Increased Risk of Infection and Mortality in Women after Cardiac Surgery Related to Allogeneic Blood Transfusion

Background: Infection and mortality rates are greater in women than in men after cardiac surgery. This study was conducted to assess whether allogeneic blood transfusion could partially account for this gender difference, as transfusion has been associated with immunomodulation. Methods: A cohort study was conducted in 380 patients at the University of Rochester Medical Center. Subjects were adult patients who underwent primary coronary artery bypass graft (CABG) surgery, primary valve replacement surgery, or both. Information was collected about blood components transfused, as well as postoperative infection, pulmonary dysfunction, and in-hospital mortality. Results: Women were more likely to receive allogeneic red blood cells (RBCs) or platelets than men (odds ratio [OR] 21.6, 95% CI 3.8, 124.2) and a greater quantity of blood than men. Patients who received allogeneic blood were 4.4 times more likely to develop an infection than those who did not (95% CI 1.5, 13.2). There was a positive linear correlation between number of units of blood received and number of days with fever (p < 0.001) and hospital length of stay (p < 0.001). This was particularly evident in patients who received four or more units of nonleukoreduced blood components. Women had a greater risk of infection (p = 0.005), pulmonary dysfunction (p = 0.005), and mortality (p = 0.007) than men during hospitalization. Conclusions: One reason for the greater mortality in women after cardiac surgery may be the increased likelihood of receiving nonleukoreduced allogeneic RBCs and platelets. Transfusion increased the risk of infection; infection, then, increased the likelihood of pulmonary dysfunction and mortality.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63383/1/jwh.2007.0397.pd

The inflection point hypothesis: The relationship between the temperature dependence of enzyme-catalyzed reaction rates and microbial growth rates.

The temperature dependence of biological rates at different scales (from individual enzymes to isolated organisms to ecosystem processes such as soil respiration and photosynthesis) is the subject of much historical and contemporary research. The precise relationship between the temperature dependence of enzyme rates and those at larger scales is not well understood. We have developed macromolecular rate theory (MMRT) to describe the temperature dependence of biological processes at all scales. Here we formalize the scaling relationship by investigating MMRT both at the molecular scale (constituent enzymes) and for growth of the parent organism. We demonstrate that the inflection point (ᵢₙ) for the temperature dependence of individual metabolic enzymes coincides with the optimal growth temperature for the parent organism, and we rationalize this concordance in terms of the necessity for linearly correlated rates for metabolic enzymes over fluctuating environmental temperatures to maintain homeostasis. Indeed, ᵢₙ is likely to be under strong selection pressure to maintain coordinated rates across environmental temperature ranges. At temperatures at which rates become uncorrelated, we postulate a regulatory catastrophe and organism growth rates precipitously decline at temperatures where this occurs. We show that the curvature in the plots of the natural log of the rate versus temperature for individual enzymes determines the curvature for the metabolic process overall and the curvature for the temperature dependence of the growth of the organism. We have called this "the inflection point hypothesis", and this hypothesis suggests many avenues for future investigation, including avenues for engineering the thermal tolerance of organisms

Learning from the UK’s research impact assessment exercise: a case study of a retrospective impact assessment exercise and questions for the future

National governments spend significant amounts of money supporting public research. However, in an era where the international economic climate has led to budget cuts, policymakers increasingly are looking to justify the returns from public investments, including in science and innovation. The so-called ‘impact agenda’ which has emerged in many countries around the world is part of this response; an attempt to understand and articulate for the public what benefits arise from the research that is funded. The United Kingdom is the most progressed in implementing this agenda and in 2014 the national research assessment exercise, the Research Excellence Framework, for the first time included the assessment of research impact as a component. For the first time within a dual funding system, funding would be awarded not only on the basis of the academic quality of research, but also on the wider impacts of that research. In this paper we outline the context and approach taken by the UK government, along with some of the core challenges that exist in implementing such an exercise. We then synthesise, together for the first time, the results of the only two national evaluations of the exercise and offer reflections for future exercises both in the UK and internationally

Patterns in recent and Holocene pollen accumulation rates across Europe - the Pollen Monitoring Programme Database as a tool for vegetation reconstruction

The collection of modern, spatially extensive pollen data is important for the interpretation of fossil pollen assemblages and the reconstruction of past vegetation communities in space and time. Modern datasets are readily available for percentage data but lacking for pollen accumulation rates (PARs). Filling this gap has been the motivation of the pollen monitoring network, whose contributors monitored pollen deposition in modified Tauber traps for several years or decades across Europe. Here we present this monitoring dataset consisting of 351 trap locations with a total of 2742 annual samples covering the period from 1981 to 2017. This dataset shows that total PAR is influenced by forest cover and climate parameters, which determine pollen productivity and correlate with latitude. Treeless vegetation produced PAR values of at least 140 grains cm−2 yr−1. Tree PAR increased by at least 400 grains cm−2 yr−1 with each 10 % increase in forest cover. Pollen traps situated beyond 200 km of the distribution of a given tree species still collect occasional pollen grains of that species. The threshold of this long-distance transport differs for individual species and is generally below 60 grains cm−2 yr−1. Comparisons between modern and fossil PAR from the same regions show similar values. For temperate taxa, modern analogues for fossil PARs are generally found downslope or southward of the fossil sites. While we do not find modern situations comparable to fossil PAR values of some taxa (e.g. Corylus), CO2 fertilization and land use may cause high modern PARs that are not documented in the fossil record. The modern data are now publicly available in the Neotoma Paleoecology Database and aid interpretations of fossil PAR data.publishedVersio

Evidence That Lipopolisaccharide May Contribute to the Cytokine Storm and Cellular Activation in Patients with Visceral Leishmaniasis

Visceral leishmaniasis (VL) affects organs rich in lymphocytes, being characterized by intense Leishmania-induced T-cell depletion and reduction in other hematopoietic cells. In other infectious and non-infectious diseases in which the immune system is affected, such as HIV-AIDS and inflammatory bowel disease, damage to gut-associated lymphocyte tissues occurs, enabling luminal bacteria to enter into the circulation. Lipopolisaccharide (LPS) is a bacterial product that stimulates macrophages, leading to the production of pro-inflammatory cytokines and other soluble factors such as MIF, which in turn activate lymphocytes. Continuous and exaggerated stimulation causes exhaustion of the T-cell compartment, contributing to immunosuppression

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Genome-wide association study of {REM} sleep behavior disorder identifies polygenic risk and brain expression effects

AbstractRapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention

Patterns in recent and Holocene pollen accumulation rates across Europe - the Pollen Monitoring Programme Database as a tool for vegetation reconstruction

The collection of modern, spatially extensive pollen data is important for the interpretation of fossil pollen assemblages and the reconstruction of past vegetation communities in space and time. Modern datasets are readily available for percentage data but lacking for pollen accumulation rates (PARs). Filling this gap has been the motivation of the pollen monitoring network, whose contributors monitored pollen deposition in modified Tauber traps for several years or decades across Europe. Here we present this monitoring dataset consisting of 351 trap locations with a total of 2742 annual samples covering the period from 1981 to 2017. This dataset shows that total PAR is influenced by forest cover and climate parameters, which determine pollen productivity and correlate with latitude. Treeless vegetation produced PAR values of at least 140 grains cm(-2) yr(-1). Tree PAR increased by at least 400 grains cm(-2) yr(-1) with each 10% increase in forest cover. Pollen traps situated beyond 200 km of the distribution of a given tree species still collect occasional pollen grains of that species. The threshold of this long-distance transport differs for individual species and is generally below 60 grains cm(-2) yr(-1). Comparisons between modern and fossil PAR from the same regions show similar values. For temperate taxa, modern analogues for fossil PARs are generally found downslope or southward of the fossil sites. While we do not find modern situations comparable to fossil PAR values of some taxa (e.g. Corylus), CO2 fertilization and land use may cause high modern PARs that are not documented in the fossil record. The modern data are now publicly available in the Neotoma Paleoecology Database and aid interpretations of fossil PAR data

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57