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ObjectivesHFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort.DesignProspective cohort study.Setting22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006–2010).Participants451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data.Main outcome measuresCox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years.Results12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson’s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes.ConclusionsMale and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.

BackgroundThe association between maternal iron status and the risk of gestational diabetes mellitus (GDM) remains elusive. Clearer evidence is needed to inform appropriate ferritin thresholds and iron supplementation guidelines during pregnancy.ObjectivesTo investigate whether first-trimester serum ferritin (SF) concentration is associated with subsequent GDM risk.DesignRetrospective cohort study.SettingA tertiary obstetrics and gynaecology hospital in Shanghai, China.ParticipantsA total of 6429 low-risk pregnant women at fewer than 14 weeks of gestation were finally included.Outcome measuresGDM was diagnosed using a 75 g oral glucose tolerance test according to the criteria established by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Women were stratified by SF concentration into three groups: <30, 30–70 and >70 µg/L. Logistic regression was used to calculate adjusted ORs and 95% CIs for GDM, with the 30–70 µg/L group serving as the reference.ResultsGDM was diagnosed in 1215 women (18.9%). Elevated SF (>70 µg/L) was independently associated with increased GDM risk (adjusted OR 1.27, 95% CI 1.05 to 1.54) compared with the reference group (30–70 µg/L). Stratified analysis revealed that the association was significant only in normal-weight women (body mass index (BMI)<24 kg/m²; OR 1.46, 95% CI 1.19 to 1.79), while no significant association was observed in overweight or obese women, indicating effect modification by prepregnancy BMI.ConclusionsElevated first-trimester SF is independently associated with GDM risk in pregnant women at low-risk, with the association most pronounced among those with normal prepregnancy BMI.

ObjectivesIron deficiency (ID) is frequent in heart failure (HF). Among patients with HF and ID, those with impaired iron transport (IIT) (transferrin saturation (TSAT) <20%) have the worst ID phenotype. In HF, exercise limitation is mainly related to abnormality in oxygen delivery (VO2) and utilisation and/or to ventilation inefficiency. We evaluated whether it is possible to identify the leading cause of exercise limitation in patients with HF and IIT.DesignObservational study.SettingRetrospective study.ParticipantsWe analysed 1043 consecutive hospitalised patients with HF (66±14 years, 49.8% females) who underwent cardiopulmonary exercise test (CPET).Outcome measuresAssociations between CPET parameters and TSAT were explored using general linear models adjusted for potential confounders (haemoglobin, left ventricle ejection fraction, age, gender, C reactive protein, serum creatinine).ResultsWe observed that: (a) 413 patients with HF and IIT had worse functional capacity compared with non-IIT cases: peak VO2 (15±3 vs 16±6 mL/min/kg, p<0.0001) and ventilation/carbon dioxide relationship (VE/VCO2) slope (38±9 vs 33±8, p<0.0001); (b) VE/VCO2 values remained significantly different between IIT and non-IIT cases after adjusting for confounding variables including peak VO2; differently, peak VO2 after adjusting also for VE/VCO2 slope, resulted not different in IIT compared with non-IIT HF cases; (c) patients with both low peak VO2 (<14 mL/min/kg) and high VE/VCO2 (≥34) had a higher B-type natriuretic peptide (BNP), lower TSAT and higher MECKI (Metabolic Exercise combined with Cardiac and Kidney Index) score compared with patients with high peak VO2 and low VE/VCO2 (BNP 951±1041 vs 413±623 pg/mL (p<0.0001); TSAT 19.5%±10.5% vs 26.9%±10.2% (p<0.0001); MECKI score 14.8%±1.4% vs 1.2%±2.3% (p<0.0001).ConclusionsHigh VE/VCO2 slope is directly associated with IIT, independent of peak VO2, suggesting a pivotal role for ventilation inefficiency in exercise impairment in patients with IIT and HF. In patients with HF, the worst exercise performance is associated with low TSAT, high BNP and the highest MECKI score.

ObjectiveThis study aimed to identify body mass index (BMI) growth trajectories from birth to 24 months of age and examine the independent and additive effects of four maternal metabolic risk factors, namely prepregnancy BMI, the rate of gestational weight gain, gestational diabetes mellitus (GDM) and gestational hypertension, on offspring growth trajectories in childhood in China.DesignA retrospective cohort study was conducted.SettingThe study used Maternal and Child Health Management Database in Chengdu, China, including the mothers’ antenatal care data, birth certificate records and 0–3-year-old children’s healthcare data.ParticipantsThe study included mothers who gave birth between January 2014 and December 2014, and followed their offspring through 31 December 2016. The final analysis included 4492 mother-child pairs.Primary outcome measuresThe primary outcomes were children’s BMI measurements from birth to 24 months of age. We performed group-based trajectories modelling to identify children’s BMI growth trajectories. Then, we applied logistic regression to examine the associations between maternal metabolic risk factors and offspring BMI trajectories in childhood.ResultsFour distinct trajectories were identified: stable low (16.83%), stable average (40.69%), stable high (32.06%) and early increase (10.42%) trajectories. Relative to the stable average trajectory, maternal prepregnancy overweight (adjusted OR (aOR)=2.001, 95% CI 1.482–2.702, p<0.001), an excessive rate of gestational weight gain (aOR=1.496, 95% CI 1.138–1.966, p=0.004) and GDM (aOR=1.470, 95% CI 1.097–1.970, p=0.010) were positively associated with their offspring being in the early increase trajectory. In addition, the children’s risk of being included in the early increase trajectory showed an increasing trend with an increasing number of adverse maternal metabolic risk factors.ConclusionExposure to maternal prepregnancy overweight, excessive rate of weight gain and GDM resulted in a greater risk of offspring exhibiting an early increase trajectory for BMI. Decreasing maternal metabolic risk before and during pregnancy and monitoring childhood growth trajectories may prevent or delay the onset of childhood obesity.

IntroductionDespite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload.Methods and analysisThis is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures.Ethics and disseminationEthical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals.Trial registration numberThe trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).

ObjectivesThis study aimed to evaluate the performance of the triglyceride glucose (TyG) index and its related markers in predicting metabolic-associated fatty liver disease (MAFLD) in healthy Chinese participants.DesignThis was a cross-sectional study.SettingThe study was conducted at Health Management Department of the Affiliated Hospital of Xuzhou Medical University.ParticipantsA total of 20 922 asymptomatic Chinese participants (56% men) were enrolled.Outcome measuresHepatic ultrasonography was performed to diagnose MAFLD based on the latest diagnostic criteria. The TyG, TyG-body mass (TyG-BMI) and TyG-waist circumference indices were calculated and analysed.ResultsCompared with the lowest quartile of the TyG-BMI, the adjusted ORs and 95% CIs for MAFLD were 20.76 (14.54 to 29.65), 92.33 (64.61 to 131.95) and 380.87 (263.25 to 551.05) in the second, third and fourth quartiles, respectively. According to the subgroup analysis, the TyG-BMI in the female and the lean groups (BMI<23 kg/m2) showed the strongest predictive value, with optimal cut-off values for MAFLD of 162.05 and 156.31, respectively. The areas under the receiver operating characteristic curves in female and lean groups were 0.933 (95% CI 0.927 to 0.938) and 0.928 (95% CI 0.914 to 0.943), respectively, with 90.7% sensitivity and 81.2% specificity in female participants with MAFLD and 87.2% sensitivity and 87.1% specificity in lean participants with MAFLD. The TyG-BMI index demonstrated superior predictive ability for MAFLD compared with other markers.ConclusionsThe TyG-BMI is an effective, simple and promising tool for predicting MAFLD, especially in lean and female participants.

BackgroundAccurate assessment of insulin resistance, sensitivity and β-cell function is essential for early detection and management of metabolic disorders. However, reference intervals (RIs) commonly used in Nepal have been adapted from Western populations, which may not accurately reflect local physiological characteristics. Thus, this study aimed to establish population-specific RIs for fasting insulin and key insulin-related indices using a direct priori method in healthy adults from Gandaki Province, Nepal.MethodThis cross-sectional study recruited 135 healthy adults (20–69 years, body mass index 18.5–24.9 kg/m²) representing different districts of Gandaki Province, Nepal. Fasting blood samples were analysed for glucose, insulin and lipids using standardised assays. Insulin was measured using the chemiluminescence immunoassay method. Nineteen different insulin-derived indices (Homeostasis Model Assessment 1 of Insulin Resistance (HOMA1-IR), Homeostasis Model Assessment 2 of Insulin Resistance (HOMA2-IR), Homeostasis Model Assessment for Triglycerides, Fasting Insulin to Glucose Ratio, Fasting Insulin Resistance Index, Metabolic Score for Insulin Resistance (METS-IR), InsuTAG, HOMA1-%S, HOMA2-%S, Quantitative Insulin Sensitivity Check Index (QUICKI), McAuley, Bennett, Raynaud, Glucose-to-Insulin Ratio, Fasting Insulin Sensitivity Index, Single Point Insulin Sensitivity Estimator (SPISE), reciprocal insulin, HOMA1-%B and HOMA2-%B) were calculated. Non-parametric 95% double-sided RIs (2.5th–97.5th percentiles) were established following outlier removal per Clinical and Laboratory Standards Institute-International Federation of Clinical Chemistry and Laboratory Medicine EP28-A3c guidelines.ResultsThe RI for fasting insulin was 2.63–14.56 µIU/mL (median 7.69 µIU/mL). Among the 19 mathematically correlated insulin-derived indices which are calculated from core measurements (fasting serum insulin and glucose), consistent patterns emerged across functional categories. Insulin resistance indices (HOMA1-IR: 0.56–3.50; HOMA2-IR: 0.30–1.70; METS-IR: 25.14–38.94) exhibited concordant right-skewed distributions with elevated upper limits. Conversely, insulin sensitivity indices (QUICKI: 0.32–0.42; HOMA2-%S: 58.83–233.20; SPISE: 5.75–10.86) demonstrated inverse, left-skewed patterns. Beta-cell function indices (HOMA1-%B: 0.54–322.21; HOMA2-%β: 40.74–159.52) also exhibited right skewed characteristics and revealed wide interindividual variability, reflecting preserved pancreatic reserve despite varying insulin resistance. Composite indices incorporating lipid parameters showed broader ranges, capturing additional metabolic heterogeneity.ConclusionThis is the first study to define the RIs of fasting insulin and a spectrum of insulin derived indices in a Nepalese population. These findings offer a valuable framework for early detection and management of metabolic disorders in South Asian populations.

IntroductionSteatotic liver disease (SLD), particularly its metabolic forms (metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis), is highly prevalent worldwide yet remains substantially underdiagnosed. Neck circumference (NC) is a simple anthropometric measure reflecting upper-body adiposity and cardiometabolic risk and has been increasingly investigated as a potential screening or risk-stratification tool for SLD. However, existing evidence is heterogeneous, and no comprehensive meta-analysis has synthesised the diagnostic performance of NC for detecting SLD. This systematic review and meta-analysis aim to evaluate the diagnostic accuracy and predictive value of NC in adults and to explore sources of heterogeneity across populations and study characteristics.Methods and analysisA systematic search of PubMed, Scopus, Web of Science and the Cochrane Library will be conducted for English-language studies published between January 2010 and September 2025. Observational studies in adults reporting NC measurements and confirmed steatotic liver disease diagnosed by imaging or biopsy will be included. Two reviewers will independently perform study selection and data extraction. Risk of bias and methodological quality will be assessed using a dual-framework approach: the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool for diagnostic accuracy domains and the Joanna Briggs Institute (JBI) critical appraisal checklists for broader observational study design considerations. The primary outcomes are pooled sensitivity and specificity of neck circumference for detecting steatotic liver disease. Secondary outcomes include ORs, relative risks, correlation coefficients and diagnostic accuracy measures, as well as comparisons with other anthropometric indicators. Random-effects meta-analyses will be conducted where appropriate, with subgroup, sensitivity and publication bias analyses planned. Certainty of evidence for primary diagnostic accuracy outcomes (pooled sensitivity and specificity) and key secondary association outcomes will be assessed using the Grading of Recommendations Assessment, Development and Evaluation framework.Ethics and disseminationEthical approval is not required, as this study synthesises published data. Results will be disseminated through peer-reviewed publication and scientific conferences to inform clinicians, researchers and policymakers on the potential role of neck circumference in screening and risk stratification for steatotic liver disease.

ObjectivesThis study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes.DesignA total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded.SettingMinhang Hospital, China.ParticipantsA total of 24 143 pregnant women were included in this study.Primary and secondary outcome measuresThe primary outcome was the adverse pregnancy outcomes.ResultsFor the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress.ConclusionsOur results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.

ObjectivesTo evaluate the associations between alpha-lipoic acid (ALA) intake and intermediate disease markers in overweight or obese adults.DesignSystematic review and meta-analysis.Data sourcesPubMed, EMBASE, Medline, APA PsycINFO, SocINDEX, CINAHL, SSRN, SocArXiv, PsyArXiv, medRxiv, and Google Scholar (from inception to October 2024).Eligibility criteriaThis study included English-language randomised controlled trials (RCTs) on adults (body mass index ≥25 kg/m²) to assess the impact of ALA on intermediate disease markers. Studies lacking outcome data, duplicates or inaccessible full texts were excluded.Data extraction and synthesisPaired reviewers independently extracted the data. We used frequentist meta-analysis to summarise the evidence, employing the DerSimonian and Laird estimator to account for heterogeneity across study designs, settings and measurement methods. Heterogeneity was assessed via the I² statistic with CIs and τ² values. The risk of bias was independently assessed by two reviewers according to the Cochrane Handbook, covering domains such as randomisation, blinding and data completeness. Publication bias was assessed using Begg’s test, while funnel plots and Egger’s test were applied to outcomes with 10 or more studies.ResultsThis meta-analysis included 11 RCTs from an initial screening of 431 studies, encompassing a total of 704 adults. The meta-analysis results revealed no significant associations were detected between ALA supplementation and changes in intermediate disease markers, including triglyceride (TG) (standardised mean difference (SMD): −0.08, 95% CI: −0.24 to 0.09, p=0.36, I²=0.00%, τ²=0.00), total cholesterol (TC) (SMD: 0.08, 95% CI: −0.55 to 0.71, p=0.80, I²=87.50%, τ²=0.52), high-density lipoprotein cholesterol (HDL-C) (SMD: −0.05, 95% CI: −0.22 to 0.11, p=0.52, I²=0.00%, τ²=0.00), low-density lipoprotein cholesterol (LDL-C) (SMD: −0.13, 95% CI: −0.40 to 0.15, p=0.37, I²=0.00%, τ²=0.00), homeostasis model assessment of insulin resistance (HOMA-IR) (SMD: −0.23, 95% CI: −0.60 to 0.15, p=0.23, I²=26.20%, τ²=0.05) and fasting blood glucose (FBS) (SMD: 0.13, 95% CI: −0.16 to 0.41, p=0.39, I²=29.40%, τ²=0.04). According to the Grading of Recommendations Assessment, Development and Evaluation bias assessment approach, eight studies were rated as having low bias (grade A), and three studies were rated as having moderate bias (grade B). Begg’s test indicated no evidence of publication bias.ConclusionsNo significant associations were detected between ALA intake and intermediate disease markers, including TG, TC, HDL-C, LDL-C, HOMA-IR and FBS levels, in overweight or obese adults. Further research is needed to explore the potential associations of ALA, especially in high-risk populations with metabolic disorders, by employing longer intervention durations, higher dosages and optimised formulations.PROSPERO registration numberCRD42023450239.