bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality risks associated with empirical antibiotic activity in E. coli bacteraemia: an analysis of electronic health records
Authors: Yoon Chang Ho , Bartlett Sean , Stoesser Nicole , Pouwels Koen B. , Jones Nicola , Crook Derrick W. , Peto Tim E.A. , Walker A. Sarah , Eyre David W. 
Published: January 2022

AbstractBackgroundReported bacteraemia outcomes following inactive empirical antibiotics (as judged by in vitro testing) are conflicting, potentially reflecting heterogeneous effects of species, minimum inhibitory concentration (MIC) breakpoints defining resistance/susceptibility, and times to rescue therapy.MethodsWe investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 04-February-2014 to 30-June-2021 receiving empirical amoxicillin-clavulanate with/without other antibiotics. We analysed 30-day all-cause mortality from index blood culture using Cox models by in vitro amoxicillin-clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2mg/L), categorical MIC, and a higher resistance breakpoint (>32/2mg/L), adjusting for other antibiotic activity and multiple confounders including comorbidities, vital signs, and blood tests.Results1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin-clavulanate. 30-day mortality was 193/1400 (14%) [any active baseline therapy] and 52/320 (16%) [inactive baseline therapy] (p=0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive vs. active amoxicillin-clavulanate (adjusted HR, aHR=1.27 [95%CI 0.83-1.93;p=0.28]), nor of an association with other antibiotic activity (p>0.18). Considering categorical amoxicillin-clavulanate MIC, MICs>32/2 were associated with mortality (aHR=1.85 vs. MIC=2/2 [0.99-3.73;p=0.054]). Using the higher resistance breakpoint, MICs>32/2 were independently associated with higher mortality (aHR=1.82 [1.07-3.10;p=0.027]), as were MICs>32/2 with active baseline aminoglycoside (aHR=2.34 [1.40-3.89;p=0.001), but not MICs>32/2 with active baseline non-aminoglycoside antibiotic(s) (aHR=0.87 [0.40-1.89;p=0.72).ConclusionsEUCAST-defined amoxicillin-clavulanate resistance was not associated with increased mortality, but a higher resistance breakpoint was. Additional active baseline non-aminoglycoside antibiotics prevented amoxicillin-clavulanate resistance-associated mortality, but active baseline aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints.SummaryIn patients with E. coli bacteraemia, high-level resistance to baseline empirical amoxicillin-clavulanate (minimum inhibitory concentration >32/2 mg/L) was associated with increased 30-day mortality, which was not compensated for by single-dose aminoglycosides.
SUSTAINED BENEFICIAL EFFECTS OF VACCINATION ON THE CASE FATALITY RATE FOR COVID-19 INFECTIONS
Authors: Murata Glen H. , Murata Allison E. , Perkins Douglas J. , Campbell Heather M. , Mao Jenny T. , Wagner Brent , Mcmahon Benjamin H. , Hagedorn Curt H. 
Published: January 2022

ABSTRACTObjectiveTo evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections.DesignMultivariate modeling of data from electronic medical recordsSetting130 medical centers of the United States Department of Veterans AffairsParticipants339,772 patients with COVID-19 confirmed by nucleic acid amplification testing as of September 30, 2021MethodsThe primary outcome was death within 60 days of the diagnosis. Patients were considered vaccinated if they had completed a full series >= 14 days prior to diagnosis. Cases presenting in July - September of 2021 were considered to have the delta variant. Logistic regression was used to derive adjusted odds ratios (OR) for vaccination and infection with delta versus earlier variants. Models were adjusted for demographic traits, standard comorbidity indices, selected clinical terms, and 3 novel parameters representing all prior diagnoses, all prior vital signs/ baseline laboratory tests, and current outpatient treatment. Patients with a delta infection were divided into 8 cohorts based upon the time from vaccination to diagnosis (in 4-week blocks). A common model was used to estimate the odds of death associated with vaccination for each cohort relative that of all unvaccinated patients.Results9.1% of subjects had been fully vaccinated, and 21.5% were presumed to have the delta variant. 18,120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for delta infection was 1.87 +/- 0.05 which corresponds to a relative risk of 1.78. The overall adjusted OR for prior vaccination was 0.280 +/- 0.011 corresponding to a relative risk of 0.291. The study of vaccine cohorts with a delta infection showed that the raw CFR rose steadily after 10-14 weeks. However, the OR for vaccination remained stable for 10-34 weeks.ConclusionsOur study confirms that delta is substantially more lethal than earlier variants and that vaccination is an effective means of preventing COVID death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks.
Universal guide for skull extraction and custom-fitting of implants to continuous and discontinuous skulls
Authors: Ahmed Zurna , Agha Naubahar , Trunk Attila , Berger Michael , Gail Alexander 
Published: January 2022

AbstractIntracranial neurophysiological recordings require chronic implants to provide transcranial access to the brain. Especially in larger animals, which participate in experiments over extended periods of time, implants should match the skull curvature to promote osseointegration and avoid tissue and bacterial ingress over time. Proposed CAD methods for designing implants to date have focused on naïve animals with continuous and even skull surfaces and calculate Boolean differences between implant and skull surface to fit the implant to the skull curvature. However, custom-fitting by calculating the difference fails, if a discontinuous skull surface needs to be matched. Also, the difference method does not allow designs with constant material thickness along the skull curvature, e.g. to allow fixed screw lengths. We present a universal step-by-step guide for custom-fitting implants which overcomes these limitations. It is suited for unusual skull conditions, like surface discontinuities or irregularities and includes virtual bending as a process to match skull surfaces while maintaining implant thickness. We demonstrate its applicability for a wide spectrum of scenarios, ranging from complex-shaped single-pieced implants to detailed multi-component implant systems built on even or discontinuous skull. The guide uses only a few software tools and the final virtual product can be manufactured using CNC milling or 3D printing. A detailed description of this process is available on GitHub including step-by-step video instructions suitable for users without any prior knowledge in CAD programming. We report the experience with these implants over several years in 11 rhesus monkeys.Significance StatementChronic implants are essential for intracranial neurophysiological recordings. In this study we show how to custom-design and –fit such implants for rhesus monkeys (Macacca mulatta). Different to existing approaches, our procedure is not limited to even skull surfaces but can be applied to discontinuous or irregular surfaces. It furthermore presents a description of virtual implant bending to match the skull curvature while maintaining implant thickness. The final virtual product can be manufactured using CNC milling or 3D printing. In contrast to previous studies, this guide is suited for users without any prior expertise in CAD programming using our step-by-step video instructions.
The spatial scale of adaptation in a native annual plant and its implications for responses to climate change
Authors: Gorton Amanda J. , Benning John W. , Tiffin Peter , Moeller David A. 
Published: January 2022

AbstractSpatial patterns of adaptation provide important insights into agents of selection and expected responses of populations to climate change. Robust inference into the spatial scale of adaptation can be gained through reciprocal transplant experiments that combine multiple source populations and common gardens. Here we examine the spatial scale of local adaptation of the North American annual plant common ragweed, Ambrosia artemisiifolia, using data from four common gardens with 22 source populations sampled from across a ∼1200 km latitudinal gradient within the native range. We found evidence of local adaptation at the northernmost common garden, but maladaptation at the two southern gardens, where more southern source populations outperformed local populations. Overall, the spatial scale of adaptation was large — at the three gardens where distance between source populations and gardens explained variation in fitness, it took an average of 820 km for fitness to decline to 50% of its predicted maximum. Taken together, these results suggest that climate change has already caused maladaptation, especially across the southern portion of the range, and may result in northward range contraction over time.
Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance
Authors: Hohberger Bettina , Prüss Harald , Mardin Christian , Lämmer Robert , Müller Johannes , Wallukat Gerd 
Published: January 2022

AbstractGlaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the ß2 adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to the elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer’s Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10-37 Aß1-40, Aß1-42, Aβ28-40, and [Pyr]-Aß3-42). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28-40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain [Pyr]-Aß3-42, representing a major neurogenic plaque component, exerted an activation that was blocked by the ß2-AR antagonist ICI118.551 indicating that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1-42, and Aβ10-37 yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer’s Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.
A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys
Authors: Qu Jiao , Yang Fa , Zhu Tao , Wang Yingshuo , Fang Wen , Ding Yan , Zhao Xue , Qi Xianjia , Xie Qiangmin , Xu Qiang , Xie Yicheng , Sun Yang , Chen Dijun 
Published: January 2022

AbstractNon-human primates (NHP) are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types from the cynomolgus monkey Macaca fascicularis (denoted as ‘Monkey Atlas’) using both single-cell chromatin accessibility (scATAC-seq) and RNA sequencing (scRNA-seq) data at the organism-wide level. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type composition and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we inferred pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identified various cell-specific cis-regulatory elements and constructed organ-specific gene regulatory networks at the single-cell level. Finally, we performed a comparative analysis of single-cell landscapes among mouse, cynomolgus monkey and human, and we showed that cynomolgus monkey has significantly higher degree of cell-type similarity to human than mouse. Taken together, our study provides a valuable resource for NHP cell biology.
Context-aware knowledge selection and reliable model recommendation with ACCORDION
Authors: Ahmed Yasmine , Telmer Cheryl A. , Zhou Gaoxiang , Miskov-Zivanov Natasa 
Published: January 2022

AbstractNew discoveries and knowledge are summarized in thousands of published papers per year per scientific domain, making it incomprehensible for scientists to account for all available knowledge relevant for their studies. In this paper, we present ACCORDION (ACCelerating andOptimizing modelRecommenDatIONs), a novel methodology and an expert system that retrieves and selects relevant knowledge from literature and databases to recommend models with correct structure and accurate behavior, enabling mechanistic explanations and predictions, and advancing understanding. ACCORDION introduces an approach that integrates knowledge retrieval, graph algorithms, clustering, simulation, and formal analysis. Here, we focus on biological systems, although the proposed methodology is applicable in other domains. We used ACCORDION in nine benchmark case studies and compared its performance with other previously published tools. We show that ACCORDION is:comprehensive, retrieving relevant knowledge from a range of literature sources; veryeffective, reducing the error of the initial baseline model by more than 80%, recommending models that closely recapitulate desired behavior, and outperforming previously published tools;selective, recommending only the most relevant, context-specific, and useful subset (15-20%) of candidate knowledge in literature;diverse, accounting for several distinct criteria to recommend more than one solution, thus enabling alternative explanations or intervention directions.
Look-up and look-down neurons in the mouse visual thalamus during freely moving exploration
Authors: Orlowska-Feuer Patrycja , Ebrahimi Aghileh S. , Zippo Antonio G. , Petersen Rasmus S. , Lucas Robert J. , Storchi Riccardo 
Published: January 2022

AbstractThe traditional view that visuomotor integration is a property of higher brain centres has recently been challenged by the discovery in head-fixed rodents that locomotion increases neuronal activity throughout the early visual system (including the retina). Any appreciation of the importance of this behavioural modulation of visual inputs must encompass a comprehensive understanding of the range of behaviours engaged by this mechanism. This information is unavailable from head-fixed preparations in which head and body postures are fundamentally constrained and dissociated from their natural coupling with visual experience.We addressed this deficit by recording spiking activity from the primary visual thalamus during freely moving exploration, while simultaneously applying frame-by-frame quantification of postures and movements to robust 3D reconstructions of head and body. We found that postures associated with the animal looking up/down affected activity in >50% neurons. The extent of this effect was comparable to that induced by locomotion. Moreover, the two effects were largely independent and jointly modulated neuronal activity. Thus, while most units were excited by locomotion, some expressed highest firing when the animal was looking up (“look up” neurons) while others when the animal was looking down (“look-down” neurons). These results were observed in the dark, thus representing a genuine behavioural modulation, and were amplified in a lit arena.These findings define the influence of natural exploratory behaviour on activity in the early visual system and reveal the importance of up/down postures in gating neuronal activity in the primary visual thalamus.
The relaxin receptor RXFP1 signals through a mechanism of autoinhibition
Authors: Erlandson Sarah C. , Rawson Shaun , Osei-Owusu James , Brock Kelly P. , Liu Xinyue , Paulo Joao A. , Mintseris Julian , Gygi Steven P. , Marks Debora S. , Cong Xiaojing , Kruse Andrew C. 
Published: January 2022

AbstractThe relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. Here, we present the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and to the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptor’s extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.
Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus
Authors: Beam Jenna E. , Wagner Nikki J. , Lu Kuan-Yi , Rowe Sarah E. , Conlon Brian P. 
Published: January 2022

AbstractStaphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. Host-pathogen interactions have been shown to have substantial impacts on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance in the host cell cytoplasm. Induction of antibiotic tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.
Beyond vaccination: A Cross-Sectional Study of the importance of Behavioral and Native Factors on COVID-19 Infection and Severity
Authors: Aouissi Hani Amir , Ababsa Mostefa , Leveau Carlos M. , Petrisor Alexandru-Ionut , Słomka Artur , Kechebar Mohamed Seif Allah , Yasuhara Jun , Epelboin Loïc , Ohmagari Norio 
Published: January 2022

AbstractThe COVID-19 pandemic has a major impact on a global scale. Understanding the innate and lifestyle-related factors influencing the rate and severity of COVID-19 is important for making evidence-based recommendations. This cross-sectional study aimed at establishing a potential relationship between human characteristics and vulnerability/resistance to SARS-CoV-2. We hypothesize that the impact of virus is not the same due to cultural and ethnic differences. A cross-sectional study was performed using an online questionnaire. The methodology included a development of a multi-language survey, expert evaluation and data analysis. Data was collected using a 13-item pre-tested questionnaire based on a literature review. Data was statistically analyzed using the logistic regression. For a total of 1125 respondents, 332 (29.5%) were COVID-19 positive, among them 130 (11.5%) required home-based treatment, and 14 (1.2%) intensive care. The significant factors included age, physical activity and health status all found to have a significant influence on the infection (p < 0.05). The severity of infection was associated with preventive measures and tobacco (p < 0.05). This suggests the importance of behavioral factors compared to innate ones. Apparently, the individual behavior is mainly responsible for the spread of the virus. Adopting a healthy lifestyle and scrupulously observing preventive measures including vaccination would greatly limit the probability of infection and prevent the development of severe COVID-19.
Predicting missing links in global host–parasite networks
Authors: Farrell Maxwell J. , Elmasri Mohamad , Stephens David A. , Davies T. Jonathan 
Published: January 2022

Abstract1. Parasites that infect multiple species cause major health burdens globally, but for many, the full suite of susceptible hosts is unknown. Predicting undocumented host–parasite associations will help expand knowledge of parasite host specificities, promote the development of theory in disease ecology and evolution, and support surveillance of multi‐host infectious diseases. The analysis of global species interaction networks allows for leveraging of information across taxa, but link prediction at this scale is often limited by extreme network sparsity and lack of comparable trait data across species.2. Here we use recently developed methods to predict missing links in global mammal‐parasite networks using readily available data: network properties and evolutionary relationships among hosts. We demonstrate how these link predictions can efficiently guide the collection of species interaction data and increase the completeness of global species interaction networks.3. We amalgamate a global mammal host–parasite interaction network (>29,000 interactions) and apply a hierarchical Bayesian approach for link prediction that leverages information on network structure and scaled phylogenetic distances among hosts. We use these predictions to guide targeted literature searches of the most likely yet undocumented interactions, and identify empirical evidence supporting many of the top ‘missing’ links.4. We find that link prediction in global host–parasite networks can successfully predict parasites of humans, domesticated animals and endangered wildlife, representing a combination of published interactions missing from existing global databases, and potential but currently undocumented associations.5. Our study provides further insight into the use of phylogenies for predicting host–parasite interactions, and highlights the utility of iterated prediction and targeted search to efficiently guide the collection of information on host–parasite interactions. These data are critical for understanding the evolution of host specificity, and may be used to support disease surveillance through a process of predicting missing links, and targeting research towards the most likely undocumented interactions.