Levosimendan for patients with severely reduced left ventricular systolic function and/or low cardiac output syndrome undergoing cardiac surgery. a systematic review and meta-analysis

Background: Previous studies have shown beneficial effects of levosimendan in high-risk patients undergoing cardiac surgery. Two large randomized controlled trials (RCTs), however, showed no advantages of levosimendan. Methods: We performed a systematic review and meta-analysis (MEDLINE and Embase from inception until March 30, 2017), investigating whether levosimendan offers advantages compared with placebo in high-risk cardiac surgery patients, as defined by preoperative left ventricular ejection fraction (LVEF) = 35% and/or low cardiac output syndrome (LCOS). The primary outcomes were mortality at longest follow-up and need for postoperative renal replacement therapy (RRT). Secondary postoperative outcomes investigated included myocardial injury, supraventricular arrhythmias, development of LCOS, acute kidney injury (AKI), duration of mechanical ventilation, intensive care unit and hospital lengths of stay, and incidence of hypotension during drug infusion. Results: Six RCTs were included in the meta-analysis, five of which investigated only patients with LVEF = 35% and one of which included predominantly patients with LCOS. Mortality was similar overall (OR 0.64 [0.37, 1.11], p = 0.11) but lower in the subgroup with LVEF < 35% (OR 0.51 [0.32, 0.82], p = 0.005). Need for RRT was reduced by levosimendan both overall (OR 0.63 [0.42, 0.94], p = 0.02) and in patients with LVEF < 35% (OR 0.55 [0.31, 0.97], p = 0.04). Among secondary outcomes, we found lower postoperative LCOS in patients with LVEF < 35% receiving levosimendan (OR 0.49 [0.27, 0.89], p = 0.02), lower overall AKI (OR 0.62 [0.42, 0.92], p = 0.02), and a trend toward lower mechanical support, both overall (p = 0.07) and in patients with LVEF < 35% (p= 0.05). Conclusions: Levosimendan reduces mortality in patients with preoperative severely reduced LVEF but does not affect overall mortality. Levosimendan reduces the need for RRT after high-risk cardiac surger

Array-based evolution of DNA aptamers allows modelling of an explicit sequence-fitness landscape

Mapping the landscape of possible macromolecular polymer sequences to their fitness in performing biological functions is a challenge across the biosciences. A paradigm is the case of aptamers, nucleic acids that can be selected to bind particular target molecules. We have characterized the sequence-fitness landscape for aptamers binding allophycocyanin (APC) protein via a novel Closed Loop Aptameric Directed Evolution (CLADE) approach. In contrast to the conventional SELEX methodology, selection and mutation of aptamer sequences was carried out in silico, with explicit fitness assays for 44 131 aptamers of known sequence using DNA microarrays in vitro. We capture the landscape using a predictive machine learning model linking sequence features and function and validate this model using 5500 entirely separate test sequences, which give a very high observed versus predicted correlation of 0.87. This approach reveals a complex sequence-fitness mapping, and hypotheses for the physical basis of aptameric binding; it also enables rapid design of novel aptamers with desired binding properties. We demonstrate an extension to the approach by incorporating prior knowledge into CLADE, resulting in some of the tightest binding sequences

Independent associations of socioeconomic factors with disability and pain in adults with knee osteoarthritis

Abstract Background The purpose of this study is to explore the relationship between function, pain and stiffness outcomes with individual and community socioeconomic status (SES) measures among individuals with radiographic knee osteoarthritis (rOA). Methods Cross-sectional data from the Johnston County Osteoarthritis Project were analyzed for adults age 45 and older with knee rOA (n = 782) and a subset with both radiographic and symptomatic knee OA (n = 471). Function, pain and stiffness were measured using the Western Ontario and McMasters Universities Index of Osteoarthritis (WOMAC). Individual SES measures included educational attainment (<12 years, ≥12 years) and occupation type (managerial, non-managerial), while community SES was measured using Census block group poverty rate (<12%, 12-25%, ≥25%). SES measures were individually and simultaneously examined in linear regression models adjusting for age, gender, race, body mass index (BMI), occupational physical activity score (PAS), comorbidity count, and presence of hip symptoms. Results In analyses among all individuals with rOA, models which included individual SES measures were observed to show that occupation was significantly associated with WOMAC Function (β =2.91, 95% Confidence Interval (CI) = 0.68-5.14), WOMAC Pain (β =0.93, 95% CI = 0.26-1.59) and WOMAC Total scores (β =4.05, 95% CI = 1.04-7.05), and education was significantly associated with WOMAC Function (β =3.57, 95% CI = 1.25-5.90) and WOMAC Total (β =4.56, 95% CI = 1.41-7.70) scores. In multivariable models including all SES measures simultaneously, most associations were attenuated. However, statistically significant results for education remained between WOMAC Function (β =2.83, 95% CI = 0.38-5.28) and WOMAC Total (β =3.48, 95% CI = 0.18-6.78), as well as for the association between occupation and WOMAC Pain (β =0.78, 95% CI = 0.08-1.48). In rOA subgroup analyses restricted to those with symptoms, we observed a significant increase in WOMAC Pain (β =1.36, 95% CI = 0.07-2.66) among individuals living in a block group with poverty rates greater than 25%, an association that remained when all SES measures were considered simultaneously (β =1.35, 95% CI = 0.06-2.64). Conclusions Lower individual and community SES are both associated with worse function and pain among adults with knee rOA

Rethinking Equality in the Global Society

The future of affirmative action, especially in the area of American higher education, has been called into question by the 1996 decision of the U.S. Court of Appeals for the Fifth Circuit in Hopwood v. State of Texas, requiring race-blind admission to state universities in Texas, and the passage of Proposition 209 in California. The seemingly endless American debate on this issue almost entirely has ignored the fact that other countries faced with comparable problems of remedying the effects of past discrimination have developed programs and acquired experience from which Americans might learn. Further, the legal debate has not been adequately informed by the social science disciplines. This conference was intended to expand discussion at a critical moment by introducing these missing perspectives

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure