KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.This work was supported by the Wellcome Trust (098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical Research Centre (ISF, IB and SOR), and European Research Council (ISF). This study makes use of data generated by the UK10K Consortium (WT091310). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.</p> <p>Methods</p> <p>6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.</p> <p>Results</p> <p>MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm³+/-243 mm³) with MRI (mean 918 mm³+/-193 mm³) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm²+/-22.8 mm²versus 32.6 mm²+/-22.6 mm²(histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm³+/-56.7 mm³after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.</p> <p>Conclusions</p> <p>This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.</p

Associations between cesarean delivery and child mortality: A national record linkage longitudinal study of 17.8 million births in Brazil.

BACKGROUND: There is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances. METHODS AND FINDINGS: We conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p < 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p < 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p < 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available. CONCLUSIONS: In this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality

Proceedings of Patient Reported Outcome Measure’s (PROMs) Conference Oxford 2017: Advances in Patient Reported Outcomes Research

A33-Effects of Out-of-Pocket (OOP) Payments and Financial Distress on Quality of Life (QoL) of People with Parkinson’s (PwP) and their Carer

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The effectiveness of two-compound formulation calcipotriol and betamethasone dipropionate gel in the treatment of moderately severe scalp psoriasis : a systematic review of direct and indirect evidence

Objectives: To evaluate the two-compound formulation (TCF) calcipotriol and betamethasone dipropionate (BDP) gel versus other topical therapies for scalp psoriasis in adults using direct and indirect comparisons. Methods: A systematic review identified 10 randomised controlled trials (RCTs) of topical treatments used in clinical practice for moderately severe scalp psoriasis. A meta-analysis was undertaken to obtain estimates of clinical effectiveness using recommended efficacy and safety outcome measures. We determined the proportion of responding patients using two definitions: i) 'controlled disease' using the Investigator Global Assessment (IGA) rating scale and ii) a score of 0 or 1 on the Total Sign Score (TSS). Tolerability was extracted in terms of percentages of patients experiencing all adverse events (AEs), skin AEs and withdrawals due to AEs. Direct comparisons were performed where head-to-head data were available. For other comparators where TCF gel was compared indirectly, 'pairs' of trials were compared on the basis of a common comparator using meta-regression in order to derive an indirect comparison estimate, while preserving randomisation within trials. Assumptions of comparability were considered regarding study homogeneity (data can be pooled in a meta-analysis), similarity of trials (clinical and methodological) and consistency of findings from direct and indirect evidence. Results: The meta-analysis showed that TCF gel was statistically significantly more effective than other topical treatments in terms of achieving a response defined according to both IGA and TSS criteria. TCF gel was generally associated with a statistically significant lower risk of AEs, skin AEs or patients withdrawing from RCTs due to AEs. Conclusions: Although direct and indirect evidence in this analysis is sparse, this indirect comparison suggests that the TCF gel has significant benefits over other topical therapies considered in the routine management of patients with moderately severe scalp psoriasis. Despite other analysis limitations in terms of study heterogeneity inevitable across an evidence base spanning decades, these results were consistent, using a number of efficacy and tolerability outcome measures

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Cost-effectiveness, Cost-utility, Pioglitazone, Rosiglitazone, Type-2-diabetes-mellitus

A Lifetime Modelled Economic Evaluation Comparing Pioglitazone and Rosiglitazone for the Treatment of Type 2 Diabetes Mellitus in the UK

Introduction: Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin. Methods: A decision-analytic model employing a first order Monte Carlo simulation of a Markov process was constructed. The model incorporated surrogate outcome measures from a large randomised controlled trial (RCT) [n_=_802] that compared the glycaemic and lipid control of pioglitazone and rosiglitazone monotherapy. These efficacy data were used with a recently validated and peer-reviewed UKPDS (UK Prospective Diabetes Study) algorithm to simulate the progression of these surrogate outcomes to final health outcomes, including quality of life (QOL) and mortality, and to calculate the risks of diabetic complications and death. The model perspective was of the UK NHS and included direct healthcare costs only (Lstg , 2004/5 values). Patient outcomes measured in the model included life-expectancy (LE) and QALYs. The base-case analysis was run for 56-year-old male Caucasions with a haemoglobin A1c (HbA1c) of 7.57% and a body mass index of 33.14 kg/m2. Results: Patients treated with pioglitazone experienced a reduction in the total cholesterol to high-density lipoprotein-cholesterol (TC___HDL-C) ratio of 0.34, whereas the TC___HDL-C ratio increased by 0.65 in those receiving rosiglitazone (p_Cost-effectiveness, Cost-utility, Pioglitazone, Rosiglitazone, Type-2-diabetes-mellitus