bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that genetic drift not adaptation drivesfast-Zandlarge-Zeffects inFicedulaflycatchers
Authors: Chase Madeline A. , Vilcot Maurine , Mugal Carina F. 
Published: February 2023

AbstractThe sex chromosomes have been hypothesized to play a key role in driving adaptation and speciation across many taxa. The reason for this is thought to be the hemizygosity of the heteromorphic part of sex chromosomes in the heterogametic sex, which exposes recessive mutations to natural and sexual selection. The exposure of recessive beneficial mutations increases their rate of fixation on the sex chromosomes, which results in a faster rate of evolution. In addition, genetic incompatibilities between sex-linked loci are exposed faster in the genomic background of hybrids of divergent species, which makes sex chromosomes contribute disproportionately to reproductive isolation. However, in birds, which show a Z/W sex determination system, the disproportionate role of the Z-chromosome in adaptation and reproductive isolation is still debated. Instead, genetic drift has been proposed as the main driver of the so-calledfast-Zandlarge-Zeffects in birds. Here, we address this question inFicedulaflycatchers based on population resequencing data of six flycatcher species. Our results provide evidence for both thefast-Zandlarge-Zeffects inFicedulaflycatchers and that these two phenomena are driven by genetic drift rather than positive selection. Genomic scans of selective sweeps and fixed differences in fact suggest a reduced action of positive selection on the Z-chromosome. We propose that the observed reduction in the efficacy of purifying selection on the Z-chromosome helps to establish genetic incompatibilities between Z-linked and autosomal loci, which could result in pronounced selective sweep signatures for compensatory mutations on the autosomes.
CAGECAT: The CompArative GEne Cluster Analysis Toolbox for rapid search and visualisation of homologous gene clusters
Authors: van den Belt Matthias , Gilchrist Cameron , Booth Thomas J. , Chooi Yit-Heng , Medema Marnix H. , Alanjary Mohammad 
Published: February 2023

ABSTRACTBackgroundCo-localized sets of genes that encode specialized functions are common across microbial genomes and occur in genomes of larger eukaryotes as well. Important examples include Biosynthetic Gene Clusters (BGCs) that produce specialized metabolites with medicinal, agricultural, and industrial value (e.g. antimicrobials). Comparative analysis of BGCs can aid in the discovery of novel metabolites by highlighting distribution and identifying variants in public genomes. Unfortunately, gene-cluster-level homology detection remains inaccessible, time-consuming and difficult to interpret.ResultsThe comparative gene cluster analysis toolbox (CAGECAT) is a rapid and user-friendly platform to mitigate difficulties in comparative analysis of whole gene clusters. The software provides homology searches and downstream analyses without the need for command-line or programming expertise. By leveraging remote BLAST databases, which always provide up-to-date results, CAGECAT can yield relevant matches that aid in the comparison, taxonomic distribution, or evolution of an unknown query. The service is extensible and interoperable and implements the cblaster and clinker pipelines to perform homology search, filtering, gene neighbourhood estimation, and dynamic visualisation of resulting variant BGCs. With the visualisation module, publication-quality figures can be customized directly from a web-browser, which greatly accelerates their interpretation via informative overlays to identify conserved genes in a BGC query.ConclusionOverall, CAGECAT is an extensible software that can be interfaced via a standard web-browser for whole region homology searches and comparison on continually updated genomes from NCBI. The public web server and installable docker image are open source and freely available without registration at:https://cagecat.bioinformatics.nl
Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and correlation with integrated, multiomic analysis in the NIBIT-M4 trial
Authors: Rosaria Noviello Teresa Maria , Di Giacomo Anna Maria , Caruso Francesca Pia , Covre Alessia , Scala Giovanni , Costa Maria Claudia , Coral Sandra , Fridman Wolf H. , Sautès-Fridman Catherine , Mortarini Roberta , Brich Silvia , Pruneri Giancarlo , Simonetti Elena , Lofiego Maria Fortunata , Bedognetti Davide , Anichini Andrea , Maio Michele , Ceccarelli Michele 
Published: February 2023

AbstractAssociation of DNA hypomethylating agents (DHA) with immune-checkpoint inhibitors (ICI) is a promising strategy to improve efficacy of ICI-based therapy. Here we report the five-year clinical outcome and an integrated multi-omics analysis of pre- and on-treatment lesions from advanced melanoma patients enrolled in the phase Ib NIBIT-M4 study, a dose-escalation trial of the DHA agent guadecitabine combined with ipilimumab. With a minimum follow-up of 45 months the median OS was 25.6 months; the 5-year OS rate was 28.9% and the median DoR was 20.6 months. Specific genomic features and extent of T and B cellmediated immunity discriminated lesions of responding compared to non-responding patients. Enrichment for proliferation and EMT-related gene programs, and immune escape mechanisms characterized lesions from non-responding patients. Integration of a genetic immunoediting index (GIE) with an adaptive immunity signature (ICR) stratified patients/lesions into four distinct subsets and discriminated 5-year OS and PFS. These results suggest that coupling of immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.
Sensitivity of Rapid Antigen Tests Against SARS-CoV-2 Omicron and Delta Variants
Authors: Rao Anuradha , Westbrook Adrianna , Bassit Leda , Parsons Richard , Fitts Eric , Greenleaf Morgan , McLendon Kaleb , Sullivan Julie A. , O’Sick William , Baugh Tyler , Bowers Heather B. , Frank Filipp , Wang Ethan , Le Mimi , Frediani Jennifer , Roychoudhury Pavitra , Greninger Alexander L. , Jerris Robert , Pollock Nira R. , Ortlund Eric A. , Roback John D. , Lam Wilbur A. , Piantadosi Anne 
Published: February 2023

AbstractRapid Antigen Tests (RAT) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of eight commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR Cycle threshold (CT) value (a proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using CTvalue as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.
Prediction of Coronary Artery Disease Using Urinary Proteomics
Authors: Wei Dongmei , Melgarejo Jesus D. , Van Aelst Lucas , Vanassche Thomas , Verhamme Peter , Janssens Stefan , Peter Karlheinz , Zhang Zhen-Yu 
Published: February 2023

AbstractAimsCoronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD.MethodsUrinary proteome was analyzed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham risk score was available in 737 participants. Bioinformatics analysis was performed based on the CAD-associated peptides.ResultsThe novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an AUC of 0.82 (95% CI: 0.78-0.87) for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53, 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with CAD (HR: 1.54, 95% CI: 1.26-1.89, P<0.0001) higher risk of CAD. The new classifier further improved the risk reclassification of CAD on top of the Framingham risk score (net reclassification index: 0.61, 95% CI: 0.25-0.95, P=0.001).ConclusionsA novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.Lay summaryA biomarker that can predict coronary artery disease (CAD) is in urgently need.We developed and validated a urinary proteomic classifier for the prediction of CAD.The proteomic classifier involved in atherosclerosis improved the risk reclassification on top of the clinical risk score.
Microbial genes outperform species and SNVs as diagnostic markers for Crohn’s disease on multicohort fecal metagenomes empowered by artificial intelligence
Authors: Gao Sheng , Gao Xiang , Zhu Ruixin , Wu Dingfeng , Feng Zhongsheng , Jiao Na , Sun Ruicong , Gao Wenxing , He Qing , Liu Zhanju , Zhu Lixin 
Published: February 2023

AbstractBackgroundDysbiosis of gut microbial community is associated with the pathogenesis of CD and may serve as a promising non-invasive diagnostic tool. We aimed to compare the performances of the microbial markers of different biological levels by conducting a multidimensional analysis on the microbial metagenomes of CD.MethodsWe collected fecal metagenomic datasets generated from eight cohorts that altogether include 870 CD patients and 548 healthy controls. The microbial alterations in CD patients were assessed at multidimensional levels including species-, gene- and SNV- level, and then diagnostic models were constructed using artificial intelligence algorithm.ResultsA total of 227 species, 1047 microbial genes and 21877 microbial SNVs were identified that differed between CD and controls. The species-, gene- and SNV- models achieved an average AUC of 0.97, 0.95 and 0.77, respectively. Notably, the gene model exhibited superior diagnostic capability, achieving average AUCs of 0.89 and 0.91 in internal and external validations, respectively. Moreover, the gene model was specific for CD against other microbiome-related diseases. Further, we found that phosphotransferase system (PTS) contributed substantially to the diagnostic capability of the gene model. The outstanding performance of PTS was mainly explained by genescelBandmanY, which demonstrated high predictabilities for CD with the metagenomic datasets and was validated in an independent cohort by qRT-PCR analysis.ConclusionsOur global metagenomic analysis unravels the multidimensional alterations of the microbial communities in CD, and identifies microbial genes as robust diagnostic biomarkers across geographically and culturally distinct cohorts.
Safety and efficacy of left bundle branch area pacing compared with right ventricular pacing in patients with bradyarrhythmia and conduction system disorders: a systematic review and meta-analysis
Authors: Leventopoulos Georgios , Travlos Christoforos K. , Aronis Konstantinos N. , Anagnostopoulou Virginia , Patrinos Panagiotis , Papageorgiou Aggeliki , Perperis Angelos , Gale Chris P. , Davlouros Periklis 
Published: February 2023

AbstractBackgroundRight Ventricular Pacing (RVP) may have detrimental effects in ventricular function. Left Bundle Branch Area Pacing (LBBAP) is a new pacing strategy that appears to have better results. The aim of this systematic review and meta-analysis is to compare the safety and efficacy of LBBAP vs RVP in patients with bradyarrhythmia and conduction system disorders.MethodsMedline, Embase and Pubmed databases were searched for studies comparing LBBAP with RVP. Outcomes were all-cause mortality, atrial fibrillation (AF) occurrence, heart failure hospitalizations (HFH) and complications. QRS duration, mechanical synchrony and LVEF changes were also assessed. Pairwise meta-analysis was conducted using random and fixed effects models.ResultsTwenty-five trials with 4250 patients (2127 LBBAP) were included in the analysis. LBBAP was associated with lower risk for HFH (RR:0.33, CI 95%:0.21 to 0.50;p<0.001), all-cause mortality (RR:0.52 CI 95%:0.34 to 0.80;p=0.003), and AF occurrence (RR:0.43 CI 95%:0.27 to 0.68;p<0.001) than RVP. Lead related complications were not different between the two groups (p=0.780). QRSd was shorter in the LBBAP group at follow-up (WMD: -32.20 msec, CI 95%: -40.70 to -23.71;p<0.001) and LBBAP achieved better intraventricular mechanical synchrony than RVP (SMD: -1.77, CI 95%: -2.45 to -1.09;p<0.001). LBBAP had similar pacing thresholds (p=0.860) and higher R wave amplitudes (p=0.009) than RVP.ConclusionsLBBAP has better clinical outcomes, preserves ventricular electrical and mechanical synchrony and has excellent pacing parameters, with no difference in complications compared to RVP.Clinical PerspectiveWhat is knownLeft bundle branch area pacing (LBBAP) is a method of conduction system pacing with higher procedural success rate and less limitations compared to His bundle pacing (HBP).Right ventricular pacing (RVP) causes electromechanical dyssynchrony, which may result in left ventricular systolic dysfunction in some patients.What the study addsWe examined in a systematic review and meta-analysis whether there was a difference in clinical outcomes, electromechanical synchronization, and safety between LBBAP and RVP in patients with bradyarrhythmia and conduction system disorders.
Mechanisms and Predictors of Acute Kidney Injury with Perioperative Rosuvastatin in Patients Undergoing Cardiac Surgery
Authors: Wijesurendra RS , Sardell R , Jayaram R , Samuel N , Chen Z , Staplin N , Collins R , Zheng Z , Haynes R , Hill M , Emberson J , Casadei B 
Published: February 2023

AbstractBackgroundIn patients undergoing cardiac surgery perioperative statin therapy has been associated with an unexpected increase in postoperative plasma creatinine. Here we investigated mechanisms and predictors of acute kidney injury (AKI) in 1922 patients enrolled in the Statin Therapy in Cardiac Surgery (STICS) randomized placebo-controlled trial of perioperative rosuvastatin (20 mg once daily).MethodsAKI was defined according to international guidelines (KDIGO) using plasma creatinine, and also by cystatin C. Potentially mechanistically relevant plasma/serum biomarkers of muscle injury, inflammation, and kidney injury were investigated, including total creatine kinase (CK), growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), procalcitonin (PCT), placental growth factor (PLGF), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL).ResultsAt 48 hours post-surgery, the incidence of AKI was greater in the rosuvastatin group than in the placebo group when defined by a rise in creatinine (24.7% vs 19.3%, p=0.005) or cystatin C (9.2% vs 5.1%, p<0.001); the majority of AKI was stage 1 in severity (87% when defined by creatinine, and 80% when defined by cystatin C). Compared with placebo, rosuvastatin led to higher postoperative serum levels of KIM-1 (278±5 pg/ml versus 259±5 pg/ml, P=0.01), and to more frequent elevations in CK to >10x and >40x the baseline level (30.9% versus 26.5%, p=0.032, and 2.1% versus 0.7%, p=0.016, respectively), whereas postoperative concentrations of GDF-15, IL-6, PCT, PLGF, and NGAL were similar between groups. In multivariable analyses, insulin treatment, baseline KIM-1, combined coronary artery bypass grafting (CABG) and aortic valve replacement (AVR) surgery, and allocation to rosuvastatin were all independently associated with AKI as defined by creatinine or cystatin C. Odds ratios for rosuvastatin compared to placebo for both creatinine- and cystatin C-defined AKI were not materially altered by further adjustment for post-randomization increases in CK.ConclusionsPerioperative rosuvastatin initiation increased the absolute risk of AKI after cardiac surgery by 4-5%, whether defined by creatinine or cystatin C, and led to higher post-operative KIM-1, suggesting a deleterious effect on renal function, possibly mediated by proximal tubular injury. Insulin treatment, baseline KIM-1, combined CABG/AVR surgery, and allocation to rosuvastatin were all independently associated with AKI by any definition.
Age-specific severity of SARS-CoV-2 in February 2020 – June 2021 in the Netherlands
Authors: de Boer Pieter T. , van de Kassteele Jan , Vos Eric R.A. , van Asten Liselotte , Dongelmans Dave A. , van Gageldonk-Lafeber Arianne B. , Hartog Gerco den , Hofhuis Agnetha , van der Klis Fiona , de Lange Dylan W. , Stoeldraijer Lenny ,   the RIVM COVID-19 epidemiology and surveillance team, de Melker Hester E. , Geubbels Eveline , van den Hof Susan , Wallinga Jacco 
Published: February 2023

AbstractBackgroundSeverity of SARS-CoV-2 infection may vary over time. Here, we estimate age-specific risks of hospitalization, ICU admission and death given infection in the Netherlands from February 2020 to June 2021.MethodsA nationwide longitudinal serology study was used to estimate numbers of infections in three epidemic periods (February 2020 – June 2020, July 2020 – February 2021, March 2021 – June 2021). We accounted for reinfections and, as vaccination started in January 2021, breakthrough infections among vaccinated persons. Severity estimates were inferred by combining numbers of infections with aligned numbers of hospitalizations and ICU admissions from a national hospital-based registry, and aligned numbers of deaths based on national excess all-cause mortality estimates.ResultsIn each period there was a nearly consistent pattern of accelerating, almost exponential, increase in severity of infection with age. The rate of increase with age was highest for death and lowest for hospitalization. In the first period, the overall risk of hospitalization, ICU admission and death were 1.5% (95%-confidence interval [CI] 1.3-1.8%), 0.36% (95%-CI: 0.31-0.42%) and 1.2% (95%-CI: 1.0-1.4), respectively. The risk of hospitalization was higher in the following periods, while the risk of ICU admission remained stable. The risk of death decreased over time, with a substantial drop among ≥70-years-olds in February 2021 – June 2021.ConclusionThe accelerating increase in severity of SARS-CoV-2 with age remained intact during the first three epidemic periods in the Netherlands. The substantial drop in risk of death among elderly in the third period coincided with the introduction of COVID-19 vaccination.
Assessing the cost-effectiveness of economic strengthening and parenting support for preventing violence against adolescents in South Africa: an economic modelling study using non-randomised data
Authors: Rudgard William E. , Obiesie Sopuruchukwu , Desmond Chris , Casale Marisa , Cluver Lucie 
Published: February 2023

AbstractThere is limited evidence around the cost-effectiveness of interventions to prevent violence against children in low- and middle-income countries. We developed a decision-analytic model to estimate the cost-effectiveness of 1) a community outreach intervention to link eligible households to anti-poverty cash grants, and 2) a group-based parenting support intervention, and 3) a group-based parenting support ‘plus’ linkage of eligible households to anti-poverty cash grants intervention for preventing adolescent violence victimisation in Mpumalanga province, South Africa.The target population was families with an adolescent living below the national food poverty line. Modelled violence outcomes were emotional, physical, and sexual abuse. Intervention effectiveness was conditional on interventions’ effect on two evidence-based protective factors for adolescent violence: food security and caregiver supervision. Cost-effectiveness ratios were expressed per DALY averted and evaluated against a South Africa-specific willingness-to-pay threshold. We varied model parameters to consider routine service delivery versus trial-based costing, and population-average versus high prevalence of violence.For routine service delivery costing, both community grant outreach and parenting support interventions were cost-effective at population-average prevalence (ACER=USD2,650, and ACER=USD2,830 per DALYs averted, respectively), and high prevalence of violence (ACER=USD1,330 and ACER=USD2,305 per DALYs averted, respectively). The incremental cost-effectiveness of adding grant linkage to parenting support was USD271 and USD177 at population-average and high prevalence of violence, respectively. For trial-based costing, none of the interventions were cost-effective at population-average prevalence of violence, and only community grant outreach was cost-effective at high prevalence of violence (ACER=USD2400 per DALY averted). Cost-effectiveness estimates are expected to be conservative based on our only modelling intervention effects on three violence outcomes via two protective factors.Findings indicate that investments in community grant outreach, and parenting support interventions are likely to be cost-effective for preventing adolescent violence. Adding a grant linkage component to parenting support would enhance this approaches cost-effectiveness.