bluuebunny/crossref_metadata_2025_split huggingface dataset:
Timing of blood draws among hospitalized patients: An evaluation of the electronic health records from a large health care system
Authors: Caraballo César , Mahajan Shiwani , Huang Chenxi , Aneja Sanjay , Murugiah Karthik , Mortazavi Bobak J. , Lu Yuan , Khera Rohan , Krumholz Harlan M. 
Published: July 2022

ABSTRACTImportanceEarly morning blood draws disrupt patients’ sleep and adversely affect patient experience.ObjectiveTo describe the trends in non-urgent early morning blood draws in a large health care system.DesignThis cross-sectional study analyzed trends in non-urgent early morning (04:00–06:59) blood draws using the electronic medical records of patients hospitalized between November 2016 and October 2019.SettingThe study was done at Yale New Haven Health System, which is Connecticut’s largest health care system consisting of 5 hospitals.ParticipantsWe included all blood draw events for hospitalized adult patients (≥18 years at the time of admission).Main outcome and measuresWe assessed the timing of non-urgent (excluding blood draws performed in the emergency department, critical care units, step-down units, and during the first 24 hours of admission) blood draws among hospitalized patients and determined if the trends of early morning (04:00–06:59) blood draws varied by patient characteristics or over the study duration.ResultsOf the 5,676,802 blood draw events included, 38.9% occurred between 04:00–06:59 with only modest differences across age, race and ethnicity, and gender subgroups. The proportion of early morning blood draws increased over the study period from 36.9% to 41.4% (P<0.001). Of the early morning samples, those collected between 04:00–04:59 decreased from 25.6% to 18.5%, those collected between 05:00–05:59 increased from 39.6% to 45.5%, and those collected between 06:00–06:59 increased from 34.6% to 36.0% (P<0.001, each).Conclusions and relevanceThe proportion of non-urgent early morning blood draws was persistently high over 3 years. There is a need to redesign hospital care to reduce sleep interruptions from non-urgent interventions.KEY POINTSQuestionWhat are the trends in non-urgent early morning (04:00–06:59) blood draws among non-critically ill hospitalized patients across a large health care system?FindingsThis cross-sectional study showed that 38.9% of all blood draws occurred between 04:00–06:59, with only modest differences across age, race and ethnicity, and gender subgroups. The proportion of early morning blood draws increased over the study period from 36.9% to 41.4% (P<0.001).MeaningThe proportion of non-urgent early morning blood draws remains persistently high, suggesting a need to redesign hospital care to reduce sleep interruptions from non-urgent interventions.
Retaining dermatology patients in primary care using dialogues with secondary care: A service evaluation
Authors: Brainard Julii , Crawford Amy , Wright Beth , Everden Paul 
Published: July 2022

SummaryBackgroundWait list sizes for specialist secondary care have soared in recent years. Dermatology is a good candidate service for retaining patients in primary care and avoiding unnecessary waits to see a specialist. A dermatology dialogue service between primary and secondary care (DDPS) was developed in Norfolk and Waveney, eastern England. The service involved primary care referrers uploading patient images of skin complaints for review by and dialogue with secondary specialists to see if the patient could be retained in primary care, or should be referred to secondary care routinely, urgently or on the two week wait cancer pathway.ObjectivesTo evaluate service performance with respect to specific targets including reduction in secondary care wait list growth in the period March 2021-March 2022 inclusive.MethodsService activity was summarized with respect to speed of resolution, case counts and dispositions. Clinician and patient satisfaction were canvased with structured questionnaires. Actual new referral counts were compared to projections based on historical data. Wait list growth was compared to other specialisms and other areas. Wait times to receive first treatment at start and end of monitoring period were monitored.ResultsOver 3600 patients were enrolled in the DDPS system. Over 98% of cases were reported by the dermatologists within 36 hours. Clinician and patient satisfaction were high. Frequently asked questions and conditions were highlighted by dermatologists to design and deliver an educational event for primary care clinicians that was well received. Wait list growth to see dermatology in the commissioning area was smaller for dermatology than other large specialisms, and mostly smaller growth than dermatology wait lists commissioned by other NHS commissioners. Negative impact on the urgent priority (cancer pathway) wait list could not be observed.ConclusionsThe DDPS was satisfactory to clinicians and patients and coincided with smaller dermatology wait list growth than might otherwise have been expected.
Continuous Bayesian Variant Interpretation Accounts for Incomplete Penetrance among Mendelian Cardiac Channelopathies
Authors: O’Neill Matthew J. , Sala Luca , Denjoy Isabelle , Wada Yuko , Kozek Krystian , Crotti Lia , Dagradi Federica , Kotta Maria-Christina , Spazzolini Carla , Leenhardt Antoine , Salem Joe-Elie , Kashiwa Asami , Ohno Seiko , Tao Ran , Roden Dan M. , Horie Minoru , Extramiana Fabrice , Schwartz Peter J. , Kroncke Brett M. 
Published: July 2022

AbstractBackgroundThe congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases which frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon and evaluate penetrance distributions and rationalize their structural underpinnings across four genotype-phenotype pairs.MethodsWe generated Bayesian penetrance estimation models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across four-genotype phenotype relationships and compared continuous estimates to ClinVar annotations. Posterior estimates were mapped onto protein structure.ResultsBayesian models of KCNQ1-LQT1 and SCN5A-LQT3 are well-calibrated to clinical observations. Variant-informed penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 heterozygote clinical phenotypes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. SCN5A-LQT3 and SCN5A-BrS had comparatively more variants with predicted low penetrance. There was a wide distribution of variant penetrance estimates among similar categories of ClinVar annotations. Structural mapping revealed heterogeneity among ‘hot spot’ regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.ConclusionsBayesian penetrance estimates provide a continuous framework for variant interpretation, provide higher resolution within ‘hot spot’ domains, and facilitate prospective clinical management of variant heterozygotes.
Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3
Authors: Kimmel Jessica , Schmitt Marius , Sinner Alexej , Jansen Pascal , Mainye Sheila , Ramón-Zamorano Gala , Toenhake Christa Geeke , Wichers Jan Stephan , Cronshagen Jakob , Sabitzki Ricarda , Mesén-Ramírez Paolo , Behrens Hannah Michaela , Bártfai Richárd , Spielmann Tobias 
Published: July 2022

ABSTRACTTaxa-specific proteins are key determinants defining the biology of all organisms and represent prime drug targets in pathogens. However, lacking comparability with proteins in other lineages makes them particularly difficult to study. In malaria parasites this is exacerbated by technical limitations. Here, we analysed the cellular location, essentiality, function and, in selected cases, interactome of all unknown non-secretory proteins encoded on an entireP. falciparumchromosome. The nucleus was the most common localisation, indicating it is a hotspot of parasite-specific biology. More in-depth functional studies with four proteins revealed essential roles in DNA replication and mitosis. The novel mitosis proteins defined a possible orphan complex and a highly diverged complex needed for the spindle-kinetochore connection. Structure-function comparisons indicated that the taxa-specific proteins evolved by different mechanisms. This work demonstrates the feasibility of gene-by-gene screens to elucidate the biology of malaria parasites and reveal critical parasite-specific processes of interest as drug targets.
Building pyramids against the evolutionary emergence of pathogens
Authors: Gandon Sylvain , Guillemet Martin , Gatchitch François , Nicot Antoine , Renaud Ariane C. , Tremblay Denise M. , Moineau Sylvain 
Published: July 2022

SummaryMutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions favoring these evolutionary emergences is key for the development of durable control strategies against pathogens. Here we compare the durability of three different control strategies: (i) a mixing strategy where the host population results from the mix of two single-resistant genotypes, (ii) a pyramiding strategy where host resistance is due to a single double-resistant genotype, (iii) a combining strategy where host resistance is due to a mix between a single-resistant genotype and a double-resistant genotype. First, we use evolutionary epidemiology theory to clarify the interplay between demographic stochasticity and evolutionary dynamics to show that the pyramiding strategy always yields lower probability of evolutionary emergence. Second, we confirm experimentally these predictions using virulent bacteriophages introduced in bacterial populations where we can manipulate the diversity and the depth of CRISPR immunity. Our work shows that pyramiding multiple defenses into the same individual host and avoiding mixing with single-defense strategies is a robust way to protect individuals and populations against pathogen evolutionary emergence. These results have practical implications for the optimal deployment of host resistance in agriculture and biotechnology but also for the optimal use of vaccination against human pathogens.
The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells
Authors: Meyer Dylan J. , Díaz-García Carlos Manlio , Nathwani Nidhi , Rahman Mahia , Yellen Gary 
Published: July 2022

ABSTRACTCellular ATP that is consumed to perform energetically expensive tasks must be replenished by new ATP through the activation of metabolism. Neuronal stimulation, an energetically demanding process, transiently activates aerobic glycolysis, but the precise mechanism underlying this glycolysis activation has not been determined. We previously showed that neuronal glycolysis is correlated with Ca2+ influx, but is not activated by feedforward Ca2+ signaling (Díaz-García, Meyer, et al., 2021). Since ATP-powered Na+ and Ca2+ pumping activities are increased following stimulation to restore ion gradients and are estimated to consume most neuronal ATP, we aimed to determine if they are coupled to neuronal glycolysis activation. By using two-photon imaging of fluorescent biosensors and dyes in dentate granule cell somas of acute mouse hippocampal slices, we observed that production of cytoplasmic NADH, a byproduct of glycolysis, is strongly coupled to changes in intracellular Na+, while intracellular Ca2+ could only increase NADH production if both forward Na+/Ca2+ exchange and Na+/K+ pump activity were intact. Additionally, antidromic stimulation-induced intracellular [Na+] increases were reduced >50% by blocking Ca2+ entry. These results indicate that neuronal glycolysis activation is predominantly a response to an increase in activity of the Na+/K+ pump, which is strongly potentiated by Na+ influx through the Na+/Ca2+ exchanger during extrusion of Ca2+ following stimulation.
Human malaria parasite cold shock protein plays an essential role in asexual and sexual stage development and presents an excellent druggable target
Authors: Behl Ankita , Saini Monika , De Leon Fernando , Kumari Geeta , Kumar Vikash , Shoaib Rumaisha , Singh Harshita , Garg Swati , Arenz Christoph , Singh Shailja 
Published: July 2022

AbstractCold shock proteins are well characterized in bacteria, plants and humans, however there is no information on their existence and role in malaria parasite. Here, we have delineated the function of a novel cold shock protein of Plasmodium falciparum (Pf) which we have annotated ‘PfCoSP’. Our results show that recombinant PfCoSP has both DNA and RNA binding activity, and also interacts with alpha and beta tubulin of Pf. PfCoSP binds with RNA and alpha tubulin simultaneously to form a complex. Expression of PfCoSP was found during asexual blood stages and gametocyte stages of malaria parasite. PfCoSP expression up-regulates many folds upon cold treatment, suggesting its role during hypothermic cold shock. Interestingly, PfCoSP showed binding with human cold shock protein LIN28A inhibitor ‘LI71’ that also inhibits PfCSP -alpha/beta tubulin interactions. LI71 showed antimalarial activity against asexual blood stage and gametocyte stage suggesting its multi-stage, transmission-blocking potential. We propose that PfCoSP may form a workbench for translation during cold stress via its interactions with target mRNAs and the cytoskeleton protein tubulin.
How to deal with toxic amino acids: the bipartite AzlCD complex exports histidine in Bacillus subtilis
Authors: Meißner Janek , Schramm Thorben , Hoßbach Ben , Stark Katharina , Link Hannes , Stülke Jörg 
Published: July 2022

ABSTRACTIn the Gram-positive model bacterium Bacillus subtilis, the presence of the amino acid glutamate triggers potassium uptake due to the glutamate-mediated activation of the potassium channel KtrCD. As a result, the intracellular accumulation of glutamate is toxic in strains lacking the second messenger cyclic di-AMP since these cells are unable to limit potassium uptake. We observed that the presence of histidine, which is degraded to glutamate, is also toxic for a B. subtilis strain that lacks all three c-di-AMP synthesizing enzymes. However, suppressor mutants emerged, and whole genome sequencing revealed mutations in the azlB gene encoding the repressor of the azl operon. This operon encodes an exporter and an importer for branched-chain amino acids. The suppressor mutations result in overexpression of the azl operon. Deletion of the azlCD genes encoding the branched-chain amino acid exporter restored the toxicity of histidine indicating that this exporter is required for histidine export and resistance to otherwise toxic levels of the amino acid. The higher abundance of the amino acid exporter AzlCD increased the extracellular concentration of histidine, thus confirming the new function of AzlCD as a histidine exporter. Unexpectedly, AzlB-mediated repression of the operon remains active even in the presence of amino acids suggesting that expression of the azl operon requires mutational inactivation of AzlB.IMPORTANCEAmino acids are building blocks for protein biosynthesis in each living cell. However, due to their reactivity as well as the similarity between several amino amino acids, they may also be involved in harmful reactions or in non-cognate interactions and thus be toxic. Bacillus subtilis can deal with otherwise toxic histidine by overexpressing a bipartite amino acid exporter AzlCD. Although encoded in an operon that also contains a gene for an amino acid importer, the corresponding genes are not expressed, irrespective of the availability or not of amino acids in the medium. This suggests that the azl operon is a last resort to deal with histidine stress that can be expressed due to mutational inactivation of the cognate repressor, AzlB.
Incorporating alternative Polygenic Risk Scores into the BOADICEA breast cancer risk prediction model
Authors: Mavaddat N , Ficorella L , Carver T , Lee A , Cunningham AP , Lush M , Dennis J , Tischkowitz M , Downes K , Donglei H , Hahnen E , Schmutzler R , Stockley T , Downs G , Zhang T , Chiarelli AM , Bojesen S , Cong L , Chung WK , Pardo M , Feliubadaló L , Balmana J , Simard J , Antoniou AC , Easton DF 
Published: July 2022

AbstractBackgroundThe multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA.MethodsThe mean, standard deviation (SD), and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. α was estimated using logistic regression, where the age-specific log-relative risk is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component.ResultsParameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates α, as compared with the RL estimates. The RL α estimates were very close to those obtained by assuming proportionality to the odds ratio per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean.ConclusionsBOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model.ImpactThe methods described enable comprehensive breast cancer risk assessment.
Post-COVID Phenotypic Manifestations are Associated with New-Onset Psychiatric Disease: Findings from the NIH N3C and RECOVER Studies
Authors: Coleman Ben , Casiraghi Elena , Callahan Tiffany J , Blau Hannah , Chan Lauren , Laraway Bryan , Clark Kevin B. , Re’em Yochai , Gersing Ken R. , Wilkins Ken , Harris Nomi L. , Valentini Giorgio , Haendel Melissa A , Reese Justin , Robinson Peter N ,   the RECOVER Consortium
Published: July 2022

AbstractAcute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19.A retrospective EHR cohort study of 1,603,767 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 65 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28-120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression.There was a significant association between six categories and newly diagnosed anxiety, mood, and psychotic disorders, with odds ratios highest for cardiovascular (1.35, 1.27-1.42) PASC-AMs. Secondary analysis revealed that the proportions of 95 individual clinical features significantly differed between patients diagnosed with different psychiatric disorders.Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.FundingNCATS U24 TR002306
Colonization of intervertebral discs byCutibacterium acnesin patients with low back pain: protocol for an analytical study with microbiological, phenotypic, genotypic, and multiomic techniques
Authors: Magno da Rocha Vinícius , Ormundo Gonçalves Ximenes Lima Carla , de Oliveira Ferreira Eliane , de Farias Gabriel Corrêa , Nogueira Fábio César Sousa , Martha Antunes Luis Caetano , Cassiano Keila Mara , Fiorelli Rossano Kepler Alvim 
Published: July 2022

AbstractLumbar disc degeneration (LDD) and low back pain (LBP) are two conditions that are closely related. Several studies have shownCutibacterium acnescolonization of degenerated discs, but whether and how these finding correlates with LBP is unknown. A prospective study was planned to identify molecules present in lumbar intervertebral discs (LLIVD) colonized byC. acnesin patients with LDD and LBP and correlate them with their clinical, radiological, and demographic profiles. The clinical manifestations, risk factors, and demographic characteristics of participants undergoing surgical microdiscectomy will be tracked. Samples will be isolated and pathogens found in LLIVD will be characterized phenotypically and genotypically. Whole genome sequencing (WGS) of isolated species will be used to phylotype and detect genes associated with virulence, resistance, and oxidative stress. Multiomic analyses of LLIVD colonized and non-colonized will be carried out to explain not only the pathogen’s role in LDD, but also its involvement in the pathophysiology of LBP. This study was approved by the Institutional Review Board (CAAE 50077521.0.0000.5258). All patients who agree to participate in the study will sign an informed consent form. Regardless of the study’s findings, the results will be published in a peer-reviewed medical journal. Trials registration numberNCT05090553; pre-results.