Association analysis of Notch pathway signalling genes in diabetic nephropathy

Several studies have provided compelling evidence implicating the Notch signalling pathway in diabetic nephropathy. Co-regulation of Notch signalling pathway genes with GREM1 has recently been demonstrated and several genes involved in the Notch pathway are differentially expressed in kidney biopsies from individuals with diabetic nephropathy. We assessed single-nucleotide polymorphisms (SNPs; n = 42) in four of these key genes (JAG1, HES1, NOTCH3 and ADAM10) for association with diabetic nephropathy using a case-control design.
Tag SNPs and potentially functional SNPs were genotyped using Sequenom or Taqman technologies in a total of 1371 individuals with type 1 diabetes (668 patients with nephropathy and 703 controls without nephropathy). Patients and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK (http://pngu.mgh.harvard.edu/similar to purcell/plink/) and haplotype frequencies in patients and controls were compared. Adjustment for multiple testing was performed by permutation testing.
In analyses stratified by centre, we identified six SNPs, rs8708 and rs11699674 (JAG1), rs10423702 and rs1548555 (NOTCH3), rs2054096 and rs8027998 (ADAM10) as being associated with diabetic nephropathy before, but not after, adjustment for multiple testing. Haplotype and subgroup analysis according to duration of diabetes also failed to find an association with diabetic nephropathy.
Our results suggest that common variants in JAG1, HES1, NOTCH3 and ADAM10 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes from involvement in the pathogenesis of diabetic nephropathy.

Choice of contracts in the British National Health Service: An empirical study

Following major reforms of the British National Health Service (NHS) in 1990, the roles of purchasing and providing health services were separated, with the relationship between purchasers and providers governed by contracts. Using a mixed multinomial logit analysis, we show how this policy shift led to a selection of contracts that is consistent with the predictions of a simple model, based on contract theory, in which the characteristics of the health services being purchased and of the contracting parties influence the choice of contract form. The paper thus provides evidence in support of the practical relevance of theory in understanding health care market reform. © 2008 Elsevier B.V. All rights reserved.

Prospective, Randomized Assessment of Transfer of Training (ToT) and Transfer Effectiveness Ratio (TER) of Virtual Reality Simulation Training for Laparoscopic Skill Acquisition

OBJECTIVES:: We assessed the effectiveness of ToT from VR laparoscopic simulation training in 2 studies. In a second study, we also assessed the TER. ToT is a detectable performance improvement between equivalent groups, and TER is the observed percentage performance differences between 2 matched groups carrying out the same task but with 1 group pretrained on VR simulation. Concordance between simulated and in-vivo procedure performance was also assessed. DESIGN:: Prospective, randomized, and blinded. PARTICIPANTS:: In Study 1, experienced laparoscopic surgeons (n = 195) and in Study 2 laparoscopic novices (n = 30) were randomized to either train on VR simulation before completing an equivalent real-world task or complete the real-world task only. RESULTS:: Experienced laparoscopic surgeons and novices who trained on the simulator performed significantly better than their controls, thus demonstrating ToT. Their performance showed a TER between 7% and 42% from the virtual to the real tasks. Simulation training impacted most on procedural error reduction in both studies (32- 42%). The correlation observed between the VR and real-world task performance was r > 0·96 (Study 2). CONCLUSIONS:: VR simulation training offers a powerful and effective platform for training safer skills.

Bioinformatic evaluation of transcriptional regulation of WNT pathway genes with reference to diabetic nephropathy

Objective: Diabetic nephropathy (DN) is a microvascular complication of diabetes. Members of the WNT/ β-catenin pathways have been implicated in interstitial fibrosis and glomerular sclerosis, characteristic hallmarks of DN. These processes are controlled, in part, by transcription factors (TFs), proteins which bind to gene promoter regions attenuating their regulation. We sought to identify predicted cis-acting transcription factor binding sites (TFBS) over-represented within the promoter regions of WNT pathway members compared to genes across the genome.Methods: We assessed the frequency of 62 TFBS motifs from the JASPAR databases on 65 WNT pathway genes. P-values were estimated on the hypergeometric distribution for each TF. Gene expression profiles of enriched motifs were examined from DN-related datasets to assess clinical significance.Results: TFBS motifs transcription factor AP-2 alpha (TFAP2A), myeloid zinc finger 1 (MZF1), and specificity protein 1 (SP1) were significantly enriched within WNT pathway genes (P-values<6.83x10-29, 1.34x10-11 and 3.01x10-6 respectively). MZF1 gene expression was significantly increased in DN in a whole kidney dataset (fold change = 1.16; 16% increase; P = 0.03). TFAP2A gene expression was decreased in an independent dataset (fold change = -1.02; P = 0.03). SP1 was not differentially expressed in any datasets examined.Conclusions: Three TFBS profiles are significantly enriched within the WNT pathway genes examined highlighting the use of in silico analyses for identifying key regulators of this pathway. Modification of TF binding to gene promoter regions involved in DN pathology may limit progression, making refinement of targeted therapeutic strategies possible through clearer delineation of their role.

Choice of commuting mode among employees: Do home neighborhood environment, worksite neighborhood environment, and worksite policy and supports matter?

BACKGROUND: Promoting the use of public transit and active transport (walking and cycling) instead of car driving is an appealing strategy to increase overall physical activity.

PURPOSE: To quantify the combined associations between self-reported home and worksite neighborhood environments, worksite support and policies, and employees' commuting modes.

METHOD: Between 2012 and 2013, participants residing in four Missouri metropolitan areas were interviewed via telephone (n = 1,338) and provided information on socio-demographic characteristics, home and worksite neighborhoods, and worksite support and policies. Commuting mode was self-reported and categorized into car driving, public transit, and active commuting. Commuting distance was calculated using geographic information systems. Commuters providing completed data were included in the analysis. Multivariate logistic regression models were used to examine the correlates of using public transit and active commuting.

RESULT: The majority of participants reported commuting by driving (88.9%); only 4.9% used public transit and 6.2% used active modes. After multivariate adjustment, having transit stops within 10-15 minutes walking distance from home (p=0.05) and using worksite incentive for public transit (p<0.001) were associated with commuting by public transit. Commuting distance (p<0.001) was negatively associated with active commuting. Having free or low cost recreation facilities around the worksite (p=0.04) and using bike facilities to lock bikes at the worksite (p<0.001) were associated with active commuting.

CONCLUSION: Both environment features and worksite supports and policies are associated with the choice of commuting mode. Future studies should use longitudinal designs to investigate the potential of promoting alternative commuting modes through worksite efforts that support sustainable commuting behaviors as well as the potential of built environment improvements.

Behavioural and cognitive behavioural training interventions for assisting foster carers in the management of difficult behaviour.

Background The provision of training for foster carers is now seen as an important factor contributing to the successful outcome of foster care placements. Since the late 1960s, foster carer training programs have proliferated, and few of the many published and unpublished training curricula have been systematically evaluated. The advent of cognitive-behavioural therapy (CBT) and the research evidence demonstrating its effectiveness as a psychotherapeutic treatment of choice for a range of emotional and behavioural problems, has prompted the development of CBT-based training programmes. CBT approaches to foster care training derive from a ’skill-based’ training format that also seeks to identify and correct problematic thinking patterns that are associated with dysfunctional behaviour by changing and/or challenging maladaptive thoughts and beliefs. Objectives To assess the effectiveness of cognitive-behavioural training interventions in improving a) looked-after children’s behavioural/relationship problems, b) foster carers’ psychological well-being and functioning, c) foster family functioning, d) foster agency outcomes. Search methods We searched databases including: CENTRAL (Cochrane Library Issue 3, 2006), MEDLINE (January 1966 to September 2006), EMBASE (January 1980 to September 2006), CINAHL (January 1982 to September 2006), PsycINFO (January 1872 to September 2006), ASSIA (January 1987 to September 2006), LILACS (up to September 2006), ERIC (January 1965 to September 2006), Sociological Abstracts (January 1963 to September 2006), and the National Research Register 2006 (Issue 3).We contacted experts in the field concerning current research. Selection criteria Random or quasi randomised studies comparing behavioural or cognitive-behavioural-base Data collection and analysis Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Main results Six trials involving 463 foster carers were included. Behavioural and cognitive-behavioural training interventions evaluated to date appear to have very little effect on outcomes relating to looked-after children, assessed in relation to psychological functioning, extent of behavioural problems and interpersonal functioning. Results relating to foster carer(s) outcomes also show no evidence of effectiveness in measures of behavioural management skills, attitudes and psychological functioning. Analysis pertaining to fostering agency outcomes did not show any significant results. However, caution is needed in interpreting these findings as their confidence intervals are wide. Authors’ conclusions There is currently little evidence about the efficacy of behavioural or cognitive-behavioural training intervention for foster carers. The need for further research in this area is highlighted.

Correlates of food choice in unemployed young people: The role of demographic factors, self-efficacy, food involvement, food poverty and physical activity

Associations between socio-demographic and psychological factors and food choice patterns were explored in unemployed young people who constitute a vulnerable group at risk of poor dietary health. Volunteers (N = 168), male (n = 97) and female (n = 71), aged 15–25 years were recruited through United Kingdom (UK) community-based organisations serving young people not in education training or employment (NEET). Survey questionnaire enquired on food poverty, physical activity and measured responses to the Food Involvement Scale (FIS), Food Self-Efficacy Scale (FSS) and a 19-item Food Frequency Questionnaire (FFQ). A path analysis was undertaken to explore associations between age, gender, food poverty, age at leaving school, food self-efficacy (FS-E), food involvement (FI) (kitchen; uninvolved; enjoyment), physical activity and the four food choice patterns (junk food; healthy; fast food; high fat). FS-E was strong in the model and increased with age. FS-E was positively associated with more
frequent choice of healthy food and less frequent junk or high fat food (having controlled for age, gender and age at leaving school). FI (kitchen and enjoyment) increased with age. Higher FI (kitchen) was associated with less frequent junk food and fast food choice. Being uninvolved with food was associated with
more frequent fast food choice. Those who left school after the age of 16 years reported more frequent physical activity. Of the indirect effects, younger individuals had lower FI (kitchen) which led to frequent junk and fast food choice. Females who were older had higher FI (enjoyment) which led to less frequent fast food choice. Those who had left school before the age of 16 had low food involvement (uninvolved) which led to frequent junk food choice. Multiple indices implied that data were a good fit to the model which indicated a need to enhance food self-efficacy and encourage food involvement in order to improve dietary health among these disadvantaged young people.