonstrated that ERα, ERβ, and GPER are expressed in a cell-specific manner in the normal prostate gland. In the androgen-independent prostate cancer cells PC-3 (derived from bone metastasis) and DU-145 (brain metastasis), used in vitro and in xenograft implants as castration-resistant prostate cancer models, ERα and ERβ are present at transcript and protein levels, as well as the GPER. Importantly the presence of ERα36 splice variant is also detected in prostate cancer cells. Although the exact contributions of these modifications to prostate cancer advancement and treatment outcomes remain under investigation, the absence of selective inhibitors for the resulting ER variant proteins restricts deeper inquiry. Developing such targeted agents is crucial to uncovering variant biology in both healthy and malignant tissues, evaluating their therapeutic value in preclinical settings, and ultimately guiding clinical management.
Objectives:Somatrogon is a long-acting growth hormone utilized for treatment of pediatric patients with growth hormone deficiency (GHD). This matched cohort analysis compared the first 3 years of height outcomes for somatrogon-treated patients from a Phase 3 somatrogon study (NCT02968004) with historical data from somatropin-treated patients in the Kabi/Pfizer International Growth Study (KIGS). Methods:In the somatrogon study, patients with GHD were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months, followed by an open-label extension, during which all patients received somatrogon (0.66 mg/kg/week or lower dose as per protocol). Patients in the somatrogon study (somatrogon cohort) were matched with patients with GHD from KIGS (KIGS cohort) who had received somatropin (0.20-0.30 mg/kg/week), using propensity score matching according to baseline characteristics of geographic region, gender, age, peak GH, and height standard deviation score (HtSDS) (ie, peak GH and HtSDS at study entry). Results:155 patients in the somatrogon study were matched to 155 somatropin-treated patients from KIGS. The somatrogon and KIGS cohorts had similar mean annualized height velocity through Years (Y) 1 to 3 of treatment (Y1: 10.03 vs 9.57; Y2: 7.70 vs 7.33; Y3: 7.15 vs 6.56). Mean changes in HtSDS (from baseline) through Y1-3 were comparable between both cohorts, though the somatrogon cohort appeared to have larger changes in Y2-3. Conclusion:Somatrogon-treated patients in the Phase 3 study had similar height outcomes compared with matched somatropin-treated patients in KIGS, strengthening the expectation that once-weekly somatrogon will have comparable efficacy to somatropin in real-world treatment of pediatric patients with GHD.
Context:Weight management is key to managing polycystic ovary syndrome (PCOS) and overweight/obesity but is challenging for many. Evidence regarding tirzepatide's efficacy in women with polycystic ovary syndrome is limited. Objectives:To quantify the effectiveness of tirzepatide for weight loss in women with (self-reported) polycystic ovary syndrome and overweight/obesity compared with women not living with PCOS and to explore associations between engagement with nonpharmacological digital adjuncts and weight loss. Methods:Retrospective open-cohort study in a digital weight management service in the United Kingdom. All women (aged 18+ years) with overweight/obesity prescribed tirzepatide for weight management between February 2024 and January 2025 were included. Percentage weight change from baseline was calculated in women reaching specific follow-up time points, stratified by PCOS status. Kaplan-Meier methods estimated cumulative probabilities of attaining total body weight loss thresholds. Results:The cohort comprised 54 114 women of whom 4241 (7.84%) women had PCOS. At 10 months, the mean weight change in women with PCOS (n = 40) was -19.40% (95% confidence interval [CI], -22.38% to -16.42%); this was not significantly different from women without PCOS (n = 397; mean weight change, -18.74%; 95% CI, -19.67% to -17.81%). A total of 57.66% of women with PCOS lost ≥20% total body weight (95% CI, 47.44% to 68.29%) by 10 months. In women living with PCOS, digitally engaged women lost 3.42% more weight in absolute terms (95% CI, 1.71% to 5.12%; P < .001) by 10 months. Conclusion:Tirzepatide may offer a highly effective therapeutic option for women with PCOS and overweight/obesity in whom weight loss is a key goal but a persistent challenge.
Context:The pathophysiology of hypothalamic obesity (HyOb) remains incompletely understood with no effective treatments. Objective:We examined differences in appetite-regulating hormone concentrations between patients with HyOb, common obesity, and lean controls. Design:Multiway cross-sectional case-control study of patients aged 2 through 19 years. Setting:Two tertiary pediatric endocrinology centers. Patients:Cases were obese (body mass index [BMI] > +2 SD score [SDS], "HyOb") and lean ("HyLean") patients with congenital (septo-optic dysplasia) or acquired (suprasellar brain tumor) hypothalamic disorders. Controls had common obesity ("Ob") or nonhypothalamic disorders and normal BMI ("Lean"). Main outcome measures:Relationships between the Dykens' Hyperphagia Questionnaire Score (DHQS), plasma or serum concentrations of leptin, insulin, α-melanocyte stimulating hormone (αMSH), brain-derived neurotrophic factor, oxytocin, acylated ghrelin, agouti-related peptide and copeptin, and BMI SDS. Results:Dykens' Hyperphagia Questionnaire Score did not differ between HyOb and Ob patients (24 [17-34] vs 24 [18-31]) but correlated with BMI SDS in patients with hypothalamic disorders (P = 0.02). HyOb and Ob patients exhibited similarly increased anorexigens (insulin, leptin) and decreased orexigens (ghrelin, agouti-related peptide) compared to HyLean and Lean patients. The rate of BMI increase was independently associated with lower αMSH (β = -0.23 [-0.36 to -0.11], P = .0007) and ghrelin (β=-0.004 [-0.01 to 0.00], P = .001) concentrations, suggesting that αMSH replacement may be a therapeutic target for HyOb. HyLean patients demonstrated intermediate insulin responses to glucose compared to other subcohorts. Conclusion:In our cohort, patients with HyOb appeared indistinguishable from Ob in terms of their appetite and appetite-regulating neuroendocrine circuitry. Higher αMSH concentrations are associated with reduced weight gain and may be a target for therapeutic intervention.
Background:Papillary thyroid carcinoma (PTC) is more common among women, including those of reproductive age. While a cancer diagnosis may influence pregnancy planning and treatment decisions in women receiving fertility treatment, the impact of PTC management on pregnancy outcomes remains unclear. We aimed to evaluate the clinical course of PTC diagnosed during fertility treatment and to clarify whether pregnancy outcomes differ according to the initial management strategy, surveillance or surgery. Methods:We retrospectively analyzed reproductive-age women diagnosed cytologically with PTC prior to pregnancy, who were referred to Ito Hospital for thyroid evaluation between January 2013 and December 2019, during fertility treatment. PTC cases were classified according to the Japanese Thyroid Tumor Treatment Guidelines 2018. Patients were followed for clinical course and pregnancy outcomes through December 2024. Results:Among 17 713 women undergoing fertility evaluation, 240 were diagnosed with PTC. Median age was 38 years, and most cases were classified as very low-risk (59.6%), followed by low-risk (27.1%) and intermediate risk (13.3%), with no high-risk cases. Among 96 surveillance patients followed for ≥12 months, disease progression occurred in 8 patients (8.3%), including 1 case during pregnancy. Patients who achieved live birth were significantly younger than those who did not (P < .001). Management strategy (surgery or surveillance) was not associated with the likelihood of live birth (P = .1868). Conclusion:Both surveillance and surgery can be safely integrated into fertility care for women with reproductive-age PTC. Tumor progression was rare and pregnancy outcomes were primarily influenced by maternal age rather than treatment strategy.
Context:The coexistence of diabetes and hyperinsulinemic hypoglycemia (HI) within a family is rare. Activating MAFA variants have been described in 3 families with this dual phenotype and are associated with sex-dependent clinical patterns. Methods:We studied a family where members were affected by HI (n = 5), diabetes (n = 5), or both conditions (n = 1). Clinical, biochemical, and imaging data were collected. Genetic testing for variants in known monogenic diabetes and HI genes was performed in the proband, followed by cascade testing in available relatives. Pancreatic tissue was examined by immunohistochemistry and immunofluorescence. Results:A heterozygous, p.(Ser64Phe) MAFA variant was identified in the male proband, who had presented with diabetes at 28 years and developed HI due to insulinomatosis 6 years later. The variant was confirmed in 5 relatives, 4 with HI and 1 with diabetes (including obligate heterozygotes). Among the 5 presenting with HI, 3 were female, whereas 4 of 6 presenting with diabetes were male, consistent with reported sex-dependent patterns.Increased nuclear expression of the transcription factor MafA (MAFA) was detected by immunofluorescence in insulin-positive tumor regions compared to the adjacent islets, supporting a pathogenic role for the variant in beta-cell regulation. Conclusion:We describe the fourth family with a pathogenic MAFA variant and the second individual with the dual phenotype of diabetes and HI. Our findings highlight challenges in clinical management of this condition and underscore the need to consider MAFA in cases of adult-onset HI or those with an atypical course of diabetes especially when there is family history.
Context:Adrenocortical carcinoma (ACC) is a rare and often fatal malignancy currently only cured by surgery. Large-scale studies have failed to capture benign to malignant transition events, and patients often present with metastatic disease. These observations suggest ACC develops rapidly without a measurable precursor lesion, forming the basis of widely implemented adrenal incidentaloma guidelines. Objective:We aimed to characterize the prevalence of antecedent adrenal nodules, quality of preoperative diagnostic workup, and the impact on survival for adults with ACC. Methods:We analyzed clinical data from 108 consecutive patients referred to a single tertiary academic medical center from 2000 to 2025. Results:Median follow-up was 86.7 months. Strikingly, 31.7% harbored antecedent nodules, indolent for a median 4.68 years before ACC presentation, and ultimately associated with a higher risk of death (adjusted hazard ratio [HR], 2.9; 95% CI, 1.39-6.0). Regarding preoperative evaluation, 46.4% were referred to endocrinology, associated with more complete hormonal assessment; 31.4% had adrenal biopsy, accompanied by increased risk of progression (adjusted HR, 2.53; 95% CI, 1.24-5.2) and death (adjusted HR, 2.22; 95% CI, 1.07-4.6). Patients with high-grade disease received more interventions; those who received mitotane and/or locoregional therapies had improved survival (adjusted HR, 0.31; 95% CI, 0.14-0.71, and adjusted HR, 0.47; 95% CI, 0.23-0.98, respectively). Conclusion:The unexpectedly high prevalence of indolent antecedent adrenal nodules suggests a prolonged, clinically premalignant phase in a subset of ACC. Initial diagnostic evaluation was often incomplete or inappropriately invasive, compromising the preoperative window and patient survival. These findings challenge current surveillance paradigms, revealing an extended but vulnerable window for surgical cure.
Context:Fusion-positive pediatric papillary thyroid carcinoma (PTC) often presents with regional nodal or distant disease, but factors explaining heterogeneity within fusion-positive tumors are incompletely defined. Objective:To determine whether age, fusion group, or sex is associated with baseline N1b and/or M1 disease in fusion-positive pediatric and young adult PTC. Design:Retrospective analysis of the international PEDIMAP cohort. Setting:Multi-institutional pediatric and young adult thyroid carcinoma cohort. Patients:Patients aged 0-25 years with PTC, documented somatic kinase fusion, and available fusion-partner information. Interventions:None. Main Outcome Measures:Advanced baseline presentation, defined as AJCC N1b and/or M1 disease. Associations were tested using Firth penalized logistic regression. Results:Of 101 kinase fusion-positive PTCs identified among 646 PTCs, 2 rearranged during transfection (RET)-fusion cases were excluded because fusion-partner information was unavailable, yielding 99 fusion-positive tumors with known fusion partners: RET, n = 52; neurotrophic receptor tyrosine kinase (NTRK), n = 28; and other non-RET/NTRK kinase fusions, n = 19. Among 95 patients with evaluable N- and M-stage, 64 (67.4%) had N1b and/or M1 disease. Age 0-14 years was associated with higher odds of advanced presentation than age 15-25 years (adjusted OR, 4.67; 95% CI, 1.84-12.75; P = .001). No significant difference in advanced presentation was found between NTRK and RET fusions (adjusted OR, 0.83; 95% CI, 0.29-2.50; P = .739). Conclusion:Within fusion-positive pediatric and young adult PTC, younger age was associated with greater baseline disease extent, whereas no significant difference in N1b/M1 presentation was found between RET and NTRK-fusion groups. These findings support careful baseline assessment of regional and distant disease in younger fusion-positive patients.
Context:Free hormone hypothesis (FHH) posits that free testosterone crosses plasma membrane to activate intracellular signaling and is biologically active fraction of circulating testosterone. Widely accepted in other fields, FHH has been debated in andrology. Objective:To disentangle the roles of free and total testosterone, we studied men with greatly elevated sex hormone-binding globulin (SHBG) levels and primary hypogonadism, who had marked divergence in total and free testosterone concentrations, in whom elevated gonadotropins provided independent evidence of primary testicular insufficiency. Design:Prospective hormonal evaluation of men with greatly elevated SHBG. Outcomes:Total and free testosterone, LH, FSH, symptom ascertainment. Results:Among 20 men with SHBG>100 nmol/L, 15 met Endocrine Society's criteria for primary hypogonadism: low free testosterone, one or more symptoms/signs, elevated LH and/or FSH. Among 15 men with elevated LH and/or FSH and unequivocally low free testosterone who met the criteria for primary hypogonadism, 4 had total testosterone that exceeded the reference range (>916 ng/dL) and 8 had total testosterone >450 ng/dL, substantially above the lower normal limit. Conclusion:In men with markedly elevated SHBG, in whom total and free testosterone diverged substantially, low free testosterone was associated with elevated gonadotropins, providing independent evidence of primary testicular insufficiency even when total testosterone levels were above the reference range or substantially above the lower normal limit. Although sample size was small, these illustrative "n-of-1" observations in uncommon patients are consistent with the primacy of free testosterone over total testosterone in the hypothalamic-pituitary-testicular feedback loop to regulate LH and FSH, and support the FHH.
Background:COVID-19 has been associated with new-onset diabetes. Prior studies are limited by lack of pre-infection data and preexisting cardiometabolic factors. Clarifying how COVID-19 and long COVID (LC) affect glucose metabolism is essential to guide prevention. We evaluated longitudinal changes in glycemic and cardiometabolic markers after SARS-CoV-2 infection in a prospective cohort with pre-infection baseline measurements. Methods:We included 821 uninfected adult participants from the RECOVER cohort who subsequently developed COVID-19, characterizing participants in their pre-COVID state. Data from up to 12 months post-infection were compared to pre-infection baseline. Participants with preexisting diabetes or pregnancy were excluded. The primary endpoint was change in HbA1c up to 12 months after infection. Analysis was stratified by LC status using the 2024 RECOVER Adult Long COVID Research Index (LCRI). Results:HbA1c remained stable from pre-infection to 12 months post-infection (5.39% vs 5.40%; P = .435). Non-HDL cholesterol and blood pressure decreased modestly, while cystatin C increased slightly; absolute changes were small. High-sensitivity C-reactive protein (hs-CRP), troponin, pro-brain natriuretic peptide (pro-BNP), body mass index, and waist circumference remained stable. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk increased slightly (6.7% to 7.3%; P < .001). Trends were similar across LC groups. New-onset metabolic syndrome incidence was comparable across LC categories (18%-20%), although persistent metabolic syndrome was more frequent in participants with more severe LC. Conclusion:In this cohort with pre-infection baseline data, we found no significant changes in HbA1c or cardiometabolic biomarkers through 12 months after infection, although 10-year ASCVD risk slightly increased. These findings emphasize the importance of longitudinal assessment in differentiating transient physiological changes from persistent cardiometabolic disease after COVID-19.
Context:A rare cause of hypocalcemia, autosomal dominant hypocalcemia type 1 (ADH1) arises from a gain-of-function variant of the calcium-sensing receptor gene (CASR). Objective:Three patients from 2 unrelated families, presenting with hypocalcemia and other biochemical parameters consistent with ADH1, were examined for variants in the CASR with the aim to functionally assess any variant detected to confirm the ADH1 diagnosis. Methods:Sanger sequencing of the coding region of the CASR from the 3 patients identified a single CASR variant that was generated by site-directed-mutagenesis in the CASR as a FLAG-tagged construct in the mammalian expression vector pcDNA3.1. The variant's expression in HEK293 cells (compared to FLAG-tagged wild-type [WT] receptor) was assessed by Western blot analysis and its activity measured following calcium dosing experiments using an IP-One enzyme-linked immunosorbent assay. Results:Sequence analysis revealed the presence of a heterozygous missense variant in the CASR, an adenine to guanine transition at nucleotide 1256 causing an asparagine to serine substitution at amino acid 419 (N419S) in the CaSR's Venus flytrap domain in all 3 patients. The N419S variant showed a modest increase in expression compared to the WT receptor. Significantly, the IP-One assay demonstrated that the variant is constitutively active in the absence of Ca++ ions and that this gain-of-function is maintained at physiologically relevant Ca++ ion concentrations. Conclusion:The N419S CASR variant affecting 2 separate families is constitutively activating and therefore causative of ADH1. This is the first report of a constitutively active variant affecting the extracellular domain of the CaSR.
Background: Thyroid cancer incidence is rising worldwide, yet comprehensive longitudinal data linking contemporary demographic, pathological, and surgical trends to recurrence risk remain scarce. Methods: A retrospective analysis was performed on 9504 thyroid cancer patients from 2008 to 2023. Based on the year of treatment, patients were categorized into 3 groups for comparative assessment. Demographic features, clinical pathological characteristics, surgical approaches, and prognostic outcomes were evaluated. Results: Over the 16-year period, the annual number of new thyroid cancer cases demonstrated a consistent upward trend, with a growing proportion detected through routine health screenings. The male-to-female ratio was 1:2.76, with a gradual increase in male patients. The peak age at diagnosis remained between 30 and 60 years, while the proportion of juvenile patients declined steadily. Papillary thyroid carcinoma constituted the predominant histologic type. Surgical management shifted toward more conservative approaches. Although tumor size decreased over time, the incidence of multifocal lesions and the BRAF V600E mutation rate rose. Lymph node metastasis rates also increased, particularly in patients with central region metastases and metastases in ≤5 lymph nodes. Multivariate analysis identified age, tumor size, and number of metastatic lymph nodes as independent risk factors for recurrence in papillary thyroid carcinoma. Patients older than 55 years, those with larger lesions, or those with more lymph node metastases exhibited a significantly elevated recurrence risk. Conclusion: Although thyroid cancers are being detected at earlier stages and smaller sizes, the burdens of molecular, multifocal, and lymph node disease are increasing. Age, tumor size, and nodal metastatic load constitute robust independent predictors of recurrence in papillary thyroid carcinoma, informing risk-adapted surveillance and surgical strategies.
