BMC Medicine[JOURNAL]
Sun
200 papers
Mechanisms underlying immunodynamics of layered defenses elicited by mRNA vaccination in children.
Liao Y, Chua HK, Law BK … +9 more , Wang Y, Polak F, Choi ANX, Tay CJX, Li H, Shek LP, Tham EH, Zhong Y, Ejima K
BMC Med · 2026 Apr · PMID 41987210 · Full text
BACKGROUND: Defining the ever-evolving correlates of protection against symptomatic infection is critical in light of the widespread deployment of mRNA vaccines in children. Since immune maturation and exposure histories...
BACKGROUND: Defining the ever-evolving correlates of protection against symptomatic infection is critical in light of the widespread deployment of mRNA vaccines in children. Since immune maturation and exposure histories differ between children and adults, immune kinetics and correlates of protection identified in adult cohorts may not directly generalize to pediatric vaccine recipients. METHODS: A prospective cohort of 5-12-year-old children (N = 70) was monitored longitudinally for 12 months after SARS-CoV-2 mRNA (BNT162b2) vaccination. Four immunological biomarkers were assessed: anti-Spike immunoglobulin G (anti-S IgG), neutralizing antibodies (nAbs), Spike-specific memory B cells (S MBCs), and S-reactive T cell response. We utilized mathematical models to reconstruct time-varying biomarker trajectories, while accounting for multiple immunity-conferring events (i.e., primary vaccination, breakthrough infection, and booster vaccination). Using the biomarker levels as time-varying covariates in survival analyses, we evaluated the circulating correlates of protection against symptomatic breakthrough SARS-CoV-2 infection across three post-primary vaccination periods (30 days to 3 months, 3 to 6 months, and 6 to 12 months), as an interpretable summary of early, intermediate, and late phases. We also repeated this evaluation in a global analysis without considering specific time windows. RESULTS: Serological markers were best described by the exponential model, while S MBC and T cell responses followed the inactivation model. While early protection was associated with antibodies, multivariable analyses identified T cell responses as the primary correlate of protection from 3 months onward, and this association was strongest in the presence of hybrid immunity. Under our prespecified threshold for the T cell response, the model-projected protection duration under hybrid immunity was estimated to be approximately 500 days after primary vaccination; however, empirical validation in independent cohorts will be required. Importantly, we obtained similar conclusions on the identity and direction of the correlates of protection in several sensitivity analyses adjusting for model structure, accounting for age and sex, and including asymptomatic infections. CONCLUSIONS: Our findings highlight the time-dependent nature of correlates of protection, emphasizing the need for employing mathematical models to reinforce the accuracy and reliability of clinical analysis so as to prevent overreliance on single-timepoint measurements of immune parameters.
Infant subcortical brain volumes associated with maternal obesity and diabetes: a large multicohort human study.
Alex AM, Rasmussen JM, Tuulari JJ … +21 more , Sigurdardottir JN, Buss C, Donald KA, Edwards AD, Entringer S, Gilmore JH, Groenewold NA, Karlsson H, Karlsson L, Lawrence KE, Mattila I, Stein DJ, Styner M, Thompson PM, Wadhwa PD, Zar HJ, Zhu X, de Los Campos G, Knickmeyer RC, Luo S, ENIGMA-ORIGINs working group
BMC Med · 2026 Apr · PMID 41987145 · Full text
BACKGROUND: Maternal diabetes and obesity are established risk factors for adverse offspring health. Emerging evidence suggests that these fetal programming effects vary by sex, yet it remains unclear whether these facto...
BACKGROUND: Maternal diabetes and obesity are established risk factors for adverse offspring health. Emerging evidence suggests that these fetal programming effects vary by sex, yet it remains unclear whether these factors independently or interactively influence early brain development. METHODS: This prospective study included 1,965 infants from six international cohorts. Infant MRI was used to derive subcortical volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate). ComBat harmonization was applied. Multiple linear regression tested main and interaction effects of maternal obesity, maternal diabetes, and sex, controlling for covariates with false discovery rate (FDR) corrections. RESULTS: Of the sample, 46% were female (N = 909), 9% were exposed to maternal diabetes (N = 172), 22% to maternal obesity (N = 386), and 3% to both (N = 61). MRI scans were performed at 25.9 ± 18.8 days. Maternal diabetes was associated with smaller thalamic volume (standardized β = -0.09, 95%CI -0.16 to -0.01, FDR P = 0.020), but this association was attenuated after adjusting for maternal obesity. Maternal obesity was associated with smaller hippocampal (standardized β = -0.13, 95%CI -0.21 to -0.05, FDR P = 0.009) and thalamic volumes (standardized β = -0.09, 95%CI -0.14 to -0.03, FDR P = 0.007). Sex-specific associations were observed. In females, maternal obesity was associated with smaller hippocampal (standardized β = -0.24, 95%CI -0.36 to -0.13, FDR P < 0.001) and amygdala volumes (standardized β = -0.18, 95% CI = -0.30 to -0.06, FDR P = 0.016). A three-way interaction (diabetes x obesity x sex) was observed for thalamus volume (standardized β = -0.50, 95%CI -0.81 to -0.18, FDR P = 0.017). In males, combined exposure had lower thalamic volume compared to those with one or neither exposure (all Ps < 0.05). In females, maternal obesity (standardized β = -0.12, 95%CI -0.20 to -0.04, FDR P = 0.015) and diabetes (standardized β = -0.16, 95%CI -0.30 to -0.02, FDR P = 0.042) showed independent associations with thalamic volume, without a significant interaction (standardized β = 0.23, 95%CI -0.01 to 0.46, FDR P = 0.092). CONCLUSIONS: Maternal obesity shows stronger associations with infant subcortical volumes than maternal diabetes. It is associated with smaller hippocampal and amygdala volumes in females, while combined exposure to maternal diabetes and obesity is associated with smaller thalamic volumes in males. These findings highlight the role of maternal metabolic health and infant sex in early neurodevelopment.
Intraoperative use of sodium oxybate to prevent postoperative delirium in older patients undergoing major orthopedic surgery.
Xue FS, Wang DF, Zheng XC
BMC Med · 2026 Apr · PMID 41975445 · Full text
BACKGROUND: This matters arising article addresses the recently published article in BMC Medicine by Cui et al., titled "Prophylactic effect of intraoperative sodium oxybate on postoperative delirium in older patients un...
BACKGROUND: This matters arising article addresses the recently published article in BMC Medicine by Cui et al., titled "Prophylactic effect of intraoperative sodium oxybate on postoperative delirium in older patients undergoing major orthopedic surgery: a randomized clinical trial." MAIN BODY: The work by Cui et al. demonstrated that intraoperative administration of sodium oxybate only significantly reduced postoperative delirium (POD) incidence in the participants undergoing morning surgery but not in those with afternoon surgery. Although this trial provided evidence that sodium oxybate may reduce POD, we raise several concerns regarding methodology and generalizability, such as incomplete control of perioperative risk factors, underestimated incidence of POD, subgroup analysis without multiple adjustments of confounding factors, and inadequate postoperative pain strategy. To verify the findings of this trial in further researches, we advocate the implementation of multi-center randomized clinical trials with large sample sizes, strict control of perioperative confounding factors, precise assessment of POD episodes, and the inclusion of subgroup analysis with multiple adjustments. CONCLUSION: This matters arising does not seek to deny the results of Cui et al.'s trial. The main purpose of the authors is to emphasize that above methodological refinements are crucial for translating this valuable evidence into generally clinical practice and improving final outcomes of patients.
The association of pregnancy complications/risk factors with the development of cancer in women: an umbrella review.
Healey J, Singh M, Richards C … +9 more , Plachcinski R, Moss N, Ghalichi L, Lee SI, Hanley S, Vowles Z, Crowe FL, Nirantharakumar K, Black M
BMC Med · 2026 Apr · PMID 41975433 · Full text
BACKGROUND: Among women in the UK, over 186,000 new cancer diagnoses and around 78,000 cancer deaths occurred annually from 2017 to 2019. Evidence suggests that pregnancy complications are linked to mortality and morbidi...
BACKGROUND: Among women in the UK, over 186,000 new cancer diagnoses and around 78,000 cancer deaths occurred annually from 2017 to 2019. Evidence suggests that pregnancy complications are linked to mortality and morbidity risks in later life. This umbrella review aims to assess the association between pregnancy complications and cancer risk. It forms part of a series of studies exploring associations between pregnancy complications and long-term health conditions. METHODS: MEDLINE, Embase, and Cochrane databases were searched from inception to April 2024. Key search terms encompassed 'cancer' and 'pregnancy complications' or 'pregnancy risk factors'. Screening data extraction and quality appraisal (AMSTAR 2) were completed by two independent reviewers. Data were synthesised narratively and quantitatively. Relative risks (RR)/odds ratio (OR)/hazard ratios (HR) with 95% confidence intervals were reported. RESULTS: Of the 25 reviews assessed for methodological quality, 2 were rated high, 12 moderate, 9 low, and 2 critically low. After excluding 10 overlapping reviews and 2 critically low reviews, 13 reviews included reviews consisted of 170 primary studies. Associations between 7 pregnancy complications and 17 cancers are reported. Women with molar pregnancy had four-fold higher risk of developing gestational trophoblastic neoplasia [OR 4.72 (1.81-12.32)]. Miscarriage was associated with thyroid cancer [OR 1.29 (95% CI 1.15-1.44)], but not with breast or ovarian cancer. Pre-eclampsia was associated with a reduced risk of breast cancer [RR 0.89 (0.83-0.95)] and an almost twofold higher risk of ovarian cancer [RR 1.82 (1.16-2.85)]. Gestational diabetes mellitus was associated with a higher risk of thyroid cancer [RR 1.28 (1.16-1.42)], stomach cancer [RR 1.43 (1.02-2.00)], liver cancer [RR 1.27 (1.03-1.55)], and blood cancer [RR 1.48 (1.04-2.09)] but was not associated with other cancers studied. Preterm birth showed a very small association with breast cancer risk (OR 1.03, 95% CI 1.00-1.07). There was no significant association between caesarean section and cervical cancer or multiple births and breast cancer. CONCLUSIONS: Some pregnancy complications were associated with selected cancer outcomes, although the evidence was heterogeneous and limited by potential bias, confounding, and inconsistent review quality.
Reply to: Intraoperative use of sodium oxybate to prevent post-operative delirium in older patients undergoing major orthopedic surgery.
Cui M, Xue H, Zhao P
BMC Med · 2026 Apr · PMID 41975428 · Full text
BACKGROUND: In our previously published article, we investigated the preventive efficacy of sodium oxybate against post-operative delirium (POD) in elderly patients undergoing orthopedic surgery and found that intraopera...
BACKGROUND: In our previously published article, we investigated the preventive efficacy of sodium oxybate against post-operative delirium (POD) in elderly patients undergoing orthopedic surgery and found that intraoperative sodium oxybate demonstrates possible time-specific efficacy, significantly reducing POD incidence exclusively in older patients undergoing morning orthopedic surgery. Main body In a Matters Arising correspondence, the authors raised several questions and suggestions regarding the methodology and interpretation of our findings. These concerns encompassed the control of perioperative factors, the definition and assessment of POD, as well as considerations related to post-operative pain management which may influence the effect of sodium oxybate on delirium prevention. We have provided point-by-point responses to each of these concerns and discussed directions for future research that may help address the limitations identified. CONCLUSIONS: In the Matters Arising, the authors put forward a number of constructive comments, to which we have responded accordingly. These insights provide valuable guidance for the design and conduct of future research in this area.
Spatiotemporal patterns of climate-sensitive vector-borne diseases in Bangladesh: leveraging machine learning and spatial regression for intervention strategies.
Rahman MS, Shiddik MAB, Chowdhury AH
BMC Med · 2026 Apr · PMID 41975424 · Full text
BACKGROUND: Bangladesh has a noticeable rise in vector-borne diseases (VBD) attributed to climate change. Accurately mapping, predicting, and identifying the risk factors of VBD is essential for prevention and control st...
BACKGROUND: Bangladesh has a noticeable rise in vector-borne diseases (VBD) attributed to climate change. Accurately mapping, predicting, and identifying the risk factors of VBD is essential for prevention and control strategies. Therefore, this study aimed to investigate the spatiotemporal pattern and associated meteorological factors of VBD in Bangladesh. METHODS: This study used district-level reported cases of VBD (dengue, chikungunya, malaria, filariasis, and yellow fever) obtained from the Bangladesh Bureau of Statistics. Simultaneously, meteorological data (temperature, relative humidity, wind speed, and precipitation) were sourced from NASA from 2017 to 2020. A combination of exploratory spatial analysis, spatial regression, and advanced tree-based machine learning models was utilized for prediction, risk factor identification, and correlation analysis. RESULTS: Dengue was the most prevalent vector-borne disease during the study period, peaking in 2019, while malaria and filariasis showed variable incidence across districts. Dhaka, Pirojpur, Jessore, Bandarban, Rangamati, and Narail districts exhibited higher incidence rates of VBD. The spatial regression model identified mean temperature as a major risk factor for VBD (β = 16.64, s.e. = 6.39). Additionally, the optimal XGBoost model also highlighted mean temperature as the primary determinant, alongside other climatic and socioeconomic factors such as GDP, population size, and healthcare infrastructure, underscoring the complex interplay between health infrastructure and socioeconomic drivers for Bangladesh's VBD from 2017 to 2020. CONCLUSIONS: The study's findings, incorporating the One Health perspective, provide insights for planning early-warning, prevention, and control strategies using machine learning to combat infectious diseases in Bangladesh and similar endemic countries. Precautionary measures and intensified surveillance must be implemented in certain high-risk districts nationwide.
Evolution with age of the relationship between sex and post-COVID symptoms: a population-based cohort study.
Pastorello A, Vuillermoz C, Meyer L … +9 more , Davisse-Paturet C, Coste J, Bajos N, Lambotte O, Noël N, Kose J, Warszawski J, Rouquette A, EpiCov study group
BMC Med · 2026 Apr · PMID 41975411 · Full text
BACKGROUND: It is unclear why women more frequently experience post-COVID symptoms than men. Sex and age-dependent immune dysregulation triggered by SARS-CoV-2 infection might be involved in this association. We assessed...
BACKGROUND: It is unclear why women more frequently experience post-COVID symptoms than men. Sex and age-dependent immune dysregulation triggered by SARS-CoV-2 infection might be involved in this association. We assessed whether age modified the association between sex and post-COVID symptoms, and whether this effect modification might be attributable to SARS-CoV-2 infection. METHODS: From the French population-based prospective cohort study with random sampling EpiCov (Spring 2020-Autumn 2022), we included two groups of participants aged ≥ 17: those with a first SARS-CoV-2 confirmed infection during the Omicron wave in 2022 (infected participants, N = 10,618), and those with no SARS-CoV-2 infection history (uninfected participants, N = 28,716). In both groups, we assessed effect modification by age on the association between sex and any self-reported persistent symptom in Autumn 2022 using modified Poisson regressions. RESULTS: Respectively, 10.0% (95% CI: 9.2%, 10.8%) infected participants and 3.1% (95% CI: 2.8%, 3.4%) uninfected participants reported persistent symptoms. In both groups, women more frequently reported persistent symptoms than men (adjusted prevalence ratios (aPRs) [95% CI]: 2.06 [1.70, 2.49] and 1.55 [1.25, 1.92], respectively). However, in infected participants, this association was stronger before than after 35 years (aPRs [95% CI]: 3.54 [2.12, 5.91], 1.77 [1.32, 2.37]; 1.65 [1.20, 2.26]; 1.74 [1.15, 2.63] for 17-34, 35-49, 50-64 and ≥ 65-year-olds, respectively, interaction P = 0.041). We found no effect modification by age in uninfected participants. CONCLUSIONS: Women are a target population in post-COVID symptoms management, especially among younger adults. Sex and age-dependent mechanisms attributable to SARS-CoV-2 infection may be involved in post-COVID symptoms.
Synergistic effects of obesity and type 2 diabetes on adiposity-related cancer risk across age strata.
Henney AE, Heague M, Alam U … +1 more , Cuthbertson DJ
BMC Med · 2026 Apr · PMID 41975400 · Full text
BACKGROUND: Obesity and type 2 diabetes (T2D) each independently increase cancer risk, but their combined impact is less understood. With rising early-onset obesity, T2D, and cancer in younger populations, we assessed ho...
BACKGROUND: Obesity and type 2 diabetes (T2D) each independently increase cancer risk, but their combined impact is less understood. With rising early-onset obesity, T2D, and cancer in younger populations, we assessed how diagnoses of both obesity and T2D affect adiposity-related cancer incidence compared to each condition alone, focussing on age-specific trends. METHODS: We performed a retrospective (real-world) cohort analysis in a large global federated database (TriNetX, Cambridge MA, USA). Three cohorts were generated and compared with a reference arm, patients without obesity or T2D: cohort 1-patients with obesity, without T2D; cohort 2-patients with T2D, without obesity, and cohort 3-patients with both obesity and T2D. Cohorts underwent propensity score matching (PSM) 1:1 of confounders. We examined 5-year rates of incident cancer (including thirteen (traditional) adiposity-related cancers and an expanded list of 24 adiposity-related cancers), performing stratified analyses by age (younger, middle-aged, and older adults (< 40, 40-60, > 60 years), respectively), ethnicity (white, and non-white), and sex (male and female). RESULTS: After PSM, we compared 2,655,891 people with only obesity, 290,965 with only T2D and 705,499 people with both obesity and T2D, against the reference (1:1). The highest risk was observed in patients with both obesity and T2D (traditional cancers (HR 1.48 [95% CI 1.15, 1.51]) and all adiposity-related cancers (1.30 [1.27, 1.32])). T2D increased the risk of both traditional (1.35 [1.31, 1.39]) and all adiposity-related cancers (1.27 [1.23, 1.31]) to a greater extent than obesity only (increased risk of traditional adiposity-related cancers (1.07 [1.05, 1.09]), but not all adiposity-related cancers (0.99 [0.98, 1.01]). Concerningly, the highest risk of all traditional and adiposity-related cancers was seen in younger (< 40 years) adults with obesity and T2D (1.40 [1.10, 1.79] and 1.58 [1.21, 2.05], respectively). CONCLUSIONS: Risk of incident adiposity-related cancer is driven most strongly by the combination of obesity and T2D, versus either alone, across all age groups, including those with early-onset disease. The impact of early-onset obesity and T2D provides a critical public health problem that demands targeted screening and management.
Experiences and service-uptake factors of receiving and providing care for meningitis and its sequelae: a qualitative systematic review.
Andreeva M, Pyatnitskaya M, Kochneva K … +17 more , Sviatskaia E, Spryshkova M, Meyer M, Baimukhambetova D, Kosenko M, Mursalova A, Avdeenko N, Kondrikova E, Zheng J, Cheung KY, Galvin AD, Jewell T, Moula Z, Neill S, Zinchuk M, Guekht A, Munblit D
BMC Med · 2026 Apr · PMID 41968310 · Full text
BACKGROUND: Meningitis is a life-threatening condition with substantial morbidity and mortality, especially in low- and middle-income countries (LMICs). While quantitative research has enhanced the understanding of diagn...
BACKGROUND: Meningitis is a life-threatening condition with substantial morbidity and mortality, especially in low- and middle-income countries (LMICs). While quantitative research has enhanced the understanding of diagnostic and treatment efficacy, qualitative data regarding the lived experiences remain underexplored. This systematic review synthesises qualitative evidence on the experiences of patients, caregivers, and healthcare providers regarding meningitis diagnosis, treatment, and care, as well as the barriers and facilitators influencing service uptake and provision. The review aimed to inform the development of World Health Organization guidelines for improving meningitis care. METHODS: This systematic review was registered in PROSPERO (CRD42024514413). A comprehensive search of EMBASE, MEDLINE, PsycINFO, and CINAHL was conducted on February 13-14, 2024. Studies were included if they explored patient, caregiver, or healthcare provider experiences with meningitis or sequelae diagnosis, treatment, or long-term management. Thematic synthesis was used for data analysis. Quality assessment of each included study was performed using the Critical Appraisal Skills Programme checklist. Confidence of evidence was assessed using the GRADE-CERQual approach. RESULTS: Out of 4735 identified studies, 19 were included in the final synthesis; seven were conducted in LMICs and 12 in high-income countries (HICs). The synthesis identified four overarching analytical constructs: diagnostic uncertainty and disparities in initial help-seeking; systemic and operational constraints on acute care delivery; the relational and psychological burden of meningitis; and barriers to long-term equity and continuity of care. Key themes included diagnostic challenges, delays in care-seeking due to cultural and socioeconomic barriers, and miscommunication between patients and healthcare providers. Critical barriers to care included systemic healthcare limitations, financial constraints, and inadequate public awareness of meningitis symptoms. Limited data on facilitators of timely care uptake were found. CONCLUSIONS: This synthesis highlights substantial context-specific disparities in meningitis care. In LMICs, the primary points of failure relate to access and resources, with financial barriers, cultural reliance on traditional healing, and systemic operational limitations impeding timely diagnosis and treatment. In HICs, the challenges are rooted in clinical processes and support systems, particularly healthcare workers' diagnostic uncertainty, failures in patient-provider communication, and the absence of psychological support. Addressing these barriers through culturally sensitive interventions, improved healthcare infrastructure, enhanced patient-provider communication, and public health education is essential.
Acute COVID-19 severity and impaired cognitive function up to 32 months after diagnosis: an observational study.
Magnúsdóttir I, Nygaard AB, Hoffart A … +35 more , Murphy G, Kõiv K, Barker MM, Lovik A, Unnarsdóttir AB, Kähler AK, Hauksdóttir A, Thordardottir EB, Eyþórsson E, Gísladóttir EU, Joyce EE, Frans EM, Tómasson G, Hjördísar Jónsdóttir HL, Rúnarsdóttir H, Harðardóttir H, Dahl JA, Jakobsdóttir J, Kalleberg KT, Ásbjörnsdóttir KH, Ellingjord-Dale M, Istre MS, Landrø NI, Shen Q, Bø R, Mägi R, Pálsson R, Brunvoll SH, Johnson SU, Søraas A, Fang F, Lehto K, Ebrahimi OV, Aspelund T, Valdimarsdóttir UA
BMC Med · 2026 Apr · PMID 41965722 · Full text
BACKGROUND: Cognitive dysfunction ("brain fog") is a commonly reported post-COVID-19 symptom. Leveraging data from five general population cohorts across four European countries (Estonia, Iceland, Norway, and Sweden), we...
BACKGROUND: Cognitive dysfunction ("brain fog") is a commonly reported post-COVID-19 symptom. Leveraging data from five general population cohorts across four European countries (Estonia, Iceland, Norway, and Sweden), we assessed long-term prevalence of impaired subjective cognitive function among individuals diagnosed with COVID-19 by acute illness severity. METHODS: The included cohorts consisted of adult participants recruited from March 2020 and followed with self-report measures of cognitive function and past COVID-19 infection (except one cohort consisting of clinically confirmed COVID-19 cases) through February 2023. In a cross-sectional analysis we contrasted the prevalence of impaired cognitive function among individuals with and without a COVID-19 diagnosis, overall and by illness severity up to 32 months post-diagnosis. We adjusted for age, gender, education, relationship status, binge drinking, body mass index, previous psychiatric diagnosis, number of chronic medical conditions, and response period. In a longitudinal analysis, we assessed potential changes in cognitive function scores before and after COVID-19 diagnosis. RESULTS: The study population consisted of 153,841 participants (71% women), with 31,359 (20.4%) reporting a positive COVID-19 test. Overall, a COVID-19 diagnosis was not statistically significantly associated with increased prevalence ratio (PR) of impaired cognitive function (PR 1.30 [95% CI: 0.98-1.71]). Individuals bedridden due to COVID-19 for 1-6 days (PR 1.38 [95% CI 0.96-1.99]) or ≥ 7 days (2.59 [1.55-4.33]) had higher prevalence of impaired cognitive function compared to those never diagnosed, while individuals never bedridden had a lower prevalence to those never diagnosed with COVID-19 (0.89 [0.80-1.00]). These findings were corroborated in the longitudinal analysis where a pre- to post diagnosis decline in cognitive function was observed among individuals bedridden due to COVID-19 (p < 0.0001). CONCLUSIONS: The data indicates that a severe COVID-19 acute illness course is associated with impaired cognitive function up to 18-32 months after COVID-19 diagnosis.
Maternal macronutrient intake and gestational diabetes: systematic review of prospective observational studies and dose-response meta-analyses.
Young CD, Garratt MG, Athukorala T … +5 more , Perry TL, Ponnampalam AP, Crengle S, Peng M, Reynolds AN
BMC Med · 2026 Apr · PMID 41963985 · Full text
BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with markedly elevated risk of type-2 diabetes in later life. Pregnancy or pre-pregnancy diet is a likely risk factor for GDM,...
BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with markedly elevated risk of type-2 diabetes in later life. Pregnancy or pre-pregnancy diet is a likely risk factor for GDM, with macronutrients-including proteins, fats, carbohydrates, and alcohol-being the primary dietary components to influence risk. In this study, we have conducted a systematic review and meta-analyses of pregnancy or pre-pregnancy dietary macronutrient intakes, including by source and type, on GDM occurrence to better elucidate the role of maternal diet on GDM. METHODS: We ran an online search on 15 August 2025 in OVID Medline, EMBASE, and EBM Reviews, augmented with reference searching to identify prospective observational studies reporting pregnancy or pre-pregnancy dietary intakes and GDM incidence. Screening, data extraction, and risk of bias assessment using the Newcastle-Ottawa Scale were performed by at least two reviewers. Macronutrient exposures and GDM incidence were considered with random effects higher versus lower (HvL) and dose-response analyses. Certainty of evidence was then considered with GRADE to comment on maternal macronutrient intakes and GDM. RESULTS: From 3990 initial titles, we identified 25 prospective observational studies of 115,496 pregnant women reporting at least one macronutrient intake and GDM. There was moderate certainty evidence that animal-sourced protein (HvL: RR 1.62 (95% CI 1.20 to 2.18) I 82%) and animal-sourced fat (HvL: RR 1.59 (95% CI 1.34 to 1.88) I 0%) intakes were associated with higher GDM in a dose-response manner. Total protein (HvL: RR 1.63 (95% CI 1.22 to 2.18) I 64%) and vegetable fat (HvL: RR 1.25 (95% CI 1.06 to 1.47) I 0%) showed positive associations with outcome in HvL but without dose response, while dietary fiber (HvL: RR 0.65 (95% CI 0.44 to 0.96) I 89%) was the only macronutrient to indicate a protective effect against GDM with higher intakes in a dose-response manner, with moderate certainty evidence. CONCLUSIONS: This study is the first to consider maternal intake of all macronutrients, including by source and type, on GDM occurrence. Our findings are largely in line with healthy dietary advice for the general population (promoting high fiber and low animal-sourced fat intakes); however, higher protein intakes (both total and animal-sourced) may be a specific concern that is not currently considered in dietary guidance during pregnancy, requiring further research. TRIAL REGISTRATION: PROSPERO (CRD420251001515).
Global, regional, and national burden of colorectal cancer attributable to central obesity: a population attributable fraction analysis.
Piovani D, Figlioli G, Nikolopoulos GK … +6 more , Tsilidis KK, Aghemo A, Hassan C, Repici A, Bretthauer M, Bonovas S
BMC Med · 2026 Apr · PMID 41963940 · Full text
BACKGROUND: Central obesity is a major risk factor for colorectal cancer (CRC) and may better reflect obesity-related risk than body mass index (BMI). Its global burden, however, remains poorly quantified. We aimed to es...
BACKGROUND: Central obesity is a major risk factor for colorectal cancer (CRC) and may better reflect obesity-related risk than body mass index (BMI). Its global burden, however, remains poorly quantified. We aimed to estimate the number and proportion of CRC cases attributable to central obesity in 2022 across global, regional, and national levels. METHODS: We estimated population attributable fractions (PAFs) by combining sex-specific prevalence of central obesity from national surveys with pooled relative risks from meta-analysis. Central obesity was defined as elevated waist circumference using standardised sex- and ethnicity-specific thresholds, accounting for variation in definitions via probabilistic modelling. We addressed missing data through multiple imputation. CRC incidence estimates for 2022 were obtained from GLOBOCAN for 185 countries. Monte Carlo simulations propagated uncertainty in exposure prevalence and risk estimates. RESULTS: In 2022, an estimated 311 418 (95% uncertainty interval 242 603-378 880) CRC cases were attributable to central obesity, corresponding to a global PAF of 16.2% (12.6-19.7). PAFs were higher in females (18.2%, 13.0-23.3) than in males (14.5%, 9.6-19.3), though age-standardised rates (ASRs) were slightly higher in males. The highest PAF was in North America, and the highest ASRs in Australia-New Zealand and northern Europe. PAFs and ASRs declined with decreasing income levels among males but not females. Regional variation in sex differences was substantial, with higher female PAFs in parts of Africa and Asia, and smaller or reversed gaps in high-income settings. In high-income countries, the estimated 10-year CRC risk at screening age (55-69 years) was 1.32% in males with central obesity versus 0.90% in those without, and 0.92% versus 0.64% in females, corresponding to one excess CRC case per 236 (180-353) men and 357 (279-502) women. CONCLUSIONS: Central obesity accounts for a substantial share of the global CRC burden, with large geographical variability. Applying established waist circumference thresholds in surveillance and incorporating central obesity into individual risk stratification may inform more effective CRC screening and prevention strategies.
Why hyperinsulinemia is detrimental to weight loss: insights from type 1 diabetes.
Martin S, Kempf K, Kolb H
BMC Med · 2026 Apr · PMID 41963916 · Full text
BACKGROUND: The global rise in obesity prevalence poses a major health challenge due to its links to hypertension, stroke, type 2 diabetes, cardiovascular disease, depression, and cancer. Effective non-pharmacological st...
BACKGROUND: The global rise in obesity prevalence poses a major health challenge due to its links to hypertension, stroke, type 2 diabetes, cardiovascular disease, depression, and cancer. Effective non-pharmacological strategies are essential to curb this epidemic. Insulin is a major regulator of body weight. It not only mediates glucose uptake but also inhibits hepatic glucose production, lipolysis, and enhances lipogenesis. MAIN BODY: Type 1 diabetes provides insights on insulin's role in weight regulation. Prior to diagnosis, insulin deficiency commonly produces unintentional weight loss, whereas initiation of exogenous insulin therapy typically restores body mass. Scientific research in non-diabetic populations, including Mendelian randomization studies, has identified elevated insulin secretion as a key contributor to weight gain. Conversely, reductions in insulin secretion have been shown to facilitate weight loss, even in the absence of caloric restriction. One strategy to keep circulating insulin concentrations low is the application of carbohydrate unit tables to estimate expected postprandial glucose excursions in insulin-deficient patients and anticipated insulin responses in non-diabetic individuals. This approach facilitates avoidance of foods that provoke large insulin responses. A complementary approach is postprandial self-monitoring of blood glucose (SMBG). In non-diabetic individuals, this allows for personalized assessment of glycemic and insulin responses to meals. The effectiveness of this approach in promoting weight reduction has been demonstrated across multiple studies. During fasting or adherence to low-carbohydrate diets, circulating insulin concentrations remain low, permitting unrestrained adipose tissue lipolysis and promoting fatty acid oxidation for energy production. Self-monitoring of breath acetone (SMBA) provides a simple, non-invasive biomarker of this metabolic state. Recent findings indicate that a single carbohydrate-rich meal during a ketogenic state suppresses fat mobilization for several days-a phenomenon suggestive of a "memory effect" of insulin on lipolysis inhibition. Although underlying mechanisms remain to be elucidated, awareness of this effect may improve dietary regimens. CONCLUSIONS: Insights from type 1 diabetes offer advice for managing weight development by minimizing episodes of hyperinsulinemia. Effective non-pharmacological measures include the use of carbohydrate unit tables combined with SMBG for avoiding post-meal hyperglycemia and hyperinsulinemia. Additionally, SMBA provides a non-invasive marker of sustained fat mobilization and can help identify and prevent periods of insulin-induced fat accumulation.
Interventions to prevent and treat multiple long-term conditions and their consequences across the life course: concepts and definitions.
Witham MD, Aithal GP, Collinson M … +17 more , Cooper R, Davies MJ, Farmer A, Fraser SDS, Hanlon P, Khunti K, Lamb SE, McDonald C, Nirantharakumar K, Sayer AA, Shah N, Sheppard JP, Taylor SJC, Yameen F, Yao L, Singh SJ, Multiple Long-Term Conditions Cross-NIHR Collaboration Interventions and Prevention Workstream
BMC Med · 2026 Apr · PMID 41963891 · Full text
Multiple long-term conditions (MLTC; also known as multimorbidity) constitute an important unmet health challenge. Designing and evaluating interventions to prevent and treat MLTC and their consequences is essential but...
Multiple long-term conditions (MLTC; also known as multimorbidity) constitute an important unmet health challenge. Designing and evaluating interventions to prevent and treat MLTC and their consequences is essential but difficult, due to heterogeneous risk factors, biological mechanisms, condition combinations, social and functional impacts of MLTC. To make progress, shared ways of describing and discussing interventions to prevent and treat MLTC and their consequences would bring consistency and clarity to this complex research area.In this position paper, we aim to provide a framework to address this recently articulated need. We propose a conceptual framework for placing MLTC interventions on a spectrum of prevention and treatment (from primordial to quaternary prevention). We consider different key intervention time points across the life course and how the focus of interventions may change from reducing risk factors in earlier life, through prevention of condition accumulation or progression in later life, to mitigating adverse consequences on symptoms and function as conditions progress. We propose taxonomies of interventions based on simple description but also on the existing World Health Organisation International Classification of Health Interventions taxonomy. We discuss principles of intervention development, focussing particularly on the need to target shared biological mechanisms and risk factors rather than attempting to treat or prevent each condition individually, and focussing on symptoms or consequences of MLTC that are prioritised by patients.Finally, we consider the attributes of effective MLTC interventions; we argue that ideal interventions should have robust evidence of efficacy and effectiveness, should be scalable and implementable within existing health and social care systems, should reduce (or at least not increase) health inequality, should be cost-effective, and should deliver major improvements over and above existing interventions, either at individual or population level. We recommend using this conceptual framework, taxonomy and criteria for assessing interventions together to organise the planning and evaluation of MLTC intervention research thereby accelerating progress in this important yet understudied field.
Concordance between nutritional cohorts and randomized trials: biological confirmation or statistical consequence? A re-analysis of Stadelmaier et al.
Calkins M, Núñez I, Soto-Mota A
BMC Med · 2026 Apr · PMID 41957646 · Full text
BACKGROUND: Stadelmaier et al. recently reported a pooled ratio of risk ratios (RRR) of 1.00 between population, intervention/exposure, comparator, outcome (PI/ECO) matched randomized controlled trials (RCTs) and cohort...
BACKGROUND: Stadelmaier et al. recently reported a pooled ratio of risk ratios (RRR) of 1.00 between population, intervention/exposure, comparator, outcome (PI/ECO) matched randomized controlled trials (RCTs) and cohort studies, interpreting this as evidence that randomized trials "confirm" observational findings in nutrition with "tremendous public health implications." We hypothesized that this apparent agreement is not a validation of concordance, but an expected statistical effect arising from the pooling of null or small effect sizes with large variances rather than pairwise concordance. METHODS: We re-analyzed the authors' binary dataset (n = 54 pairs) using a permutation framework (B = 10,000) in which cohort studies were randomly reassigned to RCTs, breaking the original pairing (both globally and restricted within exposure-type strata) while preserving marginal distributions. RESULTS: Under random pairing, 99.96% of permuted pooled RRRs fell within the authors' reported confidence interval [0.91,1.10], and the observed RRR was statistically indistinguishable from the random-pairing permutation distribution (p = 0.12). A pairwise discrepancy statistic showed no improvement with matching over random pairing (p = 0.21). A precision-weighted statistic was significant (p = 0.008), but weight was highly concentrated: 4 pairs (7% of n) accounted for 54.8% of total weight, and the effective number of pairs was 9.9 (18% of n). Qualitative concordance using the authors' prior criteria was only 13% (7/54 pairs). CONCLUSIONS: A pooled RRR near 1.00 indicates only that cohort effect sizes are not systematically different from RCT estimates. In this dataset, an RRR near 1 is a result expected under random pairing. Pairwise agreement is not improved by PI/ECO matching for typical comparisons; the significant weighted statistic reflects alignment among a small minority of high-precision pairs, not "most" findings. Pooled RRR lacks resolution as a confirmation metric in fields with small effects and should not be interpreted as evidence of replication; otherwise, it may inappropriately influence evidence synthesis practices.
Evaluating DNA methylation markers and extended HPV genotyping in first-void urine for detecting high-grade cervical lesions in HPV-positive women: a cross-sectional study.
Tranberg M, Van Keer S, Hesselink AT … +10 more , Nørgaard P, Brøndum R, Wu C, Gustafson LW, Hammer A, Bor P, Binderup KO, Blach C, Vorsters A, Steenbergen R
BMC Med · 2026 Apr · PMID 41957618 · Full text
BACKGROUND: First-void urine (FVU) collection for high-risk human papillomavirus (HPV) testing may reach un(der)-screened women in cervical cancer screening programs. This cross-sectional study investigated the clinical...
BACKGROUND: First-void urine (FVU) collection for high-risk human papillomavirus (HPV) testing may reach un(der)-screened women in cervical cancer screening programs. This cross-sectional study investigated the clinical performance of DNA methylation markers ASCL1 and LHX8 in HPV-positive FVU for detecting high-grade cervical intraepithelial neoplasia and cancer (CIN2+ and CIN3+). Additionally, results were compared with paired HPV-positive clinician-collected cervical samples (CS) and HPV genotyping. METHODS: Paired FVU and CS samples were collected from 286 women aged 23-64 years referred for colposcopy or cervical excision. Histological endpoints included 123 ≤ CIN1 (no dysplasia and CIN1), 38 CIN2, and 123 CIN3/AIS and 2 cancers. Samples were tested for HPV DNA and ASCL1/LHX8 methylation. Methylation test performance was evaluated by area under the curve (AUC) and logistic regression. Differences between paired samples and across methylation, HPV16/18, and extended HPV16/18/31/33/52 genotyping in FVU were tested using McNemar's test. RESULTS: ASCL1 and LHX8 methylation levels in HPV-positive FVU increased significantly with disease severity. Methylation testing in FVU yielded an AUC of 0.76 (95% CI: 0.70-0.82) for CIN3 + and 0.73 (95% CI: 0.67-0.79) for CIN2 + , with sensitivities of 79.2% (95% CI: 71.0-85.9%) and 75.5% (95% CI: 68.1-81.9%), respectively, and a specificity of 57.0% (95% CI: 47.8-65.8%) for ≤ CIN1. In CS, methylation testing yielded higher AUCs of 0.84 (95% CI: 0.79-0.89) for CIN3 + and 0.80 (95% CI: 0.75-0.85) for CIN2 + , with significantly higher sensitivities (p ≤ 0.02) but lower specificity (p = 0.04) than FVU. In women aged ≥ 30 years, CIN3 + sensitivity and specificity for ≤ CIN1 were similar between FVU and CS (both p = 0.09). No significant differences in accuracy were observed between methylation testing and extended genotyping (p ≥ 0.35) in FVU, while methylation testing showed higher sensitivity (p < 0.01) but lower specificity (p < 0.01) than HPV16/18 genotyping. CONCLUSIONS: ASCL1/LHX8 methylation testing in HPV-positive FVU showed promise for detecting high-grade cervical disease. Its performance in FVU did not differ significantly from extended HPV genotyping and, in women aged ≥ 30 years, was comparable to performance in CS. This supports methylation testing as a complementary triage test alongside HPV genotyping in urine-based cervical cancer screening, removing the need for follow-up cervical sampling. Further validation in HPV-positive FVU from un(der)-screened populations is warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05065853.
Response to: Matters Arising in relation to "Evaluating agreement between individual nutrition randomised controlled trials and cohort studies - a meta-epidemiological study".
Stadelmaier J, Bantle G, Gorenflo L … +3 more , Kiesswetter E, Nikolakopoulou A, Schwingshackl L
BMC Med · 2026 Apr · PMID 41957603 · Full text
We respond to the Matters Arising article by Calkins et al. commenting on our meta-epidemiological study "Evaluating agreement between individual nutrition randomised controlled trials and cohort studies". We appreciate...
We respond to the Matters Arising article by Calkins et al. commenting on our meta-epidemiological study "Evaluating agreement between individual nutrition randomised controlled trials and cohort studies". We appreciate the opportunity to respond to the points raised and to clarify the methods and interpretation of our work.
Targeted long-read genomic and epigenomic profiling enhances timely comprehensive variant discovery in hypotonia and muscle weakness.
Abuijlan E, Sinha S, Ramaswamy S … +10 more , Jain R, Chekroun I, Rabea F, El Naofal M, Khadija S, Sharaf R, Alkhnbashi OS, Ali F, Alsheikh-Ali A, Abou Tayoun A
BMC Med · 2026 Apr · PMID 41952192 · Full text
BACKGROUND: Identifying the genetic basis of hypotonia and muscle weakness is critical for patient management and family counseling. However, diagnosis is often hindered by diverse genomic alterations, including repeat e...
BACKGROUND: Identifying the genetic basis of hypotonia and muscle weakness is critical for patient management and family counseling. However, diagnosis is often hindered by diverse genomic alterations, including repeat expansions, structural variants (SVs), and methylation defects. Standard-of-care testing, largely based on short-read sequencing, is limited in its ability to detect this heterogeneous variation landscape, leaving many patients undiagnosed or requiring lengthy sequential testing. Long-read sequencing represents a promising solution. However, its application as a first-tier diagnostic assay for hypotonia remains unexplored. METHODS: We retrospectively analyzed 227 patients with hypotonia to assess diagnostic yield, time-to-diagnosis, and costs associated with standard-of-care testing. A long-read whole-genome sequencing (LR-WGS) workflow with targeted analysis of hypotonia-associated genes was developed to detect and prioritize pathogenic SNVs, SVs, and CNVs, repeat expansions, and methylation changes at key disease loci. The workflow was validated in a reference-positive cohort with known diagnoses (n = 15) and applied to an unsolved cohort (n = 14). Variant interpretation followed ACMG guidelines and was confirmed with orthogonal methods. RESULTS: Standard-of-care testing achieved a diagnostic yield of 42% with an average time-to-diagnosis of 68.7 days; however, 30% of diagnosed patients experienced significant delays (average 169 days) due to sequential testing. The LR-WGS based approach identified all known pathogenic variants in the positive cohort, including SMN1 deletions, methylation defects at 15q11.2/Prader-Willi locus, FMR1 repeat expansions, and sequence and copy-number variants in > 100 genes underlying myopathies and muscular dystrophies. The targeted long-read pipeline reduced prioritized variant calls by 97.9-99.9% and, in the unsolved cohort, yielded one definitive diagnosis (de novo COL6A3 deletion) and one possible diagnosis (aberrant methylation and copy number at POMK), for an additional 14% yield. Among patients diagnosed after sequential testing (n = 29), LR-WGS is expected to reduce time-to-diagnosis by ~ 85% and decrease cumulative diagnostic delays, with projected healthcare cost savings of $396,000-439,000. Across the entire 227 patient cohort, LR-WGS is anticipated to reduce testing costs by 6.5%, yielding an average savings of $105 per patient. CONCLUSIONS: LR-WGS enables comprehensive discovery of genomic and epigenomic variants in hypotonia and muscle weakness, improving diagnostic yield, shortening diagnostic timelines, and reducing costs compared with current standard-of-care testing.
Apolipoprotein C3 drives adverse cardiac remodeling in ischemic heart failure.
Han Y, Zhao Y, Zhou Z … +8 more , Liu C, Chen J, Miao G, Zhang L, Wang Y, Li J, Huang W, Xian X
BMC Med · 2026 Apr · PMID 41952190 · Full text
BACKGROUND: Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated wit...
BACKGROUND: Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. METHODS: ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3) mice, ApoC3 knockout (ApoC3) mice, ApoC3 hamsters, and wild-type (WT) controls underwent left anterior descending coronary artery (LAD) ligation to establish IHF models 4 weeks post-MI. Echocardiography, biochemical assays, and histopathology were employed to investigate ApoC3's role and regulatory mechanisms in MI-induced IHF. RESULTS: Overexpression of human ApoC3 in ApoC3 mice exacerbated IHF after MI surgery, characterized by cardiac hypertrophy with thinned ventricular wall thickness and decreased contractile function. Mechanistically, ApoC3 overexpression markedly upregulated its receptor TLR2 at the myocardial ischemic site, and activated the NF-κB pathway resulting in significant increases in inflammation, oxidative stress and apoptosis. Unfortunately, ApoC3 deficiency did not show an overt protective effect in mouse MI model. We subsequently introduced ApoC3 hamsters and found that unlike mouse model, plasma HDL levels were markedly higher in ApoC3hamsters 4 weeks after surgery compared with WT hamsters cardiac remodeling and contractile function were significantly ameliorated with a reduction in TLR2 gene expression, eventually inhibiting inflammation, oxidative stress, and apoptosis in MI heart. CONCLUSIONS: ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters.
Fat-soluble vitamin deficiency in children with neurodevelopmental disorders: a cross-sectional study.
Rao J, Wang X, Zhou P … +3 more , Xiang Y, Xi L, Li C
BMC Med · 2026 Apr · PMID 41952160 · Full text
BACKGROUND: Neurodevelopmental disorders (NDDs) affect 15-20% of children worldwide, and emerging evidence suggests nutritional status may influence neurodevelopmental outcomes. However, disorder-specific patterns of fat...
BACKGROUND: Neurodevelopmental disorders (NDDs) affect 15-20% of children worldwide, and emerging evidence suggests nutritional status may influence neurodevelopmental outcomes. However, disorder-specific patterns of fat-soluble vitamin deficiency remain incompletely characterized in large clinical populations. METHODS: We conducted a retrospective cross-sectional study of 14,911 children aged 1-18 years who underwent serum vitamin testing between 2022 and 2025 at a tertiary pediatric center in China. Participants included healthy controls (n = 6391) and children with attention-deficit/hyperactivity disorder (ADHD; n = 4392), tic disorders (n = 2020), autism spectrum disorder (ASD; n = 1312), and comorbid neurodevelopmental disorders (n = 796). Serum concentrations of vitamin A, 25(OH)D, and vitamin E were measured using standardized assays. Group differences were assessed using age-, sex-, and season-adjusted analyses, including Analysis of covariance (ANCOVA) and multivariable logistic regression. RESULTS: After adjustment, children with ADHD and tic disorders exhibited modestly lower serum 25(OH)D concentrations compared with controls (adjusted Cohen's d = 0.273 for ADHD, small effect), whereas ASD profiles were largely comparable to controls. Vitamin A deficiency affected approximately one quarter of participants across all groups, with a modest increase in ADHD (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.14-1.40; small effect size), indicating widespread background deficiency with a modest additive risk in ADHD. Although absolute vitamin E deficiency rates were low, children with ADHD showed higher relative odds of deficiency (OR = 2.91). Multiple concurrent deficiencies (≥ 2 vitamins) were more common in ADHD (OR = 2.81) and moderately increased in tic disorders (OR = 1.66), while triple deficiencies remained rare. Children with comorbid conditions showed intermediate patterns. Clustering analyses identified heterogeneous vitamin profiles, with low-vitamin patterns disproportionately represented in ADHD and tic-disorder groups. CONCLUSIONS: In this large pediatric cohort, fat-soluble vitamin status differed across NDD subtypes. Children with ADHD exhibited higher burdens of vitamin D deficiency and multiple concurrent deficiencies, while ASD profiles were comparatively preserved. These findings highlight nutritional heterogeneity among pediatric NDD populations and underscore the need for prospective studies to clarify temporal relationships and clinical relevance.
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