False Discovery Rate Q-value Research Articles

Prevalence of HCV Infection Among People Experiencing Homelessness in Madrid, Spain

Hepatitis C virus (HCV) microelimination aims to detect and treat hidden infections, especially in at-risk groups, like people experiencing homelessness (PEH) with alcohol or drug use disorders. Point-of-care HCV RNA testing and peer support workers are crucial for identifying and preventing HCV infection among marginalized populations, contributing to overall elimination goals. To assess risk factors, prevalence, and trends of active HCV infection among PEH in Madrid, Spain (2019-2023). This cross-sectional study was conducted between 2019 and 2023 in PEH, defined as people who lacked a fixed, regular, and adequate night residence, screened on the street or in homeless shelters via mobile unit using rapid HCV antibody testing, followed by HCV-RNA testing in Madrid, Spain. Data were analyzed from January to June 2024. Active HCV infection among PEH was the main outcome. Risk factors analyzed included being born outside of Spain, alcohol misuse, lacking financial income, benzodiazepine use, injection drug use (IDU; including nonactive IDU and active IDU within the last year), opioid substitution therapy participation, and sexual behavior patterns. Data were analyzed using logistic regression. P values were adjusted for multiple testing using the false discovery rate (q-values). A total of 4741 individuals were screened for HCV infection, of whom 2709 (mean [SD] age, 42.2 [12.7]; 1953 [72.2%] men) were PEH and included in analysis. A total of 363 PEH (13.4%) had test results positive for HCV antibodies, of whom 172 (47.4%) had test results positive for HCV-RNA, and 148 of these (91.9%) started HCV treatment. Overall, active HCV infection prevalence was 6.3%, and the main risk factors associated with active HCV infection included IDU, encompassing both nonactive IDU (adjusted odds ratio [aOR], 10.9; 95% CI, 6.1-19.4; q < .001) and active IDU in the last year (aOR, 27.0; 95% CI, 15.2-48.0; q < .001); a lack of financial income (aOR, 1.8; 95% CI, 1.1-2.9; q = .03); and alcohol misuse (aOR, 1.8; 95% CI, 1.3-2.6; q = .008). There was a significant decrease between 2019 and 2023 in active HCV infection prevalence across the entire population, from 7.2% to 3.4% (P = .04). In this cross-sectional study of PEH in Madrid, IDU, lack of income, and alcohol misuse were primary risk factors associated with HCV infection. The significant decline in HCV rates observed across all risk groups during the study period suggests preventive policies were effective in reducing HCV prevalence among the homeless population.

Micro Scale Chromatography of Human Plasma Proteins for Nano LC-ESI-MS/MS

Organic precipitation of proteins with acetonitrile demonstrated complete protein recovery and improved chromatography of human plasma proteins. The separation of 25 μL of human plasma into 22 fractions on a QA SAX resin facilitated more effective protein discovery despite the limited sample size. Micro chromatography of plasma proteins over quaternary amine (QA) strong anion exchange (SAX) resins performed best, followed by diethylaminoethyl (DEAE), heparin (HEP), carboxymethyl cellulose (CMC), and propyl sulfate (PS) resins. Two independent statistical methods, Monte Carlo comparison with random MS/MS spectra and the rigorous X!TANDEM goodness of fit algorithm protein p-values corrected to false discovery rate q-values (q≤ 0.01) that agreed on at least 12,000 plasma proteins, each represented by at least three fully tryptic corrected peptide observations. There was qualitative agreement on 9,393 protein/gene symbols between the linear quadrupole versus orbital ion trap but also quantitative agreement with a highly significant linear regression relationship between log observation frequency (F value 4,173, p-value 2.2e-16). The use of a QA resin showed nearly perfect replication of all the proteins that were also found using DEAE-, HEP-, CMC-, and PS-based chromatographic methods combined and together estimated the size of the size of the plasma proteome as ≥12,000 gene symbols.

Abstract C085: Somatic mutational profiles of breast tumors from Hispanic/Latino women

Abstract Background: Breast cancer is the leading cause of cancer mortality among Hispanic/Latina (H/L) women. Precision medicine holds promise for more effective treatments by targeting therapies based on somatic mutations, copy number changes, mutational signatures, and/or germline risk variants. However, there is a paucity of genomics data for H/L women with breast cancer leading to a disparity in the application of precision medicine. We have previously characterized mutational profiles of 146 breast tumors from 140 H/L women. Here, we analyze data from whole exome tumor/normal sequencing and tumor RNA sequencing from 430 self-reported H/L breast cancer cases and compare their profiles to 385 tumors from self-reported White breast cancer cases. Methods: All participants were treated at City of Hope and all sequencing data were generated using Ashion GEM ExTra (Exact Sciences). Tumor/germline sequence data were aligned to the human genome (Build37) and variants were called using the FreeBayes workflow. To determine significantly mutated genes, we used MutSigCV and dNdS. We used Fisher’s exact test to determine if the frequency of somatic mutations was significantly different among H/L women and White women and corrected for multiple hypothesis testing using Benjamini-Hochberg false discovery rate (FDR). Results: Seventeen genes and 19 genes had q-values &amp;lt; 0.05 in H/L and White samples, respectively. Of those, AKT1, CBFB, FOXA1, MAP2K4, MAP3K1, MLL3, PIK3CA, PTEN, RB1, RUNX1, TBX3, TP53, and ZFPM1 were significantly mutated in both. CTCF and HS6ST1 were significantly mutated only in tumors from H/L. ARID1A, CDKN1B, NCOR1, and PRRT2 were significantly mutated only in tumors from White women. There was a significantly higher frequency of TP53 mutations (FDR q-value = 0.007) and CTCF mutations (FDR q-value = 0.057) in tumors from H/L compared to tumors from Whites. Conclusions: We found TP53 and CTCF to be more commonly mutated in tumors from H/L women. CTCF mutations are seen in other tumor types, but our study is the first to demonstrate that this gene is significantly mutated in breast cancer in any population. Since CTCF is a broadly active transcriptional regulator, tumors with these mutations may be associated with broad dysregulation of gene expression. Citation Format: Yuan Chun Ding, Shu Tao, Allen Mao, Elad Ziv, Susan L. Neuhausen. Somatic mutational profiles of breast tumors from Hispanic/Latino women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C085.

Red blood cell metabolomics identify ergothioneine as a key metabolite in DMARD-naïve rheumatoid arthritis and response to methotrexate

Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment.

Sustained Long-Term Decline in Anti-HCV Neutralizing Antibodies in HIV/HCV-Coinfected Patients Five Years after HCV Therapy: A Retrospective Study.

Background: This study evaluated titers and amplitudes of anti-E2 antibodies (anti-E2-Abs) and neutralizing antibodies against hepatitis C virus (HCV; anti-HCV-nAbs) in HIV/HCV-coinfected individuals over five years after successful HCV treatment completion. Methods: We retrospectively analyzed 76 HIV/HCV-coinfected patients achieving sustained virologic response post-HCV treatment. Plasma levels of anti-E2-Abs and anti-HCV-nAbs against five HCV genotypes (Gt1a, Gt1b, Gt2a, Gt3a, and Gt4a) were determined using ELISA and microneutralization assays, respectively. Statistical analyses comparing the three follow-up time points (baseline, one year, and five years post-HCV treatment) were performed using generalized linear mixed models, adjusting p-values with the false discovery rate (q-value). Results: Compared to baseline, anti-E2-Abs titers decreased at one year (1.9- to 2.3-fold, q-value < 0.001) and five years (3.4- to 9.1-fold, q-value < 0.001) post-HCV treatment. Anti-HCV-nAbs decreased 2.9- to 8.4-fold (q-value < 0.002) at one year and 17.8- to 90.4-fold (q-value < 0.001) at five years post-HCV treatment. Anti-HCV-nAbs titers against Gt3a were consistently the lowest. Nonresponse rates for anti-E2-Abs remained low throughout the follow-up, while anti-HCV-nAbs nonresponse rates increased 1.8- to 13.5-fold (q-value < 0.05) at five years post-HCV treatment, with Gt3a showing the highest nonresponse rate. Conclusions: Humoral immune responses against HCV decreased consistently one and five years post-HCV treatment, regardless of HCV genotype and previous HCV therapy or type of treatment (IFN- or DAA-based therapy). This decline was more pronounced for anti-HCV-nAbs, particularly against Gt3.

Gestational exposure to environmental chemicals and epigenetic alterations in the placenta and cord blood mononuclear cells

BackgroundExposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations.MethodThis study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values < 0.05 and presented results by limiting results with a genomic inflation factor of 1±0.5. Additionally, gene set enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomics pathways.ResultsAmong the 29 chemical biomarkers assessed for differential methylation, maternal concentrations of PAH metabolites (1-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxypyrene), monocarboxyisononyl phthalate, mono-3-carboxypropyl phthalate, and bisphenol A were associated with altered methylation in placenta (maternal or fetal side). Among exposure biomarkers associated with epigenetic changes, 1-hydroxynaphthalene, and mono-3-carboxypropyl phthalate were consistently associated with differential CpG methylation in the placenta. Gene enrichment analysis indicated that maternal 1-hydroxynaphthalene was associated with lipid metabolism and cellular processes of the placenta. Additionally, mono-3-carboxypropyl phthalate was associated with organismal systems and genetic information processing of the placenta.ConclusionAmong the 29 chemical biomarkers assessed during delivery, 1-hydroxynaphthalene and mono-3-carboxypropyl phthalate were associated with DNA methylation in the placenta.

Phototherapy Alters the Plasma Metabolite Profile in Infants Born Preterm with Hyperbilirubinemia

To investigate the effects of gestational age (GA) and phototherapy on the plasma metabolite profile of preterm infants with neonatal hyperbilirubinemia (NHB). From a cohort of prospectively enrolled infants born preterm (n=92), plasma samples of very preterm (VPT; GA, 28+0 to 31+6weeks, n=27) and moderate/late preterm (M/LPT; GA, 32+0 to 35+6weeks, n=33) infants requiring phototherapy for NHB were collected prior to the initiation of phototherapy and 24hours after starting phototherapy. An additional sample was collected 48hours after starting phototherapy in a randomly selected subset (n=30; VPT n=15; M/LPT n=15). Metabolite profiles were determined using ultraperformance liquid chromatography tandem mass spectroscopy. Two-way ANCOVA was used to identify metabolites that differed between GA groups and timepoints after adjusting for total serum bilirubin levels (false discovery rate q-value < 0.05). Top impacted pathways were identified using pathway over-representation analysis. Phototherapy was initiated at lower total serum bilirubin (mean±SD mg/dL) levels in VPT compared with M/LPT infants (7.3±1.4 vs 9.9±1.9, P<.01). We identified 664 metabolites that were significant for a phototherapy effect, 191 metabolites significant for GA, and 46 metabolites significant for GA×phototherapy interaction (false discovery rate q-value < 0.05). Longer duration phototherapy had a larger mean effect size (24hours postphototherapy: d=0.36; 48hours postphototherapy: d=0.43). Top pathways affected by phototherapy included membrane lipid metabolism, one-carbon metabolism, creatine biosynthesis, and oligodendrocyte differentiation. Phototherapy alters the plasma metabolite profile more than GA in preterm infants with NHB, affecting pathways related to lipid and one-carbon metabolism, energy biosynthesis, and oligodendrocyte differentiation.

Pooled DNA sequencing in hairy vetch (Vicia villosa Roth) reveals QTL for seed dormancy but not pod dehiscence.

Hairy vetch (Vicia villosa Roth) is a promising legume cover crop, but its use is limited by high rates of pod dehiscence and seed dormancy. We used phenotypically contrasting pooled DNA samples (n=24 with 29-74 individuals per sample) from an ongoing cover crop breeding program across four environments (site-year combinations: Maryland 2020, Maryland 2022, Wisconsin 2021, Wisconsin 2022) to find genetic associations and genomic prediction accuracies for pod dehiscence and seed dormancy. We also combined pooled DNA sample genetic association results with the results of a prior genome-wide association study. Genomic prediction resulted in positive predictive abilities for both traits between environments and with an independent dataset (0.34-0.50), but reduced predictive ability for DNA pools with divergent seed dormancy in the Maryland environments (0.07-0.15). The pooled DNA samples found six significant (false discovery rate q-value<0.01) quantitative trait loci (QTL) for seed dormancy and four significant QTL for pod dehiscence. Unfortunately, the minor alleles of the pod dehiscence QTL increased the rate of pod dehiscence and are not useful for marker-assisted selection. When combined with a prior association study, sixteen seed dormancy QTL and zero pod dehiscence QTL were significant. Combining the association studies did not increase the detection of useful QTL.

Abstract 355: BCLxL inhibition enhances copanlisib response in colorectal cancer

Abstract Background: Anti-apoptotic signaling, including through BCLxL, is a potential mechanism of resistance to PI3K inhibition in PIK3CA mutant cancers. We have previously demonstrated enhanced activity of PI3K inhibition in combination with BCLxL inhibition in PIK3CA mutated colorectal cancer (CRC) models. Here we examine the potential impact of BCLxL expression in PIK3CA mutant CRCs and the mechanism of treatment response with the combination of copanlisib and navitoclax. Methods: PIK3CA mutant CRCs were identified within TCGA colorectal adenocarcinoma data set and two cohorts were generated based on BCL2L1 (gene that encodes protein BCLxL) expression. Differentially expressed genes and gene set enrichment analysis were performed. CRC cell lines SW48 and SW48PK (Horizon Discovery, SW48 with a PIK3CAH1047R/+ mutation) were treated with copanlisib (copan) (1-100 nM) and navitoclax (250 nM). Immunoblotting was performed quantified using ImageJ to evaluate PI3K and apoptotic signaling. Flow cytometry using annexin V and propidium iodide (PI) was performed as a measure of apoptosis. Immunohistochemistry (IHC) using Ki67 was performed as a measure of cell proliferation on SW48PK xenografts and quantified as percent positive nuclei at 40x field of view (FOV). Results: Two datasets comprised of PIK3CA mutant CRC patients with either high or low BCL2L1 expression containing 39 and 47 patients, respectively, were used in the TGCA analysis. There was no difference in age, gender, or staging between these two datasets. An increase in DNA repair (false discovery rate q-value= 0.034) and interferon alpha signaling pathways (q= 0.022) was seen in PIK3CA mutant and high BCL2L1 expression compared to PIK3CA mutant and low BCL2L1 expression patients. PIK3CA mutant patients with low expression of BCL2L1 had a greater disease-free and overall survival (p= 0.037 and p= 0.042, respectively). Combination of copan and navitoclax treatment of the SW48 and SW48PK cell lines resulted in a reduction in activated ribosomal protein S6 (pRPS6) as compared with control or navitoclax alone at both 6 and 24. Cleaved PARP increased in SW48PK cells treated with 100 nM copan plus navitoclax versus control at both 6 and 24 hour timepoints (p= 0.03, p= 0.049). SW48 and SW48PK cells that were treated with copan and navitoclax for 24 hours had an increase in annexin v, a marker for apoptosis, compared to cells treated with control or single agents. In SW48PK xenografts, a significant reduction in Ki67 percent positive nuclei was seen in combination compared to control (median percent positive nuclei: 20.5, control: 33.2, p&amp;lt;0.001). Conclusions: High BCLxL expression is a sign of poor prognosis for PIK3CA mutant CRC. Inhibiting BCLxL can enhance the sensitivity of PI3K inhibition in PIK3CA mutant cancers and deserves further investigation clinically. Citation Format: Alexa E. Schmitz, Rebecca A. DeStefanis, Alyssa K. DeZeeuw, Autumn M. Olson, Anna L. Lippert, Kennedy J. Maduscha, Katherine A. Johnson, Sean Kraus, Cheri A. Pasch, Dustin A. Deming. BCLxL inhibition enhances copanlisib response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 355.

THU214 Exploratory Study Of The Association Of Genetic Factors With Recovery Of Hypothalamic-Pituitary-Adrenal Axis In Cushing Disease

Abstract Disclosure: M.H. Nguyen: None. W. Zhang: None. N. Pankratz: None. J. Lane: None. P. Chittiboina: None. F.R. Faucz: None. A. Liu: None. J.L. Mills: None. C.A. Stratakis: None. C. Tatsi: None. Successful treatment of endogenous Cushing syndrome (CS) is often followed by a period of adrenal insufficiency of variable duration. Recovery of the hypothalamic-pituitary-adrenal (HPA) axis may range from 6 months to more than 2 years. Previous studies have investigated potential clinical and biochemical factors involved in this process with variable results. We performed an exploratory study on genetic factors potentially involved in HPA axis recovery in patients with Cushing disease (CD). Ninety (90) patients with CD, who were treated with transsphenoidal surgery (TSS), had initial remission, and a follow up of at least 3 months postoperatively, were included in the study. Recovery of the HPA axis was defined as morning cortisol level or peak cortisol during a standard dose (250 mcg) IV corticotropin stimulation test of &amp;gt;18mcg/dL. Genetic data was obtained by whole exome sequencing (WES). Variants 1) in genes potentially involved in the HPA axis, 2) rare in the general population and 3) predicted as possibly or probably damaging in silico, were selected from WES. Statistical analysis was performed for each variant or for each gene (calculating all variants present in the same gene) using a Cox proportional hazard model. Correction for multiple comparisons was assessed with the false discovery rate (FDR) method.We identified 97 variants in 47 genes of interest that met the above criteria. Although five variants showed a trend toward association with shorter duration of postsurgical adrenal insufficiency (AI), no significant association was noted after correction for multiple comparisons. Furthermore, each variant was present in only one patient. At the gene-level, the BAG1 gene showed significant correlation with shorter postsurgical duration of AI (Hazard ratio: 28.7, 95% Confidence Interval: 5.4-151.1, FDR q-value=0.004), but both patients with a BAG1 variant later experienced recurrent disease, which could suggest an independent predictor of shorter recovery time. When we excluded patients with recurrence, no significant association was reported on the gene-level. In this exploratory study, we did not identify a significant genetic modifier of HPA recovery time. Other factors, clinical or surgical, may play a more important role in the recovery process or larger cohort studies may be required. Presentation: Thursday, June 15, 2023

FRI056 Effect Of 48 Hour Of Metreleptin In Humans With Lipodystrophy During Controlled Feeding

Abstract Disclosure: K.M. Bukhari: None. B. Abel: None. R.J. Brown: None. Introduction: The lipodystrophy (LD) syndromes are a rare group of disorders characterized by a generalized or partial loss of adipose tissue resulting in a deficiency of the adipocyte-secreted hormone leptin. Leptin replacement therapy with recombinant human leptin (metreleptin) has favorable effects on the metabolic profile of patients with LD and has been shown to have significant effects on metabolic pathways such as fatty acid oxidation and protein degradation following several months of treatment. However, many of these changes may relate to negative energy balance. Whether these changes can be seen within a few days of initiating metreleptin under energy balance conditions is unknown. Objectives: To explore acute (48 hour) and sub-acute (12 days) metabolomic effects of metreleptin under energy balance conditions in human subjects with leptin deficiency due to LD. Methods: The study included 17 patients with LD (5 generalized LD, 12 partial LD) who were studied on a metabolic ward with food intake held constant to maintain energy balance for 2 weeks. Metreleptin 5 mg q12 hr was administered, and fasting blood samples were collected at baseline (T0), after 2 days of treatment (T2), and after 12 days (T12). Untargeted metabolomic (848 compounds) and lipidomic (984 compounds) analysis was completed with the goal of assessing for any physiologically relevant changes during a period of controlled food intake and prior to any clinically relevant changes in dyslipidemia and diabetes. Statistical analyses between time points were done by paired t-tests. To account for false positives, a false discovery rate (q-value) was calculated for each compound, and only those with P≤0.05 are reported. Results: There was a very consistent reduction in the plasma levels of nearly all lipids detected (except monoacylglycerols) at T2 and T12 compared to T0. This includes plasma levels of phospholipids, ceramides, sphingomyelins, cholesterol esters, diacylglycerols (DAG) and triacylglycerols (TAG). There are significantly lower levels at T12 compared to T2 as well, indicating a continued decrease over time. A number of free fatty acids were significantly lower in the T2 metreleptin treated group compared to T0, with a smaller number that were also lower at T12. These included the medium chain, long chain saturated (palmitate [16:0]), long chain mono- and polyunsaturated (nisinate [24:6n3]). In conjunction with this, the levels of acylcarnitines are lower as well. Other significant changes included evidence of increased aerobic glycolysis with increased demand for pyruvate into the TCA cycle, as well as possible increased branched-chain amino acid catabolism with increased input into the TCA cycle. Conclusion: The effects of metreleptin on metabolism in LD appear to be rapid (48 hours), increase further after 12 days, and are independent from longer term changes in food intake, diabetes, and dyslipidemia. Presentation: Friday, June 16, 2023

Differentially expressed microRNAs in peripheral blood cell are associated with downregulated expression of IgE in nonallergic childhood asthma

Childhood asthma is a heterogeneous disease characterized by chronic airway inflammation, leading to a broad range of clinical presentations. Nonallergic asthma is asthma without allergic sensitization. Both clinical manifestations and immunopathological mechanisms of nonallergic childhood asthma were rarely investigated. We aimed to compare the clinical features between nonallergic and allergic childhood asthma and apply microRNA to explore the underlying mechanism of nonallergic childhood asthma. We enrolled 405 asthmatic children (76 nonallergic, 52 allergic with total IgE < 150 IU/mL and 277 allergic with total IgE > 150 IU/mL). Clinical characteristics were compared between groups. Comprehensive miRNA sequencing (RNA-seq) was performed using peripheral blood from 11 nonallergic and 11 allergic patients with elevated IgE, respectively. Differentially expressed miRNA (DEmiRNA) were determined with DESeq2. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed to determine functional pathways involved. Publicly available mRNA expression data was applied to investigate the predicted target mRNA networks via Ingenuity Pathway Analysis (IPA). The average age of nonallergic asthma was significantly younger (5.614 ± 2.743 vs 6.676 ± 3.118 years-old). Higher severity and worse control were more common in nonallergic asthma (two-way ANOVA, P < 0.0001). Long-term severity was higher, and intermittent attacks persisted in nonallergic patients. We identified 140 top DEmiRNAs based on false discovery rate (FDR) q-value < 0.001. Forty predicted target mRNA gene were associated with nonallergic asthma. The enriched pathway based on GO included Wnt signaling pathway. IgE expression was predicted to be downregulated by a network involving simultaneous interaction with IL-4, activation of IL-10 and inhibition of FCER2. Nonallergic childhood asthma were distinct in their younger age, higher long-term severity and more persistent course. Differentially expressed miRNA signatures associate with downregulation of total IgE expression and predicted target mRNA genes related molecular networks contribute to canonical pathways of nonallergic childhood asthma. We demonstrated the negative role of miRNAs involved in regulating IgE expression indicating differences between asthma phenotypes. Identification of biomarkers of miRNAs could contribute to understand the molecular mechanism of endotypes in nonallergic childhood asthma, which can potentially allow delivery of precision medicine to pediatric asthma.

Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

BackgroundDiet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).MethodsThis analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons.ResultsConsumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5−Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk.ConclusionOur results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.

Comparing the Movement Assessment Battery for Children with the Bruininks-Oseretsky Test of Motor Proficiency in adolescents with and without schizophrenia.

As motor impairments have implications for health and functioning, they need to be addressed early, not only in childhood but also in adolescence, the period in which mental disorders as schizophrenia, typically develops. Further, the possible prognostic value of motor impairments in schizophrenia highlights theimportance. The Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) and the Movement Assessment Battery for Children (MABC-2) assess adolescent motor performance. However, MABC-2 is not valid past age 16 and has no sex-norms. Further, while the concurrent validity between the tests and their ability to distinguish between clinical and non-clinical groups has been established in children, however they have not been established in adolescence. To compare the ability of MABC-2 and BOT-2 to distinguish between adolescents with and without schizophrenia, to examine the concurrent validity between tests, to examine the agreement between tests in classifying adolescents "at risk" or scoring "below average" and to examine the influence of age and sex on MABC-2. Motor performance assessed by BOT-2 and MABC-2 was compared in 25 adolescents with schizophrenia (14-18) and age- and sex-matched controls using t-test, Cohen's D and false discovery rate's q-value. The associations between tests were assessed using Pearson's correlation and Lin's concordance correlation coefficient. The Kappa coefficient was used to assess the agreement between tests in classifying "risk/below average" and linear regression was adopted to assess the influence of age/sex on MABC-2. MABC-2 and BOT-2 significantly distinguished adolescents with schizophrenia from controls with large effect size. A strong association (p>0.001) was found between the tests. The tests revealed moderate agreement in identifying "risk" or scoring "below average". Only sex influenced MABC-2 scores. MABC-2 and BOT-2 are both useful for assessing motor performance and distinguishing between adolescents with and without schizophrenia, although BOT-2 provides a more detailed picture of the challenges in adolescent with schizophrenia.

Neighborhood environmental factors linked to hospitalizations of older people for viral lower respiratory tract infections in Spain: a case-crossover study

BackgroundLower respiratory tract viral infection (LRTI) is a significant cause of morbidity-mortality in older people worldwide. We analyzed the association between short-term exposure to environmental factors (climatic factors and outdoor air pollution) and hospital admissions with a viral LRTI diagnosis in older adults.MethodsWe conducted a bidirectional case-crossover study in 6367 patients over 65 years of age with viral LRTI and residential zip code in the Spanish Minimum Basic Data Set. Spain’s State Meteorological Agency was the source of environmental data. Associations were assessed using conditional logistic regression. P-values were corrected for false discovery rate (q-values).ResultsAlmost all were hospital emergency admissions (98.13%), 18.64% were admitted to the intensive care unit (ICU), and 7.44% died. The most frequent clinical discharge diagnosis was influenza (90.25%). LRTI hospital admissions were more frequent when there were lower values of temperature and O3 and higher values of relative humidity and NO2. The regression analysis adjusted by temperatures and relative humidity showed higher concentrations at the hospital admission for NO2 [compared to the lag time of 1-week (q-value< 0.001) and 2-weeks (q-value< 0.001)] and O3 [compared to the lag time of 3-days (q-value< 0.001), 1-week (q-value< 0.001), and 2-weeks (q-value< 0.001)] were related to a higher odds of hospital admissions due to viral LRTI. Moreover, higher concentrations of PM10 at the lag time of 1-week (q-value = 0.023) and 2-weeks (q-value = 0.002), and CO at the lag time of 3-days (q-value = 0.023), 1-week (q-value< 0.001) and 2-weeks (q-value< 0.001)], compared to the day of hospitalization, were related to a higher chances of hospital admissions with viral LRTI.ConclusionUnfavorable environmental factors (low temperatures, high relative humidity, and high concentrations of NO2, O3, PM10, and CO) increased the odds of hospital admissions with viral LRTI among older people, indicating they are potentially vulnerable to these environmental factors.Graphical

Transcriptome-wide summary data-based Mendelian randomization analysis reveals 38 novel genes associated with severe COVID-19.

Severe COVID‐19 has a poor prognosis, while the genetic mechanism underlying severe COVID‐19 remains largely unknown. We aimed to identify genes that are potentially causally associated with severe COVID‐19. We conducted a summary data‐based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) data from 49 different tissues as the exposure and three COVID‐19‐phenotypes (very severe respiratory confirmed COVID‐19 [severe COVID‐19], hospitalized COVID‐19, and SARS‐CoV‐2 infection) as the outcomes. SMR using multiple SNPs was used as a sensitivity analysis to reduce false positive rate. Multiple testing was corrected using the false discovery rate (FDR) q‐value. We identified 309 significant gene‐trait associations (FDR q value < 0.05) across 46 tissues for severe COVID‐19, which mapped to 64 genes, of which 38 are novel. The top five most associated protein‐coding genes were Interferon Alpha and Beta Receptor Subunit 2 (IFNAR2), 2′‐5′‐Oligoadenylate Synthetase 3 (OAS3), mucin 1 (MUC1), Interleukin 10 Receptor Subunit Beta (IL10RB), and Napsin A Aspartic Peptidase (NAPSA). The potential causal genes were enriched in biological processes related to type I interferons, interferon‐gamma inducible protein 10 production, and chemokine (C‐X‐C motif) ligand 2 production. In addition, we further identified 23 genes and 5 biological processes which are unique to hospitalized COVID‐19, as well as 13 genes that are unique to SARS‐CoV‐2 infection. We identified several genes that are potentially causally associated with severe COVID‐19. These findings improve our limited understanding of the mechanism of COVID‐19 and shed light on the development of therapeutic agents for treating severe COVID‐19.

Exploring associations between social determinants of health and mental health outcomes in families from socioeconomically and racially and ethnically diverse households

This cross-sectional study investigated the associations between Social Determinants of Health (SDOH) and mental health outcomes of parents and children (n = 1307) from the Latinx, Native American, Somali/Ethiopian, White, Hmong, and African American communities. Logistic regression models were used to estimate the adjusted associations between five parent and child mental health measures and 25 measures of SDOH. False discovery rate q-values were computed to account for multiple comparisons. Families of color reported 5.3–7.8 SDOH barriers while White families reported 1.7 SDOH barriers on average. Adjusted analyses indicated that low family functioning and high perceived discrimination were associated with low resiliency among parents and increased behavioral difficulties among children. Other SDOH that were adversely associated with parent or child mental health included lack of social support, recent stressful life events, and adverse childhood experiences among parents. SDOH in the social and community context were most likely to be associated with mental health problems. Community-engaged evidence-based interventions are needed to improve population mental health.

Changes in pedometer-measured physical activity are associated with weight loss and changes in body composition and fat distribution in response to reduced-energy diet interventions: The POUNDS Lost trial.

To examine whether changes in objectively measured physical activity (PA) are associated with weight loss and changes in body composition and fat distribution in response to weight-loss diet interventions. This study included 535 participants with overweight/ obesity, who were randomly assigned to four weight-loss diets varying in macronutrients. PA was measured objectively with pedometers, and body composition and fat distribution were measured using dual-energy X-ray absorptiometry and computed tomography scans at baseline, 6months and 24 months. From baseline to 6months, when the maximum weight loss was achieved, each 1000-steps/d increment in PA was associated with a greater reduction in body weight (β[SE]=-0.48[0.11]) and waist circumference (β[SE]=-0.49[0.12]). Similar inverse associations were found in changes in body composition and fat distribution (P < 0.05 and false discovery rate qvalue < 0.1 for all). The trajectory of the above adiposity measures across the 24-month intervention period differed between the patterns of PA change. Participants with the largest increase in PA maintained their weight loss from 6months to 24 months, while those with a smaller increase in PA regained their weight. In addition, dietary fat or protein intake significantly modified the associations between changes in PA and changes in body weight and waist circumference over 24 months (P∆PA*diet < 0.05). Changes in objectively measured PA were inversely related to changes in body weight, body composition and fat distribution in response to weight-loss diets, and such associations were more evident in people on a high-fat or average-protein diet compared with a low-fat or high-protein diet.

Differential Gene Expression in Bladder Tumors from Workers Occupationally Exposed to Arylamines

Occupational exposure to the arylamines benzidine and β-naphthylamine increase bladder cancer risk up to 100-fold, making them some of the most powerful human carcinogens. We hypothesize that tumors arising in people with occupational exposures have different patterns of gene expression than histologically similar tumors from people without such exposures. In a case-case study, we compare gene expression in 22 formalin-fixed paraffin-embedded (FFPE) bladder tumors from men with high-level occupational exposure to arylamines to that in 26 FFPE bladder tumors from men without such exposure. Gene expression analysis was performed on the NanoString nCounter system using a PanCancer Progression Panel comprised of 740 cancer progression-related genes and a custom panel of 69 arylamine- and bladder cancer-related genes which were chosen from in vitro studies. Although fold differences were small, there was evidence of differential expression by exposure status for 17 genes from the Progression Panel and 4 genes from the custom panel. In total, 10 genes showed dose-response association at a p < 0.01, of which 4 genes (CD46, NR4A1, BAX, and YWHAZ) passed a false discovery rate (FDR) q value cutoff of 0.05 but were not significant after Bonferroni correction. Overall, we find limited evidence for differentially expressed genes in pathways related to DNA damage signaling and epithelial-to-mesenchymal transition (EMT).

Shift Work, DNA methylation and Epigenetic Age

BACKGROUND AND AIM: Shift work has been associated with increased risk of age-related morbidity and mortality. Biological age, estimated using DNA methylation, may quantify the biological consequences of shift work on the risk of age-related disease. We examined whether prior employment in shift-working occupations was associated with epigenetic age acceleration. METHODS: In a sample of non-Hispanic white women ages 35-74 (n=2,574), we measured DNA methylation (DNAm) using the Illumina Infinium Human450 BeadChip and calculated DNAm age using three established epigenetic clocks. Age acceleration metrics were derived by regressing DNAm age on chronological age and predicting the residuals. Using linear regression, we estimated associations between shift work history and age acceleration. We also conducted an epigenome-wide association study (EWAS) using robust linear regression models corrected with false discovery rate (FDR) q-values. RESULTS:Approximately 7% of women reported any shift work. Higher age acceleration was observed for a one-year increase in overall (β=0.11, 95% CI: 0.02-0.21) and night-specific shift work (β=0.12, 95% CI: 0.03-0.21). The association was strongest for ≥10 years of night shift work (β=3.16, 95% CI: 1.17-5.15). From the EWAS, years of overall and night shift work were associated with DNAm at 66 and 85 CpG sites (FDR0.05), respectively. Years of night shift work was associated with lower methylation of a CpG in the gene body of ZFHX3 (cg04994202, q=0.04), a gene related to circadian rhythm. CONCLUSIONS:Shift work was associated with differential CpG site methylation and with differential DNAm patterns, measured by epigenetic age acceleration, consistent with long-term negative health effects. KEYWORDS: biomarkers of exposure, epidemiology, molecular epidemiology, socio-economic factors