Research techniques made simple: workflow for searching databases to reduce evidence selection bias in systematic reviews

Clinical trials and basic science studies without statistically significant results are less likely to be published than studies with statistically significant results. Systematic reviews and meta-analyses that omit unpublished data are at high risk of distorted conclusions. Here, we describe methods to search beyond bibliographical databases to reduce evidence selection bias in systematic reviews. Unpublished studies may be identified by searching conference proceedings. Moreover, clinical trial registries—databases of planned and ongoing trials—and regulatory agency websites such as the European Medicine Agency (EMA) and the United States Food and Drug Administration (FDA) may provide summaries of efficacy and safety data. Primary and secondary outcomes are prespecified in trial registries, thus allowing the assessment of outcome reporting bias by comparison with the trial report. The sources of trial data and documents are still evolving, with ongoing initiatives promoting broader access to clinical study reports and individual patient data. There is currently no established methodology to ensure that the multiple sources of information are incorporated. Nonetheless, systematic reviews must adapt to these improvements and cover the new sources in their search strategies

Carbon-Carbon bond forming reactions of organotransition metal enolate complexes

Abstract -Metal enolates play an important role in stereoselective organic synthesis. Their chemistry is affected profoundly by the metal counterion associated with the enolate fragment. In order to expand the potential of replacing main group with transition metal moieties in such species, methods have been developed for the synthesis of a number of stable, characterizable "late" transition metal ql-(C)-enolate complexes having the general structure LM-CH2COR (M = Mo, W, Re). The chemistry of these materials (e.g., functional transformations of the organic carbonyl group, transfer of the enolate moietry to organic substrates such as aldehydes and alkynes) has been investigated. The scope and mechanisms of the enolate reactions will be discussed in detail. The reaction of organic enolates with carbon electrophiles (e.g., alkyl halides, organic carbonyl compounds) gives rise to compounds containing new carbon-carbon bonds; reaction with heteroatom electrophiles results in the formation of oxidized products? There has been much interest recently in developing methods for carrying out these transformations with high stereoselectivity.3 Historically, most enolate research has focused on salts involving alkali metal anions. More recently, research efforts have been extended to enolates associated with organic cations, main group metals, and transition metals. In the transition metal area, enolates involving the so-called "early" metals (to the left of chromium, molybdenum and tungsten) have seen extensive investigationi4 in general these complexes have 0-bonded structures A in Scheme 1. This paper describes the synthesis and chemistry of middle-and late transition metal enolates, which have seen less investigation. It was our hope that such species would be more likely to have Cbound structure B, and also to react with both electrophilic and non-electrophilic species (e.g., by insertion rather than nucleophile-electrophile mechanisms). SYNTHESIS, CHARACTERIZATION AND FUNCTIONAL GROUP TRANSFORMATIONS OF TUNGSTEN AND MOLYBDENUM ENOLATES The well-known nucleophilic anionic metal salts5 Na[(qS-C5R5)(C0)3M] (M = Mo, W, R=H, Me), on treatment with a-chloroketones and esters, provide good yields of enolates 1 -8, as shown in Scheme 2. These are thermally stable complexes that may be isolated by conventional chromatographic and recrystallization methods; they have been characterized fully by elemental analysis and spectroscopic techniques. Preparation of these materials on a multi-gram scale in a one-pot procedure is possible by treatment of W(CO)6 or Mo(C0)6 with NaCp, followed by addition of the a-chlorocarbonyl compound to the resulting metal anion solution. The stability of the tungsten-carbon bond in tungsten ester enolates, fiist suggested several years ago by the work of Green and his coworkers6, has allowed us to carry out a wide range of transformations on the organic carbonyl group. Thus the reactions shown in Scheme 3 proceed in good yield, and lead to stable tungsten enolates containing ester, amide and even carboxylic acid and acid chloride functionality

Subtropical mode water variability in a climatologically forced model in the northwestern Pacific Ocean

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 42 (2012): 126–140, doi:10.1175/2011JPO4513.1.A climatologically forced high-resolution model is used to examine variability of subtropical mode water (STMW) in the northwestern Pacific Ocean. Despite the use of annually repeating atmospheric forcing, significant interannual to decadal variability is evident in the volume, temperature, and age of STMW formed in the region. This long time-scale variability is intrinsic to the ocean. The formation and characteristics of STMW are comparable to those observed in nature. STMW is found to be cooler, denser, and shallower in the east than in the west, but time variations in these properties are generally correlated across the full water mass. Formation is found to occur south of the Kuroshio Extension, and after formation STMW is advected westward, as shown by the transport streamfunction. The ideal age and chlorofluorocarbon tracers are used to analyze the life cycle of STMW. Over the full model run, the average age of STMW is found to be 4.1 yr, but there is strong geographical variation in this, from an average age of 3.0 yr in the east to 4.9 yr in the west. This is further evidence that STMW is formed in the east and travels to the west. This is qualitatively confirmed through simulated dye experiments known as transit-time distributions. Changes in STMW formation are correlated with a large meander in the path of the Kuroshio south of Japan. In the model, the large meander inhibits STMW formation just south of Japan, but the export of water with low potential vorticity leads to formation of STMW in the east and an overall increase in volume. This is correlated with an increase in the outcrop area of STMW. Mixed layer depth, on the other hand, is found to be uncorrelated with the volume of STMW.E.M.D. acknowledges support of the Doherty Foundation and National Science Foundation (OCE-0849808). S.R.J was sponsored by the National Science Foundation (OCE-0849808). Participation of S.P. and F.B. was supported by the National Science Foundation by its sponsorship of the National Center for Atmospheric Research.2012-07-0

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Correction: Volume69, Issue6 Page1306-1306 DOI10.2337/db20-er06a Published JUN 2020To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P valuePeer reviewe

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined

High-Frequency Dynamics of Ocean pH: A Multi-Ecosystem Comparison

The effect of Ocean Acidification (OA) on marine biota is quasi-predictable at best. While perturbation studies, in the form of incubations under elevated pCO2, reveal sensitivities and responses of individual species, one missing link in the OA story results from a chronic lack of pH data specific to a given species' natural habitat. Here, we present a compilation of continuous, high-resolution time series of upper ocean pH, collected using autonomous sensors, over a variety of ecosystems ranging from polar to tropical, open-ocean to coastal, kelp forest to coral reef. These observations reveal a continuum of month-long pH variability with standard deviations from 0.004 to 0.277 and ranges spanning 0.024 to 1.430 pH units. The nature of the observed variability was also highly site-dependent, with characteristic diel, semi-diurnal, and stochastic patterns of varying amplitudes. These biome-specific pH signatures disclose current levels of exposure to both high and low dissolved CO2, often demonstrating that resident organisms are already experiencing pH regimes that are not predicted until 2100. Our data provide a first step toward crystallizing the biophysical link between environmental history of pH exposure and physiological resilience of marine organisms to fluctuations in seawater CO2. Knowledge of this spatial and temporal variation in seawater chemistry allows us to improve the design of OA experiments: we can test organisms with a priori expectations of their tolerance guardrails, based on their natural range of exposure. Such hypothesis-testing will provide a deeper understanding of the effects of OA. Both intuitively simple to understand and powerfully informative, these and similar comparative time series can help guide management efforts to identify areas of marine habitat that can serve as refugia to acidification as well as areas that are particularly vulnerable to future ocean change

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation