Biology subjects

Egger, M.

Publications and source records attributed to Egger, M..

11 recordsLinked to original sources

bioRxiv2023

S100A1ct: a synthetic peptide derived from human S100A1 protein improves cardiac contractile performance and survival in pre-clinical heart failure models

BackgroundThe EF-hand Ca2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. S100A1s ability to recognize and modulate the activity of targets such as SERCA2a and RyR2 in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal -helix (residues 75-94). Objective: We therefore hypothesized that a synthetic peptide consisting of residues 75-94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. Methods and Results: Applying an integrative translational research pipeline, ranging from computational molecular modeling to large animal cardiac disease models, we characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in pre-clinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. Mechanistically, S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca2+ cycling and prevents {beta}-adrenergic receptor triggered Ca2+ imbalances by targeting SERCA2a and RyR2 activity. Modeling suggests that S100A1ct may stimulate SERCA2a by interacting with the sarcoplasmic transmembrane segments of the multi-span integral membrane Ca2+ pump. Incorporation of a cardiomyocyte targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. Conclusion: S100A1ct peptide is a promising lead for the development of a novel peptide-based therapeutic against heart failure with reduced ejection fraction.

pharmacology and toxicology↗

bioRxiv2020

How to best evaluate applications for junior fellowships? Remote evaluation and face-to-face panel meetings compared

ObjectivesTo test a simplified evaluation of fellowship proposals by analyzing the agreement of funding decisions with the official evaluation, and to examine the use of a lottery-based decision for proposals of similar quality. DesignThe study involved 134 junior fellowship proposals (Postdoc.Mobility). The official method used two panel reviewers who independently scored the application, followed by triage and discussion of selected applications in a panel. Very competitive/uncompetitive proposals were directly funded/rejected without discussion. The simplified procedure used the scores of the two panel members, with or without the score of an additional, third expert. Both methods could further use a lottery to decide on applications of similar quality close to the funding threshold. The same funding rate was applied, and the agreement between the two methods analyzed. SettingSwiss National Science Foundation (SNSF). ParticipantsPostdoc.Mobility panel reviewers and additional expert reviewers. Primary outcome measurePer cent agreement between the simplified and official evaluation method with 95% confidence intervals (95% CI). ResultsThe simplified procedure based on three reviews agreed in 80.6% (95% CI 73.9-87.3) with the official funding outcome. The agreement was 86.6% (95% CI 80.8-92.4) when using the two reviews of the panel members. The agreement between the two methods was lower for the group of applications discussed in the panel (64.2% and 73.1%, respectively), and higher for directly funded/rejected applications (range 96.7% to 100%). The lottery was used in eight (6.0%) of 134 applications (official method), 19 (14.2%) applications (simplified, three reviewers) and 23 (17.2%) applications (simplified, two reviewers). With the simplified procedure, evaluation costs could have been halved and 31 hours of meeting time saved for the two 2019 calls. ConclusionAgreement between the two methods was high. The simplified procedure could represent a viable evaluation method for the Postdoc.Mobility early career instrument at the SNSF.

scientific communication and education↗

bioRxiv2020

HIV coinfection is associated with low fitness rpoB variants in rifampicin-resistant Mycobacterium tuberculosis

We analysed 312 drug-resistant genomes of Mycobacterium tuberculosis (Mtb) collected from HIV coinfected and HIV negative TB patients from nine countries with a high tuberculosis burden. We found that rifampicin-resistant Mtb strains isolated from HIV coinfected patients carried disproportionally more resistance-conferring mutations in rpoB that are associated with a low fitness in the absence of the drug, suggesting these low fitness rpoB variants can thrive in the context of reduced host immunity.

evolutionary biology↗

bioRxiv2020

Who reviews for predatory journals? A study on reviewer characteristics

BackgroundWhile the characteristics of scholars who publish in predatory journals are relatively well-understood, nothing is known about the scholars who review for these journals. We aimed to answer the following questions: Can we observe patterns of reviewer characteristics for scholars who review for predatory journals and for legitimate journals? Second, how are reviews for potentially predatory journals distributed globally? MethodsWe matched random samples of 1,000 predatory journals and 1,000 legitimate journals of the Cabells Scholarly Analytics journal lists with the Publons database of review reports, using the Jaro-Winkler string metric. For reviewers of matched reviews, we descriptively analysed meta-data on reviewing and publishing behaviour. ResultsWe matched 183,743 unique Publons reviews that were claimed by 19,598 reviewers. 6,077 reviews were conducted for 1160 unique predatory journals (3.31% of all reviews). 177,666 were claimed for 6,403 legitimate journals (96.69% of all reviews). The vast majority of scholars either never or only occasionally submitted reviews for predatory journals to Publons (89.96% and 7.55% of all reviewers, respectively). Smaller numbers of scholars claimed reviews predominantly or exclusively for predatory journals (0.26% and 0.35% of all reviewers, respectively). The two latter groups of scholars are of younger academic age and have fewer publications and fewer reviews than the first two groups of scholars.Developing regions feature larger shares of reviews for predatory reviews than developed regions. ConclusionThe characteristics of scholars who review for potentially predatory journals resemble those of authors who publish their work in these outlets. In order to combat potentially predatory journals, stakeholders will need to adopt a holistic approach that takes into account the entire research workflow.

scientific communication and education↗

bioRxiv2019

ASSESSING CONFIDENCE IN THE RESULTS OF NETWORK META-ANALYSIS (CINEMA)

Evaluation of the credibility of results from a meta-analysis has become an intrinsic part of the evidence synthesis process. We present a methodological framework to evaluate Confidence In the results from Network Meta-Analysis (CINeMA) when multiple interventions are compared. CINeMA considers six domains and we outline the methods used to form judgements about within-study bias, across-studies bias, indirectness, imprecision, heterogeneity and incoherence. Key to judgements about within-study bias and indirectness is the percentage contribution matrix, which shows how much information each study contributes to the results from network meta-analysis. The use of contribution matrix allows the semi-automation of the process, implemented in a freely available web application (cinema.ispm.ch). In evaluating imprecision, heterogeneity and inconsistency we consider the impact of these components of variability in forming clinical decisions. Via three examples, we show that CINeMA improves transparency and avoids the selective use of evidence when forming judgements, thus limiting subjectivity in the process. CINeMA is easy to apply even in large and complicated networks, like a network involving 18 different antidepressant drugs.

epidemiology↗

bioRxiv2019

Metagenomic analysis reveals large potential for carbon, nitrogen and sulfur cycling in coastal methanic sediments of the Bothnian Sea

The Bothnian Sea is an oligotrophic brackish basin characterized by low salinity and high concentrations of reactive iron, methane and ammonium in the sediments potentially enabling an intricate microbial network. Therefore, we analyzed and compared biogeochemical and microbial profiles at one offshore and two near coastal sites in the Bothnian Sea. 16S rRNA amplicon sequence analysis revealed stratification of both bacterial and archaeal taxa in accordance with the geochemical gradients of iron, sulfate and methane. The communities at the two near coastal sites were more similar to each other than that at the offshore site located at a greater water depth. To obtain insights into the metabolic networks within the iron-rich methanic sediment layer located below the sulfate-methane transition zone (SMTZ), we performed metagenomic sequencing of sediment-derived DNA. Genome bins retrieved from the most abundant bacterial and archaeal community members revealed a broad potential for respiratory sulfur metabolism via partially reduced sulfur species. Nitrogen cycling was dominated by reductive processes via a truncated denitrification pathway encoded exclusively by bacterial lineages. Gene-centric fermentative metabolism analysis indicated the central role of acetate, formate, alcohols and hydrogen in the analyzed anaerobic sediment. Methanogenic/-trophic pathways were dominated by Methanosaetaceae, Methanosarcinaceae, Methanomassiliicoccaceae, Methanoregulaceae and ANME-2 archaea. Thorarchaeota and Bathyarchaeota encoded pathways for acetogenesis. Our results indicate flexible metabolic capabilities of core community bacterial and archaeal taxa, which can adapt to changing redox conditions, and with a spatial distribution in Bothnian Sea sediments that is likely governed by the quality of available organic substrates.

ecology↗

bioRxiv2018

Spatial epidemiology of gestational age and birth weight in Switzerland: Census-based linkage study

BackgroundGestational age and birth weight are strong predictors of infant morbidity and mortality. Understanding spatial variation can inform policies to reduce health inequalities. We examined small-area variation in gestational age and birth weight in Switzerland.\n\nMethodsAll singleton live births recorded in the Swiss Live Birth Register 2011 to 2014 were eligible. We deterministically linked the Live Birth Register with census and survey data to create datasets including neonatal and pregnancy-related variables, parental characteristics and geographical variables. We produced maps of 705 areas and fitted linear mixed-effect models to assess to what extent spatial variation was explained by these variables.\n\nResultsWe analysed all 315,177 eligible live births. Area-level averages of gestational age varied between 272-279 days, and between 3138-3467g for birth weight. The fully adjusted models explained 31% and 87% of spatial variation of gestational age and birth weight, respectively. Language region explained most of the variation, with shorter gestational age and lower birth weight in French- and Italian- than in German-speaking areas. Other variables explaining variation were, for gestational age, the level of urbanisation, the parents nationality and missing father. For birth weight, they were gestational age, altitude, born out of wedlock, and parental nationality. In a subset of 69,463 live births with data on parental education, levels of education were only weakly associated with gestational age or birth weight.\n\nConclusionsIn Switzerland, small area variation in birth weight is largely explained, and variation in gestational age partially explained by geocultural, socio-demographic and pregnancy factors.\n\nStrengths and limitations of this studyO_LIThis study was based on a large sample with national coverage, with data on neonatal and pregnancy-related predictors of gestational age and birth weight, and precise spatial data.\nC_LIO_LINo data were available on the mode of delivery, maternal smoking, mothers weight and height or gestational diabetes.\nC_LIO_LIThe fully adjusted model explained about 80% of the regional variation in birth weight and about 40% of the variation in gestational age.\nC_LIO_LILanguage region, a proxy for cultural, social and behavioural factors, was a strong explanatory factor, with lower birth weight and shorter gestation in the French and Italian compared to the German language region.\nC_LIO_LIUnknown father was associated with shorter gestation and lower birth weight, indicating that children not recognised by their fathers may be at higher risk of poor outcomes.\nC_LI

epidemiology↗

bioRxiv2018

Whole genome sequencing for drug resistance profile prediction in Mycobacterium tuberculosis

Whole genome sequencing allows rapid detection of drug-resistant M. tuberculosis isolates. However, high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data have thus far been lacking.\n\nWe determined drug resistance profiles of 176 genetically diverse clinical M. tuberculosis isolates from Democratic Republic of the Congo, Ivory Coast, Peru, Thailand and Switzerland by quantitative phenotypic DST for 11 antituberculous drugs using the BD BACTEC MGIT 960 system and 7H10 agar dilution to generate a cross-validated phenotypic DST readout. We compared phenotypic drug susceptibility results with predicted drug resistance profiles inferred by whole genome sequencing.\n\nBoth phenotypic DST methods identically classified the strains into resistant/susceptible in 73-99% of the cases, depending on the drug. Changes in minimal inhibitory concentrations were readily explained by mutations identified by whole genome sequencing. Using the whole genome sequences we were able to predict quantitative drug resistance levels where wild type and mutant MIC distributions did not overlap. The utility of genome sequences to predict quantitative levels of drug resistance was partially limited due to incompletely understood mechanisms influencing the expression of phenotypic drug resistance. The overall sensitivity and specificity of whole genome-based DST were 86.8% and 94.5%, respectively.\n\nDespite some limitations, whole genome sequencing has high predictive power to infer resistance profiles without the need for time-consuming phenotypic methods.\n\nOne sentence summaryWhole genome sequencing of clinical M. tuberculosis isolates accurately predicts drug resistance profiles and may replace culture-based drug susceptibility testing in the future.

microbiology↗

bioRxiv2018

Exchange catalysis during anaerobic methanotrophy revealed by 12CH2D2 & 13CH3D in methane

The anaerobic oxidation of methane (AOM) is a crucial component of the methane cycle, but its enzymatic versatility under environmental conditions remains poorly understood. We use sediment samples collected during IODP Expedition 347 to the Baltic Sea to show that relative abundances of 12CH2D2 and 13CH3D molecules in methane gas trace the reversibility of methyl-coenzyme M reductase during AOM by driving methane towards internal, thermodynamic isotopic equilibrium. These data suggest that 12CH2D2 and 13CH3D together can identify the influence of methanotrophy in environments where conventional bulk isotope ratios are ambiguous, and these findings may lead to new insights regarding the global significance of enzymatic back-flux in the methane cycle.

biochemistry↗

bioRxiv2018

Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries

BackgroundDrug resistance and HIV co-infection are challenges for the global control of tuberculosis.\n\nMethodsWe collected Mycobacterium tuberculosis isolates from adult patients in Cote dIvoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing (DST) was done locally and at the Swiss tuberculosis reference laboratory. We examined mortality during treatment according to DST results and treatment adequacy in logistic regression models adjusting for sex, age, sputum microscopy and HIV status.\n\nFindings634 tuberculosis patients were included; median age was 33.2 years, 239 (37.7%) were female, 272 (42.9%) HIV-positive and 69 (10.9%) patients died. Based on the reference laboratory DST, 394 (62.2%) strains were pan-susceptible, 45 (7.1%) mono-resistant, 163 (25.7%) multidrug-resistant (MDR-TB), and 30 (4.7%) had pre-extensive or extensive drug resistance (pre-XDR/XDR-TB). Results of reference and local laboratories were discordant in 121 (19.1%) cases, corresponding to a sensitivity of 84.3% and a specificity of 90.8%. In patients with drug-resistant tuberculosis, discordant results were associated with increased mortality (risk ratio 1.81; 95% CI 1.07-3.07). In logistic regression, compared to adequately treated patients with pan-susceptible strains, the adjusted odds ratio for death was 4.23 (95% CI 2.16-8.29) for adequately treated patients with drug-resistant strains and 21.54 (95% CI 3.36-138.1) for inadequately treated patients with drug-resistant strains. HIV status was not associated with mortality.\n\nInterpretationUsing a reference laboratory standard, inaccurate DST leading to inappropriate treatment of drug-resistant tuberculosis, but not HIV infection, contributed to mortality.

epidemiology↗

bioRxiv2018

Planning a future randomized clinical trial based on a network of relevant past trials

Background: The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses.\n\nMethods: Network meta-analyses can also be used to plan future trials. We introduce a four-steps framework to plan a new trial that aims to identify the optimal new design that will update the existing evidence to best serve timely clinical and public health decision making. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis.\n\nResults: A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges in the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity.\n\nConclusions: When used judiciously, conditional trial design could significantly reduce waste in clinical research.

epidemiology↗