Low immediate scientific yield of the PhD among medical doctors

BACKGROUND: We studied the scientific yield of the medical PhD program at all Danish Universities. METHODS: We undertook a retrospective observational study. Three PhD schools in Denmark were included in order to evaluate the postdoctoral research production over more than 18 years through individual publications accessed by PubMed. RESULTS: A total of 2686 PhD-graduates (1995–2013) with a medical background were included according to registries from all PhD schools in Denmark. They had a median age of 35 years (interquartile range (IQR), 32–38) and 53 % were women at the time of graduation. Scientific activity over time was assessed independently of author-rank and inactivity was measured relative to the date of graduation. Factors associated with inactivity were identified using multivariable logistic regression. 88.6 % of the PhD theses were conducted in internal medicine vs. 11.4 % in surgery. During follow-up (median 6.9 years, IQR 3.0–11.7), PubMed data searches identified that 87 (3.4 %) of the PhD graduates had no publication after they graduated from the PhD program, 40 % had 5 or less, and 90 % had 30 or less. The median number of publications per year after PhD graduation was 1.12 (IQR 0.61–1.99) papers per year. About 2/3 of the graduates became inactive after 1 year and approximately 21 % of the graduates remained active during the whole follow-up. Female gender was associated with inactivity: adjusted odds ratio 1.59 (95 % confidence interval 1.24–2.05). CONCLUSIONS: The scientific production of Danish medic PhD-graduates was mainly produced around the time of PhD-graduation. After obtaining the PhD-degree the scientific production declines suggesting that scientific advance fails and resources are not harnessed

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome\u27s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Secondary prevention in heart failure: a special focus on aspirin, statins and exercise

Heart failure (HF) is a leading killer in the Western world and is a serious financial burden on health care budgets. Moreover, the life quality of many HF patients decreases through multiple morbidities. In order to improve the prognosis of HF patients, evidence-based treatments are developing. This thesis investigated areas of secondary prevention in HF without evidence. Subjects included those accessing cardiac rehabilitation (CR) referral, exercise-based CR and aspirin and statin prescription. Outcomes consisted of all-cause mortality, hospital admission and exercise capacities. HF was evaluated mainly as the reduced ejection fraction (HF-REF) subtype, while applied statistical models were parametric and non-parametric. Missing values were assessed through multiple imputations. First, the CR referral effect on mortality after an acute myocardial infarction event was evaluated. The Evaluation of Methods and Management of Acute Coronary Events (EMMACE)-I and II observational studies demonstrated CR referral as an independent predictor of survival in 2003, but not in 1995. Similar results were shown in HF subgroups. Although decreasing between the studies, CR referral was associated with treatment inequalities, thus suggesting a risk-treatment paradox. Second, the effect of enrolment in exercise-based CR in HF patients was assessed through a meta-analysis incorporating randomised controlled trials (RCTs). Over a minimum of six months, follow-up exercise capacities and hospital admissions significantly improved in the exercise intervention group as compared with the control group. In contrast, mortality was not significantly improved through exercise, although a trend suggested exercise to be superior to a sedentary lifestyle. Confounders were patient selection in RCT recruitment and the unequal quality of care. Third, the average treatment effects of aspirin and statins in HF patients (EMMACE studies) improved survival rates during 90 months follow-up. In HF populations, CR attendance influenced key outcomes significantly, whereas aspirin and statins were beneficial to survival in observational studies

Varying effects of recommended treatments for heart failure with reduced ejection fraction:meta-analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines

The aim of this paper is to evaluate the treatment effects of recommended drugs and devices on key clinical outcomes for patients with heart failure with reduced ejection fraction (HFREF). Randomized controlled trials (RCTs) listed in the 2012 HF guideline from the European Society of Cardiology as well as the 2013 HF guideline from the American College of Cardiology Foundation and American Heart Association were evaluated for use in the meta‐analysis. RCTs written in English evaluating recommended drugs and devices for the treatment of patients with HFREF were included. Meta‐analyses, based on the outcomes of all‐cause mortality and hospitalization because of HF, were performed with relative risk ratio as the effect size. In the identified 47 RCTs, patients were on average 63 years old and 22% were female. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, cardiac resynchronization therapy (CRT), and intracardiac defibrillator devices (ICDs) significantly reduced the risk of death with reductions of 14–19, 23, 20, and 20%, respectively. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, digoxin, and CRT significantly reduced the risk of HF hospitalization with reductions of 24–37, 22, 60, and 36%, respectively, while ICDs significantly increased the risk with 34%. Ivabradine showed no significant effects on either outcome. As such, the majority of recommended HFREF treatments offered significant treatment benefits. However, many of the included studies were from the 1990s or earlier, and one must therefore be cautious when extrapolating these results to contemporary patients with HF

Right and left bundle branch block as predictors of long-term mortality following myocardial infarction

Aims: Patients with acute myocardial infarction (MI) with bundle branch block (BBB) have a poor prognosis, but distinction between left (L)- and right (R)-sided BBB is seldom made in epidemiological studies. We studied long-term mortality associated with RBBB and LBBB in the TRAndolapril Cardiac Evaluation (TRACE) study. Methods and results: TRACE screened consecutive patients presenting with an MI and recorded clinical, electro- and echo-cardiographic variables. Subsequently, deaths were recorded during a minimum follow-up of 15 years. In total, 6676 consecutive patients with MI were hospitalized at 27 centres in Denmark. Of these, 533 (8%) had BBB, of whom 260 (4%) had RBBB and 273 (4%) had LBBB. Overall, 5196 (78%) patients died, 256 (94%) with LBBB and 235 (90%) with RBBB compared with 4705 (77%) of those without BBB (P < 0.001). In multivariable analyses, hazard ratios (HRs) of RBBB and LBBB were 1.23 [95% confidence interval (CI), 1.07–1.42] and 1.05 (95% CI, 0.91–1.20), respectively. There was interaction between each type of BBB and left ventricular (LV) systolic function (P = 0.02). Right BBB was associated with a worse prognosis in patients with reduced LV systolic function [HR = 1.31 with wall motion index (WMI) ≤ 1.5 (95% CI, 1.11–1.55] while LBBB had a poor prognosis in patients with preserved LV systolic (HR if WMI > 1.5, 1.70; 95% CI, 1.12–2.57). Conclusions: Right BBB was a predictor of increased mortality in patients with reduced LV systolic function, whereas LBBB was a marker of increased mortality in patients with preserved LV systolic function

Predictors of exercise capacity following exercise-based rehabilitation in patients with coronary heart disease and heart failure:A meta-regression analysis

Background: The aim of this study was to undertake a comprehensive assessment of the patient, intervention and trial-level factors that may predict exercise capacity following exercise-based rehabilitation in patients with coronary heart disease and heart failure. Design: Meta-analysis and meta-regression analysis. Methods: Randomized controlled trials of exercise-based rehabilitation were identified from three published systematic reviews. Exercise capacity was pooled across trials using random effects meta-analysis, and meta-regression used to examine the association between exercise capacity and a range of patient (e.g. age), intervention (e.g. exercise frequency) and trial (e.g. risk of bias) factors. Results: 55 trials (61 exercise-control comparisons, 7553 patients) were included. Following exercise-based rehabilitation compared to control, overall exercise capacity was on average 0.95 (95% CI: 0.76–1.41) standard deviation units higher, and in trials reporting maximum oxygen uptake (VO2max) was 3.3 ml/kg.min−1 (95% CI: 2.6–4.0) higher. There was evidence of a high level of statistical heterogeneity across trials (I2 statistic > 50%). In multivariable meta-regression analysis, only exercise intervention intensity was found to be significantly associated with VO2max (P = 0.04); those trials with the highest average exercise intensity had the largest mean post-rehabilitation VO2max compared to control. Conclusions: We found considerable heterogeneity across randomized controlled trials in the magnitude of improvement in exercise capacity following exercise-based rehabilitation compared to control among patients with coronary heart disease or heart failure. Whilst higher exercise intensities were associated with a greater level of post-rehabilitation exercise capacity, there was no strong evidence to support other intervention, patient or trial factors to be predictive