Differential biological effect of low doses of ionizing radiation depending on the radiosensitivity in a cell line model.

PURPOSE: Exposure to low doses (LD) of ionizing radiation (IR), such as the ones employed in computed tomography (CT) examination, can be associated with cancer risk. However, cancer development could depend on individual radiosensitivity. In the present study, we evaluated the differences in the response to a CT-scan radiation dose of 20 mGy in two lymphoblastoid cell lines with different radiosensitivity. MATERIALS AND METHODS: Several parameters were studied: gene expression, DNA damage, and its repair, as well as cell viability, proliferation, and death. Results were compared with those after a medium dose of 500 mGy. RESULTS: After 20 mGy of IR, the radiosensitive (RS) cell line showed an increase in DNA damage, and higher cell proliferation and apoptosis, whereas the radioresistant (RR) cell line was insensitive to this LD. Interestingly, the RR cell line showed a higher expression of an antioxidant gene, which could be used by the cells as a protective mechanism. After a dose of 500 mGy, both cell lines were affected by IR but with significant differences. The RS cells presented an increase in DNA damage and apoptosis, but a decrease in cell proliferation and cell viability, as well as less antioxidant response. CONCLUSIONS: A differential biological effect was observed between two cell lines with different radiosensitivity, and these differences are especially interesting after a CT scan dose. If this is confirmed by further studies, one could think that individuals with radiosensitivity-related genetic variants may be more vulnerable to long-term effects of IR, potentially increasing cancer risk after LD exposure.

Impact of tobacco, alcohol, and marijuana on genome-wide DNA methylation and its relationship with hypertension.

Tobacco, alcohol, and marijuana consumption is an important public health problem because of their high use worldwide and their association with the risk of mortality and many health conditions, such as hypertension, which is the commonest risk factor for death throughout the world. A likely pathway of action of substance consumption leading to persistent hypertension is DNA methylation. Here, we evaluated the effects of tobacco, alcohol, and marijuana on DNA methylation in the same cohort (N = 3,424). Three epigenome-wide association studies (EWAS) were assessed in whole blood using the InfiniumHumanMethylationEPIC BeadChip. We also evaluated the mediation of the top CpG sites in the association between substance consumption and hypertension. Our analyses showed 2,569 CpG sites differentially methylated by alcohol drinking and 528 by tobacco smoking. We did not find significant associations with marijuana consumption after correcting for multiple comparisons. We found 61 genes overlapping between alcohol and tobacco that were enriched in biological processes involved in the nervous and cardiovascular systems. In the mediation analysis, we found 66 CpG sites that significantly mediated the effect of alcohol consumption on hypertension. The top alcohol-related CpG site (cg06690548, P-value = 5.9·10-83) mapped to SLC7A11 strongly mediated 70.5% of the effect of alcohol consumption on hypertension (P-value = 0.006). Our findings suggest that DNA methylation should be considered for new targets in hypertension prevention and management, particularly concerning alcohol consumption. Our data also encourage further research into the use of methylation in blood to study the neurological and cardiovascular effects of substance consumption.

The consumption of tobacco, alcohol, and marijuana is very high worldwide and is associated with common diseases, like cardiovascular and neurological disorders.This study found that tobacco and alcohol have large effects on genome wide DNA methylation while marijuana consumption has nonsignificant effects.The genes differentially methylated were enriched in pathways related to neurodevelopment, suggesting the mediation between recreational drug consumption and neurological disorders.More remarkably, 66 alcohol related CpG sites significantly mediated the association between heavy drinking and hypertension.Our findings suggest that DNA methylation changes should be considered for new targets in disease prevention for recreational drug consumers.

Multi-omics signatures of the human early life exposome.

Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations ( https://helixomics.isglobal.org/ ) will serve to guide future investigation into the biological imprints of the early life exposome.

ATP Bioluminescence Assay To Evaluate Antibiotic Combinations against Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa.

Time-kill curves are used to study antibiotic combinations, but the colony count method to obtain the results is time-consuming. The aim of the study was to validate an ATP assay as an alternative to the conventional colony count method in studies of antibiotic combinations. The cutoff point for synergy and bactericidal effect to categorize the results using this alternative method were determined in Pseudomonas aeruginosa. The ATP assay was performed using the GloMax 96 microplate luminometer (Promega), which measures bioluminescence in relative light units (RLU). To standardize this assay, background, linearity, and the detection limit were determined with one strain each of multidrug-resistant P. aeruginosa and Klebsiella pneumoniae. Twenty-four-hour time-kill curves were performed in parallel by both methods with 12 strains of P. aeruginosa. The conventional method was used as a "gold" standard to establish the pharmacodynamic cutoff points in the ATP method. Normal saline solution was established as washing/dilution medium. RLU signal correlated with CFU when the assay was performed within the linear range. The categorization of the pharmacodynamic parameters using the ATP assay was equivalent to that of the colony count method. The bactericidal effect and synergy cutoff points were 1.348 (93% sensitivity, 81% specificity) and 1.065 (95% sensitivity, 89% specificity) log RLU/mL, respectively. The ATP assay was useful to determine the effectiveness of antibiotic combinations in time-kill curves. This method, less laborious and faster than the colony count method, could be implemented in the clinical laboratory workflow. IMPORTANCE Combining antibiotics is one of the few strategies available to overcome infections caused by multidrug-resistant bacteria. Time-kill curves are usually performed to evaluate antibiotic combinations, but obtaining results is too laborious to be routinely performed in a clinical laboratory. Our results support the utility of an ATP measurement assay using bioluminescence to determine the effectiveness of antibiotic combinations in time-kill curves. This method may be implemented in the clinical laboratory workflow as it is less laborious and faster than the conventional colony count method. Shortening the obtention of results to 24 h would also allow an earlier guided combined antibiotic treatment.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

The early-life exposome and epigenetic age acceleration in children.

The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath's Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PMabs) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PMabs may accelerate epigenetic aging from an early age.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

MADloy: robust detection of mosaic loss of chromosome Y from genotype-array-intensity data.

BACKGROUND: Accurate protocols and methods to robustly detect the mosaic loss of chromosome Y (mLOY) are needed given its reported role in cancer, several age-related disorders and overall male mortality. Intensity SNP-array data have been used to infer mLOY status and to determine its prominent role in male disease. However, discrepancies of reported findings can be due to the uncertainty and variability of the methods used for mLOY detection and to the differences in the tissue-matrix used. RESULTS: We created a publicly available software tool called MADloy (Mosaic Alteration Detection for LOY) that incorporates existing methods and includes a new robust approach, allowing efficient calling in large studies and comparisons between methods. MADloy optimizes mLOY calling by correctly modeling the underlying reference population with no-mLOY status and incorporating B-deviation information. We observed improvements in the calling accuracy to previous methods, using experimentally validated samples, and an increment in the statistical power to detect associations with disease and mortality, using simulation studies and real dataset analyses. To understand discrepancies in mLOY detection across different tissues, we applied MADloy to detect the increment of mLOY cellularity in blood on 18 individuals after 3 years and to confirm that its detection in saliva was sub-optimal (41%). We additionally applied MADloy to detect the down-regulation genes in the chromosome Y in kidney and bladder tumors with mLOY, and to perform pathway analyses for the detection of mLOY in blood. CONCLUSIONS: MADloy is a new software tool implemented in R for the easy and robust calling of mLOY status across different tissues aimed to facilitate its study in large epidemiological studies.

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children.

BACKGROUND: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. METHODS: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. RESULTS: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. CONCLUSION: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein-protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.

Association of Fish Consumption and Mercury Exposure During Pregnancy With Metabolic Health and Inflammatory Biomarkers in Children.

Importance: The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown. Objective: To assess the associations of fish intake and mercury exposure during pregnancy with metabolic syndrome in children and alterations in biomarkers of inflammation in children. Design, Setting, and Participants: This population-based prospective birth cohort study used data from studies performed in 5 European countries (France, Greece, Norway, Spain, and the UK) between April 1, 2003, and February 26, 2016, as part of the Human Early Life Exposome (HELIX) project. Mothers and their singleton offspring were followed up until the children were aged 6 to 12 years. Data were analyzed between March 1 and August 2, 2019. Exposures: Maternal fish intake during pregnancy (measured in times per week) was assessed using validated food frequency questionnaires, and maternal mercury concentration (measured in micrograms per liter) was assessed using maternal whole blood and cord blood samples. Main Outcomes and Measures: An aggregate metabolic syndrome score for children was calculated using the z scores of waist circumference, systolic and diastolic blood pressures, and levels of triglyceride, high-density lipoprotein cholesterol, and insulin. A higher metabolic syndrome score (score range, -4.9 to 7.5) indicated a poorer metabolic profile. Three protein panels were used to measure several cytokines and adipokines in the plasma of children. Results: The study included 805 mothers and their singleton children. Among mothers, the mean (SD) age at cohort inclusion or delivery of their infant was 31.3 (4.6) years. A total of 400 women (49.7%) had a high educational level, and 432 women (53.7%) were multiparous. Among children, the mean (SD) age was 8.4 (1.5) years (age range, 6-12 years). A total of 453 children (56.3%) were boys, and 734 children (91.2%) were of white race/ethnicity. Fish intake consistent with health recommendations (1 to 3 times per week) during pregnancy was associated with a 1-U decrease in metabolic syndrome score in children (ß = -0.96; 95% CI, -1.49 to -0.42) compared with low fish consumption (<1 time per week) after adjusting for maternal mercury levels and other covariates. No further benefit was observed with fish intake of more than 3 times per week. A higher maternal mercury concentration was independently associated with an increase in the metabolic syndrome score of their offspring (ß per 2-fold increase in mercury concentration = 0.18; 95% CI, 0.01-0.34). Compared with low fish intake, moderate and high fish intake during pregnancy were associated with reduced levels of proinflammatory cytokines and adipokines in children. An integrated analysis identified a cluster of children with increased susceptibility to metabolic disease, which was characterized by low fish consumption during pregnancy, high maternal mercury levels, decreased levels of adiponectin in children, and increased levels of leptin, tumor necrosis factor α, and the cytokines interleukin 6 and interleukin 1ß in children. Conclusions and Relevance: Results of this study suggest that moderate fish intake consistent with current health recommendations during pregnancy was associated with improvements in the metabolic health of children, while high maternal mercury exposure was associated with an unfavorable metabolic profile in children.

Extreme Downregulation of Chromosome Y and Cancer Risk in Men.

BACKGROUND: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer. METHODS: We advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the Genotype Tissue-Expression Project (n = 371) and its association with cancer status across 12 cancer studies from The Cancer Genome Atlas (n = 1774) and seven other studies (n = 7562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, and a Fisher's test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided. RESULTS: EDY was likely to occur in multiple nondiseased tissues (P < .001) and was statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (false discovery rate = 0.028). EDY strongly associated with cancer risk in men (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.58 to 8.46, P = .002), adjusted by LOY and age, and its variability was largely explained by several genes of the nonrecombinant region whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95% CI = 1.32 to 6.01, P = .007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95% CI = 3.70 to 8.59, false discovery rate < 0.001) and EGFR overexpression along with SRY hypomethylation and nonrecombinant region hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns. CONCLUSIONS: EDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect women compared with men from cancer risk.

Acute appendicitis in Amyand's hernia: ultrasound findings and histopathology correlation. A case report.

Amyand's hernia is an uncommon form of inguinal hernia. It represents <1% of all hernias and its complication with appendicitis is still rarer with 0.1-0.13% being reported. A 78-year-old woman was taken to the emergency room with pain in the right groin. The patient was assessed by ultrasound with the clinical suspicion of an inguinal hernia. We present the ultrasonographic features of appendicitis within an inguinal hernia sac. A tubular image that terminated in a blind-ended tip in the longitudinal plane and a target image on the cross-sectional plane were consistent with the sonographically demonstrated appendix. The diagnosis of Amyand's hernia is difficult in the clinical setting. The patient is frequently referred to surgery with the diagnosis of an incarcerated hernia. Ultrasound is a good imaging modality that detects and characterizes this uncommon condition.

Common polymorphic inversions at 17q21.31 and 8p23.1 associate with cancer prognosis.

BACKGROUND: Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are also associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers. RESULTS: Using data from The Cancer Genome Atlas (TCGA), we observed that inv8p23.1 was associated with overall survival in breast cancer and that inv17q21.31 was associated with overall survival in stomach cancer. In the meta-analysis of two independent studies, inv17q21.31 heterozygosity was significantly associated with colorectal disease-free survival. We found that the association was mediated by the de-methylation of cg08283464 and cg03999934, also linked to lower disease-free survival. CONCLUSIONS: Our results suggest that chromosomal inversions are important genetic factors of tumor prognosis, likely affecting changes in methylation patterns.

Is non-operative management warranted in ventral hernia patients with comorbidities? A case-matched, prospective 3 year follow-up, patient-centered study.

BACKGROUND: We hypothesized that long-term quality of life (QoL) is improved among patients with ventral hernias (VHs) and comorbid conditions managed operatively than with non-operative management. METHODS: This was the 3-year follow-up to a prospective observational study of patients with comorbid conditions and VHs. Primary outcome was change in QoL measured utilizing the modified Activities Assessment Scale (AAS), a validated, hernia-specific survey. Outcomes were compared using: (1)paired t-test on matched subset and (2)multivariable linear regression on the overall cohort. RESULTS: In the matched cohort (n = 80; 40/group), the operative group experienced a significantly greater improvement in QoL compared to the non-operative group (28.4 ±â€¯27.1 vs. 11.8 ±â€¯23.8,p = 0.005). The operative group, had 10 (25.0%) reported recurrences while the non-operative group, reported 4/15 (26.7%) recurrences among the 15 (37.5%) patients that underwent repair. On multivariable analysis of the whole cohort (n = 137), operative management was associated with a 19.5 (95% CI7.0-31.9) point greater improvement in QoL compared to non-operative management. CONCLUSIONS: This is the first long term prospective study showing the benefits of operative as opposed to non-operative management of patients with comorbid conditions and VHs.

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

When pitch adds to volume: coregulation of transcript diversity predicts gene function.

BACKGROUND: Genes corregulate their overall transcript volumes to perform their physiological functions. However, it is unknown if they additionally coregulate their transcript diversities. We studied the reliability, consistency and functional associations of co-splicing correlations of genes of interest, across two independent studies, multiple tissues and two statistical methods. We thoroughly investigated the reproducibility of co-splicing correlations of APP, the candidate gene of Azheimer's disease (AD). We then studied how co-splicing correlations in different tissues contributed to predict functional interactions of three other genes and finally computed co-splicing frequency for 17 thousand genes across 52 human tissues. RESULTS: We replicated co-splicing correlations between APP and 5 AD-related genes and reproduced expected enrichment of APP co-splicing in synaptic vesicle cycle and proteosome pathways. We observed novel associations for tissue vulnerability to disease with enrichment in APP co-splicing, co-expression and epistasis in AD. APP co-splicing was the strongest predictor and replicated between studies. We confirmed known gene interactions of PRPF8 and GRIA1 in testis and brain cortex, and observed a novel interaction of FGFR2, in breast and prostate, modulated by cancer risk-variants. We produced a co-splicing map across 52 human tissues to help predict the function of over 17 thousand genes. CONCLUSIONS: We show that coregulation of transcript diversities provides novel biological insights in gene physiology and helps to interpret GWAS results. Co-splicing correlations are reliable and frequent and should be further pursued to help predict gene function. Our results additionally support current AD interventions aiming at the ubiquitin proteosome pathway but unveil the need to consider transcript diversity in addition to volume to assess treatment response and susceptibility to the disease.

Impact of Abdominal Wall Hernias and Repair on Patient Quality of Life.

BACKGROUND: The modified Activities Assessment Scale (AAS) is a 13-question abdominal wall quality of life (AW-QOL) survey validated in patients undergoing ventral hernia repair (VHR). No studies have assessed AW-QOL among individuals without abdominal wall pathology. The minimal clinically important difference (MCID) of the modified AAS and its implications for the threshold at which VHR should be offered also remain unknown. Our objectives were to (1) establish the AW-QOL of patients with a clinical abdominal wall hernia versus those with no hernia, (2) determine the MCID of the modified AAS, and (3) identify the baseline quality of life (QOL) score at which patients derive little clinical benefit from VHR. METHODS: Patient-centered outcomes data for all patients presenting to General Surgery and Hernia Clinics October-December 2016 at a single safety-net institution were collected via a prospective, cross-sectional observational study design. Primary outcome was QOL measured using the modified AAS. Secondary outcome was the MCID. RESULTS: Patients with no hernia had modified AAS scores of 81.6 (50.4-94.4), while patients with a clinically apparent hernia had lower modified AAS scores of 31.4 (12.6-58.7) (p < 0.001). The MCID threshold was 7.6 for a "slight" change and 14.9 for "definite" change. Above a modified AAS score of 81, the risk of worsening a patient's QOL by surgery is higher than the chances of improvement. CONCLUSIONS: VHR can improve 1-year postsurgical AW-QOL to levels similar to that of the general population. The MCID of the modified AAS is 7.6 points. Patients with high baseline scores should be counseled about the lack of potential benefit in QOL from elective VHR.

Redundancy analysis allows improved detection of methylation changes in large genomic regions.

BACKGROUND: DNA methylation is an epigenetic process that regulates gene expression. Methylation can be modified by environmental exposures and changes in the methylation patterns have been associated with diseases. Methylation microarrays measure methylation levels at more than 450,000 CpGs in a single experiment, and the most common analysis strategy is to perform a single probe analysis to find methylation probes associated with the outcome of interest. However, methylation changes usually occur at the regional level: for example, genomic structural variants can affect methylation patterns in regions up to several megabases in length. Existing DMR methods provide lists of Differentially Methylated Regions (DMRs) of up to only few kilobases in length, and cannot check if a target region is differentially methylated. Therefore, these methods are not suitable to evaluate methylation changes in large regions. To address these limitations, we developed a new DMR approach based on redundancy analysis (RDA) that assesses whether a target region is differentially methylated. RESULTS: Using simulated and real datasets, we compared our approach to three common DMR detection methods (Bumphunter, blockFinder, and DMRcate). We found that Bumphunter underestimated methylation changes and blockFinder showed poor performance. DMRcate showed poor power in the simulated datasets and low specificity in the real data analysis. Our method showed very high performance in all simulation settings, even with small sample sizes and subtle methylation changes, while controlling type I error. Other advantages of our method are: 1) it estimates the degree of association between the DMR and the outcome; 2) it can analyze a targeted or region of interest; and 3) it can evaluate the simultaneous effects of different variables. The proposed methodology is implemented in MEAL, a Bioconductor package designed to facilitate the analysis of methylation data. CONCLUSIONS: We propose a multivariate approach to decipher whether an outcome of interest alters the methylation pattern of a region of interest. The method is designed to analyze large target genomic regions and outperforms the three most popular methods for detecting DMRs. Our method can evaluate factors with more than two levels or the simultaneous effect of more than one continuous variable, which is not possible with the state-of-the-art methods.