Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]

Background Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS). Methods The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance. Results There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype. Conclusions We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases

Systematic review and meta-analysis of the provision of preventive care for modifiable chronic disease risk behaviours by mental health services

People with mental illness experience increased chronic disease burden, contributed to by a greater prevalence of modifiable chronic disease risk behaviours. Policies recommend mental health services provide preventive care for such risk behaviours. Provision of such care has not previously been synthesised. This review assessed the provision of preventive care for modifiable chronic disease risk behaviours by mental health services. Four databases were searched from 2006 to 2017. Eligible studies were observational quantitative study designs conducted in mental health services, where preventive care was provided to clients for tobacco smoking, harmful alcohol consumption, inadequate nutrition, or inadequate physical activity. Two reviewers independently screened studies, conducted data extraction and critical appraisal. Results were pooled as proportions of clients receiving or clinicians providing preventive care using random effects meta-analyses, by risk behaviour and preventive care element (ask/assess, advise, assist, arrange). Subgroup analyses were conducted by mental health service type (inpatient, outpatient, other/multiple). Narrative synthesis was used where meta-analysis was not possible. Thirty-eight studies were included with 26 amenable to meta-analyses. Analyses revealed that rates of assessment were highest for smoking (78%, 95% confidence interval [CI]:59%–96%) and lowest for nutrition (17%, 95% CI:1%–35%); with variable rates of care provision for all behaviours, care elements, and across service types, with substantial heterogeneity across analyses. Findings indicated suboptimal and variable provision of preventive care for modifiable chronic disease risk behaviours in mental health services, but should be considered with caution due to the very low quality of cumulative evidence

Targeted screening strategies to detect Trypanosoma cruzi infection in children

Background: Millions of people are infected with Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. Anti-trypanosomal drug therapy can cure infected individuals, but treatment efficacy is highest early in infection. Vector control campaigns disrupt transmission of T. cruzi, but without timely diagnosis, children infected prior to vector control often miss the window of opportunity for effective chemotherapy. Methods and Findings: We performed a serological survey in children 2-18 years old living in a peri-urban community of Arequipa, Peru, and linked the results to entomological, spatial and census data gathered during a vector control campaign. 23 of 433 (5.3% [95% Cl 3.4-7.9]) children were confirmed seropositive for T. cruzi infection by two methods. Spatial analysis revealed that households with infected children were very tightly clustered within looser clusters of households with parasite-infected vectors. Bayesian hierarchical mixed models, which controlled for clustering of infection, showed that a child's risk of being seropositive increased by 20% per year of age and 4% per vector captured within the child's house. Receiver operator characteristic (ROC) plots of best-fit models suggest that more than 83% of infected children could be identified while testing only 22% of eligible children. Conclusions: We found evidence of spatially-focal vector-borne T. cruzi transmission in peri-urban Arequipa. Ongoing vector control campaigns, in addition to preventing further parasite transmission, facilitate the collection of data essential to identifying children at high risk of T. cruzi infection. Targeted screening strategies could make integration of diagnosis and treatment of children into Chagas disease control programs feasible in lower-resource settings

Sedentary behavior and dietary intake in children, adolescents and adults: A systematic review

Context: Sedentary behavior is implicated in youth and adult overweight and obesity. However, the relationship between sedentary behavior and weight status is often small or inconsistent, with few studies controlling for confounding factors such as diet and physical activity. Diet has been hypothesized to covary with some sedentary behaviors. It is opportune, therefore, to review whether dietary intake is associated with sedentary behavior in young people and adults. This may allow for better interpretation of the diversity of findings concerning sedentary behavior and weight status. Evidence acquisition: Published English-language studies were located from computerized and manual searches in early 2010. Included studies were observational studies assessing an association between at least one sedentary behavior and at least one aspect of dietary intake in children (aged <11 years), adolescents (aged 1218 years), or adults (aged >18 years). Evidence synthesis: Fifty-three studies, totaling 111 independent samples, were eligible for this review. Sedentary behavior in children (n=19, independent samples=24), adolescents (n=26, independent samples=72), and adults (n=11, independent samples=14) appears to be clearly associated with elements of a less healthy diet including lower fruit and vegetable consumption; higher consumption of energy-dense snacks, drinks, and fast foods; and higher total energy intake. Strengths of association were mainly in the small-to-moderate range. Conclusions: The association drawn mainly from cross-sectional studies is that sedentary behavior, usually assessed as screen time and predominantly TV viewing, is associated with unhealthy dietary behaviors in children, adolescents, and adults. Interventions need to be developed that target reductions in sedentary time to test whether diet also changes. © 2011 American Journal of Preventive Medicine

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy