• Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration.

    26 April 2018

    The effects of immunosuppressive regimens on the outcomes of patients with hematological malignancies undergoing allogeneic stem cell transplantation remain uncertain. We conducted an individual patient data meta-analysis using data from nine randomized trials comparing allogeneic peripheral blood stem cell (PBSCT) transplants to bone marrow (BMT) transplants, focusing on the administration of three vs four doses of methotrexate (MTX) as part of a regimen for graft-versus-host-disease (GVHD) prophylaxis which included cyclosporine. Six trials containing 573 patients prescribed four doses of MTX while three trials containing 534 patients prescribed three doses of MTX. Four doses of MTX conferred a statistically significant survival advantage, resulting in death odds ratio (OR) 0.67 (CI 0.52-0.88) (P=0.0036) for recipients of PBSC compared to BM; with three doses, there was no statistically significant difference. In the four-dose studies relapse rates were 36.6% among recipients of BM compared to 19.2% among recipients of PBSC (P=0.0015). The rates of relapse in the three dose studies were 26% for both PBSC and BM. We hypothesize that the fourth dose of MTX provides extra immunosuppression among BM recipients resulting in a reduced anti-leukemic effect. This hypothesis can only be proved or disproved by a prospective, randomized trial.

  • Natural health product-drug interactions: a systematic review of clinical trials.

    26 April 2018

    Interactions between natural health products (NHP) and prescription medications are of increasing concern. This paper aims to identify all clinical trials of NHP-drug interactions. To determine the prevalence and outcomes of clinical investigations of NHP-drug pharmacokinetic interactions, electronic databases were searched from inception through March 2004, as well as reference lists from published reports and experts in the field for unpublished studies. Eligible studies were clinical investigations of the interaction between a NHP and the metabolism of a regulated medication in humans. Studies were excluded that only investigated the metabolism of an NHP or examined food-drug or NHP-NHP interactions. Two reviewers selected studies for inclusion and independently extracted data. Forty-seven trials were identified, studying an average of 14 participants/study (95% confidence interval [CI] 11-18), examined drug interactions with 19 different herbal preparations. All trials were pharmacokinetic studies, 41 of healthy volunteers and 6 of patients. Ten different herbal medicines as well as 5 different traditional herbal concoctions were studied. Potentially clinically significant drug interactions were observed with St. John wort (16/24 studies), garlic (2/5 studies), and American ginseng (1 study). Research on NHP-drug interactions is limited in number and scope. With the exception of St. John wort, clinicians and the public do not have information that permits strong inferences about interactions between NHPs and conventional medications.

  • The importance of preservation of the ethical principle of equipoise in the design of clinical trials: relative impact of the methodological quality domains on the treatment effect in randomized controlled trials.

    2 February 2018

    Previous research has identified methodological problems in the design and conduct of randomized trials that could, if left unaddressed, lead to biased results. In this report we discuss one such problem, inadequate control intervention, and argue that it can be by far the most important design characteristic of randomized trials in overestimating the effect of new treatments. Current guidelines for the design and reporting of randomized trials, such as the Consolidated Standards of Reporting Trials (CONSORT) statement, do not address the choice of the comparator intervention. We argue that an adequate control intervention can be selected if people designing a trial explicitly take into consideration the ethical principle of equipoise, also known as "the uncertainty principle."

  • Education and coronary heart disease: mendelian randomisation study.

    26 April 2018

    Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.

  • Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015

    26 April 2018

    Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health.