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Biopsy of phaeochromocytomas and paragangliomas (PPGLs) is discouraged due to the perceived risk of catecholamine-related complications. However, a systematic review showed that this recommendation is primarily supported by case reports. We aimed to assess the safety of percutaneous biopsy in patients with PPGLs. This international, multicentre, retrospective study included patients of any age with PPGLs referred to participating centres who had had percutaneous core-needle biopsy or fine-needle aspiration. Biopsies of head and neck paragangliomas were excluded. Participating centres completed standardised data-collection forms. The primary outcome was biopsy-related mortality rate for all patients who had biopsies performed at participating centres, given that biopsies done elsewhere that had fatal outcomes would be unlikely to be referred. Secondary outcomes included the incidence of serious catecholamine-related and non-catecholamine-related complications among all included patients. Between Sep 1, 1993, and May 31, 2025, 222 patients (110 [50%] female, 112 [50%] male) underwent 234 biopsies in 19 hospitals across 11 countries. 139 (67%) of 207 patients had elevated epinephrine or norepinephrine (or metabolites) and 27 (12%) of 232 biopsies were preceded by the administration of α-adrenoceptor blockade. One (mortality rate 0·9% [95% CI 0·0-5·1]) of 106 biopsies led to death due to biopsy-related infection. Serious catecholamine-related complications occurred after four (1·7% [0·5-4·3]) of 233 biopsies and included tachyarrhythmia, hypertensive crisis, and cardiogenic shock. No serious catecholamine-related complications occurred in patients without catecholamine excess (n=59), receiving fine-needle aspiration (n=46), or after biopsy of metastatic lesions (n=114). Serious non-catecholamine-related complications occurred after ten (4·3% [2·1-7·8]) of 233 biopsies, mainly bleeding and infection. Percutaneous biopsy of PPGLs was associated with a low mortality rate. Serious complication rates were also low, most of which were not catecholamine-related. These findings challenge current recommendations that biopsy should be avoided in suspected or confirmed PPGLs, and instead support a personalised, risk-benefit-based approach to the procedure. Cancerfonden. For the Chinese and French translations of the abstract see Supplementary Materials section.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1·3 billion (95% uncertainty interval [UI] 1·2 to 1·4) individuals were estimated to be living with MASLD (ie, 16·1% of the global population), with an age-standardised prevalence rate of 14 429·3 (95% UI 13 268·3 to 15 990·6) per 100 000 population, representing a percentage increase of 142·7% (95% UI 139·2 to 146·7) in crude numbers from 1990 (0·5 billion [0·5 to 0·6]) and of 28·6% (27·8 to 29·5) in the rate (11 217·2 [10 276·8 to 12 467·0] per 100 000 in 1990). An estimated 3·6 million (2·8 to 4·5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39·6 (31·2 to 49·9) per 100 000 population. Despite a 116·3% (93·3 to 139·4) increase in crude DALYs (from 1·7 million [1·3 to 2·1] in 1990), its age-standardised estimate remained consistent (1·8% [-8·6 to 12·8]) from 1990 (38·9 [30·1 to 49·8] per 100 000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29 246·1 [26 848·3 to 32 048·7] per 100 000) and Andean Latin America showed the highest DALY rate (152·3 [114·1 to 194·7] per 100 000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653·5 [7923·7 to 9592·8] per 100 000) and east Asia had the lowest DALY rate (16·3 [13·5 to 19·9] per 100 000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15 616·4 [14 349·2 to 17 263·3] per 100 000 people in 2023) than in females (13 245·2 [12 132·0 to 14 692·6] per 100 000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2·2 [95% UI 1·6 to 3·1] per 100 000 people), followed by high BMI (1·4 [0·6 to 2·4] per 100 000 people) and smoking (1·0 [0·3 to 1·8] per 100 000 people). Our forecasting model estimates that 1·8 billion (95% UI 1·6 to 2·0) individuals are likely to have MASLD by 2050, representing a 42·0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15 774·9 (95% UI 14 613·9 to 17 336·2) per 100 000 people in 2050, representing an average annual percentage change of 0·3% (95% UI 0·3-0·3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16·1% and approximately 1·3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.

Dysnatremia is the most common electrolyte abnormality detected during hospitalizations and outpatient visits and is associated with adverse outcomes in older adults. However, data on its prevalence and incidence in community-dwelling older individuals remain limited. This study aimed to estimate the prevalence and incidence of dysnatremia in this population across 5 European countries (Austria, France, Germany, Portugal, and Switzerland). Observational analysis of DO-HEALTH, a 3-year multicenter clinical trial including 2157 community-dwelling, generally healthy adults aged 70 years and older. Sodium blood levels were collected at baseline, 12, 24, and 36 months. Dysnatremia was defined as sodium levels <135&#x2005;mmol/L (hyponatremia) or >145&#x2005;mmol/L (hypernatremia). Baseline prevalence and 3-year incidence were estimated overall and by predefined subgroups based on sex, age, country of residence, body mass index, prevalent chronic conditions, polypharmacy, and use of thiazide-like diuretics. At baseline, 2141 participants (99.3%) had available sodium data. The prevalence of dysnatremia was 3.4% (2.4% hyponatremia; 1.0% hypernatremia), with higher prevalence in participants aged &#x2265;75 years (4.8%) and those using thiazide or thiazide-like diuretics (5.4%). Over 3 years, 150 participants (7.0%) experienced at least 1 episode of dysnatremia (3.8% hyponatremia; 3.2% hypernatremia). Higher incidence of dysnatremia was observed among participants living in Switzerland, using thiazide or thiazide-like diuretics, and with prevalent dysnatremia at baseline. Dysnatremia, previously linked to adverse outcomes in older adults, was observed in a non-negligible proportion of generally healthy, community-dwelling older individuals. These findings provide valuable epidemiologic data and identify subgroups that may warrant closer clinical attention.

Paediatric population screening for type 1 diabetes is emerging internationally. It is critically important to understand the acceptability of screening to inform these initiatives. In this systematic review, we aimed to assess the psychosocial impact, acceptability and ethics of screening for paediatric type 1 diabetes. We searched MEDLINE, EMBASE, APA PsycInfo, ASSIA, CINAHL, Web of Science, Scopus, and included quantitative, mixed methods and qualitative articles until 25 November 2025. We assessed the emotional, cognitive and behavioural implications, acceptability or ethics of type 1 diabetes early detection for parents and/or children. We used the mixed methods appraisal tool and critical appraisal skills checklists for quality assessment. We performed a mixed methods evidence synthesis, identifying key themes from qualitative data and merging with quantitative data to generate meta-inferences. Seventy articles (12 qualitative, 57 quantitative and one mixed methods) involving 62,244 parents and 6363 children aged <18 years were included. Seven articles (10.0%) met all quality criteria (high quality), 43 (61.4%) met 60-80% of criteria (moderate quality) and 20 (28.6%) met <50% of criteria (low quality). We generated five themes and 19 sub-themes. Identification of early-stage type 1 diabetes generated anxiety, which waned over time but could recur. Overall, parents who opted into an early detection research programme valued knowing their child's risk and perceived benefits to outweigh harms, although paediatric blood sampling was considered challenging. Research ethics of screening centred on joint decision making according to the child's age, right to results disclosure and importance of data integrity. We synthesised a large pool of heterogenous studies, reflecting how understanding of early disease has evolved, but likely influencing the acceptability of screening. This, the most comprehensive review of the literature to date, demonstrates that despite the emotional, cognitive and behavioural implications, thus far, screening and early detection of paediatric type 1 diabetes appears to be acceptable to parents/guardians who take part but critical evidence gaps remain. PROSPERO registration no. CRD42024566937 FUNDING: EDENT1FI (grant no. 101132379).

Glucocorticoid withdrawal syndrome (GWS) is a frequent and clinically significant consequence of reducing chronic endogenous or exogenous glucocorticoid exposure. The syndrome presents with a range of symptoms involving musculoskeletal, gastrointestinal, neuropsychiatric, cardiovascular, and metabolic domains, which can closely resemble adrenal insufficiency or recurrence of an underlying autoimmune/inflammatory disease. As a result, the true prevalence, history, and clinical burden of GWS remain poorly defined, and recognition varies widely across clinical settings. The lack of treatment options for GWS contributes to detrimental exogenous glucocorticoid exposure in patients with rheumatologic, oncologic, and endocrine diseases. The underlying biological mechanisms of GWS remain incompletely understood, which represents a major barrier to the recognition and treatment of this syndrome. This review synthesizes current evidence on the epidemiology, clinical manifestations, and management challenges of GWS. We integrate mechanistic insights from studies of chronic glucocorticoid excess, postoperative recovery of Cushing syndrome, and experimental models of glucocorticoid excess and deficiency. Glucocorticoid excess leads to central and peripheral adaptations involving the hypothalamic-pituitary-adrenal axis, glucocorticoid receptor signaling, circadian rhythms, immune and inflammatory pathways, metabolic and autonomic regulation, and glucocorticoid-sensitive neural circuits. We propose that GWS arises due to the confluence of these persisting adaptations with relative glucocorticoid deficiency and tissue- or cell-specific adaptations and recovery timelines. Thus, we provide a mechanistic framework for understanding the diverse manifestations of GWS and highlight key gaps that need to be addressed to improve mechanistic understanding, diagnosis, and clinical management.

Multiple retractions from the same author often uncover issues affecting their entire work, such as having systematically altered or fabricated data. To evaluate the contribution of authors with the most retractions (ie, superretractors) and top-cited scientists with multiple retractions to the retracted randomized clinical trial (RCT) literature. This retrospective cohort study linked an openly available cohort of retracted RCTs (VITALITY) to 3 lists of scientists: (1) superretractors, totaling most retractions in the Retraction Watch Leaderboard; (2) scientists in the top 100&#x202f;000 or 2% of their subfield in terms of citations (ie, top-cited scientists) over their entire careers who accumulated 10 or more retractions not due to editor or publisher errors; and (3) top-cited scientists in the most recent year (ie, 2024) who accumulated 10 or more retractions not due to editor or publisher errors. The VITALITY cohort was updated up to November 2024. The 3 author lists were updated in August 2025. The main outcomes were authorship and the characteristics of retracted RCTs (publication and retraction year, time between publication and retraction, number of citations). A total of 30 superretractors, 163 career-long top-cited scientists with 10 or more retractions, and 174 recent-year top-cited scientists with 10 or more retractions were included; 1330 retracted RCTs were included. Overall, 6 superretractors (20%), representing anesthesiology as well as endocrinology and metabolism, coauthored 290 retracted RCTs (22%); 18 career-long top-cited scientists with at least 10 retractions, representing 10 fields, coauthored 327 trials (25%), 275 (84%) of which were also coauthored by a superretractor; 7 single-year top-cited scientists with at least 10 retractions coauthored 50 retracted RCTs (4%), all of which were also included in the list of articles authored by career-long top-cited scientists with at least 10 retractions. Articles with superretractor authors vs not were published earlier (median [IQR], 2000 [1997-2005] vs 2020 [2014-2022]); retracted earlier (median [IQR], 2013 [2012-2019] vs 2023 [2018.5-2023]); had a longer lag between publication and retraction (median [IQR], 5111 [3560-6820] days vs 482 [330-1119] days); and accrued more citations (median [IQR], 21 [12-42] vs 5 [1-19]). In multivariable regression models, only time to retraction (&#x3b2;&#x2009;=&#x2009;0.02; P&#x2009;<&#x2009;.001) was significantly and positively associated with total citations. Results were similar when comparing retracted articles from top-cited scientists with at least 10 retractions vs other articles. In this cohort study of 1330 retracted RCTs, a small number of influential authors, often coauthors and concentrated across few fields of medicine, accounted for a significant proportion of retracted clinical trials.

The scarcity of robust long-term safety data has contributed to increasing restrictions on the use of gonadotropin-releasing hormone analog (GnRHa) treatment in transgender and gender diverse adolescents (TGDAs) in several countries. Methodological limitations of earlier studies have led to controversy and debate, underscoring the urgent need for high-quality evidence in this field. To present a study design using target trial emulation (TTE) to evaluate long-term safety of GnRHa treatment in TGDAs using observational data from national healthcare registries, and highlight methodological challenges. We applied a stepwise TTE approach, to emulate a randomized trial using real-world data. The main methodological challenges were identified as the selection of the control group and the definition of time zero. To address these, we engaged independent experts in causal inference to review the concept design and provide feedback on potential solutions. Expert feedback was systematically summarized and discussed. The resulting study design will select late-presenting TGDA individuals as the control group and defines time zero as the initiation of GnRHa treatment for the intervention group, with the equivalent age assigned as time zero in controls. Sensitivity analyses using alternative control groups and time zero definitions will be included to assess robustness. This approach allows for adjustment of confounders and aims to emulate the conditions of a randomized trial as closely as possible within the constraints of observational data. This discussion paper serves as a methodological example of target trial emulation with observational data to study long-term safety of GnRHa in TGDA. By transparently addressing methodological challenges and incorporating expert input, this approach offers a feasible and ethically sound alternative to RCTs, and contributes to the evidence base needed for informed clinical and policy decisions in transgender healthcare.

X-linked hypophosphataemia (XLH) is a rare genetic disorder characterised by defective bone and tooth mineralisation. Burosumab is a recombinant, human, anti-fibroblast growth factor 23 monoclonal antibody approved for treating XLH. Due to the rarity of the disease, additional safety data for treatment of XLH with burosumab are required. A post-authorisation safety study analysis of data for paediatric participants from the International X-linked Hypophosphataemia Registry. This study included standard diagnostic and monitoring clinical data at participating centres, regardless of treatment. This was a second interim analysis performed 5 years after study initiation in the paediatric population. Primary objectives assessed safety outcomes in children and adolescents with XLH. The secondary objective compared safety outcomes with burosumab vs phosphate and/or active vitamin D. In total, 340 participants were treated with &#x2265;1 dose of burosumab, and 91 were treated with phosphate and/or active vitamin D. Overall, 37.4% and 22.0% of participants in the burosumab or phosphate and/or active vitamin D cohorts, respectively, experienced &#x2265;1 adverse event. The proportions of participants with events were similar among children and adolescents. Forty-nine (14.4%) participants reported events possibly/probably related to burosumab. No events led to withdrawal of burosumab. In both cohorts, no serious adverse events were considered related to treatment, and there were no deaths. Hospitalisations occurred in &#x223c;71% of participants. Hyperphosphataemia, elevated parathyroid hormone, and ectopic mineralisation events were rare. The safety profile of burosumab was consistent with previous studies, and no new safety concerns were reported for children or adolescents.

PTH(1-34), used off-label, effectively controls serum calcium in patients with chronic hypoparathyroidism inadequately managed by standard-of-care therapy. PTH(1-34) also strongly stimulates bone remodeling and often raises bone turnover markers above normal levels. This study aimed to visually assess the risk of excessive bone stimulation associated with prolonged PTH(1-34) replacement therapy. An observational study (N&#xb0;20201026100318) was conducted in adults with chronic hypoparathyroidism treated with PTH(1-34) for over 2 years at 3 referral centers. Patients underwent whole-body 99mTc-methylenediphosphonate scintigraphy, biochemical evaluation, and bone mineral density assessment. The primary endpoint was the proportion of patients with pathological increases in bone tracer uptake. Forty-one patients received a mean daily dose of 29.9&#x2005;&#xb5;g [Q1; Q3 22.5; 39.9] of PTH(1-34) for a duration of 57 months [40; 70], representing an exposure of 218.3 patient-years. Median age at imaging was 44 years [30; 55]; 31 (75.6%) were women. Pathological bone uptake was observed in 25 (61%) patients despite serum calcium predominantly in the target therapeutic values. Osteoarticular pain did not differentiate affected individuals. These patients had higher weight-adjusted PTH(1-34) doses (0.44&#x2005;&#xb5;g/kg [0.32; 0.56] vs 0.34&#x2005;&#xb5;g/kg [0.24;0.40], P = .045), elevated bone remodeling markers, lower serum magnesium, and increased urinary calcium excretion. A score combining serum C-telopeptides of collagen I, osteocalcin, and magnesium correctly classified 97% of patients (95% CI: 91%-100%). Long-term PTH(1-34) therapy in chronic hypoparathyroidism is frequently associated with excessive bone remodeling despite adequate calcemic control. Careful monitoring is therefore essential, especially in patients with elevated bone remodeling markers and hypomagnesemia.

Glycated haemoglobin A1c (HbA1c) measurement is essential for managing diabetes, yet limited data exist on the performance of point-of-care (POC) HbA1c devices in low- and middle-income countries (LMICs). This study evaluated the analytical performance and usability of HbA1c devices in different LMIC settings. This prospective, cross-sectional multicentre study evaluated the accuracy and usability of four POC devices (i-SENS A1Care, HemoCue HbA1c 501 System, Abbott Afinion 2 and Siemens DCA Vantage) against a laboratory-based HbA1c method at two hospitals in Nigeria and Cambodia. Adults with or without diabetes and haemoglobin &#x2265;8&#x2009;g/dL were enrolled. The primary objective was to evaluate HbA1c POC device accuracy versus laboratory reference testing; secondary objectives evaluated device usability and technical characteristics when used by trained professionals. Capillary and venous blood samples were tested on all devices using two cartridge lots followed by reference testing. Usability was assessed via operator questionnaires. Accuracy was evaluated using regression slopes, intercept, absolute bias at 30, 48 and 75&#x2009;mmol/mol, and Bland-Altman analysis, including capillary-venous concordance. A total of 248 participants completed all study procedures (n=125 in Cambodia, n=123 in Nigeria). Siemens DCA Vantage and Abbott Afinion 2 showed strong agreement with the reference method, with no clinically significant differences and narrow limits of agreement. In contrast, i-SENS A1Care and HemoCue HbA1c 501 System displayed greater bias, especially at elevated HbA1c levels. Most results fell within limits of agreement, though high-HbA1c outliers were more common with the A1Care and HbA1c 501 System devices. Usability feedback was positive overall, when devices were rated across various dimensions, such as clarity of instructions, safety and labelling, although limited user sample size constrains the generalisability of these findings. Siemens DCA Vantage and Abbott Afinion 2 demonstrated reliable accuracy and usability. In contrast, i-SENS A1Care and HemoCue HbA1c 501 System require cautious interpretation at high HbA1c levels. Ongoing evaluation is critical to ensure the appropriate use of POC devices in diverse clinical settings. NCT06170515.

Hyponatremia is the most common electrolyte disorder. While overly rapid correction can cause osmotic demyelination syndrome (ODS), hyponatremia itself is linked to neurocognitive impairment. Despite this, the neurological burden remains underappreciated, and subclinical neuronal and astrocytic injury due to hyponatremia or its correction may be more frequent than recognized. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal and astrocytic injury. Whether hyponatremia and its treatment are associated with changes in serum NfL and GFAP levels. Two randomized, double-blind, placebo-controlled trials. Study 1: healthy adults underwent experimentally induced hyponatremia within 8&#x2005;hours. Study 2: hospitalized patients with hyponatremia were treated over 4 days. Biomarkers were measured at baseline and follow-up and analyzed as age- and BMI-adjusted Z-scores (for GFAP, also sex-adjusted). In healthy adults, blood sodium decreased by a median of 7&#x2005;mmol/L [-8(-)-6] within 8&#x2005;hours, associated with an increase in NfL (+0.48 Z-units [0.09-0.78]) and GFAP (+1.02 Z-units [0.84-1.39]). Patients with hyponatremia showed a baseline sodium of 126&#x2005;mmol/L [122-127], which increased by 4&#x2005;mmol/L [2-6] within 24&#x2005;hours. NfL increased from a Z-score of 1.90 [1.06-2.51] by +0.21 [-0.03-0.66]; GFAP increased from 0.16 [-0.55-0.58] by +0.46 [0.12-0.81]. In multivariable models predicting biomarker Z-scores on day 5, both baseline biomarker levels and the degree of sodium increase within 24&#x2005;hours were significant predictors. Hyponatremia and its correction are associated with measurable neuronal and astrocytic injury. NfL and GFAP may serve as early indicators of osmotic brain stress, suggesting ODS may represent only the visible part of a broader spectrum of cerebral vulnerability.

To systematically evaluate the impact of adrenal tumour diagnosis and targeted interventions on health-related quality of life (HRQoL) and neuropsychiatric outcomes across tumour subtypes. Systematic review. A literature search of MEDLINE, Embase, Cochrane Library, and CINAHL (January 1990-March 2026) identified studies reporting HRQoL and neuropsychiatric outcomes in adults with adrenal tumours, including non-functioning adrenal tumours (NFAT), mild autonomous cortisol secretion (MACS), adrenal Cushing's syndrome (CS), primary aldosteronism (PA), phaeochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). Study quality was assessed using CONSORT-PRO and Newcastle-Ottawa criteria. Due to methodological heterogeneity, findings were synthesized narratively. A total of 117 studies involving 35 361 patients were included. CONSORT-PRO quality was good but heterogeneous, whereas observational study quality was mostly moderate or low. Across tumour subtypes, adrenal tumours were consistently associated with impaired HRQoL and neuropsychiatric outcomes. A gradient of burden was evident, with mild impairment in NFAT, intermediate impairment in MACS and PA, and the most pronounced and persistent deficits in adrenal CS, PPGL, and ACC. Targeted interventions were often associated with improved patient-reported outcomes, though the magnitude and consistency of benefit varied across tumour subtypes and study design. Recovery was frequently incomplete. Most studies relied on generic HRQoL instruments, and no disease-specific neuropsychiatric tools were identified. Adrenal tumours are associated with substantial and often persistent impairment in patient well-being across tumour subtypes. Although treatment generally improves outcomes, residual symptoms are common, underscoring the need for long-term, patient-centred care and for the development of adrenal tumour-specific patient-reported outcome measures.

Esophageal adenocarcinoma (EAC) represents one of the most increasing malignancies in Western countries. The disease is multifactorial, involving modifiable risk factors and genetic susceptibility variants. These variants can be aggregated to a polygenic risk score (PRS) that reflects individual genetic risk. Investigation of the effects of lifestyle factors, PRS, and co-medication on EAC age at onset (AAO) is critical for shaping prevention strategies. A detailed questionnaire was used to assess pre-diagnostic exposure to lifestyle factors and clinical information from a large German EAC cohort. Linear regression analysis was performed to identify factors associated with EAC AAO in 1742 EAC patients. PRS was available for 1190 patients. Subgroup analyses were conducted to estimate the effects of the analyzed factors on AAO according to age group (early vs. late onset), sex, and prior diagnosis of Barrett's esophagus (BE). Earlier AAO was significantly associated with gastroesophageal reflux (GER), smoking and a higher PRS, whereas later AAO was associated with physical activity and higher consumption of fish and fruits. Among co-medication, combined use of proton pump inhibitors (PPIs) and acetylsalicylic acid (ASA) showed the most significant effect on AAO, whereas the use of PPIs and ASA alone showed weaker effects. This study represents the largest questionnaire-based analysis to date investigating factors influencing EAC development. Our findings show that the combined use of PPIs and ASA, both cost-effective medications, is associated with delayed EAC onset. In addition, lifestyle and genetics contribute to EAC AAO.

Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. While gene mutations in APA trigger aldosterone overproduction via calcium signaling, their precise regulatory mechanisms remain unclear. Our prior proteomic analysis identified significant upregulation of tumor protein D52 (TPD52), an oncogene protein implicated in cancer progression, in APA. This study investigates the role of TPD52 in regulating aldosterone synthesis and its molecular mechanism. TPD52 expression was validated in APA specimens. Gain- and loss-of-function studies in NCI-H295R cells were performed to assess its role in aldosterone synthesis. Mechanistic insights were obtained through transcriptomics and Co-immunoprecipitation-mass spectrometry (Co-IP-MS), with key results validated in NCI-H295R and HEK-293T cells. Finally, we overexpressed TPD52 in primary APA cells to assess its regulation of aldosterone. TPD52 was upregulated in APA tissues. Functionally, TPD52 overexpression suppressed aldosterone synthesis in NCI-H295R cells, whereas its knockdown enhanced aldosterone production. Transcriptomic analysis confirmed that TPD52 knockdown promoted CYP11B2 (aldosterone synthase) expression and aldosterone synthesis. Co-IP-MS identified calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) as a novel TPD52-interacting protein. This interaction suppressed phosphorylation of calmodulin-dependent protein kinase 4 (CAMK4) and CREB. Importantly, CAMKK2 overexpression rescued the TPD52-mediated suppression of CYP11B2 expression and aldosterone synthesis. Overexpression of TPD52 in primary APA cells also reduced CYP11B2 expression and aldosterone production. TPD52 acts as a negative regulator of aldosterone synthesis by inhibiting the CAMKK2-CAMK4-CREB signaling axis.

Navepegritide, a prodrug of C-type natriuretic peptide, has demonstrated improved growth and additional benefits, including lower limb alignment, in children with achondroplasia. The well-described mechanism of action of navepegritide in the growth plate is hypothesized to enhance its receptivity to lonapegsomatropin, a prodrug of somatropin, to provide benefits beyond those seen with monotherapies in achondroplasia. In the proof-of-concept phase 2 COACH trial, children with achondroplasia aged 2 to 11 received weekly navepegritide and lonapegsomatropin. The primary efficacy endpoint was annualized growth velocity (AGV) at week 52 vs AGV with navepegritide monotherapy in the ApproaCH trial (NCT05598320). Twenty-one children were enrolled: 12 received no prior growth-promoting treatment (treatment-naive, TN) and 9 had been receiving navepegritide monotherapy for >1 year (navepegritide-experienced, NE). At week 52, TN children receiving navepegritide and lonapegsomatropin had a least squares mean AGV of 8.69&#x2005;cm/year versus 5.95&#x2005;cm/year for matched children who received navepegritide monotherapy, a difference of 2.74&#x2005;cm/year (P < .0001). Observed mean AGV for TN children was 8.80&#x2005;cm/year, a +3.89&#x2005;cm/year increase from baseline (P = .0015). NE children had an observed mean AGV of 8.42&#x2005;cm/year, a +3.28&#x2005;cm/year increase from navepegritide-treated baseline (P < .0001). An improvement in body proportionality was observed and arm span increased substantially (+9.4&#x2005;cm in TN and +7.9&#x2005;cm in NE children), in line with gains in height. Treatments were well-tolerated with generally mild adverse events and no treatment discontinuations. In this prospective trial, the robust growth and anthropometric results suggest that by continuously relieving the pre-hypertrophic block in achondroplasia, navepegritide may make the growth plate more responsive to the strong complementary effect of lonapegsomatropin. ClinicalTrials.gov NCT06433557.

To map real-world management of paediatric differentiated thyroid carcinoma (DTC) across Europe and identify targets for harmonization. Cross-sectional, web-based survey of centres providing paediatric DTC care. One consolidated response per centre was requested from a clinician overseeing paediatric DTC. The instrument covered centre profile/multidisciplinary tumour (MDT) board organization; staging and guideline use; risk stratification and dynamic response; diagnostics; surgery/lymph node management; radioactive iodine therapy (RAIT) policy and activity selection; and thyroid-stimulating hormone targets, follow-up, shared-care/transition. Analyses were descriptive at centre level. Forty-two centres from 18 countries participated in the survey. Response denominators varied by item. Among responding centres, &#x2248;75% were university or academic hospitals, &#x2248;70% used a paediatric age cut-off of &#x2264;18 years, and &#x2248;60% reported having a dedicated MDT board. Staging and guideline use were heterogeneous: centres most often reported mixed or centre-specific guidance, followed by the American Thyroid Association (ATA) 2015 guideline, national guidelines, and the European Thyroid Association (ETA) 2022 guideline. Dynamic response-to-therapy categories were commonly used. For unilateral presumed low-risk disease, hemithyroidectomy was the usual initial surgery in approximately two-thirds to three-quarters of centres, whereas total thyroidectomy was less common. For low-risk patients, RAIT policy were split between de-escalation and risk-adapted use. When administered, RAIT activity was determined using weight-based, dosimetric, or fixed empirical approaches. Country-level patterns suggested clustering around ETA-leaning, ATA-leaning, and national guideline frameworks. Across Europe, centres broadly endorse risk-adapted care but diverge at key decision nodes-extent of surgery, formal risk framework, and RAIT in low-risk disease-reflecting guidance plurality and organizational context. Leveraging existing infrastructures offers pragmatic avenues to reduce unwarranted variation while generating paediatric-specific evidence to refine recommendations.

Molecular imaging has emerged as a promising adjunct for the evaluation of pituitary neuroendocrine tumors (PitNETs), as magnetic resonance imaging (MRI), despite being the primary imaging modality, remains inconclusive in a substantial proportion of patients. Molecular imaging techniques, including single photon emission computed tomography (SPECT) and positron emission tomography (PET), can complement anatomical MR imaging by enabling in vivo visualization of tumor metabolism, receptor expression, and amino acid transport. This narrative review summarizes current evidence on the clinical utility of molecular imaging across corticotroph, somatotroph, lactotroph, and nonfunctioning PitNETs, with a focus on diagnostic performance and impact on patient management. Among available tracers, amino acid PET shows the most consistent added diagnostic value in patients with inconclusive MRI findings, particularly when integrated into hybrid or coregistered PET-MRI protocols. Emerging data indicate that this approach improves tumor localization and supports clinical decision-making, including surgical planning and management of persistent or recurrent disease. Defining the precise role of molecular imaging within endocrine diagnostic pathways will require larger-scale prospective clinical trials using standardized acquisition and interpretation protocols. Broader clinical implementation is further supported by emerging European interdisciplinary collaborations between experts in endocrinology, nuclear medicine, radiology, neurosurgery, and radiotherapy, with a shared focus on advancing individualized PitNET care.

Patients with Cushing's syndrome (CS) have a high prevalence of cardiovascular disease, and other recognized risk factors for atrial fibrillation/flutter (AF/AFL); however, the prevalence of AF/AFL has not been well characterized in this population. We conducted a retrospective matched-cohort study using the Clalit Health Services database, including patients with CS and 1:5 matched controls. We assessed the risk of new-onset AF/AFL overall and according to disease etiology and remission status. Pre-existing AF/AFL was defined as >30 days before CS, and new-onset as within 30 days or thereafter. The cohort included 609 patients with CS and 3018 controls. Pre-existing AF/AFL was more common among patients with CS than controls (3.6% vs. 2.1%; OR 1.70, 95% CI 1.04-2.78). During a mean follow-up of 15 years, patients with CS had a significantly higher risk of developing new-onset AF/AFL compared with controls (HR 1.55, 95% CI 1.19-2.03). This increased risk was observed in both Cushing's disease (CD) (HR 1.53, 95% CI 1.01-2.32) and adrenal CS (HR 1.70, 95% CI 1.06-2.74). AF/AFL risk did not significantly differ according to remission status, although a trend toward lower risk was observed. Multivariate analysis identified older age at diagnosis, male sex, hypertension, vascular disease, and higher BMI as predictors for new-onset AF/AFL. CS is associated with an increased risk of AF/AFL. This elevated risk is observed across both CD and adrenal CS and persists despite disease remission, underscoring the need for heightened awareness and close cardiovascular surveillance in this population. The increased risk of AF/AFL appears to be primarily driven by coexisting cardiovascular comorbidities rather than cortisol excess or other CS-specific features.

Osteoporosis increases fracture risk in older adults and is associated with impaired health-related quality of life (HRQoL). Osteoporosis-specific HRQoL instruments are widely used, but their measurement performance in older populations has not been comprehensively synthesised. To systematically identify and synthesise development and validation studies of osteoporosis-specific HRQoL instruments for older adults, and to appraise their measurement properties using COSMIN criteria and a modified GRADE approach to inform instrument selection for clinical trials, routine care, and research. Systematic review. Community-dwelling; Long-term care facility; Primary care facility. Older persons aged 60&#xa0;years or over. We searched Medline (Ovid), Embase, PsycINFO (Ovid), and AMED (Ovid) from inception to August 2024. We extracted and appraised evidence for COSMIN-defined measurement properties: content validity, structural validity, internal consistency, cross-cultural validity or measurement invariance, reliability, measurement error, criterion validity, hypothesis testing for construct validity, and responsiveness. Methodological quality was assessed using the COSMIN Risk of Bias checklist, measurement properties were rated against COSMIN criteria for good measurement properties, and certainty of evidence was graded using a modified GRADE approach. Forty-three studies reported the development and/or validation of nine osteoporosis-specific HRQoL instruments; language and version adaptations resulted in 15 instrument variants. Content validity was the most prominent limitation: only OPTQoL and the English Mini-OQLQ demonstrated sufficient evidence for multiple content validity components, while most widely used instruments lacked adequate evidence on item relevance, comprehensiveness, or comprehensibility. Evidence for internal structure was limited, with structural validity sufficient for ECOS-16 and QoLOS-NVFX, insufficient for QUALEFFO-41, and indeterminate for most other instruments. Cross-cultural validity and measurement invariance were almost entirely unexamined. By contrast, reliability and hypothesis testing for construct validity were more consistently supported, often with moderate-to-high certainty. Measurement error, interpretability, and responsiveness were poorly reported across instruments. The evidence base supports purpose-driven selection of osteoporosis-specific HRQoL instruments rather than a single preferred instrument. Across included studies, ECOS-16 shows the most consistently supported measurement properties in older adults for longitudinal assessment, although important evidence gaps remain (notably measurement error and cross-cultural validity). When brevity is the primary feasibility constraint in routine care, the Mini-OQLQ may be considered; however, evidence for responsiveness is limited.