Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis

Context: Identifying susceptibility genes for schizophrenia may be complicated by phenotypic heterogeneity, with some evidence suggesting that phenotypic heterogeneity reflects genetic heterogeneity. Objective: To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes. Design: Latent class and linkage analysis. Setting: Taiwanese field research centers. Participants: The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3. Main Outcome Measures: Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores. Results: Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling "deficit schizophrenia." The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region. Conclusion: Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies

Short sleep duration is associated with risk of future diabetes but not cardiovascular disease: a prospective study and meta-analysis

Epidemiologic studies have observed association between short sleep duration and both cardiovascular disease (CVD) and type 2 diabetes, although these results may reflect confounding by pre-existing illness. This study aimed to determine whether short sleep duration predicts future CVD or type 2 diabetes after accounting for baseline health. Baseline data for 241,949 adults were collected through the 45 and Up Study, an Australian prospective cohort study, with health outcomes identified via electronic database linkage. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals. Compared to 7h sleep, <6h sleep was associated with incident CVD in participants reporting ill-health at baseline (HR=1.38 [95% CI: 1.12-1.70]), but not after excluding those with baseline illness and adjusting for baseline health status (1.03 [0.88-1.21]). In contrast, the risk of incident type 2 diabetes was significantly increased in those with <6h versus 7h sleep, even after excluding those with baseline illness and adjusting for baseline health (HR=1.29 [1.08-1.53], P=0.004). This suggests the association is valid and does not simply reflect confounding or reverse causation. Meta-analysis of ten prospective studies including 447,124 participants also confirmed an association between short sleep and incident diabetes (1.33 [1.20-1.48]). Obtaining less than 6 hours of sleep each night (compared to 7 hours) may increase type 2 diabetes risk by approximately 30%.The Sax Institute; Cancer Council New South Wales; the National Heart Foundation of Australia (New South Wales Division); The New South Wales Ministry of Health; Beyondblue: the National Depression Initiative; Ageing, Disability and Home Care, New South Wales Family and Community Services; the Australian Red Cross Blood Service; Uniting Care Ageing; the Australian National Health and Medical Research Council

What is the effect of interrupting prolonged sitting with frequent bouts of physical activity or standing on first or recurrent stroke risk factors? A scoping review

The objective of this review was to ascertain the scope of the available literature on the effects of interrupting prolonged sitting time with frequent bouts of physical activity or standing on stroke and recurrent stroke risk factors. Databases Medline, Embase, AMED, CINAHL and Cochrane library were comprehensively searched from inception until 21st February 2018. Experimental trials which interrupted sitting time with frequent bouts of physical activity or standing in adults (≥ 18 years) were included. Comparison to a bout of prolonged sitting and a measure of at least one first or recurrent stroke risk factor was required to be included. Overall, 30 trials (35 articles) were identified to meet the inclusion criteria. Fifteen trials were completed in participants at an increased risk of having a first stroke and one trial in participants at risk of a recurrent stroke. Outcomes of hypertension and dysglycemia were found to be more favourable following predominately light- to moderate-intensity bouts of physical activity or standing compared to sitting in the majority of trials in participants at risk of having a first stroke. In the one trial of stroke survivors, only outcomes of hypertension were significantly improved. These findings are of significant importance taking into consideration hypertension is the leading risk factor for first and recurrent stroke. However, trials primarily focused on measuring outcomes of dysglycemia and without assessing a dose-response effect. Additional research is required on the dose-response effect of interrupting sitting with frequent bouts of physical activity or standing on first and recurrent stroke risk factors, in those high risk population groups

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

Emergency department referral patterns of Australian general practitioner registrars: A cross-sectional analysis of prevalence, nature and associations

Objective: Limited international evidence suggests general practice registrars' emergency department (ED) referral rates exceed those of established general practitioners (GPs). The aim of the present study was to fill an evidence gap by establishing the prevalence, nature and associations of Australian GP registrar ED referrals. Methods: A cross-sectional analysis was performed of the Registrar Clinical Encounters in Training (ReCEnT) cohort study of GP registrars' consultation experiences, between 2010 and 2015. The outcome factor in logistic regression analysis was referral to an ED. Independent variables included patient-level, registrar-level, practice-level and consultation-level factors. Results: In all, 1161 GP registrars (response rate 95.5%) contributed data from 166 966 consultations, comprising 258 381 individual problems. Based on responses, 0.5% of problems resulted in ED referral, of which nearly 25% comprised chest pain, abdominal pain and fractures. Significant (P 34 years, the patient being new to the registrar, one particular regional training provider (RTP), in-consultation information or assistance being sought and learning goals being generated. Outer regional-, remote-or very remote-based registrars made significantly fewer ED referrals than more urban registrars. Of the problems referred to the ED, 45.5% involved the seeking of in-consultation information or assistance, predominantly from supervisors. Conclusions: Registrars' ED referral rates are nearly twice those of established GPs. The findings of the present study suggest acute illnesses or injuries present registrars with clinical challenges and real learning opportunities, and highlight the importance of continuity of care, even for acute presentations

Transitions in general practice training : quantifying epidemiological variation in trainees' experiences and clinical behaviours

Background: General Practice training in Australia is delivered through the apprenticeship model. General Practice supervisors support trainees transitioning from hospital-based work towards competent independent community-based practice. The timing and manner in which support should be provided is still not well understood. This study aimed to establish the variation in clinical and educational experiences and behaviours, and location, of general practice trainees’ consultations by stage of their vocational training. It was hypothesised that change is greater in earlier stages of training. Methods: A cross-sectional analysis of data (2010–2018) from the Registrar Clinical Encounters in Training (ReCEnT) study, an ongoing cohort study of Australian GP registrars’ in-consultation clinical and educational experience and behaviours. Multinomial logistic regression assessed the association of demographic, educational, and clinical factors in different stages of training. The outcome factor was the training term. Results: Two thousand four hundred sixteen registrars contributed data for 321,414 patient consultations. For several important variables (seeing patients with chronic disease; new patients; seeking in-consultation information or assistance; ordering pathology and imaging; and working in a small or regional practice), odds ratios were considerably greater for comparisons of Term 1 and 3, relative to comparisons of Term 2 and 3. Conclusion: Differences experienced in demographic, clinical and educational factors are significantly more pronounced earlier in registrars’ training. This funding has educational and training implications with respect to resource allocation, trainee supervision and curriculum design. Sociocultural learning theory enables an understanding of the impact of transitions on, and how to support, general practice trainees and supervisors

Exposure to Stress and Air Pollution from Bushfires during Pregnancy: Could Epigenetic Changes Explain Effects on the Offspring?

Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.Vanessa Murphy is supported by an Investigator Grant from the Medical Research Future Fund (grant ID 1196252)

Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11\u2005326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 710(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

School-based physical activity intervention for older adolescents: rationale and study protocol for the Burn 2 Learn cluster randomised controlled trial

Introduction This trial aims to investigate the impact of a school-based physical activity programme, involving high-intensity interval training (HIIT), on the physical, mental and cognitive health of senior school students. Methods and analysis The Burn 2 Learn (B2L) intervention will be evaluated using a two-arm parallel group cluster randomised controlled trial with allocation occurring at the school level (to treatment or wait-list control). Schools will be recruited in two cohorts from New South Wales, Australia. The trial will aim to recruit ∼720 senior school students (aged 16-18 years) from 20 secondary schools (ie, 10 schools per cohort). A range of implementation strategies will be provided to teachers (eg, training, equipment and support) to facilitate the delivery of HIIT sessions during scheduled classes. In phase I and II (3 months each), teachers will facilitate the delivery of at least two HIIT sessions/week during lesson-time. In phase III (6 months), students will be encouraged to complete sessions outside of lesson-time (teachers may continue to facilitate the delivery of B2L sessions during lesson-time). Study outcomes will be assessed at baseline, 6 months (primary end point) and 12 months. Cardiorespiratory fitness (shuttle run test) is the primary outcome. Secondary outcomes include: vigorous physical activity, muscular fitness, cognition and mental health. A subsample of students will (i) provide hair samples to determine their accumulated exposure to stressful events and (ii) undergo multimodal MRI to examine brain structure and function. A process evaluation will be conducted (ie, recruitment, retention, attendance and programme satisfaction)