Benjamini-Hochberg Correction Research Articles

Inflammatory and cardiovascular markers in placenta following SARS-CoV-2 infection during pregnancy: A Swedish prospective cohort study

IntroductionMaternal SARS-CoV-2 infection can affect pregnancy outcome, but the placental response to and the effect of timing of infection is not well studied. The aim of this study was to investigate the placental levels of inflammatory and cardiovascular markers in pregnancies complicated by SARS-CoV-2 infection compared to non-infected pregnancies, and to investigate whether there was an association between time point of infection during pregnancy and placental inflammatory and cardiovascular protein levels. MethodsPlacental samples from a prospectively recruited pregnancy cohort of SARS-CoV-2-infected (n = 53) and non-infected (n = 50) women were analysed for 177 inflammatory and cardiovascular proteins, using an antibody-based proximity extension assay. In the SARS-CoV-2-infected group, half of the women were infected before 20 weeks of gestation, and five women were hospitalised for severe SARS-CoV-2 infection. Single-protein analyses were performed with linear mixed effects models, followed by Benjamini-Hochberg correction for multiple testing. Multi-protein analyses were performed using principal component analysis and machine learning algorithms. ResultsThe perinatal outcomes and the placental levels of inflammatory or cardiovascular proteins in women with SARS-CoV-2 infection were similar to those in non-infected women. There were no differences in inflammatory or cardiovascular protein levels between early and late pregnancy SARS-CoV-2 infection, nor any linear correlations between protein levels and gestational age at time of infection. DiscussionWomen with SARS-CoV-2 infection during pregnancy without clinical signs of placental insufficiency have no changes in inflammatory or cardiovascular protein patterns in placenta at time of birth regardless of the timing of the infection.

A Comprehensive Monte Carlo Simulation Study on Multiple Comparison Methods after ANOVA

Multiple comparison methods are applied to control the type I error rate at the nominal level. In this study, we investigate the performance of multiple comparison methods after analysis of variance (ANOVA) is implemented under different conditions. We include Bonferroni, Holm, Hochberg, Hommel, Benjamini-Hochberg (BH), and Benjamini-Yekutieli (BY) correction methods. Monte-Carlo simulation study is applied to assess their performances under different patterns, including sample size and group number combinations. Wide inferences are drawn on considered methods, and suggestions are provided for selecting appropriate methods. Moreover, the methods are implemented on three different types of real-life data sets to emphasize the importance of these correction methods in the research.

Depression severity and verbal comprehension in children and adolescents with a major depressive episode.

Severe depression is a prevalent psychiatric illness in children and adolescents associated with high levels of morbidity, disability, and a high risk of suicidal behavior. Cognitive factors associated with depression severity in juveniles have been poorly reported. We investigated the relationship between depression severity and intelligence quotient (IQ)with its subscales in 65 juveniles (aged 10-17 years) with a current major depressive episode evaluated at the Mood Disorder Program of Bambino Gesù Children's Hospital in Rome. Pearson's correlation analyses were followed by a Benjamini-Hochberg correction and linear multivariable regression model. Depression severity measured with the total score of the Children's Depression Rating Scale-Revised (CDRS-R) was positively associated with the Verbal Comprehension Index (VCI; Pearson's r = 0.309 [0.042-0.534]; p = 0.024). The CDRS-R subscales positively associated with VCI by Pearson's correlation were depressed feelings, suicidal ideation, excessive weeping, and reduced facial expressions. Suicidal ideation was the only factor independently and significantly associated with higher VCI in the multivariable linear regression model. Suicidal ideation was significantly and independently associated with higher verbal comprehension, indicating that depressed juveniles with better verbal ability may be at a greater risk of showing suicidal ideation.

Observational and genetic evidence disagree on the association between loneliness and risk of multiple diseases.

Loneliness-the subjective experience of social disconnection-is now widely regarded as a health risk factor. However, whether the associations between loneliness and multiple diseases are consistent with causal effects remains largely unexplored. Here we combined behavioural, genetic and hospitalization data from the UK Biobank to examine the associations of loneliness with a wide range of non-overlapping diseases. During a median 12.2-year follow-up, loneliness was associated with greater risks in 13 of 14 disease categories and 30 of 56 individual diseases considered. Of the 30 diseases significantly associated with loneliness, 26 had genetic data available for Mendelian randomization (MR) analyses. After Benjamini‒Hochberg correction and multiple sensitivity analyses within the MR framework, non-causal associations were identified between genetic liability to loneliness and 20 out of the 26 specific diseases, including cardiovascular diseases, type 2 diabetes mellitus, obesity, chronic liver diseases, chronic kidney disease, most neurological diseases and the other common diseases. Genetic liability to loneliness was only potentially causally associated with the remaining six diseases. Socioeconomic factors, health behaviours, baseline depressive symptoms and comorbidities largely explained the associations between loneliness and diseases. Overall, our study revealed a dissociation between observational and genetic evidence regarding the associations of loneliness with multiple diseases. These findings suggest that loneliness may serve as a potential surrogate marker rather than a causal risk factor for most diseases tested here.

Longitudinal Assessment of Selective Motor Dysfunction in Service Members With Combat-Related Mild TBI.

Evaluations of clinical outcomes in service members with mild traumatic brain injury (TBI) sustained in combat have largely focused on neurobehavioral and somatic symptoms, neurocognitive functioning, and psychological/psychiatric health. Questions remain regarding other domains, such as gross or fine motor abilities, that could be impacted and are mission-critical to functional warfighters. The objective of the current study was to evaluate longitudinal motor function in U.S. Military personnel with and without mild TBI sustained in combat to assess the possible long-term impact. Data from the EValuation Of Longitudinal outcomes in mild TBI active duty military and VEterans (EVOLVE) study were leveraged for analysis. The EVOLVE study has evaluated and followed service members from combat and following medical evacuation with and without blast-related mild TBI, as well as blunt impact mild TBI, and noninjured combat-deployed service members, tracking 1-, 5-, and 10-year outcomes. Longitudinal demographic, neuropsychological, and motor data were leveraged. Cross-sectional differences in outcomes at each year among the 4 injury groups were assessed using rank regression, adjusting for age, education, sex, branch of service (Army vs. other), subsequent head injury exposure, and separation from service. To understand the possible performance impact of time on all the measures, mixed-effects rank regression was employed, assessing time with adjustments for group, age, education, subsequent head injury exposure, and service separation status, followed by Benjamini-Hochberg correction for multiple comparisons. Evaluation for cognitive performance across 19 primary measures of interest at 1, 5, and 10 years did not identify any significant differences; however, gross motor function was found to be significantly different across groups at all time points (adjusted P < .001 at 1 year, P = .004 at 5 years, and P < .001 at 10 years) with both TBI groups consistently performing slower on the 25-Foot Walk and Grooved Pegboard than the nonblast control groups. While there were no cross-sectional differences across groups, many cognitive and motor measures were found to have significant changes over time, though not always in the direction of worse performance. Selective motor impairment in both TBI groups was identified compared to nonblast controls, but all groups were also found to exhibit a level of motor slowing when comparing performance at 1- to 10-year follow-ups. Assessment of gross motor function reflected a consistent pattern of significantly slower performances for blast and nonblast TBI groups compared to controls, over all follow-up intervals. Fine motor function performance reflected a similar significant difference pattern at 1- and 5-year follow-up intervals, with a reduced difference from control groups at the 10-year follow-up. Maintenance of high-level motor functions, including overall motor speed, coordination, and reaction time, is a primary component for active warfighters, and any motor-related deficits could create an increased risk for the service member or unit. While the service members in this longitudinal study did not meet criteria for any specific clinical motor-related diagnoses or movement disorders, the finding of motor slowing may reflect a subclinical but significant change that could be a focus for intervention to return to preinjury levels.

Validity of task-specific metrics for assessment in perineal proctectomy.

Perineal proctectomy is a complex procedure that requires advanced skills. Currently, there are no simulators for training in this procedure. As part of our objective of developing a virtual reality simulator, our goal was to develop and validate task-specific metrics for the assessment of performance for this procedure. We conducted a three-phase study to establish task-specific metrics, obtain expert consensus on the appropriateness of the developed metrics, and establish the discriminant validity of the developed metrics. In phase I, we utilized hierarchical task analysis to formulate the metrics. In phase II, a survey involving expert colorectal surgeons determined the significance of the developed metrics. Phase III was aimed at establishing the discriminant validity for novices (PGY1-3) and experts (PGY4-5 and faculty). They performed a perineal proctectomy on a rectal prolapse model. Video recordings were independently assessed by two raters using global ratings and task-specific metrics for the procedure. Total scores for both metrics were computed and analyzed using the Kruskal-Wallis test. A Mann-Whitney U test with Benjamini-Hochberg correction was used to evaluate between-group differences. Spearman's rank correlation coefficient was computed to assess the correlation between global and task-specific scores. In phase II, a total of 23 colorectal surgeons were recruited and consensus was obtained on all the task-specific metrics. In phase III, participants (n = 22) included novices (n = 15) and experts (n = 7). There was a strong positive correlation between the global and task-specific scores (rs = 0.86; P < 0.001). Significant between-group differences were detected for both global (χ2 = 15.38; P < 0.001; df = 2) and task-specific (χ2 = 11.38; P = 0.003; df = 2) scores. Using a biotissue rectal prolapse model, this study documented high IRR and significant discriminant validity evidence in support of video-based assessment using task-specific metrics.

Association between the third trimester maternal serum metabolome and child growth and development through the first year of life

Evidence suggests that maternal metabolome may be associated with child health outcomes. We analyzed the association between the maternal metabolome between 28–35 gestational weeks and child growth and development during the first year. A prospective cohort of 98 mother–child dyads was followed at birth, 1, 6, and 12 months. Maternal serum samples were collected for targeted LC–MS/MS analysis, which measured 132 metabolites. The child's growth and development were assessed at each time-point. Z-scores were calculated based on WHO growth standards, and the domains of development were assessed using the Ages and Stages Questionnaires (ASQ-3). Multiple linear mixed-effects models were performed and confounders were identified using a Diagram Acyclic Graph. The Benjamini–Hochberg correction was used for multiple comparison adjustments. We found a positive association between lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) with the z-score of weight-for-age, and lysophosphatidylcholines (14:0; 16:0; 16:1; 18:0) and taurine with the z-score of weight-for-length, and lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) and glycine with the z-score of BMI-for-age. The leucine, methionine, tryptophan, and valine were negatively associated with the fine motor skills domain. We observed an association between maternal metabolome and the growth and child's development throughout the first year.

24 Applying genomic analysis to refine unclassified renal cell carcinoma

Abstract Background Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets. Methods The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate. Results Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P&amp;gt;0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q&amp;lt;0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2 (15.8%), TP53 (13.9%), TERT (13.4%), and VHL (11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q&amp;lt;0.001), chRCC (0.7%, Q&amp;lt;0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2 (n=29) than in those with unaltered NF2 (n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q&amp;lt;0.001), followed by VHL and BAP1 (Q&amp;lt;0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%). Conclusions uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2 alterations were frequent and correlated with a poorer prognosis.

Comparative Transcriptomic Analyses of Peripheral Blood Mononuclear Cells of COVID-19 Patients without Pneumonia and with Severe Pneumonia in the First Year of Follow-Up.

The multisystemic effects of COVID-19 may continue for a longer time period following the acute phase, depending on the severity of the disease. However, long-term systemic transcriptomic changes associated with COVID-19 disease and the impact of disease severity are not fully understood. We aimed to investigate the impact of COVID-19 and its severity on transcriptomic alterations in peripheral blood mononuclear cells (PBMCs) following 1 year of the disease. PBMCs were isolated from the peripheral blood of healthy control donors who did not have COVID-19 (C; n = 13), from COVID-19 patients without pneumonia (NP; n = 11), and from COVID-19 patients with severe pneumonia (SP; n = 10) after 1-year of follow-up. Following RNA isolation from PBMCs, high-quality RNAs were sequenced after creating a library. Differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs) were identified using Benjamini-Hochberg correction and they were analysed for hierarchical clustering and principal component analysis (PCA). Intergroup comparisons (C vs. NP, C vs. SP, and NP vs. SP) of DEGs and DElncRNAs were performed and hub genes were determined. Functional enrichment analyses of DEGs and DElncRNAs were made using Metascape (v3.5.20240101) and the first version of NCPATH. The RNA sequencing analysis revealed 4843 DEGs and 1056 DElncRNAs in "C vs. NP", 1651 DEGs and 577 DElncRNAs in "C vs. SP", and 954 DEGs and 148 DElncRNAs in "NP vs. SP", with 291 DEGs and 70 DElncRNAs shared across all groups, respectively. We identified 14 hub genes from 291 DEGs, with functional enrichment analysis showing upregulated DEGs mainly linked to inflammation and osteoclast differentiation and downregulated DEGs to viral infections and immune responses. The analysis showed that 291 common and 14 hub genes were associated with pneumonia and that these genes could be regulated by the transcription factors JUN and NFκB1 carrying the NFκB binding site. We also revealed unique immune cell signatures across DEG categories indicating that the upregulated DEGs were associated with neutrophils and monocytes, while downregulated DEGs were associated with CD4 memory effector T cells. The comparative transcriptomic analysis of NP and SP groups with 52 gene signatures suggestive of IPF risk showed a lower risk of IPF in the SP group than the NP patients. Our findings suggest that COVID-19 may cause long term pathologies by modulating the expression of various DEGs, DeLncRNAs, and hub genes at the cellular level.

Rate control or rhythm control in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention

BackgroundRestoring and maintaining sinus rhythm in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has been studied in clinical trials to reduce symptoms and improve quality of life. Limited data exist on the effectiveness of rate or rhythm control therapy in these patients. MethodsConsecutive patients with AF and ACS or referred for PCI were prospectively recruited in Fuwai Hospital during 2017–2020. The primary endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular mortality, myocardial infarction, ischemic stroke, non-central nervous system embolism and ischemia-driven revascularization. Kaplan–Meier curves and Cox regressions were performed to evaluate the association between rhythm/rate control and subsequent outcomes. For the primary endpoints, we used the Benjamini–Hochberg correction for multiple comparisons. ResultsA total of 1499 patients with AF and ACS or undergoing PCI were included, with a median follow-up of 34.7 months. Compared to non-rate control, rate control strategy reduced the risk of subsequent MACCEs (adjusted HR, 0.320; 95 % CI 0.220–0.466; p <0.001; *p <0.002) and all-cause death (adjusted HR, 0.148; 95 % CI 0.093–0.236; p <0.001; *p <0.002). Similar trends were observed across all predefined subgroups (p <0.001). In the final multivariate model, rhythm control was not associated with a lower subsequent MACCEs but significantly improved all-cause mortality compared to non-rhythm control (adjusted HR, 0.546; 95 % CI 0.313–0.951; p =0.033; *p =0.044). ConclusionsIn this real-world study, rate control strategy was associated with lower risk of MACCEs and all-cause death in AF and ACS or undergoing PCI. Besides, management with rhythm control strategy may improve all-cause mortality.

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.

P-172 Mitochondria are dysregulated in poor quality oocytes and can be targeted in vitro to alter oocyte quality

Abstract Study question Does mitochondrial gene expression differ between good and poor quality oocytes and can mitochondria be targeted in vitro to alter oocyte quality? Summary answer Mitochondrial-related genes are dysregulated in poor quality oocytes and mitochondrial inhibitors can be used during IVM to alter oocyte quality. What is known already Good oocyte quality is essential for successful pregnancy yet we still have a poor understanding of the optimal composition of a good egg. Mitochondrial number and activity are important for oocyte quality and during maturation the ultrastructure of the mitochondria changes to a hooded or ring form. We have observed differences in the timing of this morphological change between good and poor quality oocytes in a sheep model. Oligomycin treatment of oocytes decreases the proportion of hooded mitochondria and increases mitochondrial membrane potential (MMP) indicating that hooded mitochondria may form during maturation to reduce mitochondrial activity prior to fertilisation. Study design, size, duration Gene expression differences were compared between poorer quality peripubertal lamb oocytes and adult oocytes harvested during estrus from pools of ∼80 abattoir-derived ovaries on three separate dates for each age. Denuded oocytes (GV stage) were frozen in three pools of ∼20 per age and total RNA isolated. Sheep oocytes (∼30 per group) were treated with oligomycin, FCCP or vehicle control in final 2 hours of IVM on five separate dates, fertilised and cultured. Participants/materials, setting, methods RNA sequencing cleaned reads were mapped using HISAT2 on sheep genome version ARS-UI_Ramb_v2. Count matrix were generated using featureCount and differential gene expression was performed using DESeq2. After normalisation, Wald test was used to define genes differentially expressed. Genes were considered significantly altered with a FDR &amp;lt; 5% after Benjamini-Hochberg correction. Mean cleavage rate was compared to vehicle control in five replicate experiments using one-way ANOVA with Benjamini, Krieger and Yekutieli FDR &amp;lt; 5%. Main results and the role of chance Oligomycin (ATP synthase inhibitor) decreased cleavage rate compared to control (P &amp;lt; 0.001) while FCCP (electron transport chain uncoupler) had no effect. There were 163 genes up-regulated and 194 genes down-regulated in lamb GV oocytes compared to adult GV stage (FDR &amp;lt;5%). Metascape pathway analysis of the up-regulated genes in lamb oocytes showed the most enriched pathway was Thermogenesis which included these genes: ACOT9, AJUBA, ATP5ME, ATP5MF, CALML4, CREB3L3, CRPPA, DNAJC15, DPM3, FMC1, LDHA, NDUFA12, NDUFAF2, NDUFS5, NT5C, PHGDH, POLR2G, PPARG, PRPS1L1, SDHAF3, SLIRP, TIMM8B and UBB. Six of these up-regulated genes were in the top 20 most highly expressed genes. Thermogenesis is the process by which the mitochondrial electron transport chain becomes uncoupled to dissipate heat and may also control production of free radicals by mitochondria and their response to oxidants. These genes and other mitochondrial related genes that were up-regulated in lamb GV oocytes (CKS2, DCN, PCP4L1, SLC51B) are involved in formation of the electron transport chain complexes, oxidative phosphorylation, ATP synthesis, mitochondrial organization and regulation of membrane potential. Together these results indicate that mitochondrial function is dysregulated in poorer quality oocytes and that treatment with mitochondrial inhibitors during IVM can alter oocyte quality. Limitations, reasons for caution This study was carried out in sheep oocytes and results would need to be confirmed in human oocytes if possible. Further research is needed to determine if decreasing MMP can improve oocyte quality and embryo development. Wider implications of the findings This animal model study indicates that mitochondria may be targeted during IVM to alter oocyte quality and this knowledge could be applied to develop ways of increasing human IVM and ART success rates. Trial registration number not applicable

Deep learning for 3D cephalometric landmarking with heterogeneous multi-center CBCT dataset.

Cephalometric analysis is critically important and common procedure prior to orthodontic treatment and orthognathic surgery. Recently, deep learning approaches have been proposed for automatic 3D cephalometric analysis based on landmarking from CBCT scans. However, these approaches have relied on uniform datasets from a single center or imaging device but without considering patient ethnicity. In addition, previous works have considered a limited number of clinically relevant cephalometric landmarks and the approaches were computationally infeasible, both impairing integration into clinical workflow. Here our aim is to analyze the clinical applicability of a light-weight deep learning neural network for fast localization of 46 clinically significant cephalometric landmarks with multi-center, multi-ethnic, and multi-device data consisting of 309 CBCT scans from Finnish and Thai patients. The localization performance of our approach resulted in the mean distance of 1.99 ± 1.55 mm for the Finnish cohort and 1.96 ± 1.25 mm for the Thai cohort. This performance turned out to be clinically significant i.e., ≤ 2 mm with 61.7% and 64.3% of the landmarks with Finnish and Thai cohorts, respectively. Furthermore, the estimated landmarks were used to measure cephalometric characteristics successfully i.e., with ≤ 2 mm or ≤ 2° error, on 85.9% of the Finnish and 74.4% of the Thai cases. Between the two patient cohorts, 33 of the landmarks and all cephalometric characteristics had no statistically significant difference (p < 0.05) measured by the Mann-Whitney U test with Benjamini-Hochberg correction. Moreover, our method is found to be computationally light, i.e., providing the predictions with the mean duration of 0.77 s and 2.27 s with single machine GPU and CPU computing, respectively. Our findings advocate for the inclusion of this method into clinical settings based on its technical feasibility and robustness across varied clinical datasets.

Genetic variations of low-density lipoprotein cholesterol on metabolic disorders in obstructive sleep apnea

BackgroundThe study aimed to explore the relationship between low-density lipoprotein cholesterol (LDL-C) genetic variants and obstructive sleep apnea (OSA) and its complications, including cardiovascular diseases (CVD), insulin resistance (IR), and metabolic syndrome (MS).Method4329 individuals with suspected OSA who underwent a comprehensive assessment of anthropometric, biochemical, and polysomnography (PSG) data, along with 30 LDL-C single nucleotide polymorphisms (SNPs) were enrolled. The 10-year Framingham CVD risk score (FRS), IR and MS were evaluated for each subject. Linear regression and logistic regression were utilized to examine the correlations among these variables.ResultsAfter the Benjamini-Hochberg correction, linear regression results indicated positive correlations between variants rs3741297 and rs629301 with FRS (β = 0.031, PBH=0.002; β = 0.026, PBH=0.015). Logistic regression revealed that rs3741297 increased MS risk among total subjects [OR = 1.67 (95% CI:1.369–2.038), PBH=1.32 × 10− 5] and increased IR risk in females [OR = 3.475 (95% CI:1.653–7.307), PBH=0.03]. In males, rs2642438 decreased MS risk [OR = 0.81 (95% CI:0.703–0.933), PBH=0.045].ConclusionsThe rs3741297 variant correlated with susceptibility to CVD, IR, and MS in the OSA population. OSA, CVD, IR and MS share a potentially common genetic background, which may promote precision medicine.Cinical trial registrationThe study protocol was registered with the Chinese Clinical Trial Registry (ChiCTR1900025714).

Genetic association of the gut microbiota with epigenetic clocks mediated by inflammatory cytokines: a Mendelian randomization analysis.

A new aging biomarker epigenetic clock has been developed. There exists a close link between aging and gut microbiota, which may be mediated by inflammatory cytokines. However, the relationship between the epigenetic clock, gut microbiota, and the mediating substances is unclear. Two large genome-wide association meta-analyses were analyzed by two-sample Mendelian randomization. The results between gut microbiota and epigenetic clock were investigated using the four methods (Inverse variance weighted, MR-Egger, weighted median, MR-PRESSO). Genetic correlation was measured by Linked disequilibrium score regression (LDSC). The correctness of the study direction was checked by the Steiger test. Cochran's Q statistic and MR-Egger intercept were used as sensitivity analyses of the study. The two-step method was used to examine the mediating role of inflammatory cytokines. We use the Benjamini-Hochberg correction method to correct the P value. After FDR correction, multiple bacterial genera were significantly or suggestively associated with four epigenetic clocks (GrimAge, HannumAge, IEAA, PhenoAge). And we detected several inflammatory factors acting as mediators of gut microbiota and epigenetic clocks. This study provides genetic evidence for a positive and negative link between gut microbiota and aging risk. We hope that by elucidating the genetic relationship and potential mechanisms between aging and gut microbiota, we will provide new avenues for continuing aging-related research and treatment.

Radiomics analysis of ultrasound images to discriminate between benign and malignant adnexal masses with solid ultrasound morphology.

Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound-based machine learning models that include radiomics features to discriminate between benign and malignant solid adnexal masses. Our secondary aim was to compare the diagnostic performance of our radiomics models with that of the ADNEX model and subjective assessment by an experienced ultrasound examiner. This is a retrospective observational single center study. Patients with a histological diagnosis of an adnexal tumor with solid morphology at preoperative ultrasound examination performed between 2014 and 2021 were included. The patient cohort was split into training and validation sets with a ratio of 70:30 and with the same proportion of benign and malignant (borderline, primary invasive and metastatic) tumors in the two subsets. The extracted radiomic features belonged to two different families: intensity-based statistical features and textural features. Models to predict malignancy were built based on a random forest classifier, fine-tuned using 5-fold cross-validation over the training set, and tested on the held-out validation set. The variables used in model building were patient's age, and those radiomic features that were statistically significantly different between benign and malignant adnexal masses (Wilcoxon-Mann-Whitney Test with Benjamini-Hochberg correction for multiple comparisons) and assessed as not redundant based on the Pearson correlation coefficient. We describe discriminative ability as area under the receiver operating characteristics curve (AUC) and classification performance as sensitivity and specificity. 326 patients were identified and 775 preoperative ultrasound images were analyzed. 68 radiomic features were extracted, 52 differed statistically significantly between benign and malignant tumors in the training set, and 18 features were selected for inclusion in model building. The same 52 radiomic features differed statistically significantly between benign, primary invasive malignant and metastatic tumors. However, the values of the features manifested overlap between primary malignant and metastatic tumors and did not differ statistically significantly between them. In the validation set, 25/98 tumors (25.5%) were benign, 73/98 (74.5%) were malignant (6 borderline, 57 primary invasive, 10 metastases). In the validation set, a model including only radiomics features had an AUC of 0.80, and 78% sensitivity and 76% specificity at its optimal risk of malignancy cutoff (68% based on Youden's index). The corresponding results for a model including age and radiomics features were 0.79, 86% and 56% (cutoff 60% based on Youden's method), while those of the ADNEX model were 0.88, 99% and 64% (at 20% malignancy cutoff). Subjective assessment had sensitivity 99% and specificity 72%. Even though our radiomics models had discriminative ability inferior to that of the ADNEX model, our results are promising enough to justify continued development of radiomics analysis of ultrasound images of adnexal masses. This article is protected by copyright. All rights reserved.

Causal inference between pernicious anemia and cancers: a bidirectional two-sample mendelian randomization analysis

BackgroundObservational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis.MethodsThe European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests.ResultsOur study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P’ < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P’> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P‘< 0.05), while prostate cancer shows an implied reverse causal relationship(P’> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy.ConclusionsPA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.

Comparison of the cytokines levels in aqueous humor in vitrectomized eyes versus non-vitrectomized eyes with diabetic macular edema.

This study was conducted to compare concentrations of VEGF family growth factors, inflammation-related factors, and adhesion molecules in the aqueous humor of eyes with diabetic macular edema (DME), with and without prior vitrectomy. A total of 31 eyes were included, 11 with DME that had undergone vitrectomy, 9 with DME but without vitrectomy, and 11 from age-related cataract patients as controls. The concentrations of cytokines including TNF-α, IL-6, IL-8, IP-10, MCP-1, IFN-γ, MIP-1 α, MIP-1 β, PECAM-1, MIF, VCAM-1, ICAM-1, PIGF were quantified using Luminex Human Discovery Assay. Central macular thickness (CMT) values of all eyes were measured using optical coherence tomography (OCT). (1) Vitrectomized DME eyes exhibited significantly higher levels of IL-6 and IL-8 compared to non-vitrectomized eyes (P < 0.05). (2) In vitrectomized group, after Benjamini-Hochberg correction, there was a significant positive correlation between the levels of VEGF and PlGF (rs = 0.855, P < 0.05), as well as the levels of TNF-α and IFN-γ (rs = 0.858, P < 0.05). In non-vitrectomized group, significant positive correlations were found between VEGF and PlGF levels after correcting for multiple comparisons (rs = 0.9, P < 0.05). (3) In non-vitrectomized group, the concentrations of VEGF and PlGF in aqueous humor were significantly positively correlated with CMT values (rs = 0.95, P < 0.05; rs = 0.9, P < 0.05, respectively). The concentrations of IL-6 and IL-8 in the aqueous humor were significantly higher in vitrectomized DME eyes compared to nonvitrectomized DME eyes and the levels of VEGF were similar in the two groups, suggesting that inflammation after vitrectomy may be a key factor in the occurrence and development of DME.

PSVI-19 No apparent association between the microbiome in the distal part of the small intestine and feed efficiency in grower-finisher pigs fed three different levels of dietary crude protein

Abstract Improving feed efficiency (FE) of grower-finisher pigs is important considering its production, environmental and climate impact. The biological background describing variation in FE between pen mates, is difficult to establish as feed intake (FI) and FE is not estimated on an individual level. In this study advanced feeding stations were used to estimate FI and further calculate feed conversion ratio (FCR) on individual level. The study aimed to investigate the possible association between FCR and microbiome (alpha and beta diversity; observed features and Shannon index, and Bray-Curtis dissimilarity and Jaccard Distance) in the distal part of the small intestine (SI) in grower-finisher pigs fed three different levels of dietary crude protein (CP). The study included 60 newly weaned gilts divided in two series, housed as 10 pigs/pen. The 30 pigs per series were distributed between three pens (10 pigs/pen) and were balanced by body weight (BW) and litter with ad libitum access to the same diet. Pigs were redistributed among the grower-finisher pens to balance FCR levels between dietary treatments (CP levels) and to reduce any carry over effect from the weaner to the grower-finisher pens. From 30-115 kg BW, pigs were fed either a low (L; 14.8% CP), standard (Std; 15.2% CP) or high (H; 15.8% CP) CP diet equal in energy, where BW, average weekly gain (AWG), and FCR were determined on weekly basis, while FI was estimated on daily basis. Three low FE (20% least) and three high FE (20% greatest) pigs were selected based on the final 4 wk of growth within station and CP level. All low-FE and high-FE pigs within each dietary treatment were euthanized around 115 kg BW and content and mucosa scrabe from the distal part of the SI was sampled and subjected to 16S rRNA gene amplicon sequencing. Data were analyzed in R using a generalized linear mixed-effects model with FE, CP, and their interaction as explanatory variables, start BW of weaner and grower phase as covariables, and series as random effect. High-FE and H-CP pigs continuously displayed numerically greater BW, while AWG and FCR were, respectively, numerically greater, and less in L-CP than H-CP group during last 2 wk of the experimental period. While FE and CP individually had no significant impact [Pr(&amp;gt; Chisq] &amp;gt; 0.05), their interaction could be important in explaining the variation (Chisq = 6.42, Df = 2, Pr(&amp;gt;Chisq) = 0.04) as expressed by observed features. But a pairwise comparison with a Benjamini–Hochberg correction showed no difference between groups. Concerning the Shannon index, no significance was found between groups, and no difference with respect to beta diversity was observed. In conclusion, the microbiome as expressed by alpha and beta diversity did not explain the variation between low and high FE in grower-finisher pigs.

Sex-Specific Transcriptome Responses in Circulating Immune Cells During Exercise-Heat Stress and Acclimation

Objective: To examine the sex-based differences in heat stress and acclimation we used transcriptomic analysis to test the hypotheses that 1) gene expression varies by biological sex before and after acute heat exposure and 2) circulating immune cell transcriptome responses differ between naïve and acclimated state. Methods: Participants (3F/3M, VO2max &gt;40/45 ml×kg×min−1) completed two heat tolerance tests (HTT), termed HTT1 (120min walking at 1.39 m/s at 2% grade) and HTT2 (~70% vVO2max until rectal temperature (Trec) reached 39.5°C) before and after a 5-day heat acclimation (HA1-5, daily 60min run/jog at Trec 38.5-39.5°C), in a hot environment (40°C, 40%RH). Blood was collected in PAXgene blood RNA tubes PRE and POST HTT1, HTT2, HA1, and HA5 with a recovery (REC) timepoint ~30min after HTT2. Paired end sequencing of ribodepleted total RNA from 84 samples (14 timepoints) was performed on a NovaSeq 6000 (Illumina, Inc., San Diego, CA). All samples passed quality checks with Fastp read trimming retaining 98.2% of reads with a GC content of 49.1%. HISAT2 indexed and mapped an average of 75.9M reads to GrCh38.105. Expression was quantified with htseq-counts, excluding genes with &lt;3 mapped fragments per sample resulting in 26,671 genes. Principal component analysis indicated 36% of variation could be attributed to sex. Differential expression was assessed using DESeq2's generalized linear model, applying a Benjamini-Hochberg correction with an FDR of 0.1 and an adjusted p-value threshold of 0.1. DE genes were analyzed for functional annotation and pathways. Results: In total, we detected 8611 unique DE genes composed of protein coding (6241), lncRNA (1498), and 636 pseudogenes. Males and Females exhibited significant differences in gene expression at baseline, in naïve state (PREHA) with &gt;1555 genes showing sex differences (FDR&lt;0.1). Reactome pathways differing between M and F included cytokine signaling, response, and regulation, cell senescence, cell growth and death, cell cytoskeleton and extracellular structure and innate immunity processes (p&lt;0.05). Interestingly, heat acclimation increased the responsiveness of the transcriptome while reducing the overall magnitude of the response. PREHA HTT2 had 86 DE genes at POST rising to 3170 at REC (vs. PRE, FDR&lt;0.1). While POSTHA HTT2 had 602 DE genes at POST rising to 1236 at REC (vs. PRE, FDR&lt;0.1). GO terms protein serine kinase activity, GTPase binding, and GDP binding were present at PREHA, but absent POSTHA. Conclusion: Acute exercise-heat stress induces marked changes in circulating immune cell transcriptional landscape, while acclimation reduces this response to the same challenge in an adapted state. Sex differences exist and are the subject of ongoing analyses. Funding: DoD BA200299. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.