Frailty and functional outcomes after open and endovascular procedures for patients with peripheral arterial disease:A systematic review

Background: Frailty has been associated with postoperative complications and mortality across surgical specialties, including vascular surgery. However, the influence of frailty on postoperative functional outcomes is unclear. We sought to determine the influence of frailty on functional outcomes after open or endovascular vascular procedures in patients with peripheral arterial disease. Methods: This systematic review was conducted according to the PRISMA guidelines. Eligible articles were identified through database searches of Pubmed and EMBASE in April 2017. Studies reporting on frailty and functional outcomes after vascular interventions for peripheral artery disease (PAD) were included. Outcomes of interest were dependency in activities of daily living (ADL), dependent mobility, discharge destination, disability-free survival, and quality of life. Individual studies were assessed for quality and risk of bias using the Quality in Prognosis Studies tool. Results: Eight studies met the eligibility criteria and were included. The risk of bias was low in two studies, intermediate in three studies, and high in three studies. Methods for frailty assessment were different for each study. Frailty was a predictor for discharge to a higher level of care, dependent mobility, and dependency in ADL after vascular procedures for PAD. Both frailty models and individual frailty characteristics seem to be associated with these adverse functional outcomes. Conclusions: Despite a limited amount of literature and an overall intermediate quality of the included studies, this systematic review shows an association between frailty and adverse functional outcomes after peripheral arterial procedures for PAD, including discharge to a care facility, dependent mobility, and a decline in ADL functioning

Season of Sampling and Season of Birth Influence Serotonin Metabolite Levels in Human Cerebrospinal Fluid

BACKGROUND: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults. METHODOLOGY/PRINCIPAL FINDINGS: Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations. CONCLUSION: In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and

Flow cytometric immunobead assay for fast and easy detection of PML-RARA fusion proteins for the diagnosis of acute promyelocytic leukemia

The PML-RARA fusion protein is found in approximately 97% of patients with acute promyelocytic leukemia (APL). APL can be associated with life-threatening bleeding complications when undiagnosed and not treated expeditiously. The PML-RARA fusion protein arrests maturation of myeloid cells at the promyelocytic stage, leading to the accumulation of neoplastic promyelocytes. Complete remission can be obtained by treatment with all-trans-retinoic acid (ATRA) in combination with chemotherapy. Diagnosis of APL is based on the detection of t(15;17) by karyotyping, fluorescence in situ hybridization or PCR. These techniques are laborious and demand specialized laboratories. We developed a fast (performed within 4-5 h) and sensitive (detection of at least 10% malignant cells in normal background) flow cytometric immunobead assay for the detection of PML-RARA fusion proteins in cell lysates using a bead-bound anti-RARA capture antibody and a phycoerythrin-conjugated anti-PML detection antibody. Testing of 163 newly diagnosed patients (including 46 APL cases) with the PML-RARA immunobead assay showed full concordance with the PML-RARA PCR results. As the applied antibodies recognize outer domains of the fusion protein, the assay appeared to work independently of the PML gene break point region. Importantly, the assay can be used in parallel with routine immunophenotyping for fast and easy diagnosis of APL

Circadian Preference Modulates the Neural Substrate of Conflict Processing across the Day

Human morning and evening chronotypes differ in their preferred timing for sleep and wakefulness, as well as in optimal daytime periods to cope with cognitive challenges. Recent evidence suggests that these preferences are not a simple by-product of socio-professional timing constraints, but can be driven by inter-individual differences in the expression of circadian and homeostatic sleep-wake promoting signals. Chronotypes thus constitute a unique tool to access the interplay between those processes under normally entrained day-night conditions, and to investigate how they impinge onto higher cognitive control processes. Using functional magnetic resonance imaging (fMRI), we assessed the influence of chronotype and time-of-day on conflict processing-related cerebral activity throughout a normal waking day. Sixteen morning and 15 evening types were recorded at two individually adapted time points (1.5 versus 10.5 hours spent awake) while performing the Stroop paradigm. Results show that interference-related hemodynamic responses are maintained or even increased in evening types from the subjective morning to the subjective evening in a set of brain areas playing a pivotal role in successful inhibitory functioning, whereas they decreased in morning types under the same conditions. Furthermore, during the evening hours, activity in a posterior hypothalamic region putatively involved in sleep-wake regulation correlated in a chronotype-specific manner with slow wave activity at the beginning of the night, an index of accumulated homeostatic sleep pressure. These results shed light into the cerebral mechanisms underlying inter-individual differences of higher-order cognitive state maintenance under normally entrained day-night conditions

Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial)

Background: Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome.Methods/design: This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditio

Eukaryote DIRS1-like retrotransposons: an overview

<p>Abstract</p> <p>Background</p> <p>DIRS1-like elements compose one superfamily of tyrosine recombinase-encoding retrotransposons. They have been previously reported in only a few diverse eukaryote species, describing a patchy distribution, and little is known about their origin and dynamics. Recently, we have shown that these retrotransposons are common among decapods, which calls into question the distribution of DIRS1-like retrotransposons among eukaryotes.</p> <p>Results</p> <p>To determine the distribution of DIRS1-like retrotransposons, we developed a new computational tool, ReDoSt, which allows us to identify well-conserved DIRS1-like elements. By screening 274 completely sequenced genomes, we identified more than 4000 DIRS1-like copies distributed among 30 diverse species which can be clustered into roughly 300 families. While the diversity in most species appears restricted to a low copy number, a few bursts of transposition are strongly suggested in certain species, such as <it>Danio rerio </it>and <it>Saccoglossus kowalevskii</it>.</p> <p>Conclusion</p> <p>In this study, we report 14 new species and 8 new higher taxa that were not previously known to harbor DIRS1-like retrotransposons. Now reported in 61 species, these elements appear widely distributed among eukaryotes, even if they remain undetected in streptophytes and mammals. Especially in unikonts, a broad range of taxa from Cnidaria to Sauropsida harbors such elements. Both the distribution and the similarities between the DIRS1-like element phylogeny and conventional phylogenies of the host species suggest that DIRS1-like retrotransposons emerged early during the radiation of eukaryotes.</p

Coordinating Environmental Genomics and Geochemistry Reveals Metabolic Transitions in a Hot Spring Ecosystem

We have constructed a conceptual model of biogeochemical cycles and metabolic and microbial community shifts within a hot spring ecosystem via coordinated analysis of the “Bison Pool” (BP) Environmental Genome and a complementary contextual geochemical dataset of ∼75 geochemical parameters. 2,321 16S rRNA clones and 470 megabases of environmental sequence data were produced from biofilms at five sites along the outflow of BP, an alkaline hot spring in Sentinel Meadow (Lower Geyser Basin) of Yellowstone National Park. This channel acts as a >22 m gradient of decreasing temperature, increasing dissolved oxygen, and changing availability of biologically important chemical species, such as those containing nitrogen and sulfur. Microbial life at BP transitions from a 92°C chemotrophic streamer biofilm community in the BP source pool to a 56°C phototrophic mat community. We improved automated annotation of the BP environmental genomes using BLAST-based Markov clustering. We have also assigned environmental genome sequences to individual microbial community members by complementing traditional homology-based assignment with nucleotide word-usage algorithms, allowing more than 70% of all reads to be assigned to source organisms. This assignment yields high genome coverage in dominant community members, facilitating reconstruction of nearly complete metabolic profiles and in-depth analysis of the relation between geochemical and metabolic changes along the outflow. We show that changes in environmental conditions and energy availability are associated with dramatic shifts in microbial communities and metabolic function. We have also identified an organism constituting a novel phylum in a metabolic “transition” community, located physically between the chemotroph- and phototroph-dominated sites. The complementary analysis of biogeochemical and environmental genomic data from BP has allowed us to build ecosystem-based conceptual models for this hot spring, reconstructing whole metabolic networks in order to illuminate community roles in shaping and responding to geochemical variability

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Peer reviewe

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates