Correction For Multiple Testing Research Articles

Unravelling the Metabolic Underpinnings of Gestational Diabetes Mellitus: A Comprehensive Mendelian Randomisation Analysis Identifying Causal Metabolites and Biological Pathways.

Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis. This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM. A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites. MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM. This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study

BackgroundHER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors. Methods84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2+n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2+n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value <0.05, adjusted for multiple testing correction. Results83 biopsies were eligible for analyses following quality control (TRAP cohort n = 40; control cohort n = 43); there were no significant differences in clinical characteristics between the TRAP vs. control the cohort or HER2 positive vs. HER2 negative biopsies. HER2 expression was found to associate with epithelial markers (EPCAM p < 0.001; E-cadherin p < 0.001). Moreover, HER2 expression was associated with a lower expression of immune cell infiltration, such as NK-cells (p < 0.001) and CD8 T-cells (p < 0.001), but also lower expression of immune exhaustion markers (PDCD1LG2, CTLA4; p < 0.001). In non-responders to anti-HER2 treatment, baseline biopsies showed increased expression of immune exhaustion markers, as well as hypoxia and VEGF signalling. DiscussionHER2 expression was associated with epithelial tumor characteristics. The HER2 positive TIME showed reduced immune cell infiltration but also lower expression of inhibitory signals associated with immune exhaustion, questioning the mechanism behind potential clinical benefit of co-administration of anti-HER2 agents and checkpoint inhibitors. As limited response was associated with increased VEGF signalling, studies could investigate potential synergism of targeting VEGF and HER2.

Detrimental effect of COVID-19 pandemic on patients with extremity bone sarcoma. Reference center experience

1 BACKGROUND: COVID-19 pandemic had a major impact on the healthcare system globally. This work aims to evaluate COVID-19 impact on local treatment in bone sarcoma treated in a single, high-throughput institution. 2 METHODS: We have analyzed the local outcomes (i.e., possibility of limb sparing surgery) in all bone sarcoma patients treated between January 2016 and November 2022 in the main sarcoma reference center in Poland. Patients treated in the 2016-2019 period were regarded as "pre-pandemic" group, patients treated in 2020-2022 - "pandemic". Mann-Whitney U and Chi-square tests were used in the statistical analysis. No correction for multiple testing was applied. Tests with p<0.05 were deemed significant. 3 RESULTS: There were 302 eligible patients identified. The group characteristics are presented in table 1. There were no differences in patient-related variables and histological subtypes of tumors between two groups. The tumor size did not differ (p=0.053), when all tumor grades were considered, but high grade tumors were larger in the "pandemic" group (p=0.034). This was reflected in the percentage of limb sparing surgeries which dropped from 83.3% to 68.2% ("pre-pandemic" vs. "pandemic", p=0.004). This difference was even more stark in case of high grade tumors - 78% vs. 54% respectively (p=0.001). 4 CONCLUSION: To our knowledge, this is the first report of the long lasting impact of COVID-19 pandemic on oncologic treatment outcomes in patients with malignant bone tumors.

A Bayesian flexible model for testing Granger causality

A new Bayesian hypothesis testing procedure for evaluating the Granger causality between two or more time series is proposed. The test is based on a flexible model for the joint evolution of multiple series, where a latent binary matrix indicates whether there is a Granger-causal relationship between such time series. The model is specified through a dependent Geometric stick-breaking process that generalizes the standard parametric Gaussian vector autoregression model, whereas the prior distribution of the latent matrix ensures a multiple testing correction. A Monte Carlo simulation study is provided for comparing the robustness of the proposed hypothesis test with state-of-the-art alternatives. The results show that this proposal performs better than competing approaches. Finally, the new test is applied to real economic data.

Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study

BackgroundInfections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. MethodsUsing data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13–16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration – a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). ResultsWe observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 − 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. ConclusionIn contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.

No sex-based differences in odds of starting or time to treatment of generalized myasthenia gravis: A single center cohort study.

Females with generalized myasthenia gravis (gMG) report lower quality of life (QoL) and have more severe disease than males. Sex differences in disease characteristics exist, however whether there are sex differences in the treatment of gMG that may contribute to QoL disparities is unknown. Our objective is to determine whether there are sex differences in the treatment of gMG. We performed a single-center retrospective study of people diagnosed with gMG at the University of Calgary between 1997 and 2021. Primary outcome was proportion starting treatment and secondary outcome was time from diagnosis to treatment initiation. Treatments included pyridostigmine, prednisone, steroid sparing therapies (azathioprine, mycophenolate mofetil [MMF], methotrexate [MTX], or tacrolimus), intravenous immunoglobulin (IVIg), plasmapheresis, rituximab, eculizumab, cyclosporine, stem cell transplantation, and thymectomy. Multivariable logistic and Cox proportional hazards regression models were used to examine treatment associations with sex, adjusted for time from onset to diagnosis, age at diagnosis, presence of thymoma, and antibody status. A total of 179 people with gMG were included (41.9% female). Odds of starting treatment were not statistically associated with sex after adjustment for confounders and correction for multiple testing. Results of the secondary analysis using time to treatment initiation as the outcome were similar. We found no sex differences in odds of starting treatment or time to treatment initiation that might explain previously observed sex-based differences in QoL. Future work should capture physician and patient treatment preferences that may influence disease management.

Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.

Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival. Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate. Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029). We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Cholinergic nucleus degeneration and its association with gait impairment in Parkinson’s disease

BackgroundThe contribution of cholinergic degeneration to gait disturbance in Parkinson’s disease (PD) is increasingly recognized, yet its relationship with dopaminergic-resistant gait parameters has been poorly investigated. We investigated the association between comprehensive gait parameters and cholinergic nucleus degeneration in PD.MethodsThis cross-sectional study enrolled 84 PD patients and 69 controls. All subjects underwent brain structural magnetic resonance imaging to assess the gray matter density (GMD) and volume (GMV) of the cholinergic nuclei (Ch123/Ch4). Gait parameters under single-task (ST) and dual-task (DT) walking tests were acquired using sensor wearables in PD group. We compared cholinergic nucleus morphology and gait performance between groups and examined their association.ResultsPD patients exhibited significantly decreased GMD and GMV of the left Ch4 compared to controls after reaching HY stage > 2. Significant correlations were observed between multiple gait parameters and bilateral Ch123/Ch4. After multiple testing correction, the Ch123/Ch4 degeneration was significantly associated with shorter stride length, lower gait velocity, longer stance phase, smaller ankle toe-off and heel-strike angles under both ST and DT condition. For PD patients with HY stage 1–2, there were no significant degeneration of Ch123/4, and only right side Ch123/Ch4 were corrected with the gait parameters. However, as the disease progressed to HY stage > 2, bilateral Ch123/Ch4 nuclei showed correlations with gait performance, with more extensive significant correlations were observed in the right side.ConclusionsOur study demonstrated the progressive association between cholinergic nuclei degeneration and gait impairment across different stages of PD, and highlighting the potential lateralization of the cholinergic nuclei’s impact on gait impairment. These findings offer insights for the design and implementation of future clinical trials investigating cholinergic treatments as a promising approach to address gait impairments in PD.

Peripheral blood immune parameters, response, and adverse events after neoadjuvant chemotherapy plus durvalumab in early-stage triple-negative breast cancer.

We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment. Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing. TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs. Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.

Metabolic profiling reveals circulating biomarkers associated with incident and prevalent Parkinson’s disease

The metabolic profile predating the onset of Parkinson’s disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P < 0.05), spanning lipids, lipid constituent of lipoprotein subclasses and ratios of lipid constituents. After multiple testing corrections (P < 9×\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ imes$$\\end{document}10−4), polyunsaturated fatty acids (PUFA) and omega-6 fatty acids remained significantly associated with incident PD, and PUFA was shared by incident and prevalent PD. Additionally, 14 metabolites were exclusively associated with prevalent PD, including amino acids, fatty acids, several lipoprotein subclasses and ratios of lipids. Adding these metabolites to the conventional risk factors yielded a comparable predictive performance to the risk-factor-based model (AUC = 0.766 vs AUC = 0.768, P = 0.145). Our findings suggested metabolic profiles provided additional knowledge to understand different pathways related to PD before and after its onset.

Memory effects of prior subculture may impact the quality of multiomic perturbation profiles

Mass spectrometry-based omics technologies are increasingly used in perturbation studies to map drug effects to biological pathways by identifying significant molecular events. Significance is influenced by fold change and variation of each molecular parameter, but also by multiple testing corrections. While the fold change is largely determined by the biological system, the variation is determined by experimental workflows. Here, it is shown that memory effects of prior subculture can influence the variation of perturbation profiles using the two colon carcinoma cell lines SW480 and HCT116. These memory effects are largely driven by differences in growth states that persist into the perturbation experiment. In SW480 cells, memory effects combined with moderate treatment effects amplify the variation in multiple omics levels, including eicosadomics, proteomics, and phosphoproteomics. With stronger treatment effects, the memory effect was less pronounced, as demonstrated in HCT116 cells. Subculture homogeneity was controlled by real-time monitoring of cell growth. Controlled homogeneous subculture resulted in a perturbation network of 321 causal conjectures based on combined proteomic and phosphoproteomic data, compared to only 58 causal conjectures without controlling subculture homogeneity in SW480 cells. Some cellular responses and regulatory events were identified that extend the mode of action of arsenic trioxide (ATO) only when accounting for these memory effects. Controlled prior subculture led to the finding of a synergistic combination treatment of ATO with the thioredoxin reductase 1 inhibitor auranofin, which may prove useful in the management of NRF2-mediated resistance mechanisms.

O-136 A comprehensive evaluation of spermatogenesis-related genes identifies novel common and rare risk loci for idiopathic severe spermatogenic failure

Abstract Study question Can genome-wide genotyping data be analysed in a hypothesis-driven fashion to better understand the genetic component of male infertility due to severe spermatogenic failure (SPGF)? Summary answer We revealed that both common and rare genetic variants in genomic regions involved in spermatogenesis contribute to the development of idiopathic SPGF. What is known already Spermatogenesis is a tightly regulated process involving the controlled expression of over 2,000 genes. Mutations in spermatogenesis-related genes have been associated with SPGF development. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of this condition. Additionally, genome-wide association studies (GWAS) have provided valuable insights into the role of common polymorphisms in complex forms of SPGF. Interestingly, novel methods have shown that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes, but this approach has never been applied to characterise the genetic component of a whole case-control cohort. Study design, size, duration We conducted a thorough examination of both common (minor allele frequency, MAF &amp;gt; 0.01) and rare (MAF &amp;lt; 0.01) genetic variation within a set of 1,797 spermatogenesis genes. This gene panel was meticulously curated through an exhaustive search in the literature and in different databases of male infertility genetics. The genotype data were obtained from a previously published GWAS in Europeans, encompassing over 6 million polymorphisms. Participants/materials, setting, methods We analysed a cohort that included 1,274 SPGF patients and 1,951 unaffected controls with European ancestry. Three independent approaches were follow: (1) variant-wise analysis using logistic regression models followed by a meta-analysis of the study cohorts; (2) gene-wise analysis using a Combined Multivariate and Collapsing (CMC) burden test; and (3) identification and characterisation of highly damaging rare coding variants in homozygosity. Multiple testing correction was applied to determine statistical significance Main results and the role of chance Our results suggested a potential association between SPGF and the rs12347237*T variant of the SHOC1 gene in the GWAS population (P = 3.17E-05, OR = 2.94). This association was subsequently validated in an independent Iberian cohort (Pcombined = 6.992E-06, OR = 2.61). Furthermore, our gene-wise analysis showed putative associations through the cumulative effect of some rare and low-frequency variants in SHOC1 (P = 4.9E-03), PCSK4 (P = 1E-04), AP3B1 (P = 5E-04), and DLK1 (P = 5E-04). Remarkably, the rare and common variants identified in SHOC1 are part of the same haplotype block, impacting both coding and non-coding regions. Additionally, we identified 35 individuals carrying 32 very rare and potentially pathogenic variants in homozygosity within the coding regions of the selected genes. Limitations, reasons for caution The analysis of low-frequency variants presents challenges in achieving sufficient statistical power to detect genetic associations. Consequently, independent studies involving large sample sets are essential to replicate our findings. In addition, the specific role of the identified variants in the pathogenic mechanisms of SPGF should be assessed using functional experiments. Wider implications of the findings The discovery of novel genetic risk factors for SPGF and the elucidation of the genetic causes underlying both monogenic and complex forms of SPGF provide new perspectives for personalized medicine and reproductive counselling. Trial registration number not applicable

Trends in hair cortisol from preconception to the postpartum period

IntroductionCortisol is a biological marker of stress, and its levels reflect the hypothalamic-pituitary-adrenal (HPA) axis response to stress over time. Saliva, blood, and urine cortisol reflect acute stress, whereas assessment of hair cortisol is a better reflection of chronic stress. There is limited information on hair cortisol concentration (HCC) in the perinatal period, particularly, in the preconception and postpartum periods. In addition to being a biomarker for stress, high levels of cortisol are typically associated with poor psychosocial outcomes, and adverse pregnancy outcomes. The objectives of this study were: (1) to measure HCC from six months preconception to six months postpartum; (2) to examine the relationship between HCC and demographic characteristics, depressive symptoms, and perceived stress in the first six months postpartum period; (3) and to assess the associations between HCC and systemic inflammatory markers in the first six months postpartum. MethodsThe analysis included 96 women from a longitudinal study with up to 3 study visits in the first six months postpartum. Blood and hair samples were collected at 1–2 months (PP1), 3–4 months (PP2), and 5–6 months (PP3) postpartum. We obtained sociodemographic information, depressive symptoms, and perceived stress scores at PP1-PP3. To quantify cortisol levels over time, 8 segments were derived corresponding to 6 (PC1) and 3 (PC2) months preconception as well as for each trimester (T1-T3) and postpartum (PP1-PP3). Eight cytokines (Granulocyte-macrophage colony-stimulating factor (GM-CSF), Interferon- gamma [IFN- γ], Interleukin [IL]-10, IL-2, IL-4, IL-6, IL-8, and Tumor necrosis factor-alpha (TNF- α) were measured in plasma in the postpartum samples. Univariate, bivariate, correlations, and linear mixed modelling were performed using SAS 9.4. Multiple testing correction was conducted for correlations using false discovery rate and a Q value of <0.05 was deemed significant. ResultsMedian HCC varied over time peaking in the third trimester and declining in the postpartum. Significant differences were noted in median cortisol levels by race with Black/African American postpartum women experiencing higher levels at all timepoints. Significantly, higher median cortisol levels were also observed at PP1 and PP2 for mothers who reported their relationship status as single. Ethnicity, education, median age, depressive symptoms, and perceived stress were not associated with median cortisol levels. Pro-inflammatory cytokines IFN- γ (q= 0.01; r=-0.50) and IL-8 (q= 0.00; r=-0.55) showed correlations with HCC at PP1. ConclusionHCC increased during pregnancy, peaking at T3 and declining PP consistent with previous work. Black/African American women and single women have significantly higher median cortisol levels in the postpartum period. The marked increase of HCC in Black women may be an important factor in understanding maternal health racial inequities. Future studies should investigate how the relationships between HCC, sociodemographics, and systemic cytokines impact perinatal outcomes.

Associations of modifiable factors with risk of irritable bowel syndrome.

Modifiable factors were found to be associated with the risk of irritable bowel syndrome (IBS) in observational studies, but whether these associations are causal is uncertain. We conducted a Mendelian randomization (MR) study to systematically explore the causal associations of modifiable factors with IBS. Summary-level statistical data for IBS was obtained from a genome-wide association study (GWAS) meta-analysis of UK Biobank (40,548 cases and 293,220 controls) and the international collaborative Bellygenes initiative (12,852 cases and 139,981 controls). Genetic instruments associated with the exposures at the genome-wide significance (p < 5 × 10-8) level were selected from previous GWASs. Mendelian randomization was performed using inverse-variance weighted (IVW) method, supplemented with several sensitivity analyses to evaluate potentially causal relationships between identified contributing factors and IBS. Furthermore, we applied another database from FinnGen (8,116 IBS cases and 276,683 controls) to testify the reliability of the significant associations. Seven convincing modifiable factors were significantly associated with IBS after correction for multiple testing. Genetically predicted smoking initiation (OR = 1.12, 95% CI = 1.06-1.18, p = 1.03 × 10-4), alcohol consumption (OR = 0.47, 95% CI = 0.34-0.64, p = 3.49 × 10-6), sedentary behavior (OR = 1.17, 95% CI = 1.07-1.28, p = 4.02 × 10-4), chronotype (OR = 0.92, 95% CI = 0.88-0.96, p = 4.42 × 10-4), insomnia (OR = 1.19, 95% CI = 1.15-1.24, p = 7.59 × 10-19), education (OR = 0.80, 95% CI = 0.74-0.88, p = 5.34 × 10-7), and visceral adiposity (OR = 1.15, 95% CI = 1.06-1.24, p = 7.96 × 10-4). We additionally identified several suggestive factors, including serum magnesium, serum phosphorus, physical activity, lifetime smoking, intelligence, lean body mass, and body mass index (BMI). After pooling the effect estimates from FinnGen, the associations remained significant except for chronotype. This MR analysis verified several modifiable risk factors for IBS, thus prevention strategies for IBS should be considered from multiple perspectives on these risk factors.

The BLUP method in evaluation of breeding values of Russian spring wheat lines using micro- and macroelements in seeds.

Genomic selection is a technology that allows for the determination of the genetic value of varieties of agricultural plants and animal breeds, based on information about genotypes and phenotypes. The measured breeding value (BV) for varieties and breeds in relation to the target trait allows breeding stages to be thoroughly planned and the parent forms suitable for crossing to be chosen. In this work, the BLUP method was used to assess the breeding value of 149 Russian varieties and introgression lines (4 measurements for each variety or line, 596 phenotypic points) of spring wheat according to the content of seven chemical elements in the grain - K, Ca, Mg, Mn, Fe, Zn, Cu. The quality of the evaluation of breeding values was assessed using cross-validation, when the sample was randomly divided into five parts, one of which was chosen as a test population. The following average values of the Pearson correlation were obtained for predicting the concentration of trace elements: K - 0.67, Ca - 0.61, Mg - 0.4, Mn - 0.5, Fe - 0.38, Zn - 0.46, Cu - 0.48. Out of the 35 models studied, the p-value was below the nominal significant threshold (p-value < 0.05) for 28 models. For 11 models, the p-value was significant after correction for multiple testing (p-value < 0.001). For Ca and K, four out of five models and for Mn two out of five models had a p-value below the threshold adjusted for multiple testing. For 30 varieties that showed the best varietal values for Ca, K and Mn, the average breeding value was 296.43, 785.11 and 4.87 mg/kg higher, respectively, than the average breeding value of the population. The results obtained show the relevance of the application of genomic selection models even in such limited-size samples. The models for K, Ca and Mn are suitable for assessing the breeding value of Russian wheat varieties based on these characteristics.

Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing

BackgroundFolate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. ObjectiveWe examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. DesignParticipants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. ResultsWe included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. ConclusionsFolate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.

Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis

Abstract Background It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC. Methods As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses. Results After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites. Conclusions In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.

Green spaces and respiratory, cardiometabolic, and neurodevelopmental outcomes: An individual-participant data meta-analysis of >35.000 European children

Studies evaluating the benefits and risks of green spaces on children’s health are scarce. The present study aimed to examine the associations between exposure to green spaces during pregnancy and early childhood with respiratory, cardiometabolic, and neurodevelopmental outcomes in school-age children. We performed an Individual-Participant Data (IPD) meta-analysis involving 35,000 children from ten European birth cohorts across eight countries. For each participant, we calculated residential Normalized Difference Vegetation Index (NDVI) within a 300 m buffer and the linear distance to green spaces (meters) during prenatal life and childhood. Multiple harmonized health outcomes were selected: asthma and wheezing, lung function, body mass index, diastolic and systolic blood pressure, non-verbal intelligence, internalizing and externalizing problems, and ADHD symptoms. We conducted a two-stage IPD meta-analysis and evaluated effect modification by socioeconomic status (SES) and sex. Between-study heterogeneity was assessed via random-effects meta-regression. Residential surrounding green spaces in childhood, not pregnancy, was associated with improved lung function, particularly higher FEV1 (β = 0.06; 95 %CI: 0.03, 0.09 I2 = 4.03 %, p < 0.001) and FVC (β = 0.07; 95 %CI: 0.04, 0.09 I2 = 0 %, p < 0.001) with a stronger association observed in females (p < 0.001). This association remained robust after multiple testing correction and did not change notably after adjusting for ambient air pollution. Increased distance to green spaces showed an association with lower FVC (β = −0.04; 95 %CI: −0.07, −0.02, I2 = 4.8, p = 0.001), with a stronger effect in children from higher SES backgrounds (p < 0.001). No consistent associations were found between green spaces and asthma, wheezing, cardiometabolic, or neurodevelopmental outcomes, with direction of effect varying across cohorts. Wheezing and neurodevelopmental outcomes showed high between-study heterogeneity, and the age at outcome assessment was only associated with heterogeneity in internalizing problems.. This large European meta-analysis suggests that childhood exposure to green spaces may lead to better lung function. Associations with other respiratory outcomes and selected cardiometabolic and neurodevelopmental outcomes remain inconclusive.

Unravelling relationships between obesity, diabetes, and factors related to somatosensory functioning in knee osteoarthritis patients.

This study explores the association between obesity, diabetes, and somatosensory functioning in patients with knee osteoarthritis (OA), aiming to understand how metabolic conditions are related to pain mechanisms in this patient population. We hypothesized that higher body mass index (BMI), fat mass, and glycated hemoglobin levels (HbA1c) are associated with signs of altered somatosensory functioning. A cross-sectional analysis was conducted as part of a larger multicentre prospective cohort study. Data were collected from patients awaiting total knee arthroplasty in Belgium and the Netherlands. Associations between BMI, fat mass, HbA1c, and various pain-related variables were examined employing Pearson and Spearman correlation analyses which were further analyzed with linear regression techniques. The study included 223 participants. Analysis revealed a significant although weak negative correlation between fat mass and pressure pain thresholds (PPT) at multiple locations, suggesting a link between higher fat mass and increased mechanical hyperalgesia. There were no significant correlations between BMI and pain-related outcomes. HbA1c levels showed very weak positive correlations with pain measures but did not withstand correction for multiple testing. The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA. However, no significant correlations were found between BMI or HbA1c levels and pain-related outcomes. Future research should focus on longitudinal studies to elucidate the causal relationships and further explore the impact of metabolic factors on pain mechanisms in this patient population. Key Points • The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA.