Replication of fifteen loci involved in human plasma protein N-glycosylation in 4,802 samples from four cohorts

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4,802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the sixteen loci reported previously, fifteen were replicated in our study. For the remaining locus (near the KREMEN1 gene) the replication power was low, and hence replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The fifteen replicated loci present a good target for further functional studies. Among these, eight genes encode glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4, and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo

Does Reviewing Lead to Better Learning and Decision Making? Answers from a Randomized Stock Market Experiment

status: publishe

Cost effectiveness of epidural steroid injections to manage chronic lower back pain

Background The efficacy of epidural steroid injections in the management of chronic low back pain is disputed, yet the technique remains popular amongst physicians and patients alike. This study assesses the cost effectiveness of injections administered in a routine outpatient setting in England. Methods Patients attending the Nottingham University Hospitals’ Pain Clinic received two injections of methylprednisolone plus levobupivacaine at different dosages, separated by at least 12 weeks. Prior to each injection, and every week thereafter for 12 weeks, participants completed the EQ-5D health-related quality of life instrument. For each patient for each injection, total health state utility gain relative to baseline was calculated. The cost of the procedure was modelled from observed clinical practice. Cost effectiveness was calculated as procedure cost relative to utility gain. Results 39 patients provided records. Over a 13-week period commencing with injection, mean quality adjusted life year (QALY) gains per patient for the two dosages were 0.028 (SD 0.063) and 0.021 (SD 0.057). The difference in QALYs gained by dosage was insignificant (paired t-test, CIs -0.019 – 0.033). Based on modelled resource use and data from other studies, the mean cost of an injection was estimated at £219 (SD 83). The cost utility ratio of the two injections amounted to £8,975 per QALY gained (CIs 5,480 – 22,915). However, at costs equivalent to the tariff price typically paid to providers by health care purchasers, the ratio increased to £27,459 (CIs 16,779 – 70,091). Conclusions When provided in an outpatient setting, epidural steroid injections are a short term, but nevertheless cost effective, means of managing chronic low back pain. However, designation of the procedure as a day case requires the National Health Service to reimburse providers at a price which pushes the procedure to the margin of cost effectiveness

INDIGO-DataCloud: a Platform to Facilitate Seamless Access to E-Infrastructures

[EN] This paper describes the achievements of the H2020 project INDIGO-DataCloud. The project has provided e-infrastructures with tools, applications and cloud framework enhancements to manage the demanding requirements of scientific communities, either locally or through enhanced interfaces. The middleware developed allows to federate hybrid resources, to easily write, port and run scientific applications to the cloud. In particular, we have extended existing PaaS (Platform as a Service) solutions, allowing public and private e-infrastructures, including those provided by EGI, EUDAT, and Helix Nebula, to integrate their existing services and make them available through AAI services compliant with GEANT interfederation policies, thus guaranteeing transparency and trust in the provisioning of such services. Our middleware facilitates the execution of applications using containers on Cloud and Grid based infrastructures, as well as on HPC clusters. 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Targeting young drinkers online: the effectiveness of a web-based brief alcohol intervention in reducing heavy drinking among college students: study protocol of a two-arm parallel group randomized controlled trial

Contains fulltext : 99751.pdf (publisher's version ) (Open Access)Background: The prevalence of heavy drinking among college students and its associated health related consequences highlights an urgent need for alcohol prevention programs targeting 18 to 24 year olds. Nevertheless, current alcohol prevention programs in the Netherlands pay surprisingly little attention to the drinking patterns of this specific age group. The study described in this protocol will test the effectiveness of a web-based brief alcohol intervention that is aimed at reducing alcohol use among heavy drinking college students aged 18 to 24 years old. Methods/Design: The effectiveness of the What Do You Drink web-based brief alcohol intervention will be tested among 908 heavy drinking college students in a two-arm parallel group randomized controlled trial. Participants will be allocated at random to either the experimental (N = 454: web-based brief alcohol intervention) or control condition (N = 454: no intervention). The primary outcome measure will be the percentage of participants who drink within the normative limits of the Dutch National Health Council for low-risk drinking. These limits specify that, for heavy alcohol use, the mean consumption cannot exceed 14 or 21 glasses of standard alcohol units per week for females and males, respectively, while for binge drinking, the consumption cannot exceed five or more glasses of standard alcohol units on one drinking occasion at least once per week within one month and six months after the intervention. Reductions in mean weekly alcohol consumption and frequency of binge drinking are also primary outcome measures. Weekly Ecological Momentary Assessment will measure alcohol-related cognitions, that is, attitudes, self-efficacy, subjective norms and alcohol expectancies, which will be included as the secondary outcome measures. Discussion: This study protocol describes the two-arm parallel group randomized controlled trial developed to evaluate the effectiveness of a web-based brief alcohol intervention. We expect a reduction of mean weekly alcohol consumption and frequency of binge drinking in the experimental condition compared to the control condition as a direct result of the intervention. If the website is effective, it will be implemented in alcohol prevention initiatives, which will facilitate the implementation of the protocol.8 p

Cost-effectiveness of minimal interventional procedures for chronic mechanical low back pain: design of four randomised controlled trials with an economic evaluation

Background: Minimal interventional procedures are frequently applied in patients with mechanical low back pain which is defined as pain presumably resulting from single sources: facet, disc, sacroiliac joint or a combination of these. Usually, these minimal interventional procedures are an integral part of a multidisciplinary pain programme. A recent systematic review issued by the Dutch Health Insurance Council showed that the effectiveness of these procedures for the total group of patients with chronic low back pain is yet unclear and cost-effectiveness unknown. The aim of the study is to evaluate whether a multidisciplinary pain programme with minimal interventional procedures is cost-effective compared to the multidisciplinary pain programme alone for patients with chronic mechanical low back pain who did not respond to conservative primary care and were referred to a pain clinic. Methods. All patients with chronic low back pain who are referred to one of the 13 participating pain clinics will be asked to participate in an observational study. Patients with a suspected diagnosis of facet, disc or sacroiliac joint problems will receive a diagnostic block to confirm this diagnosis. If confirmed, they will be asked to participate in a Randomized Controlled Trial (RCT). For each single source a separate RCT will be conducted. Patients with a combination of facet, disc or sacroiliac joint problems will be invited for participation in a RCT as well. An economic evaluation from a societal perspective will be performed alongside these four RCTs. Patients will complete questionnaires at baseline, 3 and 6 weeks, 3, 6, 9 and 12 months after start of the treatment

Contribution of parental and school personnel smoking to health risk behaviours among Finnish adolescents

This study compared parental smoking with school personnel smoking in relation to adolescents' smoking behaviours, alcohol use, and illicit drug use

A randomized controlled trial testing the effectiveness of a universal school-based depression prevention program 'Op Volle Kracht' in the Netherlands

Contains fulltext : 102521.pdf (publisher's version ) (Open Access)Background: The incidence of depressive symptoms increases during adolescence, from 10.0% to 24.5% at age 11 to 15, respectively. Experiencing elevated levels of depressive symptoms increases the risk of a depressive disorder in adulthood. A universal school-based depression prevention program Op Volle Kracht (OVK) was developed, based on the Penn Resiliency Program, aimed at preventing the increase of depressive symptoms during adolescence and enhancing positive development. In this study the effectiveness of OVK will be tested and possible mediators of program effects will be focus of study as well. Method: The effectiveness of OVK will be tested in a randomized controlled trial with two conditions, intervention (OVK) and control condition (care as usual). Schools are randomly assigned to research conditions. OVK will be incorporated in the school curriculum, maximizing program attendance. OVK consists of 16 lessons of 50 min, given by trained psychologists to groups of 11-15 students. OVK contains Cognitive Behavioral Therapy, social skills training, problem solving and decision making. Outcomes are measured at 6, 12, 18 and 24 months follow up, to monitor long term program effects. Primary outcome is level of depressive symptoms, secondary outcomes are: anxiety, hopelessness, cognitive bias, substance use, truancy, life satisfaction, coping, self-efficacy, optimism, happiness, friendship, school performance and school attitude. The questionnaires for students will be administered in the school setting. Parents will complete a questionnaire at baseline only. Discussion: In this paper the study into the effectiveness of the depression prevention program OVK was described. It is expected that OVK will prevent the increase in depressive symptoms during adolescence and enhance positive development in the intervention condition, compared to the control condition. If OVK will be effective, it can be implemented in the school context by which numerous adolescents can be reached.9 p

Differential relationships of family drinking with alcohol expectancy among urban school children

<p>Abstract</p> <p>Background</p> <p>Positive alcohol outcome expectancy has consistently been linked with problematic drinking, but there is little population-based evidence on its role on early stages of drinking in childhood. The present study seeks to understand the extent to which drinking of family members is differentially associated with the endorsement of alcohol expectancy in late childhood.</p> <p>Methods</p> <p>A representative sample of 4th and 6th graders (N = 2455) drawn from 28 public schools in an urban region of Taiwan completed a self-administered paper-and-pencil questionnaire. Each student provided information on alcohol expectancy, drinking experiences, and individual and family attributes. Complex survey analyses were performed to evaluate the relationship, with stratification by children's alcohol drinking history.</p> <p>Results</p> <p>An estimated 29% of the 4^thgraders and 43% of the 6^thgraders had initiated alcohol consumption (over 40% of them had drank on three or more occasions). Alcohol drinking-related differences appear in both the endorsement and the correlates of alcohol expectancy. Positive alcohol expectancy was strongly associated with family drinking, particularly the dimension of "enhanced social behaviors"; negative alcohol expectancy was inversely associated with drinking frequency. Among alcohol naïve children, significant connections appear between paternal drinking and three dimensions of positive alcohol expectancy (i.e., enhanced social behaviors:β_wt= 0.15, promoting relaxation or tension reduction:β_wt= 0.18, and global positive transformation:β_wt= 0.22).</p> <p>Conclusions</p> <p>Individual tailored strategies that address family influences on alcohol expectancy may be needed in prevention programs targeting drinking behaviors in children.</p

Reliable identification of protein-protein interactions by crosslinking mass spectrometry

Protein-protein interactions govern most cellular pathways and processes, and multiple technologies have emerged to systematically map them. Assessing the error of interaction networks has been a challenge. Crosslinking mass spectrometry is currently widening its scope from structural analyses of purified multi-protein complexes towards systems-wide analyses of protein-protein interactions (PPIs). Using a carefully controlled large-scale analysis of Escherichia coli cell lysate, we demonstrate that false-discovery rates (FDR) for PPIs identified by crosslinking mass spectrometry can be reliably estimated. We present an interaction network comprising 590 PPIs at 1% decoy-based PPI-FDR. The structural information included in this network localises the binding site of the hitherto uncharacterised protein YacL to near the DNA exit tunnel on the RNA polymerase.TU Berlin, Open-Access-Mittel – 2021DFG, 390540038, EXC 2008: Unifying Systems in Catalysis "UniSysCat"DFG, 392923329, GRK 2473: Bioaktive Peptide - Innovative Aspekte zur Synthese und BiosyntheseDFG, 426290502, Erfassung der strukturellen Organisation des Mycoplasma pneumoniae Proteoms mittels in-Zell Crosslinking-Massenspektrometri