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Importance: Statins appear to lower serum prostate-specific antigen (PSA) and improve prostate cancer (PCa) outcomes through cholesterol-dependent and independent mechanisms. While dietary modifications have an established role in serum cholesterol reduction, whether diet-driven cholesterol reductions yield similar PCa benefits to that observed with statins is unclear. We aimed to study the effect of diet-driven cholesterol reduction on serum PSA and estimated-PCa risk. Methods: A total of 291 men from six published randomized controlled trials of dietary interventions were included. Men were aged ≥40 years, free of PCa, and had baseline PSA

Summary Background Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? Aims We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. Methods The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator’s early life educational history in order to predict the innovator’s likely success at medical school entry, assuming excellence in all entrance requirements. Results Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today’s standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. Conclusion These data show that today’s medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

ImportanceEpidemiological evidence supports a role for statins in improving survival in advanced prostate cancer, particularly among men receiving androgen-ablative therapies.ObjectiveTo study the association between statin use and survival among men with prostate cancer receiving androgen deprivation therapy (ADT) or androgen receptor axis–targeted therapies (ARATs).Data SourcesThis systemic review and meta-analysis used sources from MEDLINE, EMBASE, Epub Ahead of Print, Cochrane Clinical Trials, Cochrane Systematic Reviews, and Web of Science from inception to September 6, 2022.Study SelectionObservational studies reporting associations of concurrent statin use and survival outcomes (in hazard ratios [HRs]).Data Extraction and SynthesisTwo authors independently abstracted all data. Summary estimates pooled multivariable HRs with 95% CIs using the generic inverse variance method with random-effects modeling. A priori specified subgroup and sensitivity analyses were undertaken, and heterogeneity, study quality, and publication bias were evaluated. Confidence in the evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.Main Outcomes and MeasuresOverall mortality and prostate cancer–specific mortality (PCSM).ResultsTwenty-five cohorts of 119 878 men (65 488 statin users [55%]) with more than 74 416 deaths were included. Concurrent statin use was associated with a 27% reduction in the risk of overall mortality (HR, 0.73 [95% CI, 0.66-0.82]; I2 = 83%) and a 35% reduction in the risk of PCSM (HR, 0.65 [95% CI, 0.58-0.73]; I2 = 74%), with substantial heterogeneity in both estimates. Subgroup analyses identified a PCSM advantage associated with statins for men receiving ARATs compared with ADT alone (HR, 0.40 [95% CI, 0.30-0.55] vs 0.68 [95% CI, 0.60-0.76]; P = .002 for difference). Confidence in the evidence was rated low for both outcomes.Conclusions and RelevanceThe findings of this meta-analysis show that concurrent statin use was associated with reduced overall mortality and PCSM among men receiving androgen-ablative therapies for advanced prostate cancer. These findings are limited by the observational nature of the data and residual unexplained interstudy heterogeneity. Randomized clinical trials are warranted to validate these results.

The relationship between metformin use and prostate cancer risk remains controversial. Genetic variation in metformin metabolism pathways appears to modify metformin glycemic control and the protective association with some cancers. However, no studies to date have examined this pharmacogenetic interaction and prostate cancer chemoprevention. Clinical data and germline DNA were collected from our prostate biopsy database between 1996 and 2014. In addition to a genome-wide association study (GWAS), 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism were included on a custom SNP array. Associations between metformin use and risk of high-grade (Grade Group ≥ 2) and overall prostate cancer were explored using a case-control design. Interaction between the candidate/GWAS SNPs and the metformin-cancer association was explored using a case-only design. Among 3481 men, 132 (4%) were taking metformin at diagnosis. Metformin users were older, more likely non-Caucasian, and had higher body mass index, Gleason score, and number of positive cores. Overall, 2061 (59%) were diagnosed with prostate cancer, of which 922 (45%) were high-grade. After adjusting for baseline characteristics, metformin use was associated with higher risk of high-grade prostate cancer (OR = 1.76, 95% CI 1.1–2.9, p = 0.02) and overall prostate cancer (OR = 1.77, 95% CI 1.1–2.9, p = 0.03). None of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. Among the GWAS SNPs, one SNP (rs149137006) had genome-wide significant interaction with metformin for high-grade prostate cancer, and another, rs115071742, for overall prostate cancer. They were intronic and intergenic SNPs, respectively, with largely uncharacterized roles in prostate cancer chemoprevention. In our cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. While SNPs involved in metformin metabolism did not have modifying effects on the association with disease risk, one intronic and one intergenic SNP from the GWAS study did, and these require further study.

BACKGROUND: Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies. METHODS: We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Fifteen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76–1.09) or fructose (RR 1.04, 95% CI 0.84–1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80–0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories. INTERPRETATION: Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates. Trial registration: ClinicalTrials.gov, no. NCT01608620

BACKGROUND Metformin is the first-line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate-specific antigen (PSA) levels—the primary prostate cancer biomarker. METHODS We conducted a cross-sectional study of 326 prostate cancer-free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10-ng/ml, or used >2,550-mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log-PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions. RESULTS Median PSA was 0.9-ng/ml (IQR: 0.5–1.6-ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL-C. In multivariate models, PSA changed by −8% (95%CI: −13 to −2%, P = 0.011) per 500-mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500-mg/d metformin (−12% [95% CI: −19 to −4%, P = 0.002], P-interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross-sectional design of this study. CONCLUSIONS Metformin dose-dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose-dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445–1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

Recent evidence suggests that statins may improve prostate cancer outcomes; however, their role in active surveillance (AS) is poorly characterized. We aimed to evaluate the association between statin use at diagnosis and time to progression on AS. Data were obtained from a prospectively maintained cohort of men undergoing AS between 1995 and 2016 at our institution. All men satisfied the low-risk criteria: Gleason score

Objectives: Although most controlled feeding trials have failed to show an adverse effect of fructose on blood pressure, concerns continue to be raised regarding the role of fructose in hypertension. To quantify the association between fructose-containing sugar (high-fructose corn syrup, sucrose, and fructose) intake and incident hypertension, a systematic review and meta-analysis of prospective cohort studies was undertaken. Methods: MEDLINE, EMBASE, CINAHL and the Cochrane Library (through February 5, 2014) were searched for relevant studies. Two independent reviewers reviewed and extracted relevant data. Risk estimates were aggregated comparing the lowest (reference) quintile with highest quintile of intake using inverse variance random effect models and expressed as risk ratios (RR) with 95% confidence intervals (CIs). Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I 2 statistic). The Newcastle–Ottawa Scale assessed study quality. Clinicaltrials.gov NCT01608620. Results: Eligibility criteria were met by 3 prospective cohorts (n = 37,375 men and 185,855 women) with 58,162 cases of hypertension observed over 2,502,357 person-years of follow-up. Median fructose intake was 5.7–6.0% total energy in the lowest quintile and 13.9–14.3% total energy in the highest quintile. Fructose intake was not associated with incident hypertension (RR = 1.02, 95% CI, 0.99–1.04), with no evidence of heterogeneity (I 2 = 0%, p = 0.59). Spline curve modeling showed a U-shaped relationship with a negative association at intakes ≤50th percentile (∼10% total energy) and a positive association at higher intakes. Conclusions: Total fructose intake was not associated with an increased risk of hypertension in 3 large prospective cohorts of U.S. men and women.

Objective: To assess the effect of dietary pulses (beans, peas, chickpeas, lentils) on acute satiety and second meal intake, a systematic review and meta-analysis was conducted. Methods: MEDLINE, EMBASE, CINAHL, and the Cochrane Registry (through May 6, 2013) were searched for acute controlled trials examining the effect of dietary pulses on postprandial satiety or second meal intake compared with isocaloric controls. Two independent reviewers extracted data and assessed methodological quality and risk of bias. Data were pooled by generic inverse variance random effects models and expressed as ratio of means (RoMs) for satiety and mean differences (MDs) for second meal food intake, with 95% confidence intervals (95% CIs). Heterogeneity was assessed (Q statistic) and quantified (I 2 statistic). Protocol registration: clinicaltrials.gov identifier, NCT01605422. Results: Nine trials met the eligibility criteria. Dietary pulses produced a 31% greater satiety incremental area under the curve (IAUC) (RoM 51.31, 95% CI: 1.09 to 1.58, P 50.004; Phet 50.96; I 2 50%) without affecting second meal intake (MD 52 19.94, 95% CI: 275-35, P 50.48; Phet 50.01; I 2 563%). Our data are limited by the small sample sizes, narrow participant characteristics and significant unexplained heterogeneity among the available trials. Conclusions: Pooled analyses show that dietary pulses contribute to acute satiety but not second meal intake.

Previous research on the effect of replacing sources of animal protein with plant protein on glycemic control has been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of this replacement on glycemic control in individuals with diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August 2015. We included RCTs ≥ 3-weeks comparing the effect of replacing animal with plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two independent reviewers extracted relevant data, assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2-statistic). Thirteen RCTs (n = 280) met the eligibility criteria. Diets emphasizing a replacement of animal with plant protein at a median level of ~35% of total protein per day significantly lowered HbA1c (MD = −0.15%, 95%-CI: −0.26, −0.05%), FG (MD = −0.53 mmol/L, 95%-CI: −0.92, −0.13 mmol/L) and FI (MD = −10.09 pmol/L, 95%-CI: −17.31, −2.86 pmol/L) compared with control arms. Overall, the results indicate that replacing sources of animal with plant protein leads to modest improvements in glycemic control in individuals with diabetes. Owing to uncertainties in our analyses there is a need for larger, longer, higher quality trials. Trial Registration: ClinicalTrials.gov registration number: NCT02037321.

Background and aim Compared to a DASH-type diet, an intensively applied dietary portfolio reduced diastolic blood pressure at 24 weeks as a secondary outcome in a previous study. Due to the importance of strategies to reduce blood pressure, we performed an exploratory analysis pooling data from intensively and routinely applied portfolio treatments from the same study to assess the effect over time on systolic, diastolic and mean arterial pressure (MAP), and the relation to sodium (Na + ), potassium (K + ), and portfolio components. Methods and results 241 participants with hyperlipidemia, from four academic centers across Canada were randomized and completed either a DASH-type diet (control n = 82) or a dietary portfolio that included, soy protein, viscous fibers and nuts (n = 159) for 24 weeks. Fasting measures and 7-day food records were obtained at weeks 0, 12 and 24, with 24-h urines at weeks 0 and 24. The dietary portfolio reduced systolic, diastolic and mean arterial blood pressure compared to the control by 2.1 mm Hg (95% CI, 4.2 to −0.1 mm Hg) (p = 0.056), 1.8 mm Hg (CI, 3.2 to 0.4 mm Hg) (p = 0.013) and 1.9 mm Hg (CI, 3.4 to 0.4 mm Hg) (p = 0.015), respectively. Blood pressure reductions were small at 12 weeks and only reached significance at 24 weeks. Nuts, soy and viscous fiber all related negatively to change in mean arterial pressure (ρ = −0.15 to −0.17, p ≤ 0.016) as did urinary potassium (ρ = −0.25, p = 0.001), while the Na + /K + ratio was positively associated (ρ = 0.20, p = 0.010). Conclusions Consumption of a cholesterol-lowering dietary portfolio also decreased blood pressure by comparison with a healthy DASH-type diet. Clinical Trial Reg. No. NCT00438425, clinicaltrials.gov.

Background: Improving glycemic control with Metformin therapy, glycemic index (GI), and glycemic load (GL) have been protectively associated with prostate cancer risk. No studies have yet assessed ...

Background: Tree nut consumption is associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent. Aim: We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of tree nuts on glycemic control in individuals with diabetes. Methods: We searched MEDLINE, EMBASE, CINAHL, and Cochrane databases through 14 May 2013 for relevant randomized trials 蠅3-weeks reporting HbA1c, fasting glucose, fasting insulin, and/or HOMA-IR. Two independent reviewers extracted relevant data. Data were pooled using the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CI). Heterogeneity was assessed by Cochran’s Q and quantified by I2. Results: 10 trials (n=374) met the eligibility criteria. Diets emphasizing tree nuts significantly lowered HbA1c (MD=-0.11 %, 95% CI:-0.18, -0.04 %; P=0.001) and fasting glucose (MD=-0.20 mmol/L, 95% CI:-0.38, -0.03 mmol/L; P=0.02) compared wit...

Background and Aims: Elevated postprandial glucose (PPG) levels have been associated with higher incidence of cardiovascular disease and all-cause mortality. Dietary pulses including beans, lentils and chickpeas have resulted in low and medium PPG responses, however most studies have included few subjects and their overall PPG responses, when taken in equicarbohydrate amounts either alone or in mixed meals, have not been systematically summarized and quantitated. Objective: to synthesize the evidence of the effect of dietary pulses on PPG responses in individuals with diabetes. Methods: MEDLINE, EMBASE, CINAHL and Cochrane were searched through Oct 31, 2013 for all acute human trials in individuals with type 1 and type 2 diabetes reporting data for areas under the PPG curve or glycemic indices. Data were pooled by the generic inverse variance method using random effect models and expressed as ratio of means (RoM) with 95% confidence intervals (CI). Heterogeneity was assessed by Chi2 and quantified by I2. ...

Excessive fructose intake from high-fructose corn syrup (HFCS) and sucrose has been implicated as a driving force behind the increasing prevalence of obesity and its downstream cardiometabolic complications including hypertension, gout, dyslidpidemia, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease (NAFLD). Most of the evidence to support these relationships draws heavily on ecological studies, animal models, and select human trials of fructose overfeeding. There are a number of biological mechanisms derived from animal models to explain these relationships, including increases in de novo lipogenesis and uric acid-mediated hypertension. Differences between animal and human physiology, along with the supraphysiologic level at which fructose is fed in these models, limit their translation to humans. Although higher level evidence from large prospective cohorts studies has shown significant positive associations comparing the highest with the lowest levels of intake of sugar-sweetened beverages (SSBs), these associations do not hold true at moderate levels of intake or when modeling total sugars and are subject to collinearity effects from related dietary and lifestyle factors. The highest level of evidence from controlled feeding trials has shown a lack of cardiometabolic harm of fructose and SSBs under energy-matched conditions at moderate levels of intake. It is only when fructose-containing sugars or SSBs are consumed at high doses or supplement diets with excess energy that a consistent signal for harm is seen. The available evidence suggests that confounding by excess energy is an important consideration in assessing the role of fructose-containing sugars and SSBs in the epidemics of hypertension and other cardiometabolic diseases.

Background Randomized controlled trials (RCT) provide the strongest evidence to justify interventions in patients. However, trials with inadequate methods are associated with bias and exaggerated treatment effects. A search of the literature was conducted to review RCTs in testicular cancer (TC) to assess demographic and trial reporting quality patterns over time. Methods MEDLINE and CENTRAL were queried for TC RCTs from 1989 to 2014. Demographic information was abstracted and reporting quality score was evaluated using the Consolidated Standards of Reporting Trials criteria. Linear regression was used to assess the trend in reporting quality over time. Results A total of 39 RCTs were identified, of which 25 were published from 1989 to 2001 and 14 were published from 2002 to 2014. Most (59%) of the RCTs involved chemotherapy as the intervention, had a medical oncologist as the first author (87%), and took place in Europe (59%). RCTs published between 2002 and 2014 had longer enrollment periods (mean = 6.1 [2.7] vs. 3.7 [1.5] years, P = 0.007), whereas the number of patients randomized, median follow-up, or time from manuscript submission to acceptance were not significantly different between the periods. For each increasing year of publication, there was a significant improvement of 1.34% points (95% CI: 0.86–1.83, P Conclusions Fewer RCTs in TC were published in the recent 13-year period. Although the quality of trial reporting improved compared with the preceding 13-year period, deficiencies remain. Urologists can play an important role in trial design, recruitment, and execution, and ensuring trial methodology and reporting quality is prioritized.

s / Can J Diabetes 36 (2012) S2eS22 S10 tissues insulin resistance and inflammation. In the present study, we investigated the effect of 4-phenylbutyrate (4-PBA), a chemical chaperon that prevents ER stress, on the regulation of tissues’ nonesterified fatty acids metabolism and diet-induced insulin resistance. Research Design and Methods: Control (chow fed) vs. diabetic (high-fat/high-fructose fed + small dose streptozotocin-treated e HFHFS) male Wistar rats were treated with 4-PBA (1g/kg/day) by oral gavage for 6 weeks. At the end of the treatment period, [8, 9-3H]-palmitate was infused during an euglycemic ehyperinsulinemic clamp followed by an i.v. bolus of [1-14C]-2bromopalmitate at steady-state to determine oxidative and non-oxidative nonesterified fatty acid (NEFA) metabolism in tissues. Results: HFHFS-fed rats displayed insulin resistance with high levels of fasting glucose and insulin. Increased NEFA fractional uptake by the gastrocnemius and reduced myocardial NEFA nonoxidative disposal was observed. Animals treated with 4-PBA displayed greater plasmatic NEFA rate of appearance and clearance. 4-PBA normalized gastrocnemius fractional uptake and increased NEFA oxidation and fractional uptake by the liver. SCAT of treated rats are characterized larger SC adipocytes with greater fractional and net NEFA uptake. In vitro, 4-PBA inhibits differentiation of adipocytes precursors but stimulates fatty acids uptake by mature adipocytes. Conclusions: Redistribution of NEFA fluxes by 4-PBA treatment does not restore insulin sensitivity in a nutritional model of T2D but reduced fasting glucose.