Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Background: Approximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families. Methods: A total of 78 participants (from 29 families) with a mutation in MSH6 and 7 participants (from 6 families) with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis. Results: MSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females) and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females. Conclusion: Novel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations

Characterising chromosome rearrangements: recent technical advances in molecular cytogenetics

Genomic rearrangements can result in losses, amplifications, translocations and inversions of DNA fragments thereby modifying genome architecture, and potentially having clinical consequences. Many genomic disorders caused by structural variation have initially been uncovered by early cytogenetic methods. The last decade has seen significant progression in molecular cytogenetic techniques, allowing rapid and precise detection of structural rearrangements on a whole-genome scale. The high resolution attainable with these recently developed techniques has also uncovered the role of structural variants in normal genetic variation alongside single-nucleotide polymorphisms (SNPs). We describe how array-based comparative genomic hybridisation, SNP arrays, array painting and next-generation sequencing analytical methods (read depth, read pair and split read) allow the extensive characterisation of chromosome rearrangements in human genomes

Effects of a fall prevention program in elderly: a pragmatic observational study in two orthopedic departments

Bodil Røyset,1 Bente A Talseth-Palmer,2–4 Stian Lydersen,5 Per G Farup6,7 1Department for Medicine and Rehabilitation, Møre og Romsdal Hospital Trust, Ålesund, Norway; 2Department for Research, Innovation, Education and Competence Development, Møre og Romsdal Hospital Trust, Molde, Norway; 3Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; 4School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia; 5Regional Centre for Child and Youth Mental Health and Child Welfare, Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; 6Department of Research, Innlandet Hospital Trust, Brumunddal, Norway; 7Unit for Applied Clinical Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway Purpose: Falls are a common adverse event experienced by elderly in hospitals. This study assessed the effects of a fall prevention program on the rate of fallers, the patient safety culture, and patient-perceived safety.Materials and methods: Two orthopedic departments in different towns in Norway participated in the study. A comprehensive, multifactorial fall prevention program was implemented in one of the departments, the other one was used for control. The changes in the outcomes in the two departments from before to after the intervention were compared. All patients above 64 years of age admitted to the two departments in a 1-year period before and after the intervention were included. All employees at the two departments were invited to participate in surveys measuring the patient safety culture, and a selection of the patients reported patient-perceived safety. The primary outcome was the rate of fallers. Secondary outcomes were the employees’ perceived patient safety culture (measured with the Safety Attitudes Questionnaire) and patient-perceived safety (measured with Norwegian Patient Experience Questionnaire).Results: Falls were registered in 114 out of 3,143 patients (3.6%) with 17,006 days in the hospital. Ten patients had two falls, giving a fall rate of 7.3 falls/1,000 days in the hospital. The number of fallers before and after the intervention in the intervention department were 37/734 (5.04%) and 31/735 (4.22%), P=0.46, and in the control department, 25/811 (3.08%) and 21/863 (2.43%), P=0.46. The difference between the changes in the two departments was not statistically significant; 0.17% (95% CI: -2.49 to 2.84; P=0.90). There were also no significant differences in the changes in patient safety culture and patient-perceived safety.Conclusion: The fall prevention program revealed no significant effect on the rate of fallers, the patient safety culture, or patient-perceived safety. Keywords: accidental falls, accident prevention, adverse effects, patient safety, safety cultur

8q23.3 and 11q23.1 as modifying loci influencing the risk for CRC in Lynch syndrome

Recently, Houlle et al reported results of two modifier SNPs in Lynch syndrome, rs16892766 on 8q23.3 and rs3802842 on 11q23.1 previously identified as low-susceptibility colorectal cancer (CRC) loci, challenging earlier reported findings. In 2009 Wijnen et al demonstrated that two SNPs located on 8q23.3 (rs16892766) and 11q23.1 (rs3802842) were associated with an increased risk of developing CRC in Dutch Lynch syndrome patients. The study revealed that patients’ homozygote for SNP rs16892766 were associated with an elevated risk of CRC in a dose-dependent manner with a 2.16-fold increased risk of developing CRC, whereas the variant (CC) genotype of SNP rs3802842 was associated with an increased risk of CRC in female carriers only (HR=3.08). In a combined analysis of the two SNPs, the risk was significantly associated with the number of risk alleles and the effect was shown to be stronger in female carriers than in male carriers