No Association of Obesity and Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer

Background: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer. Methods: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls. Results: None of these SNPs were statistically significantly associated with colon cancer in our sample. Conclusions: Overall, these results suggest that these obesity and T2D genetic susceptibility loci are unlikely to influence the risk of colon cancer

Oncogenic Features in Histologically Normal Mucosa: Novel Insights Into Field Effect From a Mega-Analysis of Colorectal Transcriptomes

Introduction: Colorectal cancer is a common malignancy that can be cured when detected early, but recurrence among survivors is a persistent risk. A field effect of cancer in the colon has been reported and could have implications for surveillance, but studies to date have been limited. A joint analysis of pooled transcriptomic data from all available bulk RNA-sequencing data sets of healthy, histologically normal tumor-adjacent, and tumor tissues was performed to provide an unbiased assessment of field effect. Methods: A novel bulk RNA-sequencing data set from biopsies of nondiseased colon from screening colonoscopy along with published data sets from the Genomic Data Commons and Sequence Read Archive were considered for inclusion. Analyses were limited to samples with a quantified read depth of at least 10 million reads. Transcript abundance was estimated with Salmon, and downstream analysis was performed in R. Results: A total of 1,139 samples were analyzed in 3 cohorts. The primary cohort consisted of 834 independent samples from 8 independent data sets, including 462 healthy, 61 tumor-adjacent, and 311 tumor samples. Tumor-adjacent gene expression was found to represent an intermediate state between healthy and tumor expression. Among differentially expressed genes in tumor-adjacent samples, 1,143 were expressed in patterns similar to tumor samples, and these genes were enriched for cancer-associated pathways. Discussion: Novel insights into the field effect in colorectal cancer were generated in this mega-analysis of the colorectal transcriptome. Oncogenic features that might help explain metachronous lesions in cancer survivors and could be used for surveillance and risk stratification were identified

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways

A functional variant on 20q13.33 related to glioma risk alters enhancer activity and modulates expression of multiple genes.

Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with glioma risk on 20q13.33, but the biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 20q13.33 impacted the activity of an enhancer, leading to an altered expression of nearby genes. To identify candidate functional SNPs, we identified all SNPs in linkage disequilibrium with the risk-associated SNP rs2297440 that mapped to putative enhancers. Putative enhancers containing candidate functional SNPs were tested for allele-specific effects in luciferase enhancer activity assays against glioblastoma multiforme (GBM) cell lines. An enhancer containing SNP rs3761124 exhibited allele-specific effects on activity. Deletion of this enhancer by CRISPR-Cas9 editing in GBM cell lines correlated with an altered expression of multiple genes, including STMN3, RTEL1, RTEL1-TNFRSF6B, GMEB2, and SRMS. Expression quantitative trait loci (eQTL) analyses using nondiseased brain samples, isocitrate dehydrogenase 1 (IDH1) wild-type glioma, and neurodevelopmental tissues showed STMN3 to be a consistent significant eQTL with rs3761124. RTEL1 and GMEB2 were also significant eQTLs in the context of early CNS development and/or in IDH1 wild-type glioma. We provide evidence that rs3761124 is a functional variant on 20q13.33 related to glioma/GBM risk that modulates the expression of STMN3 and potentially other genes across diverse cellular contexts

When is forgetting not forgetting? A discursive analysis of differences in forgetting talk between adults with cystic fibrosis with different levels of adherence to nebulizer treatments

Forgetting is often cited as a reason why people struggle to adhere to treatments for chronic conditions. Interventions have tried to improve forgetting behavior using reminders. We used a discursive psychological approach to explore differences in how high and low adherers constructed forgetting their nebulizer treatments for cystic fibrosis. Interviews were conducted with 18 adults from a cystic fibrosis center in the United Kingdom. High adherers constructed forgetting treatments as occasional lapses in automaticity and temporary lapses in memory that they found easy to repair. Low adherers utilized forgetting to normalize more consistent nonadherence to treatments. However, it is important to contextualize forgetting as a discursive resource that helped these participants to negotiate moral discourses around adherence to treatment that reminder interventions cannot address; we therefore recommend a more behavioral, patient-focused, theory-driven approach to intervention development

Inter-model comparison of global hydroxyl radical (OH) distributions and their impact on atmospheric methane over the 2000–2016 period

The modeling study presented here aims to estimate how uncertainties in global hydroxyl radical (OH) distributions, variability, and trends may contribute to resolving discrepancies between simulated and observed methane (CH4) changes since 2000. A multi-model ensemble of 14 OH fields was analyzed and aggregated into 64 scenarios to force the offline atmospheric chemistry transport model LMDz (Laboratoire de Meteorologie Dynamique) with a standard CH4 emission scenario over the period 2000–2016. The multi-model simulated global volume-weighted tropospheric mean OH concentration ([OH]) averaged over 2000–2010 ranges between 8:7*10^5 and 12:8*10^5 molec cm-3. The inter-model differences in tropospheric OH burden and vertical distributions are mainly determined by the differences in the nitrogen oxide (NO) distributions, while the spatial discrepancies between OH fields are mostly due to differences in natural emissions and volatile organic compound (VOC) chemistry. From 2000 to 2010, most simulated OH fields show an increase of 0.1–0:3*10^5 molec cm-3 in the tropospheric mean [OH], with year-to-year variations much smaller than during the historical period 1960–2000. Once ingested into the LMDz model, these OH changes translated into a 5 to 15 ppbv reduction in the CH4 mixing ratio in 2010, which represents 7%–20% of the model-simulated CH4 increase due to surface emissions. Between 2010 and 2016, the ensemble of simulations showed that OH changes could lead to a CH4 mixing ratio uncertainty of > 30 ppbv. Over the full 2000–2016 time period, using a common stateof- the-art but nonoptimized emission scenario, the impact of [OH] changes tested here can explain up to 54% of the gap between model simulations and observations. This result emphasizes the importance of better representing OH abundance and variations in CH4 forward simulations and emission optimizations performed by atmospheric inversions

Group cognitive–behavioural programme to reduce the impact of rheumatoid arthritis fatigue: The RAFT RCT with economic and qualitative evaluations

BACKGROUND: Fatigue is a major problem in rheumatoid arthritis (RA). There is evidence for the clinical effectiveness of cognitive-behavioural therapy (CBT) delivered by clinical psychologists, but few rheumatology units have psychologists. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of a group CBT programme for RA fatigue [named RAFT, i.e. Reducing Arthritis Fatigue by clinical Teams using cognitive-behavioural (CB) approaches], delivered by the rheumatology team in addition to usual care (intervention), with usual care alone (control); and to evaluate tutors' experiences of the RAFT programme. DESIGN: A randomised controlled trial. Central trials unit computerised randomisation in four consecutive cohorts within each of the seven centres. A nested qualitative evaluation was undertaken. SETTING: Seven hospital rheumatology units in England and Wales. PARTICIPANTS: Adults with RA and fatigue severity of ≥ 6 [out of 10, as measured by the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale (BRAF-NRS)] who had no recent changes in major RA medication/glucocorticoids. INTERVENTIONS: RAFT - group CBT programme delivered by rheumatology tutor pairs (nurses/occupational therapists). Usual care - brief discussion of a RA fatigue self-management booklet with the research nurse. MAIN OUTCOME MEASURES: Primary - fatigue impact (as measured by the BRAF-NRS) at 26 weeks. Secondary - fatigue severity/coping (as measured by the BRAF-NRS); broader fatigue impact [as measured by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ)]; self-reported clinical status; quality of life; mood; self-efficacy; and satisfaction. All data were collected at weeks 0, 6, 26, 52, 78 and 104. In addition, fatigue data were collected at weeks 10 and 18. The intention-to-treat analysis conducted was blind to treatment allocation, and adjusted for baseline scores and centre. Cost-effectiveness was explored through the intervention and RA-related health and social care costs, allowing the calculation of quality-adjusted life-years (QALYs) with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Tutor and focus group interviews were analysed using inductive thematic analysis. RESULTS: A total of 308 out of 333 patients completed 26 weeks (RAFT, n/N = 156/175; control, n/N = 152/158). At 26 weeks, the mean BRAF-NRS impact was reduced for the RAFT programme (-1.36 units; p

A Systematic Review of Individual and Contextual Factors Affecting ART Initiation, Adherence, and Retention for HIV-Infected Pregnant and Postpartum Women

BACKGROUND: Despite progress reducing maternal mortality, HIV-related maternal deaths remain high, accounting, for example, for up to 24 percent of all pregnancy-related deaths in sub-Saharan Africa. Antiretroviral therapy (ART) is effective in improving outcomes among HIV-infected pregnant and postpartum women, yet rates of initiation, adherence, and retention remain low. This systematic literature review synthesized evidence about individual and contextual factors affecting ART use among HIV-infected pregnant and postpartum women. METHODS: Searches were conducted for studies addressing the population (HIV-infected pregnant and postpartum women), intervention (ART), and outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. Individual and contextual enablers and barriers to ART use were extracted and organized thematically within a framework of individual, interpersonal, community, and structural categories. RESULTS: Thirty-four studies were included in the review. Individual-level factors included both those within and outside a woman’s awareness and control (e.g., commitment to child’s health or age). Individual-level barriers included poor understanding of HIV, ART, and prevention of mother-to-child transmission, and difficulty managing practical demands of ART. At an interpersonal level, disclosure to a spouse and spousal involvement in treatment were associated with improved initiation, adherence, and retention. Fear of negative consequences was a barrier to disclosure. At a community level, stigma was a major barrier. Key structural barriers and enablers were related to health system use and engagement, including access to services and health worker attitudes. CONCLUSIONS: To be successful, programs seeking to expand access to and continued use of ART by integrating maternal health and HIV services must identify and address the relevant barriers and enablers in their own context that are described in this review. Further research on this population, including those who drop out of or never access health services, is needed to inform effective implementation

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci

Background & aims: The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource. Methods: We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. Results: We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application. Conclusions: We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue