Exclusion of Class III malocclusion candidate loci in Brazilian families

The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies

Dietary fibre to reduce colon cancer risk in Alaska Native people: the Alaska FIRST randomised clinical trial protocol

Introduction Diet, shown to impact colorectal cancer (CRC) risk, is a modifiable environmental factor. Fibre foods fermented by gut microbiota produce metabolites that not only provide food for the colonic epithelium but also exert regulatory effects on colonic mucosal inflammation and proliferation. We describe methods used in a double-blinded, randomised, controlled trial with Alaska Native (AN) people to determine if dietary fibre supplementation can substantially reduce CRC risk among people with the highest reported CRC incidence worldwide. Methods and analyses Eligible patients undergoing routine screening colonoscopy consent to baseline assessments and specimen/data collection (blood, urine, stool, saliva, breath and colon mucosal biopsies) at the time of colonoscopy. Following an 8-week stabilisation period to re-establish normal gut microbiota post colonoscopy, study personnel randomise participants to either a high fibre supplement (resistant starch, n=30) or placebo (digestible starch, n=30) condition, repeating stool sample collection. During the 28-day supplement trial, each participant consumes their usual diet plus their supplement under direct observation. On day 29, participants undergo a flexible sigmoidoscopy to obtain mucosal biopsy samples to measure the effect of the supplement on inflammatory and proliferative biomarkers of cancer risk, with follow-up assessments and data/specimen collection similar to baseline. Secondary outcome measures include the impact of a high fibre supplement on the oral and colonic microbiome and biofluid metabolome. Ethics and dissemination Approvals were obtained from the Alaska Area and University of Pittsburgh Institutional Review Boards and Alaska Native Tribal Health Consortium and Southcentral Foundation research review bodies. A data safety monitoring board, material transfer agreements and weekly study team meetings provide regular oversight throughout the study. Study findings will first be shared with AN tribal leaders, health administrators, providers and community members. Peer-reviewed journal articles and conference presentations will be forthcoming once approved by tribal review bodies

Current state of quality of life and patient-reported outcomes research

The 5th EORTC Quality of Life in Cancer Clinical Trials Conference presented the current state of quality of life and other patient-reported outcomes (PROs) research from the perspectives of researchers, regulators, industry representatives, patients and patient advocates and health care professionals. A major theme was the assessment of the burden of cancer treatments, and this was discussed in terms of regulatory challenges in using PRO assessments in clinical trials, patients' experiences in cancer clinical trials, innovative methods and standardisation in cancer research, innovative methods across the disease sites or populations and cancer survivorship. Conferees demonstrated that PROs are becoming more accepted and major efforts are ongoing internationally to standardise PROs measurement, analysis and reporting in trials. Regulators are keen to collaborate with all stakeholders to ensure that the right questions are asked and the right answers are communicated. Improved technology and increased flexibility of measurement instruments are making PROs data more robust. Patients are being encouraged to be patient partners. International collaborations are essential, because this work cannot be accomplished on a national level

Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis fo

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Final report "PathOrganic. Risks and Recommendations Regarding Human Pathogens in Organic Vegetable Production Chains"

PathOrganic assesses risks associated with the consumption of fresh and minimally processed vegetables due to the prevalence of bacterial human pathogens (e.g. Salmonella enterica, pathogenic E. coli, Campylobacter spp., Listeria monocytogenes) in organically grown plant produce. The project aims at evaluating whether organic production poses a risk on food safety and addresses the food chain by taking into consideration potential sources of pathogen transmission (e.g. animal manure). In addition, it evaluates whether organic production may reduce the risk of pathogen manifestation. From a European perspective, vegetable-linked outbreaks are not well investigated. Within the PathOrganic project, surveys of organically grown vegetables are carried out in five European countries, and regionally different environmental and management factors are taken into consideration for performing risk assessment. In order to carry out a meaningful survey and to choose appropriate experimental plans, a model for pathogen transfer to selected plants is built in work package 1 (WP 1) to describe relevant food chains. Based on this model sampling strategies and methodological adjustments are made. A questionnaire is set up to describe current management practices (WP 1). WP 2 of the project is dedicated to surveying the presence of food pathogens in organic plant produce. As a major part of the project, field surveys of organic farming systems are performed and vegetable plants are sampled in five European countries. The analysis of relevant parameters is done by the respective partners with the appropriate expertise. “Risk crops” and “risk factors” are identified and specific production procedures shall be investigated, leading to the determination of critical control points (CCPs). Factors suggesting a problem concerning food safety are subjected to more detailed analysis in WP3 by performing specifically targeted greenhouse and field experiments. These experiments allow analyzing critical environmental and management factors and at the same time enable to re-assess the critical control points. Finally, based on the results obtained in the previous WPs, in WP 4 recommendations will be provided for improving procedures which secure consumer-oriented food safety and the quality of certified organic vegetable food chains. Thus, project results shall enable producers and other stakeholders to prevent and better control plant produce-associated outbreaks