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The number of meta-analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy-to-use, and specialised statistical software. Even when meta-analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta-analysis provides an example of the variation of effect "naturally" observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (1) breakdown of the total observed variability with quantification of the variability generated by the replication process and (2) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta-analysis results, a bivariate linear mixed-effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta-analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism.

Background Epigenome‐wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study‐ or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards‐based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross‐study learning approach to integrate these individual scores into an ensemble predictor. The methylation‐based risk score was associated with CVD time‐to‐event in a held‐out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10–1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58–2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation‐based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof‐of‐concept for a genome‐wide, CVD‐specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high‐risk individuals who would be missed by alternative risk metrics.

The number of meta‐analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy‐to‐use, and specialised statistical software. Even when meta‐analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta‐analysis provides an example of the variation of effect 'naturally' observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta‐analysis results, a bivariate linear mixed‐effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta‐analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism. [ABSTRACT FROM AUTHOR]

Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

Recent researches conducted on nucleosynthesis have spawned a variety of new knowlege about the nature and properties of intergalactic gamma rays. One of the most notable findings is the fact that gamma rays that exist in galaxy behave differently with those found in wavelength bands.

Background: It is unclear whether high-dose regimens of tranexamic acid in cardiac surgery (total dose, 80 to 100 mg/kg) confer a clinical advantage over low-dose regimens (total dose, approximately 20 mg/kg), particularly as tranexamic acid-associated seizure may be dose-related. The authors' aim was to characterize the exposure-response relationship of this drug.Methods: Databases were searched for randomized controlled trials of intravenous tranexamic acid in adult patients undergoing cardiopulmonary bypass surgery. Observational studies were added for seizure assessment. Tranexamic acid concentrations were predicted in each arm of each study using a population pharmacokinetic model. The exposure-response relationship was evaluated by performing a model-based meta-analysis using nonlinear mixed-effect models.Results: Sixty-four randomized controlled trials and 18 observational studies (49,817 patients) were included. Seventy-three different regimens of tranexamic acid were identified, with the total dose administered ranging from 5.5 mg/kg to 20 g. The maximum effect of tranexamic acid for postoperative blood loss reduction was 40% (95% credible interval, 34 to 47%), and the EC50 was 5.6 mg/l (95% credible interval, 0.7 to 11 mg/l). Exposure values with low-dose regimens approached the 80% effective concentration, whereas with high-dose regimens, they exceeded the 90% effective concentration. The predicted cumulative blood loss up to 48 h postsurgery differed by 58 ml between the two regimens, and the absolute difference in erythrocyte transfusion rate was 2%. Compared to no tranexamic acid, low-dose and high-dose regimens increased the risk of seizure by 1.2-fold and 2-fold, respectively. However, the absolute risk increase was only clinically meaningful in the context of prolonged open-chamber surgery.Conclusions: In cardiopulmonary bypass surgery, low-dose tranexamic acid seems to be an appropriate regimen for reducing bleeding outcomes. This meta-analysis has to be interpreted with caution because the results are observational and dependent on the lack of bias of the predicted tranexamic acid exposures and the quality of the included studies.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Haiti and the Dominican Republic, which share the island of Hispaniola, are the last locations in the Caribbean where malaria still persists. Malaria is an important public health concern in Haiti with 17,094 reported cases in 2014. Further, on January 12, 2010, a record earthquake devastated densely populated areas in Haiti including many healthcare and laboratory facilities. Weakened infrastructure provided fertile reservoirs for uncontrolled transmission of infectious pathogens. This situation results in unique challenges for malaria epidemiology and elimination efforts. To help Haiti achieve its malaria elimination goals by year 2020, the Laboratoire National de Santé Publique and Henry Ford Health System, in close collaboration with the Direction d'Épidémiologie, de Laboratoire et de Recherches and the Programme National de Contrôle de la Malaria, hosted a scientific meeting on 'Elimination Strategies for Malaria in Haiti' on January 29-30, 2015 at the National Laboratory in Port-au-Prince, Haiti. The meeting brought together laboratory personnel, researchers, clinicians, academics, public health professionals, and other stakeholders to discuss main stakes and perspectives on malaria elimination. Several themes and recommendations emerged during discussions at this meeting. First, more information and research on malaria transmission in Haiti are needed including information from active surveillance of cases and vectors. Second, many healthcare personnel need additional training and critical resources on how to properly identify malaria cases so as to improve accurate and timely case reporting. Third, it is necessary to continue studies genotyping strains of Plasmodium falciparum in different sites with active transmission to evaluate for drug resistance and impacts on health. Fourth, elimination strategies outlined in this report will continue to incorporate use of primaquine in addition to chloroquine and active surveillance of cases. Elimination of malaria in Haiti will require collaborative multidisciplinary approaches, sound strategic planning, and strong ownership of strategies by the Haiti Ministère de la Santé Publique et de la Population. [ABSTRACT FROM AUTHOR]

Purpose: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. Methods: A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. Results: Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). Conclusions: This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. [ABSTRACT FROM AUTHOR]

Background and Objectives: Regional anesthesia preserves perioperative immune competence and may reduce the risk of recurrence and metastasis after cancer surgery. Cervical epidural anesthesia provides adequate analgesia for head and neck cancer surgery, but its impact on cancer recurrence is unknown.Methods: This study was a single-center retrospective cohort study of patients undergoing larynx or hypopharynx cancer surgery between January 1984 and December 2008. One hundred eleven patients had general anesthesia combined with intraoperative and postoperative cervical epidural; 160 had general anesthesia alone with postoperative morphine. From this cohort, matched pairs were selected using a propensity score to balance potential confounders of receiving epidural anesthesia. The primary end point was the length of cancer-free survival after surgery until September 2009.Results: Propensity-based matching produced 65 pairs. Matching was effective in achieving balance between groups for each of the preoperative variables collected. Combined epidural and general anesthesia (68% 5-year cancer-free survival; 95% confidence interval [CI], 57%-82%) was associated with significantly increased cancer-free survival compared with general anesthesia alone (37% 5-year cancer-free survival; 95% CI, 25%-54%) with a corresponding adjusted hazard ratio of 0.49 (95% CI, 0.25-0.96; P = 0.04). Patients in the epidural group had an increased overall survival compared with the non-epidural group (P = 0.03).Conclusions: The association between cervical epidural anesthesia and increased cancer-free survival found in this retrospective study should be an important hypothesis to further investigate in head and neck cancer surgery. [ABSTRACT FROM AUTHOR]

Objectives: To review the contribution of the Nurses' Health Study (NHS) to understanding the genetic and lifestyle factors that influence the risk of cataract, age-related macular degeneration, and glaucoma., Methods: We performed a narrative review of the publications of the NHS between 1976 and 2016., Results: The NHS has helped to elucidate the roles of genetics, lifestyle factors (e.g., cigarette smoking associated with cataract extraction and age-related macular degeneration), medical conditions (e.g., diabetes associated with cataract extraction and glaucoma), and dietary factors (e.g., greater carotenoid intake and lower glycemic diet associated with lower risk of age-related macular degeneration) in the etiology of degree and progression of lens opacities, cataract extraction, age-related macular degeneration, primary open-angle glaucoma, and exfoliation glaucoma., Conclusions: The findings from the NHS, combined with those of other studies, have provided compelling evidence to support public health recommendations for helping to prevent age-related eye diseases: abstinence from cigarette smoking, maintenance of healthy weight and diabetes prevention, and a healthy diet rich in fruits and vegetables.

The observed 511 keV emission from the galactic bulge could be due to very light (MeV) annihilating dark matter particles. To distinguish this hypothesis from conventional astrophysical sources, we study dwarf spheroidals in the region observed by the International Gamma-Ray Astrophysics Laboratory/SPI such as Sagittarius. As these galaxies have comparatively few stars, the prospects for 511 keV emission from standard astrophysical scenarios are minimal. The dwarf spheroidals do, however, contain copious amounts of dark matter. The observation of 511 keV emission from Sagittarius should be a "smoking gun" for MeV dark matter.

An intriguing feature of extra dimensions is the possible production of Kaluza-Klein gravitons by nucleon-nucleon bremsstrahlung, in the course of core collapse of massive stars, with gravitons then being trapped around the newly born neutron stars and decaying into two gamma rays, making neutron stars gamma-ray sources. We strengthen the limits on the radius of compactification of extra dimensions for a small number n of them, or alternatively the fundamental scale of quantum gravity, considering the gamma-ray emission of the whole population of neutron stars sitting in the Galactic bulge, instead of the closest member of this category. For n=1 the constraint on the compactification radius is R<400 microm.

We discuss the possibility that the recent detection of 511 keV gamma rays from the galactic bulge, as observed by INTEGRAL, is a consequence of low mass (1-100 MeV) particle dark matter annihilations. We discuss the type of halo profile favored by the observations as well as the size of the annihilation cross section needed to account for the signal. We find that such a scenario is consistent with the observed dark matter relic density and other constraints from astrophysics and particle physics.