Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances.Design Systematic review and meta-analysis of observational studies and randomised controlled trials.Data sources Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. Study selectionObservational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes.Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. ResultsIn the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements . In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D 3 supplementation and 1.04 (0.97 to 1.11) for vitamin D 2 supplementation . The effects observed for vitamin D 3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D 2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. ConclusionsEvidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D 3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D 3 and D 2 have different effects on mortality risk.

BackgroundThere are few studies of atrial fibrillation (AF) outside of North America or Europe. The aim of the present study was to assess the prevalence, incidence, management and outcomes of patients with new atrial fibrillation, in a large contemporary cohort (2004–2012) of adult patients.Methods and ResultsThe Clalit Health Services (CHS) computerized database of 2 420 000 adults, includes data of community clinic visits, hospital discharge records, medical diagnoses, medications, medical interventions, and laboratory test results. The prevalence of AF on January 1, 2004 was 71 644 (3%). Prevalence and incidence of AF increased with age and was higher in men versus women. During the study period (2004–2012) 98 811 patients developed new non‐valvular AF (mean age −72, 50% women, 46% with cardiovascular disease, 6% with prior stroke). The rate of persistent warfarin use (dispensed for >3 months in a calendar year) was low (25.7%) and it increased with increasing stroke risk score. Individual Time in Therapeutic Range (TTR) among warfarin users was 42%. The incidence rate of ischemic stroke and death increased with age. The rate of stroke increased from 2 per 1000 person years in patients with CHA2DS2_VASC SCORE of 0, to 58 per 1000 person years in those with a score of 9.ConclusionsIn the present study the prevalence and incidence of AF, stroke, and death were comparable to those reported in Europe and North America. The low use of anticoagulation calls for measures to increase adherence to current treatment recommendations in order to improve outcomes.

Purpose The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. Patients and Methods We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). Results We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r=−0.72) but not with the log of the regression rate constants, log(d)(r=−0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median had a mortality hazard of 5.14 (95% confidence interval, 3.10–8.52) when compared with those with log(g) values below the median. Mathematically, the minimum PSA value (nadir) and the time to this minimum are determined by the kinetic parameters d and g, and can be viewed as surrogates. Conclusions This mathematical model has applications to many tumor types and may aid in evaluating patient outcomes. Modeling tumor progression using data gathered while patients are on study, may help evaluate the ability of therapies to prolong survival and assist in drug development.

The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3-untranslated region, was consistently down-regulated by miR-31 introduction and upregulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumorsuppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome.

Among obese patients in a large integrated health fund in Israel, bariatric surgery using laparoscopic banding, gastric bypass, or laparoscopic sleeve gastrectomy, compared with usual care nonsurgical obesity management, was associated with lower all-cause mortality over a median follow-up of approximately 4.5 years. The evidence of this association adds to the limited literature describing beneficial outcomes of these 3 types of bariatric surgery compared with usual care obesity management alone.