PCASTt/SPCG-17-a randomised trial of active surveillance in prostate cancer : rationale and design

Introduction Overtreatment of localised prostate cancer is substantial despite increased use of active surveillance. No randomised trials help define how to monitor patients or when to initiate treatment with curative intent. Methods and analysis A randomised, multicentre, intervention trial designed to evaluate the safety of an MRI-based active surveillance protocol, with standardised triggers for repeated biopsies and radical treatment. The aim is to reduce overtreatment of prostate cancer. 2000 men will be randomly allocated to either surveillance according to current practice or to standardised triggers at centres in Sweden, Norway, Finland and the UK. Men diagnosed in the past 12 months with prostate cancer, 0.2ng/mL/cc, any International Society of Urological Pathology (ISUP) grade 1 are eligible. Men with ISUP grade 2 in Ethics and dissemination Ethical approval was obtained in each participating country. Results for the primary and secondary outcome measures will be submitted for publication in peer-reviewed journals. Trial registration number NCT02914873.Peer reviewe

Change in lifestyle behaviors and diabetes risk: evidence from a population-based cohort study with 10 year follow-up

Abstract Background Promoting positive changes in lifestyle behavior in the whole population may be a feasible and effective approach to reducing type 2 diabetes burden, but the impact of population shifts of modifiable risk factors remains unclear. Currently most of the evidence on modifiable lifestyle behavior and type 2 diabetes risk on a population level comes from studies of between-individual differences. The objective of the study was to investigate the association and potential impact on disease burden for within-individual change in lifestyle behavior and diabetes risk. Methods Population-based prospective cohort study of 35,680 participants aged 30–50 at baseline in 1990–2003 in Västerbotten County, Sweden (follow-up until 2013). Five self-reported modifiable lifestyle behaviors (tobacco use, physical activity, alcohol intake, dietary fiber intake and dietary fat intake) were measured at baseline and 10 year follow-up. Lifestyle behaviors were studied separately, and combined in a score. Incident diabetes was detected by oral glucose tolerance tests. Multivariate logistic regression models and population attributable fractions (PAF) were used to analyze the association between change in lifestyle behavior between baseline and 10 year follow-up, and risk of incident diabetes. Results Incident diabetes was detected in 1,184 (3.3%) participants at 10 year follow-up. There was a reduced diabetes risk associated with increase in dietary fiber intake, odds ratio (OR) 0.79 (95% confidence interval (CI) 0.66, 0.96) for increase of at least one unit standard deviation (3.0 g/1,000 kcal) of the baseline distribution, PAF 16.0% (95% CI 4.2, 26.4%). Increase in the lifestyle behavior score was associated with reduced diabetes risk, OR 0.92 (95% CI 0.85, 0.99) per unit increase of the score. Conclusions These results support a causal link between lifestyle behavior and type 2 diabetes incidence. A small shift in lifestyle behaviors, in particular intake of dietary fiber, has the potential to reduce diabetes burden in the population and might be a suitable target for public health intervention

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis