GeneTIER: prioritization of candidate disease genes using tissue-specific gene expression profiles.

Motivation In attempts to determine the genetic causes of human disease, researchers are often faced with a large number of candidate genes. Linkage studies can point to a genomic region containing hundreds of genes, while the high-throughput sequencing approach will often identify a great number of non-synonymous genetic variants. Since systematic experimental verification of each such candidate gene is not feasible, a method is needed to decide which genes are worth investigating further. Computational gene prioritization presents itself as a solution to this problem, systematically analyzing and sorting each gene from the most to least likely to be the disease-causing gene, in a fraction of the time it would take a researcher to perform such queries manually. Results Here we present GeneTIER (Gene TIssue Expression Ranker), a new web-based application for candidate gene prioritization. GeneTIER replaces knowledge-based inference traditionally used in candidate disease gene prioritization applications with experimental data from tissue-specific gene expression datasets and thus largely overcomes the bias towards the better characterized genes/diseases that commonly afflict other methods. We show that our approach is capable of accurate candidate gene prioritization and illustrate its strengths and weaknesses using case study examples. Availability and Implementation Freely available on the web at http://dna.leeds.ac.uk/GeneTIER/ Contact: [email protected]

Associations between data-driven lifestyle profiles and cognitive function in the AusDiab study

Background: Mounting evidence highlights the importance of combined modifiable lifestyle factors in reducing risk of cognitive decline and dementia. Several a priori additive scoring approaches have been established; however, limited research has employed advanced data-driven approaches to explore this association. This study aimed to examine the association between data-driven lifestyle profiles and cognitive function in community-dwelling Australian adults. Methods: A cross-sectional study of 4561 Australian adults (55.3% female, mean age 60.9 ± 11.3 years) was conducted. Questionnaires were used to collect self-reported data on diet, physical activity, sedentary time, smoking status, and alcohol consumption. Cognitive testing was undertaken to assess memory, processing speed, and vocabulary and verbal knowledge. Latent Profile Analysis (LPA) was conducted to identify subgroups characterised by similar patterns of lifestyle behaviours. The resultant subgroups, or profiles, were then used to further explore associations with cognitive function using linear regression models and an automatic Bolck, Croon & Hagenaars (BCH) approach. Results: Three profiles were identified: (1) “Inactive, poor diet” (76.3%); (2) “Moderate activity, non-smokers” (18.7%); and (3) “Highly active, unhealthy drinkers” (5.0%). Profile 2 “Moderate activity, non-smokers” exhibited better processing speed than Profile 1 “Inactive, poor diet”. There was also some evidence to suggest Profile 3 “Highly active, unhealthy drinkers” exhibited poorer vocabulary and verbal knowledge compared to Profile 1 and poorer processing speed and memory scores compared to Profile 2. Conclusion: In this population of community-dwelling Australian adults, a sub-group characterised by moderate activity levels and higher rates of non-smoking had better cognitive function compared to two other identified sub-groups. This study demonstrates how LPA can be used to highlight sub-groups of a population that may be at increased risk of dementia and benefit most from lifestyle-based multidomain intervention strategies

Australian Enterococcal Sepsis Outcome Programme, 2011

From 1 January to 31 December 2011, 29 institutions around Australia participated in the Australian Enterococcal Sepsis Outcome Programme (AESOP). The aim of AESOP 2011 was to determine the proportion of enterococcal bacteraemia isolates in Australia that are antimicrobial resistant, with particular emphasis on susceptibility to ampicillin and the glycopeptides, and to characterise the molecular epidemiology of the Enterococcus faecalis and E. faecium isolates. Of the 1,079 unique episodes of bacteraemia investigated, 95.8% were caused by either E. faecalis (61.0%) or E. faecium (34.8%). Ampicillin resistance was detected in 90.4% of E. faecium but not detected in E. faecalis. Using Clinical and Laboratory Standards Institute breakpoints (CLSI), vancomycin non-susceptibility was reported in 0.6% and 31.4% of E. faecalis and E. faecium respectively and was predominately due to the acquisition of the vanB operon. Approximately 1 in 6 vanB E. faecium isolates however, had an minimum inhibitory concentration at or below the CLSI vancomycin susceptible breakpoint of ≤ 4 mg/L. Overall, 37% of E. faecium harboured vanA or vanB genes. Although molecular typing identified 126 E. faecalis pulsed-field gel electrophoresis (PFGE) pulsotypes, more than 50% belonged to 2 pulsotypes that were isolated across Australia. E. faecium consisted of 73 PFGE pulsotypes from which 43 multilocus sequence types were identified. Almost 90% of the E. faecium were identified as clonal complex 17 clones, of which approximately half were characterised as sequence type 203, which was isolated Australia-wide. In conclusion, the AESOP 2011 has shown that although polyclonal, enterococcal bacteraemias in Australia are frequently caused by ampicillin-resistant vanB E. faecium

Are antenatal interventions effective in improving multiple health behaviours among pregnant women? A systematic review protocol.

BACKGROUND: Maternal behaviours in pregnancy associated with adverse pregnancy, birth and health outcomes include tobacco smoking, poor nutrition, alcohol consumption and low physical activity, collectively referred to as the SNAP risk factors. Due to the high prevalence, co-occurrence and possible interactive health effects of such health behaviours in pregnancy, antenatal interventions that support pregnant women to improve multiple SNAP behaviours have a greater potential impact on the health outcomes of women and their children than interventions addressing single behaviours. The objective of this review is to determine the effectiveness of interventions delivered as part of antenatal care that aim to improve multiple SNAP behaviours among pregnant women. METHODS: Seven electronic databases will be searched for potentially eligible studies. Eligible studies will include those where pregnant women are attending antenatal care. Studies that examine the effect of an intervention that addresses multiple SNAP behaviours (≥ 2 behaviours) during pregnancy and are delivered or instigated through antenatal care in a healthcare service will be included. Systematic reviews of randomised controlled trials (RCTs), RCTs, cluster RCTs, stepped-wedge RCTs and non-randomised control trials will be eligible. Studies that include a no-intervention control, wait-list control group, standard/usual care, or another active single behavioural intervention (e.g. addressing one behaviour only) will be considered. Two independent reviewers will conduct study screening, data extraction and risk of bias assessment. Discrepancies will be resolved by consensus or a third reviewer if required. A random effects model will be used to synthesise the results. Alternative synthesis methods will be investigated in instances where a meta-analysis is not appropriate, such as summarising effect estimates, combining P values, vote counting based on direction of effect, or synthesis in narrative form. DISCUSSION: The review will synthesise the evidence on the effect of interventions that address multiple SNAP behaviours in antenatal care and will help researchers, policy-makers and health services to develop and deliver best practice integrated models of antenatal care that have the potential to impact on both the short- and long-term health outcomes for women and their children. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018095315

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Evidence based medicine as science

Evidence based medicine has claimed to be science on a number of occasions but it is not clear that this status is deserved. Within philosophy of science four main theories about the nature of science are historically recognised: inductivism, falsificationism, Kuhnian paradigms and research programmes. If evidence based medicine is science knowledge claims should be derived using a process that corresponds to one of these theories. This paper analyses whether this is the case. In the first section, different theories about the nature of science are introduced. In the second section, the claim that evidence based medicine is science is reinterpreted as the claim that knowledge claims derived from randomised controlled trails and meta-analyses are science. In the third section the knowledge claims valued within evidence based medicine are considered from the perspective of inductivism, falsificationism, Kuhnian paradigms and research programmes. In the final section possible counter arguments are considered. It is argued that the knowledge claims valued by evidence based medicine are not justified using inductivism, falsificationism, Kuhnian paradigms or research programmes. If these are the main criteria for evaluating if something is science or not, evidence based medicine does not meet these criteria

Recent Salmon Declines: A Result of Lost Feeding Opportunities Due to Bad Timing?

As the timing of spring productivity blooms in near-shore areas advances due to warming trends in global climate, the selection pressures on out-migrating salmon smolts are shifting. Species and stocks that leave natal streams earlier may be favoured over later-migrating fish. The low post-release survival of hatchery fish during recent years may be in part due to static release times that do not take the timing of plankton blooms into account. This study examined the effects of release time on the migratory behaviour and survival of wild and hatchery-reared coho salmon (Oncorhynchus kisutch) using acoustic and coded-wire telemetry. Plankton monitoring and near-shore seining were also conducted to determine which habitat and food sources were favoured. Acoustic tags (n = 140) and coded-wire tags (n = 266,692) were implanted into coho salmon smolts at the Seymour and Quinsam Rivers, in British Columbia, Canada. Differences between wild and hatchery fish, and early and late releases were examined during the entire lifecycle. Physiological sampling was also carried out on 30 fish from each release group. The smolt-to-adult survival of coho salmon released during periods of high marine productivity was 1.5- to 3-fold greater than those released both before and after, and the fish's degree of smoltification affected their downstream migration time and duration of stay in the estuary. Therefore, hatchery managers should consider having smolts fully developed and ready for release during the peak of the near-shore plankton blooms. Monitoring chlorophyll a levels and water temperature early in the spring could provide a forecast of the timing of these blooms, giving hatcheries time to adjust their release schedule

The effects of progressive resistance training combined with a whey-protein drink and vitamin D supplementation on glycaemic control, body composition and cardiometabolic risk factors in older adults with type 2 diabetes: study protocol for a randomized controlled trial

Background - While physical activity, energy restriction and weight loss are the cornerstone of type 2 diabetes management, less emphasis is placed on optimizing skeletal muscle mass. As muscle is the largest mass of insulin-sensitive tissue and the predominant reservoir for glucose disposal, there is a need to develop safe and effective evidence-based, lifestyle management strategies that optimize muscle mass as well as improve glycaemic control and cardiometabolic risk factors in people with this disease, particularly older adults who experience accelerated muscle loss. Methods/Design - Using a two-arm randomized controlled trial, this 6-month study builds upon the community-based progressive resistance training (PRT) programme Lift for Life® to evaluate whether ingestion of a whey-protein drink combined with vitamin D supplementation can enhance the effects of PRT on glycaemic control, body composition and cardiometabolic health in older adults with type 2 diabetes. Approximately 200 adults aged 50 to 75 years with type 2 diabetes, treated with either diet alone or oral hypoglycaemic agents (not insulin), will be recruited. All participants will be asked to participate in a structured, supervised PRT programme based on the Lift for Life® programme structure, and randomly allocated to receive a whey-protein drink (20 g daily of whey-protein plus 20 g after each PRT session) plus vitamin D supplements (2000 IU/day), or no additional powder and supplements. The primary outcome measures to be collected at baseline, 3 and 6 months will be glycated haemoglobin (HbA1c) and insulin sensitivity (homeostatic model assessment). Secondary outcomes will include changes in: muscle mass, size and intramuscular fat; fat mass; muscle strength and function; blood pressure; levels of lipids, adipokines and inflammatory markers, serum insulin-like growth factor-1 and 25-hydroxyvitamin D; renal function; diabetes medication; health-related quality of life, and cognitive function. Discussion - The findings from this study will provide new evidence on whether increased dietary protein achieved through the ingestion of a whey-protein drink combined with vitamin D supplementation can enhance the effects of PRT on glycaemic control, muscle mass and size, and cardiometabolic risk factors in older adults with type 2 diabetes

TRPV1 enhances the afferent response to P2X receptor activation in the mouse urinary bladder

Both TRPV1 and P2X receptors present on bladder sensory nerve fibres have been implicated in mechanosensation during bladder filling. The aim of this study was to determine possible interactions between these receptors in modulating afferent nerve activity. In wildtype (TRPV1+/+) and TRPV1 knockout (TRPV1−/−) mice, bladder afferent nerve activity, intravesical pressure, and luminal ATP and acetylcholine levels were determined and also intracellular calcium responses of dissociated pelvic DRG neurones and primary mouse urothelial cells (PMUCs). Bladder afferent nerve responses to the purinergic agonist αβMethylene-ATP were depressed in TRPV1−/− mice (p ≤ 0.001) and also in TRPV1+/+ mice treated with the TRPV1-antagonist capsazepine (10 µM; p ≤ 0.001). These effects were independent of changes in bladder compliance or contractility. Responses of DRG neuron to αβMethylene-ATP (30 µM) were unchanged in the TRPV1−/− mice, but the proportion of responsive neurones was reduced (p ≤ 0.01). Although the TRPV1 agonist capsaicin (1 µM) did not evoke intracellular responses in PMUCs from TRPV1+/+ mice, luminal ATP levels were reduced in the TRPV1−/− mice (p ≤ 0.001) compared to wildtype. TRPV1 modulates P2X mediated afferent responses and provides a mechanistic basis for the decrease in sensory symptoms observed following resiniferatoxin and capsaicin treatment for lower urinary tract symptoms

Food consumption habits in two states of Australia, as measured by a Food Frequency Questionnaire

BACKGROUND: Obesity is an important public health problem in Australia, and monitoring the nutritional intake of the population is an important endeavour. One way to assess food habits is via Food Frequency Questionnaires (FFQ). This pilot study used a routine telephone risk factor surveillance survey to recruit participants in South Australia (SA) and Western Australia (WA) to a postal survey investigating food consumption habits, using a FFQ. Respondents were also asked specific additional questions about their fruit and vegetable consumption and also about their height and weight so that comparisons could be made between the data collected in the risk factor surveillance system and the postal survey. FINDINGS: In total, 1275 respondents (65% of eligible telephone respondents) completed the postal survey. The results of the FFQ were very similar for WA and SA. Western Australians consumed statistically significantly more serves of vegetables than South Australians (t = 2.69 df = 1245 p <= 0.01), and females consumed statistically significantly more serves of both fruit and vegetables than males (t = 4.51 df = 1249 p <= 0.01 and t = 4.83 df = 1249 p <= 0.01 respectively). Less than 10% of respondents met the daily guidelines for vegetable consumption. Over half of respondents were overweight or obese. CONCLUSIONS: Although a wide variety of foods were consumed, guidelines for fruit and vegetable consumption were not being met and overweight and obesity continue to be issues in this population.Alison M. Daly, Jacqueline E. Parsons, Nerissa A. Wood, Tiffany K. Gill and Anne W. Taylo