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PubMed2026

Causal Relationships Between Modifiable Risk Factors and Gastroesophageal Reflux Disease: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Gastroesophageal reflux disease (GERD) is a prevalent digestive disorder, yet the causal roles of modifiable risk factors remain unclear. This study aims to investigate the causal relationships between 28 modifiable risk factors (including obesity traits, mental health disorders, sleep traits, metabolic comorbidities, and serum parameters) and GERD using two-sample Mendelian randomization (MR). Gastroesophageal reflux disease (GERD). Our findings aim to inform targeted prevention and treatment strategies for GERD. METHODS: This study obtained data from extensive genome-wide association studies (GWAS). Pooled data associated with gastroesophageal reflux associations were obtained from the 23andMe Research team's research, which included a total of 129,080 cases of gastroesophageal reflux and 473,524 controls of European ancestry. We conducted a univariable Mendelian randomization (MR) analysis to ascertain whether genetic evidence of exposure demonstrated a statistically significant association with the risk of GERD. Subsequently, a multivariable MR analysis was carried out to estimate the independent effects of the exposures on GERD. RESULTS: Univariable MR analysis utilizing extensive GWAS data suggested that genetic factors such as BMI, Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), Attention Deficit and Hyperactivity Disorder (ADHD), Major Depressive Disorder (MDD), Schizophrenia, Negative emotions (including nervousness, anxiety, tension, or depression), Insomnia, Sleep apnea syndrome, Sleep duration, and Snoring, as well as Total cholesterol levels and Apolipoprotein B levels, are associated with the development of GERD. Multivariate Mendelian randomization of BMI and Negative emotion as correction factors showed that Waist circumference, Arm fat mass (left and right), Leg fat mass (left and right), ADHD, Insomnia, Sleep apnea syndrome, and Snoring were associated with an increased risk of GERD (p< 0.05). Conversely, longer sleep duration was associated with a reduced risk of GERD (p< 0.05). DISCUSSION: This MR study reveals novel causal mechanisms in GERD pathogenesis: (1) Peripheral adiposity (arm/leg fat mass) exerts independent effects beyond central obesity, indicating site-specific fat distribution significance; (2) ADHD emerges as a distinct psychiatric risk factor independent of mental disorders; (3) Sleep apnea operates through BMI-independent pathways. Collectively, these findings redefine GERD pathophysiology, highlighting fat depot specificity and brain-gut interactions as critical mechanistic drivers. CONCLUSION: Overall, our findings suggest that multiple risk factors are associated with the risk of GERD. These results provide a theoretical basis for controlling body weight and plasticity, improving sleep habits, and preventing and timely seeking medical attention to reduce the occurrence of psychiatric disorders, which will be important strategies to prevent and alleviate GERD.

Humans↗

PubMed2025

Causal relationships between modifiable risk factors and heart failure: A comprehensive Mendelian randomization study.

Heart failure threatens human health across the globe. Comprehensively identifying its risk factors has public health importance. This work utilized the Mendelian randomization (MR) method to evaluate the effects of over 200 modifiable factors on heart failure. The data from genome-wide association studies (GWAS) was used, with the sample size ranging from 711 to 1232,091. Two distinct GWAS datasets for heart failure were employed for results validation. The inverse variance weighted (IVW) method was used and other supplementary models were employed for comparison. Sensitivity analysis was conducted to verify the results. After integrating the MR estimates derived from heart failure GWAS datasets from integrative epidemiology unit (IEU) and Finngen, we found that body measurement indices like body mass index, whole body fat mass, trunk fat mass, basal metabolic rate, body fat percentage, waist circumference, and waist-hip ratio, were associated with a higher risk of heart failure. Similarly, smoking behavior, sedentary behavior, overall health rating, and type 2 diabetes were determined to increase the risk of heart failure. In contrast, college or university degree showed a protective effect on heart failure. Among these significant findings, body mass index, whole body fat mass, trunk fat mass, basal metabolic rate, body fat percentage, overall health rating, smoking initiation, waist circumference, lifetime smoking index, college or university degree, sedentary behavior, waist-hip ratio, and type 2 diabetes were replicated validated. This MR work figured out that obesity, socioeconomic factors, lifestyle factors, and metabolic features showed broad relations with heart failure. The findings would provide evidence for future policy development for the management of heart failure.

Humans↗

PubMed2025

Modifiable risk factors associated with the risk of developing Parkinson's disease: a critical review.

The etiology of Parkinson's disease (PD) is complex and multifactorial, depending on interactions involving environmental/lifestyle and genetic factors. The genetic aspects of the disease are becoming well characterized, while the environmental factors still need further investigation. In the present narrative review, we have described the most concrete evidence of associations between environmental factors and the risk of developing PD. Physical activity, healthy dietary patterns, smoking, and caffeine intake are protective factors against PD. Head trauma, consumption of milk and dairy products, and pesticide exposure were associated with a higher risk of developing PD. The associations of alcohol consumption, living in rural areas, farming, and consumption of well water with PD are still controversial. Results of several studies strongly suggest that diabetes mellitus is a risk factor for the development of PD, as well as the pre-diabetic state. Lower serum levels of uric acid were associated with an increased risk of developing PD and with worse clinical features and faster progression of symptoms. The protective effects of nonsteroidal antiinflammatory drugs use are controversial. Several other factors were potentially associated with the risk of developing PD: environmental pollutants such as organic solvents, exposure to sunlight, vitamin D deficiency, bullous pemphigoid, bipolar disorder, inflammatory bowel disease, irritable bowel syndrome, certain infections and agents, and essential tremor. Environmental factors are important risk markers for the development of PD. Understanding these risks and protective factors could lead to the implementation of risk-modifying actions for PD.

Humans↗

PubMed2026

Chronic postsurgical pain: risk assessment and mitigation.

PURPOSE OF THE REVIEW: Chronic postsurgical pain (CPSP) and persistent postoperative opioid use (PPOU) are two of the most common complications of a number of surgical interventions, which can cause significant personal and economic negative consequences. This review outlines known and potential risk factors for CPSP and PPOU and approaches to reduce these risk factors. RECENT FINDINGS: Modifiable risk factors for developing CPSP include psychological distress, preoperative pain intensity, and perioperative opioid exposure. Although less studied, psychological comorbidities are also risk factors for PPOU. Evidence-based mitigation strategies include psychological interventions and perioperative opioid sparing. SUMMARY: A number of perioperative risk factors for developing CPSP and PPOU have been identified, and anesthesiologists should be cognizant of these risk factors and potential risk mitigation strategies. Additional prospective studies are needed to further develop easily adoptable, evidence-based interventions to reduce the incidence of CPSP and PPOU.

Humans↗

PubMed2026

Exposome influences: a multi-omics perspective on the combined toxic effects of pharmaceuticals and personal care products in Alzheimer's disease.

According to WHO data, approximately 57 million people worldwide were affected by dementia in 2021, with prevalence projected to rise. Alzheimer's disease (AD), responsible for 60%-80% of dementia cases, continues to be a leading cause of mortality, with current treatments offering limited efficacy and disease-modifying therapies lacking widespread adoption or conclusive safety evidence, shifting the focus toward prevention and risk modification. Risk factors for AD include both non-modifiable elements, such as age, genetics, and gender, and modifiable factors, like environmental pollution, health status, and diet. While age remains the primary non-modifiable risk factor, early-onset dementia represents only up to 9% of cases. Addressing modifiable factors is essential, as it could prevent or delay almost half of dementia cases, with interventions-such as increased physical activity, smoking cessation, alcohol limitation, and overall health management-being significantly associated with a reduced risk. In this context, the exposome approach offers a comprehensive, integrative framework in which both modifiable and non-modifiable risk factors interact to influence individual susceptibility. Within the neural exposome, chronic low-dose exposure to xenobiotics-such as industrial chemicals, pesticides, metals, pharmaceuticals and personal care products (PPCPs), and air pollutants-may induce neurodegeneration via mechanisms including oxidative stress, neuroinflammation, proteinopathies, and epigenetic modifications, although establishing causality remains challenging. Integration of genomics, transcriptomics, proteomics, metabolomics, and lipidomics, combined with artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL), provides promising avenues for biomarker discovery, enhanced preventive strategies, early non-invasive diagnosis, and therapeutic target identification by integrating multi-layered biological data with exposure profiles. This review highlights emerging AD risk factors-including PPCPs-underscoring complex, multifactorial nature of AD and exposome, and the requirement for an interdisciplinary research approach, while also addressing several critical research gaps and methodological limitations.

Alzheimer’s disease↗

PubMed2026

The presence or absence of standard modifiable cardiovascular risk factors in patients with myocardial infarction impacts long-term but not 30-day mortality: a UK Biobank prospective cohort study.

AIMS: Prior studies reported higher early mortality after acute myocardial infarction (MI) in patients without standard modifiable cardiovascular risk factors (SMuRFs), warranting further validation. We aimed to evaluate whether SMuRF-absence is associated with increased 30-day cardiovascular mortality following MI. METHODS AND RESULTS: We conducted a population-based cohort study using UK Biobank data (n = 487 177). Incident MI cases occurring between 2006 and 2022 were identified through linkage to hospital and death registries. Standard modifiable cardiovascular risk factors (diabetes, hypertension, hypercholesterolaemia, current smoker) were defined at baseline and continuously assessed until MI onset. Thirty-day mortality following MI was estimated using Cox proportional hazards models, adjusted for sociodemographic, clinical, and cardiogenomic variables, were used to estimate 30-day mortality risks. Logistic regression model was used to estimate mortality risk at 10 years post-MI. Among 15 463 patients experiencing an MI (1034 without SMuRFs), SMuRF-absence was not significantly associated with 30-day mortality (HR: 0.82, 95% CI: 0.65-1.04, P = 0.103). Propensity score-matched analyses supported these findings (HR: 0.95, 95% CI: 0.69-1.29, P = 0.729). Further analyses stratified by distinct time intervals (2006-2022) revealed no significant modification of this association by advancements in acute MI management. Interaction analyses indicated no significant effect modification by sex, age, socioeconomic status, or period of MI occurrence. However, extended analysis to 10 years revealed that SMuRF absence was significantly associated with lower long-term mortality (OR: 0.61, 95% CI: 0.49-0.75, P < 0.01). CONCLUSION: In this population-based cohort, SMuRF status significantly impacted long-term but not short-term mortality following MI, indicating early survival is predominantly driven by acute-phase factors rather than baseline cardiovascular risk profiles.

Humans↗

PubMed2026

Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.

Although individual traits related to metabolic dysfunction-associated steatotic liver disease (MASLD) have been investigated through large-scale genome-wide association studies (GWASs), the shared genetic susceptibility across these traits remains unclear. We therefore conducted a multivariate GWAS of key MASLD-related traits to elucidate their common genetic architecture. We applied genomic structural equation modeling to model a latent genetic factor (MASLD-F) underlying genetically correlated MASLD-related traits, leveraging their GWAS-derived genetic correlations. We then performed functional annotations, including fine-mapping, transcriptome-wide association study, and cell- and tissue-type-specific enrichment analyses, and conducted Mendelian randomization analyses to identify modifiable risk factors. Our multivariate MASLD-F GWAS identified 50 independent variants across 48 genomic loci. Transcriptomic imputation identified several MASLD-F-associated genes, including ARNTL, NPC1, BTBD10, VDAC2, TSKU, SFMBT1, and ABHD17C. We observed significant enrichment of MASLD-F-related genetic signals predominantly in brain tissues, pancreatic islets, and the adrenal gland. Additionally, six modifiable risk factors and four modifiable protective factors for MASLD-F were identified. These findings reveal a complex shared genetic architecture underlying MASLD components, thereby expanding our understanding of disease pathogenesis and providing novel insights for precision medicine and public health interventions.

Humans↗

PubMed2028

Parental son preference in childhood and sex differences in the risk of cardiovascular disease in middle-aged and older adults.

INTRODUCTION: Sex differences in cardiovascular disease (CVD) risk are examined through biological and clinical factors, with less attention to early-life social exposures. This study examined associations of childhood parental son preference with CVD risk, sex differences, and mediation by modifiable risk factors. METHODS: This cohort analysis included China Health and Retirement Longitudinal Study participants aged ≥45 years without baseline CVD. Parental son preference was assessed retrospectively in 2014; incident CVD was self-reported physician-diagnosed heart disease or stroke through 2020. Sampling-weighted, community-clustered Cox models estimated adjusted hazard ratios (aHRs) and 95% CIs. Sex was prespecified as an effect modifier; mediation by 13 risk factors used inverse-odds-ratio weighting. Data were collected from 2011 to 2020 and analyzed from 2025 to 2026. RESULTS: Among 8,079 participants (mean age, 57.5 years; 4,216 women [52.2%]), 1,820 (22.5%) reported parental son preference. Son preference was associated with higher CVD risk overall (aHR 1.23 [95% CI 1.04, 1.46]) and among women (aHR 1.25 [95% CI 1.03, 1.53]); among men, the estimate was 1.16 (95% CI 0.87, 1.56), with limited heterogeneity by sex (ratio of aHRs 1.06 [95% CI 0.72, 1.58]). Among women, risk was concentrated in the highest paternal (aHR 1.47 [95% CI 1.14, 1.90]) and maternal (aHR 1.50 [95% CI 1.12, 1.99]) preference categories. Modifiable risk factors mediated 5.8% (95% CI 1.9%, 9.7%) of the association among women, mainly through socioeconomic and psychosocial factors. CVD risk was highest with both son preference and high risk-factor burden overall (aHR 1.97 [95% CI 1.43, 2.73]) and among women (aHR 2.23 [95% CI 1.61, 3.10]). CONCLUSIONS: Parental son preference was associated with higher incident CVD risk, with the largest estimates in the highest paternal or maternal categories among women. Modifiable risk factors explained a modest proportion, supporting life-course cardiovascular prevention that considers sex-differentiated childhood environments alongside risk-factor modification.

cardiovascular disease↗

PubMed2026

Embedding cardiovascular risk assessment into routine BTK inhibitor management in chronic lymphocytic leukemia.

INTRODUCTION: Cardiovascular (CV) toxicities remain a major challenge during Bruton tyrosine kinase inhibitor (BTKi) therapy for chronic lymphocytic leukemia (CLL). Selecting the optimal BTKi based solely on a history of overt CV disease may underestimate underlying cardiovascular vulnerability. AREAS COVERED: We performed a targeted, non-systematic review of PubMed and MEDLINE to examine the association between baseline CV comorbidities and BTKi-related CV toxicities in CLL. Current evidence indicates that preferential use of BTKis with more favorable CV safety profiles, coupled with appropriate cardio-oncology surveillance, reduces the risk of CV adverse events in patients with pre-existing CV disease. In patients without established CV disease, the Systematic Coronary Risk Evaluation 2 (SCORE2) and SCORE2-Older Persons (SCORE2-OP) may help identify clinically meaningful latent CV risk, enabling early optimization of modifiable risk factors in line with the proactive cardiovascular management strategy endorsed by the 2026 European Hematology Association (EHA) CLL guidelines. EXPERT OPINION: A structured, risk-adapted approach integrating standardized CV risk assessment, early management of modifiable risk factors, individualized BTKi selection, and multidisciplinary cardio-oncology collaboration may improve the safety and tolerability of BTKi therapy in CLL. Pending prospective validation, SCORE2 and SCORE2-OP should complement, rather than replace, dedicated cardio-oncology evaluation.

Humans↗

PubMed2025

Association Between Ratio of Triglycerides to HDL-C and Cognitive Impairment: A Longitudinal Population-Based Analysis and Mendelian Randomization Study.

OBJECTIVES: This study aimed to explore the longitudinal association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and cognitive impairment in older adults and further assess potential causality using Mendelian randomization (MR). DESIGN: Longitudinal population-based analysis combined with two-sample MR. Data from Waves 6-8 (2015-2019) of the Survey of Health, Ageing, and Retirement in Europe (SHARE) were analyzed using hierarchical regression models and mixed linear effects models. MR utilized genome-wide association studies (GWAS) summary data. PARTICIPANTS: 11,444 adults aged ≥60 years from SHARE Wave 6, with longitudinal follow-up in Waves 7 (N = 2,775) and 8 (N = 5,469). MEASUREMENTS: TG/HDL-C ratio, cognitive function (orientation, immediate/delayed recall, verbal fluency, numeracy), and cognitive impairment (defined as scores >1.5 SD below age-group mean). Covariates included socio-demographics, health behaviors, comorbidities, and national-level factors. MR employed genetic variants associated with TG/HDL-C as instrumental variables. RESULTS: Higher TG/HDL-C ratios were negatively associated with total cognitive scores (β = -0.115, χ² = 15.44, df = 1, p < 0.001), immediate recall (β = -0.029, χ² = 12.34, df = 1, p < 0.001), delayed recall (β = -0.028, χ² = 7.33, df = 1, p < 0.001), verbal fluency (β = -0.038, χ² = 11.53, df = 1, p < 0.001), and numeracy (β = -0.019, χ² = 4.55, df = 1, p < 0.05) in fully adjusted models. Longitudinal analysis revealed increased cognitive impairment risk in the highest TG/HDL-C quartile (OR=1.43, 95% CI:1.01-2.03, χ² = 9.24, df = 1) over 4 years. MR supported a causal link between elevated TG/HDL-C and cognitive decline. CONCLUSIONS: Elevated TG/HDL-C ratios are longitudinally associated with cognitive decline in older adults. Managing lipid metabolism may mitigate cognitive impairment, highlighting the importance of TG/HDL-C as a modifiable risk factor in aging populations.

Humans↗

PubMed2026

Long-term mortality in pediatric sepsis: a systematic review and meta-analysis.

BACKGROUND: Pediatric sepsis represents a significant factor in the mortality rates among children, with survivors remaining highly fragile during the period following discharge. While in-hospital and short-term mortality have been widely studied, the long-term mortality of pediatric sepsis is not adequately synthesized or appreciated. This study aims to estimate the long-term mortality associated with pediatric sepsis, providing a basis for optimizing post-discharge surveillance and care protocols. METHODS: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420251137504). Exhaustive searches were conducted in PubMed, Embase, the Cochrane Library, and Web of Science for studies published from the inception of each database to June 30, 2025. Studies reporting long-term mortality in pediatric sepsis patients diagnosed using international consensus criteria were included. After literature screening, long-term mortality was pooled using a random effects meta-analysis in R statistical software. RESULTS: A total of 72,065 records were identified through database searching. After removing duplicates and screening, six studies comprising 11,318 pediatric sepsis patients were included. The pooled long-term mortality in pediatric sepsis was 11% (95% CI: 7-16%), though significant heterogeneity was observed (I2 = 98.2%, p < 0.001). Sensitivity analyses yielded similar results, and evidence of publication bias was limited. CONCLUSION: Long-term mortality after pediatric sepsis was 11%, highlighting the persistent risk of mortality after hospital discharge. Further high-quality longitudinal studies are required to identify modifiable risk factors and guide evidence-based follow-up and personalized care.

Humans↗

PubMed2026

Wearable Sleep Monitoring in Pediatric Acute Lymphoblastic Leukemia: Associations With Subjective Sleep Ratings and Neurocognitive Functioning.

BACKGROUND: Sleep disturbances are associated with increased fatigue, reduced quality of life, and neurocognitive dysfunction and have emerged as a common complication among pediatric cancer survivors. Sleep disturbances are particularly concerning given their potential to exacerbate existing neurocognitive impacts of cancer treatments. This pilot study examined the feasibility and acceptability of a home-wearable EEG-based sleep device (Sleep ProfilerTM) for acute lymphoblastic leukemia (ALL) survivors as well as associations between specific sleep parameters and neurocognitive functioning. PROCEDURE: Children (ages 8-12; M = 10 years, SD = 1.6; N = 23) >6 months post-treatment for ALL were enrolled at clinical visits and wore the Sleep ProfilerTM for two consecutive nights at home, followed by neurocognitive testing of attention, inhibitory control, working memory, and processing speed. Parents completed subjective measures of child sleep, anxiety, depression, and acceptability. Feasibility reflected the percentage of children wearing the device at least one night and the percentage of nights with good EEG quality data. RESULTS: All participants wore the device both nights, with 84% meeting the threshold for good quality measurement. Few children met recommended quantity and quality sleep thresholds based on objective measurement, including 5 patients with elevated snoring levels; 43.5% of subjective ratings fell above the threshold for sleep disturbance. Greater sleep latency was associated with worse inhibitory control (r = -0.42, p = 0.046), and total sleep time was positively associated with inhibitory control and attention. CONCLUSIONS: Findings confirm the feasibility and acceptability of home EEG sleep monitoring in school-age survivors, and associations of sleep latency and snoring with reduced neurocognitive functioning may offer modifiable risk factors for aspects of neuropsychological dysfunction common in pediatric survivorship. CLINICAL TRIAL REGISTRATION: At the time this study was conducted, we were not required to register the study on ClinicalTrials.gov. It was a single-institution feasibility study without intervention, which was not considered a clinical trial.

Humans↗

PubMed2025

Glioma mutational signatures associated with haloalkane exposure are enriched in firefighters.

BACKGROUND: Glioma is the most common malignant primary brain tumor and is associated with significant morbidity and mortality. Modifiable risk factors remain unidentified. New advances in exposure assessment, genomic analyses, and statistical techniques permit more accurate evaluation of glioma risk associated with exogenous occupational or environmental exposures. METHODS: By using whole-exome sequencing data from matched germline and glioma tumor samples, the authors compared tumor mutational signatures for 17 persons with glioma and a documented occupational history of firefighting with those of 18 persons with glioma without an occupational history of firefighting. All 35 individuals were participants in the University of California, San Francisco Adult Glioma Study. RESULTS: There was a positive correlation among firefighters between the median number of sample variants attributable to single-base substitution signature 42, a single-base substitution mutational signature associated with haloalkane exposure (from the Catalogue of Somatic Mutational Signatures in Cancer) and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to single-base substitution signature 42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic. CONCLUSIONS: In summary, the authors identified gliomas that had mutational signatures associated with haloalkane exposure that were enriched in firefighters and other occupations.

Humans↗

PubMed2026

Effectiveness of psychosocial and lifestyle interventions in promoting behaviour change and improving cognitive outcomes in older people with memory concerns: A systematic review.

BACKGROUND: Older adults with mild cognitive impairment or subjective cognitive decline have a greater dementia risk, particularly those from minority ethnic and socioeconomically disadvantaged backgrounds. Psychosocial and lifestyle interventions targeting modifiable risk factors offer hope for reducing risk, yet behavioural mechanisms remain unclear. This systematic review examines these mechanisms and associated outcomes. METHOD: We searched PubMed, Embase (Ovid), PsycINFO (Ovid), Web of Science, and Scopus for randomised control trials testing interventions that aimed to improve lifestyle and cognition in older adults with memory concerns. We explored behavioural mechanisms using the COM-B model and synthesised intervention effectiveness, overall and within underserved groups. We prioritised lower risk of bias studies. RESULTS: 26 studies described 23 randomised controlled trials (14 multidomain, 9 single domain interventions). Certainty of evidence that behaviour change was associated with cognition was low. Moderate-certainty evidence indicated that interventions providing a socially supportive environment and combining nutritional education and counselling for 6 + months improved diet. Physical activity improved primarily in interventions incorporating education, structured training, and enablement strategies (e.g., tailored programmes, providing tools). Interventions simultaneously targeting capability, opportunity and motivation showed greater overall effectiveness. Few studies recorded ethnicity (13%) or sociodemographic status (9%), and none explored their impact. CONCLUSIONS: Non-pharmacological interventions can help this population improve their lifestyles if they feel capable, equipped and motivated, highlighting the value of careful design and implementation. There is scarce evidence on how these interventions work for underserved populations. Future research should explore this to inform tailored interventions and develop equitable dementia prevention strategies.

Humans↗

PubMed2025

Treatment response variations to a single large bolus of enteral cholecalciferol in vitamin D deficient critically Ill children: Metabolomic insights for precision nutrition.

Vitamin D deficiency (VDD) is prevalent globally and in pediatric intensive care units, where it represents a modifiable risk factor that may impact patient recovery during hospitalization. Herein, we performed a retrospective analysis of serum samples from a phase-II randomized placebo-controlled trial involving a single large bolus of 10,000 IU/kg vitamin D3 ingested by critically ill children with VDD (25-OH-D < 50 nmol/L). Targeted and untargeted methods were used to comprehensively measure 6 vitamin D metabolites, 239 lipids, 68 polar metabolites, and 4 electrolytes using a multi-step data workflow for compound authentication. Complementary statistical methods classified circulating metabolites/lipids associated with vitamin D repletion following high-dose vitamin D3 intake (n = 20) versus placebo (n = 11) comprising an optional standard of care maintenance dose (< 1000 IU/day). There was a striking increase in median serum concentrations of 25-OH-D3 (4.7-fold), 3-epi-25-OH-D3 (24-fold) and their C3-epimer ratio (6.7-fold) in treated patients on day 3, whereas serum vitamin D3 peaked on day 1 (128-fold) unlike placebo. Treatment response differences were attributed to D3 bioavailability and C3-epimerase activity without evidence of hypercalcemia. For the first time, we report the detection of circulating 3-epi-D3 that was strongly correlated with vitamin D3 uptake (r = 0.898). Metabolomic studies revealed that vitamin D sufficiency (serum 25-OH-D >75 nmol/L) coincided with lower circulating levels of 3-methylhistidine, cystine, S-methylcysteine, uric acid, and two lysophosphatidylcholines 7 days after treatment. Rapid correction of VDD was associated with indicators of lower oxidative stress, inflammation, and muscle protein turn-over that may contribute clinical benefits in high-risk critically ill children.

Humans↗

PubMed2026

The interplay between circadian misalignment or sleep disturbances and cognition and brain function in individuals with different degrees of insulin resistance - a systematic review.

Disruption of sleep increases the risk of type 2 diabetes and worsens cognitive outcomes, yet few studies have evaluated the interaction between insulin resistance and sleep parameters in relation to cognitive outcomes or the risk of dementia. This systematic review examines how circadian misalignment and sleep disturbances affect cognition and neuroimaging findings in individuals with varying degrees of insulin resistance. Across 27 studies, disrupted circadian rhythmicity and sleep disturbances were negatively associated with brain health, possibly through its effects on insulin sensitivity, whereas the impact of sleep duration and quality were inconclusive. Methodological heterogeneity, reliance on cross-sectional designs, and limited control for confounders restricted definitive conclusions and highlighted the need for longitudinal and interventional studies with objective measurements. Nonetheless, the findings support circadian rhythmicity as a potentially modifiable risk factor for preserving cognition in insulin-resistant populations. Future research should prioritise prospective and interventional studies and focus on biological markers rather than self-reported outcomes.

Humans↗

PubMed2026

The Association of Diabetes-Related Dietary Patterns with Pancreatic Cancer Risk in the European Prospective Investigation into Cancer and Nutrition Study.

BACKGROUND: Pancreatic cancer is relatively rare but remains one of the most lethal tumors. Identifying modifiable risk factors is a crucial step to reduce disease burden. Evidence suggests a potential role of type 2 diabetes mellitus in its pathogenesis. OBJECTIVES: The objective of this study is to examine the association between dietary patterns related to diabetes and pancreatic cancer risk in a European population. METHODS: A total of 367,395 participants from the European Prospective Investigation into Cancer and Nutrition study were included. After a median follow-up of 14.9 y, 926 incident cases were identified. The Diabetes Risk Reduction Diet (DRRD), the Empirical Dietary Index for Hyperinsulinemia (EDIH), and the Empirical Dietary Index for Insulin Resistance (EDIR) were estimated from food frequency questionnaires at recruitment. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between dietary patterns and pancreatic cancer were calculated using multivariable Cox proportional hazards regression models, adjusted for relevant confounders. RESULTS: Adherence to DRRD showed no association with risk of pancreatic cancer (HRT3vsT1: 0.94; 95% CI: 0.79, 1.12). Higher adherence to EDIH was associated with a borderline 19% increased pancreatic cancer risk (HRT3vsT1: 1.19; 95% CI: 0.99, 1.44). No significant associations were observed in relation to EDIR. No heterogeneity was observed among the subgroups. CONCLUSIONS: Higher adherence to a hyperinsulinemic dietary pattern may contribute to risk of developing pancreatic cancer in our population. Further research is warranted to elucidate the potential role of dietary factors in cancer risk prevention.

Humans↗

PubMed2024

Bidirectional association between abnormal cardiac conditions and epilepsy: A two-sample Mendelian randomization study.

BACKGROUND: Observational studies have consistently indicated a significant correlation between abnormal cardiac conditions and epilepsy. However, the association and direction of this relationship remain a subject of debate. This study employs a two-sample bidirectional Mendelian randomization (MR) approach to investigate the association between abnormal cardiac conditions and epilepsy. METHODS: Instrumental variables, represented by single nucleotide polymorphisms (SNPs) associated with epilepsy and various abnormal cardiac conditions, were derived from large-scale genome-wide association studies databases, including FinnGen and UK Biobank. Bidirectional MR analysis was conducted to estimate the association between epilepsy and abnormal cardiac conditions. Sensitivity analyses were performed using MR-Egger, weighted median, Inverse Variance Weighted, and MR pleiotropy residual sum and outlier methods. RESULTS: The forward MR analysis suggested a potential positive effect of atrial fibrillation and flutter (AF) and valvular heart diseases (VHD) on the risk of epilepsy. Conversely, the reverse MR analysis indicated that epilepsy might increase the susceptibility to AF, VHD, and heart failure. CONCLUSION: The findings support a bidirectional relationship between AF, VHD, and epilepsy, indicating that AF and VHD can elevate the risk of developing epilepsy, while epilepsy, in turn, can also increase the risk of developing AF and VHD. Furthermore, the study suggest that epilepsy may contribute to the development of heart failure. These results underscore the importance of screening for cardiac abnormalities in patients with epilepsy and vice versa, to better understand their clinical significance and potential as modifiable risk factors.

Humans↗