bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional Variation in COVID-19 Scarce Resource Allocation Protocols
Authors: Gandhi Rupali , Piscitello Gina M. , Parker William F. , Michelson Kelly 
Published: January 2021

ABSTRACTBackgroundScarce resource allocation policies vary across the United States. Little is known about regional variation in hospital-level resource allocation protocols and variation in their application.ObjectiveTo evaluate how scarce resource allocation policies throughout the Chicagoland area vary and whether there are differences in policy application within and amongst hospitals.DesignTwo cross-sectional surveys.SettingChicagoland hospitals.ParticipantsRepresentatives from Chicagoland hospitals and triage officers at these hospitals.MeasurementsSurvey responses and categorical variables are described by frequency of occurrence. Intra- and interhospital variation in ranking of hypothetical patients was assessed using Kappa coefficients.ResultsEight Chicago area hospitals responded to the survey assessing scarce resource allocation protocols. For hospitals willing to describe their specific ventilator allocation protocol (n=7), the initial scoring system varied with most utilizing the sequential organ failure assessment (SOFA) score (86%) and medical comorbidities (57%). A majority gave priority to pre-defined groups in their initial scoring system (86%), all discussed withdrawal of mechanical ventilation for adult patients (100%), and a minority had exclusion criteria (43%). Forty-nine triage officers from nine hospitals responded to the second survey. Triage officer rankings of hypothetical patients had slight agreement amongst all hospitals (Kappa 0.158) and fair agreement within two hospitals with the most respondents (Kappa 0.21 and 0.25). Almost half of triage officer respondents reported using tiebreakers to rank patients (N=23/49, 47%).ConclusionAlthough most Chicago area hospitals surveyed created guidelines for resource allocation during the COVID-19 pandemic, these guidelines and application of these protocols by triage officers varied significantly.Funding SourceNone.
High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation
Authors: Cretin Emma , Lopes Priscilla , Vimont Elodie , Tatsuta Takashi , Langer Thomas , Yu-Wai-Man Patrick , Reynier Pascal , Wai Timothy 
Published: January 2021

AbstractMutations affecting the mitochondrial fusion protein Optic Atrophy 1 (OPA1) cause autosomal dominant optic atrophy (DOA) – one of the most common form of mitochondrial disease. The majority of patients develop isolated optic atrophy, but about 20% ofOPA1mutation carriers manifest more severe neurological deficits as part of a “DOA+” phenotype. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae organization, oxidative phosphorylation, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. To better understand the genetic regulation of mitochondrial dynamics, we established a high-throughput imaging pipeline using supervised machine learning (ML) to perform unbiased, quantitative mitochondrial morphology analysis that was coupled with a bespoke siRNA library targeting the entire known mitochondrial proteome (1531 genes), providing a detailed phenotypic screening of human fibroblasts. In control fibroblasts, we identified known and novel genes whose depletion promoted elongation or fragmentation of the mitochondrial network. In DOA+ patient fibroblasts, we identified 91 candidate genes whose depletion prevents mitochondrial fragmentation, including the mitochondrial fission genesDNM1L,MIEF1, andSLC25A46, but also genes not previously linked to mitochondrial dynamics such as Phosphatidyl Glycerophosphate Synthase (PGS1), which belongs to the cardiolipin (CL) synthesis pathway. PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation. This study illustrates the power of a first-in-kind objective automated imaging approach to uncover genetic modifiers of mitochondrial disease through high-throughput phenotypic screening of patient fibroblasts.
MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging
Authors: Singh Priti , Fragoza Robert , Blengini Cecilia S. , Tran Tina N. , Pannafino Gianno , Al-Sweel Najla , Schimenti Kerry J. , Schindler Karen , Alani Eric A. , Yu Haiyuan , Schimenti John C. 
Published: January 2021

AbstractMost spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genesMLH1andMLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine ifMLH1/3variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nineMLH1andMLH3variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.
Mutation rates and selection on synonymous mutations in SARS-CoV-2
Authors: De Maio Nicola , Walker Conor R. , Turakhia Yatish , Lanfear Robert , Corbett-Detig Russell , Goldman Nick 
Published: January 2021

AbstractThe COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G→U and C→U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. While previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.
Polygenic adaptation, clonal interference, and the evolution of mutators in experimentalPseudomonas aeruginosapopulations
Authors: Harris Katrina B. , Flynn Kenneth M. , Cooper Vaughn S. 
Published: January 2021

AbstractIn bacterial populations, switches in lifestyle from motile, planktonic growth to surface-grown biofilm is associated with persistence in both infections and non-clinical biofilms. Studies have identified the first steps of adaptation to biofilm growth but have yet to replicate the extensive genetic diversity observed in chronic infections or in the natural environment. We conducted a 90-day long evolution experiment withPseudomonas aeruginosaPA14 in growth media that promotes biofilm formation in either planktonic culture or in a biofilm bead model. Surprisingly, all populations evolved extensive genetic diversity with hundreds of mutations maintained at intermediate frequencies, while fixation events were rare. Instead of the expected few beneficial mutations rising in frequency through successive sweeps, we observe a remarkable 40 genes with parallel mutations spanning both environments and often on coexisting genotypes within a population. Additionally, the evolution of mutator genotypes (mutSormutLmutator alleles) that rise to high frequencies in as little as 25 days contribute to the extensive genetic variation and strong clonal interference. Parallelism in several transporters (includingpitA, pntB, nosD, andpchF) indicate probable adaptation to the arginine media that becomes highly alkaline during growth. Further, genes involved in signal transduction (includinggacS, aer2, bdlA, andPA14_71750) reflect likely adaptations to biofilm-inducing conditions. This experiment shows how extensive genetic and phenotypic diversity can arise and persist in microbial populations despite strong selection that would normally purge diversity.ImportanceHow biodiversity arises and is maintained in clonally reproducing organisms like microbes remains unclear. Many models presume that beneficial genotypes will outgrow others and purge variation via selective sweeps. Environmental structure like biofilms may oppose this process and preserve variation. We tested this hypothesis by evolvingP. aeruginosapopulations in biofilm-promoting media for three months and found both adaptation and diversification that were mostly uninterrupted by fixation events that eliminate diversity. Genetic variation tended to be greater in lines grown using a bead model of biofilm growth but many lineages also persisted in planktonic lines. Convergent evolution affecting dozens of genes indicates that selection acted on a wide variety of traits to improve fitness, causing many adapting lineages to co-occur and persist. This result demonstrates that some environments may expose a large fraction of the genome to selection and select for many adaptations at once, causing enduring diversity.
Mitotic R-loops direct Aurora B kinase to maintain centromeric cohesion
Authors: Moran Erin C. , Liu Limin , Zasadzinska Ewelina , Kestner Courtney A. , Sarkeshik Ali , DeHoyos Henry , Yates John R. , Foltz Daniel , Stukenberg P. Todd 
Published: January 2021

AbstractRecent work has shown that R-loops exist at mitotic centromeres, but the function of these R-loops is not well understood. Here, we report that mitotic R-loops arise in distinct locations from those formed during interphase. They accumulate on chromosome arms in prophase, where they are quickly resolved and continue to be produced at repetitive sequences including centromeres during a mitotic stall. Aurora B kinase activity is required to resolve R-loops during prophase and R-loops promote the localization of the Chromosome Passenger Complex (CPC) to the inner centromere. CPC purified from mitotic chromosomes interacts with thirty-two proteins involved with R-loop biology. One of these, the RNA regulator RBMX, controls Aurora B localization and activity in vivo. Perturbations in R-loop homeostasis or RBMX cause defects in the maintenance of centromeric cohesion due to the mislocalization of the CPC. We conclude that R-loops are generated by mitotic processes in repetitive DNA sequences, they play important roles in mitotic fidelity, and we have identified a set of mitotic R-loop regulators including the CPC and RBMX that will enable future studies of mitotic R-loops.
Phases of cortical actomyosin dynamics coupled to the neuroblast polarity cycle
Authors: Oon Chet Huan , Prehoda Kenneth E. 
Published: January 2021

AbstractThe Par complex dynamically polarizes to the apical cortex of asymmetrically dividingDrosophilaneuroblasts where it directs fate determinant segregation. Previously we showed that apically directed cortical movements that polarize the Par complex require F-actin (Oon and Prehoda, 2019). Here we report the discovery of cortical actomyosin dynamics that begin in interphase when the Par complex is cytoplasmic but ultimately become tightly coupled to cortical Par dynamics. Interphase cortical actomyosin dynamics are unoriented and pulsatile but rapidly become sustained and apically-directed in early mitosis when the Par protein aPKC accumulates on the cortex. Apical actomyosin flows drive the coalescence of aPKC into an apical cap that is depolarized in anaphase when the flow reverses direction. Together with the previously characterized role of anaphase flows in specifying daughter cell size asymmetry, our results indicate that multiple phases of cortical actomyosin dynamics regulate asymmetric cell division.
Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments
Authors: Cake Caroline , Ogburn Emma , Pinches Heather , Coleman Garry , Seymour David , Woodard Fran , Manohar Sinduja , Monsur Marjia , Landray Martin , Dalton Gaynor , Morris Andrew D , Chinnery Patrick F. ,   UK COVID-19 National Core Studies Consortium, Hobbs FD Richard , Butler Christopher 
Published: January 2021

ABSTRACTBackgroundThe COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment.This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within 24-48 hours of their test result.MethodsA multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (within 24-48 hours of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology.ResultsPrior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1,013 recruits to PRINCIPLE at the start of October 2020 to 2,802 recruits by 20th December 2020.While procedural caveats were identified by the public consultation, out of 2,639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached.ConclusionsThis paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness.This approach increased recruitment, and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions.Trial registrationPRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research.EudraCT number: 2020-001209-22ISRCTN registry: ISRCTN86534580REC number: 20/SC/058IRAS number: 281958
Sterilization of disposable face masks with respect to COVID-19 shortages; a nationwide field study including 19 sterilisation departments
Authors: van Straten B. , Robertson P.D. , Oussoren H. , Espindola S. Pereira , Ghanbari E. , Dankelman J. , Picken S. , Horeman T. 
Published: January 2021

ABSTRACTObjectiveFace masks also referred to as half masks are essential to protect healthcare professionals, working in close contact with patients having Covid-19 related symptoms. During the threating deficit, healthcare institutions sought an approach to re-use face masks or to acquire imported masks. The objective of this study is to assess the quality of sterilised and imported FFP2/KN95 face mask materials.Designprospective, bench-to-bedsideSettingGeneral healthcare including 19 hospitals in the NetherlandsInterventionsFace masks were reprocessed using a medical autoclave at 121°C.MethodsA 48 minutes steam sterilization process of single-use face masks with 15 min holding time at a 121 °C was developed, validated and implemented in 19 different hospitals. Steam and H2O2 plasma sterilized as well as new, imported masks are tested in a custom-made, non-standard EN-149, test set-up that measures Particle Filtration Efficiency (PFE) and pressure drops.ResultsPFE validation data of 84 masks indicated differences of 2.3±2 % (mean±SD) between the custom build test set-up and a continues flow according to the EN-149. Test data showed the mean PFE values of 444 sterilised FFP2 face masks from 19 CSSD were 90±11% (mean±SD) and of 474 imported KN95/FFP2 face masks 83±16% (mean±SD). Differences in PFE between sterilisation departments were found.ConclusionFace masks can be reprocessed with 121 0 C steam or H2O2 plasma sterilization with minimum reduction of PFE. PFE comparison between sterilised mask and new, imported mask filter material indicates that most reprocessed masks of high quality brands outperform new imported face masks of unknown brands. Although the PFE of tested face mask material from different sterilisation departments remained efficient, different types of sterilisation equipment can result in different PFE outcomes.Strengths and limitations of this study–Reprocessing face masks at 121 °C steam Sterilization, a simple method to be used by hospitals in times of shortages–Laboratory findings to evaluate the safety and quality of face mask material–The study is limited and restricted to selected FFP-2 face masks–This study is a first of its kind in quality and safety check of the vast growing face masks, entering our markets–The study focusses on testing environmental dry particles in a rapid test setup
Antibiotic Prescribing Patterns at COVID-19 Dedicated Wards in Bangladesh: A Single Center Point-Prevalence Survey
Authors: Molla Md. Maruf Ahmed , Yeasmin Mahmuda , Islam Md. Khairul , Sharif Md. Mohiuddin , Amin Mohammad Robed , Nafisa Tasnim , Ghosh Asish Kumar , Parveen Monira , Hossain Arif Md. Masum , Jamiul Alam Junaid Abdullah , Raza Rizvi Syed Jafar , Saif-Ur-Rahman KM , Akram Arifa , Shamsuzzaman AKM 
Published: January 2021

SummaryThere is a clear deficiency in antimicrobial usage data and ongoing stewardship programs both in government and private health care facilities in Bangladesh. As evidences are mounting regarding irrational and often unnecessary use of antibiotics during COVID-19 pandemic, a point prevalence survey (PPS) was conducted across COVID-19 dedicated wards in Dhaka Medical College and Hospital (DMCH). Antibiotic usage data were collected from 193 patients at different COVID-19 dedicated wards at DMCH between 21 May, 2020 and 10 June, 2020. Comparisons in antibiotic usage were made between different groups using Pearson chi-square and Fisher exact test. Factors associated with multiple antibiotic prescription were evaluated using binary logistic regression model.On survey date all (100%) patients were receiving at least one antibiotic with 133 patients (68.91%) receiving multiple antibiotics. Overall, patients presenting with severe disease received more antibiotics on average. Third generation cephalosporin ceftriaxone (53.8%), meropenem (40.9%), moxifloxacin (29.5%) and doxycycline (25.4%) were the four most prescribed antibiotics among survey patients. Among comorbidities diabetes mellitus (DM) was independently associated with increased antibiotic prescribing. Abnormal C-reactive protein (CRP) and serum d-dimer were linked with higher odds of antibiotic prescribing among survey patients. Overall, prevalence of antibiotic prescribing in COVID-19 patients at DMCH was very high. This could be attributed to a lack of clear treatment protocol against COVID-19 till date as well as lack of modern laboratory facilities to support judicial antibiotic prescribing in Bangladesh. A well-functioning antibiotic stewardship program in Bangladesh is required to prevent an impending health crisis.
A framework for measuring customer loyalty for 3PL industry: a case of evolving market
Authors: Ahmed Waqar , Najmi Arsalan , Kusi-Sarpong Simonov , Khan Sharfuddin Ahmed , Khushal Asad , Quartey Joseph 
Published: January 2021

PurposeThis research aims to propose a framework for measuring customer loyalty for third party logistics (3PL) industry by exploring the attributes that are more attractive to customers and ascertain the mechanisms for increasing customer loyalty in 3PL industry.Design/methodology/approachData were collected from one hundred and thirty-three (133) respondents who were employees of different industries that outsource 3PL services. The partial least square structural equation modeling (PLS–SEM) was deployed for analysis.FindingsThe results showed that service quality has a significant positive impact on customer orientation, customer satisfaction and relationship quality. On the other hand, customer orientation has been observed to positively impact customer satisfaction but an insignificant impact on customer loyalty and relationship quality. Customer satisfaction has a significant positive impact on relationship quality but an insignificant impact on customer loyalty. Also, relationship quality has a significant positive impact on customer loyalty.Practical implicationsThe results recommend that 3PL companies' managers focus more on developing quality relationships with their customers, delivering exemplary service quality and offering customer orientation.Originality/valueThis study will help the stakeholders gain much more understanding and insights on how competitive advantage can be achieved and, consequently, help 3PL become the market leaders.