bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world evidence: telemedicine for complicated cases of urinary tract infection
Authors: Daumeyer Natalie M. , Kreitzberg Daniel , Gavin Kathleen M. , Bauer Timothy A. 
Published: October 2022

AbstractBackgroundTelemedicine programs for the treatment of urinary tract infections (UTIs) offer an opportunity to reduce burdens on patients and providers. However, these programs are typically restricted to patients with uncomplicated UTIs. This real-world analysis evaluated treatment and resolution rates in a large-scale, national UTI telemedicine program inclusive of patients with uncomplicated and complicated UTIs.Methods and findingsWe conducted a retrospective analysis of data obtained from a commercially available telemedicine program for the treatment of UTIs among adult women in the US between 2017 and 2021 (n=51,474). The primary outcomes were the number of women who presented with symptoms of uncomplicated UTI, complicated UTI, and vaginal infection; prescription use and antibiotic type; symptom resolution within 7 days after appointment; and treatment failure or relapse. Most patients reported frequent urination (94.4%), urgency (94.5%), and dysuria (97.6%). Those with uncomplicated UTI symptoms represented the majority of patients (61.6%); however, a substantial number of patients (36.5%) also reported at least 1 symptom associated with a complicated UTI. One-fifth of patients (19.2%) reported at least 1 co-occurring symptom of vaginal infection or sexually transmitted infection. Across all treated patients, 94.0% received recommended antibiotics according to the clinical protocol. Of the treated patients who provided follow-up data (n=3,521), 89.7% reported 7-day symptom resolution. Symptom resolution rates were similar between patients with uncomplicated UTI symptoms (90.8%) and complicated UTI symptoms (87.9%), and symptom resolution among all treated patients (89.7%) was similar to reports for in-person standard of care.ConclusionsThese findings suggest that large-scale telemedicine programs for the treatment of UTIs can be effective in the treatment of complicated UTIs.
Development and Validation of ‘Patient Optimizer’ (POP) Algorithms for Predicting Surgical Risk with Machine Learning
Authors: Kowadlo Gideon , Mittelberg Yoel , Ghomlaghi Milad , Stiglitz Daniel , Kishore Kartik , Guha Ranjan , Nazareth Justin , Weinberg Laurence 
Published: October 2022

AbstractBackgroundPre-operative risk assessment can help clinicians prepare patients for surgery, reducing the risk of perioperative complications, length of hospital stay, readmission and mortality. Further, it can facilitate collaborative decision-making and operational planning.ObjectiveTo develop effective pre-operative risk assessment algorithms (referred to as Patient Optimizer or POP) using Machine Learning (ML) that predicts the development of post-operative complications and provides pilot data to inform the design of a larger prospective study.MethodsAfter institutional ethics approval, we developed a baseline model that encapsulates the standard manual approach of combining patient-risk and procedure-risk. In an automated process, additional variables were included and tested with 10-fold cross-validation, and the best performing features were selected. The models were evaluated and confidence intervals calculated using bootstrapping. Clinical expertise was used to restrict the cardinality of categorical variables (e.g. pathology results) by including the most clinically relevant values. The models were created with extreme gradient-boosted trees using XGBoost [1]. We evaluated performance using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Data was obtained from a metropolitan university teaching hospital from January 2015 to July 2020. Data collection was restricted to adult patients undergoing elective surgery.ResultsA total of 11,475 adult admissions were included. For predicting the risk of any postoperative complication, kidney failure and length-of-stay (LOS), POP achieved an AUROC (95%CI) of 0.755 (0.744, 0.767), 0.869 (0.846, 0.891) and 0.841 (0.833, 0.847) respectively and AUPRC of 0.651 (0.632, 0.669), 0.326 (0.293, 0.359) and 0.741 (0.729, 0.753) respectively. For 30-day readmission and in-patient mortality, POP achieved an AUROC (95%CI) of 0.61 (0.587, 0.635) and 0.866 (0.777, 0.943) respectively and AUPRC of 0.116 (0.104, 0.132) and 0.031 (0.015, 0.072) respectively.ConclusionThe POP algorithms effectively predicted any post-operative complications, kidney failure and LOS in the sample population. A larger study is justified to improve the algorithm to better predict complications and length of hospital stay. A larger dataset may also improve the prediction of additional specific complications, readmissions and mortality.
Ultrasonic measures of prestin (SLC26a5) charge movements in membrane patches
Authors: Santos-Sacchi Joseph , Bai Jun-Ping , Navaratnam Dhasakumar 
Published: October 2022

AbstractCharged moieties in the outer hair cell (OHC) molecular motor protein, prestin, are driven by transmembrane voltage to ultimately provide for cochlear amplification. The speed of voltage-dependent conformational switching underlies its ability to influence micromechanics of the cell and the organ of Corti. Corresponding voltage-sensor charge movements in prestin, classically assessed as a voltage-dependent, nonlinear membrane capacitance (NLC), have been used to gauge its frequency response. Using megahertz sampling of prestin charge movements, we extend interrogations of prestin performance into the ultrasonic range (up to 120 kHz) and find response magnitude larger than previously reported. We also confirm kinetic model predictions of prestin by directly observing its cut-off frequency under voltage-clamp as the intersection frequency (Fis) of the real and imaginary components of complex NLC (cNLC), showing values near 19 kHz. At higher frequencies, the imaginary component roll-off exactly tracks that of Abs(cNLC). The frequency response of prestin displacement current noise determined from the Nyquist relation aligns with this cut-off. On the other hand, previous measures of stationary thermal-driven noise of prestin indicated that the cut-off was several fold greater than that of NLC, in violation of the fluctuation-dissipation theorem. We have attempted to confirm this apparent paradox, but find that low frequency (<10kHz), voltage-dependent 1/f noise, likely due to intrinsic prestin conductance, can limit the accessible bandwidth for stationary noise analysis. Nevertheless, within those bandwidths, frequency response comparisons of stationary measures and Nyquist relation measures are consistent. We conclude that voltage stimulation accurately assesses the spectral limits of prestin activity.SignificanceUsing megahertz sampling, we extend measures of prestin charge movement into the ultrasonic range and find that the frequency roll-off is less than previously reported. Nevertheless, analysis of complex nonlinear capacitance confirms low-pass behavior, with a characteristic cut-off frequency near 19 kHz. The frequency response of prestin noise garnered by the admittance-based Nyquist relation confirms this cut-off frequency. In conflict with previous results, however, we find a similar low-pass frequency response using direct measures of prestin noise in the absence of voltage stimulation. Our data indicate that voltage perturbation provides an accurate assessment of prestin performance.
Myosin-Binding Protein C Stabilizes, But Is Not the Sole Determinant of SRX Myosin in Cardiac Muscle
Authors: Nelson Shane , Previs Samantha Beck , Sadayappan Sakthivel , Tong Carl , Warshaw David M. 
Published: October 2022

AbstractThe myosin Super Relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with Myosin-Binding Protein C (MyBP-C) in the C-zone, proximal to the sarcomere center. To define how MyBP-C and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic MyBP-C null mice and those expressing MyBP-C with a 271 residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and sub-sarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin was highest in the C-zone (71±6%) and lower in the D-zone (45±10%) which lies farther from the sarcomere center and lacks MyBP-C, suggesting a possible role for MyBP-C in stabilizing the SRX state within the C-zone. However, myofibrils from MyBP-C null mice demonstrated an ~40% SRX reduction, not only within the now MyBP-C-free C-zone (49±9% SRX), but also within the D-zone (22±5% SRX). These data suggest that the influence of MyBP-C on the SRX state is not limited to the C-zone, but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated MyBP-C had an SRX content and spatial gradient similar to the MyBP-C null, indicating that the N terminus of cardiac MyBP-C is necessary for MyBP-C’s role in establishing SRX along the entire thick filament. Given that SRX myosin are enriched in the C-zone, even in the absence of MyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state. One candidate may be a differential in the super repeats of titin that interact with MyBP-C and myosin and which template the thick filament.
Dynamic trade-offs between biomass accumulation and division determine bacterial cell size and proteome in fluctuating nutrient environments
Authors: Kratz Josiah C. , Banerjee Shiladitya 
Published: October 2022

AbstractBacteria dynamically regulate cell size and growth rate to thrive in changing environments. While much work has been done to characterize bacterial growth physiology and cell size control during steady-state exponential growth, a quantitative understanding of how bacteria dynamically regulate cell size and growth in time-varying nutrient environments is lacking. Here we develop a dynamic coarse-grained proteome sector model which connects growth rate and division control to proteome allocation in time-varying environments in both exponential and stationary phase. In such environments, growth rate and size control is governed by trade-offs between prioritization of biomass accumulation or division, and results in the uncoupling of single-cell growth rate from population growth rate out of steady-state. Specifically, our model predicts that cells transiently prioritize ribosome production, and thus biomass accumulation, over production of division machinery during nutrient upshift, explaining experimentally-observed size control behaviors. Strikingly, our model predicts the opposite behavior during downshift, namely that bacteria temporarily prioritize division over growth, despite needing to upregulate costly division machinery and increasing population size when nutrients are scarce. Importantly, when bacteria are subjected to pulsatile nutrient concentration, we find that cells exhibit a transient memory of the previous metabolic state due to the slow dynamics of proteome reallocation. This phenotypic memory allows for faster adaptation back to previously-seen environments when nutrient fluctuations are short-lived.
Integration of primary contact physiotherapists in the emergency department for individuals presenting with minor musculoskeletal disorders: Protocol for an economic evaluation
Authors: Gagnon Rose , Hébert Luc J. , Guertin Jason R. , Berthelot Simon , Desmeules François , Perreault Kadija 
Published: October 2022

AbstractObjectives1) To compare the average cost of an emergency department (ED) visit for various minor musculoskeletal disorders between two models of care (physiotherapist and ED physician or ED physician alone); 2) To evaluate the incremental cost-effectiveness ratio (ICER) of these two models of care over a 3-month period post-initial visit; and 3) To estimate the ICER of three ED models of care (physiotherapist and ED physician, ED physician alone, physiotherapist alone) over a two-year period.MethodsA randomized clinical trial was conducted among individuals (n=78) aged 18 to 80 years presenting with a musculoskeletal disorder at a Quebec City (Canada) hospital in 2018-2019. Two models of care were compared: management by a physiotherapist and an ED physician versus usual management by an ED physician. Participants follow-ups were conducted at 1 and 3 months post-initial ED visit. Obj.1: The health care costs incurred by the two groups during their ED visit will be calculated using the Time-Driven Activity-Based Costing (TDABC) method and compared using generalized linear models. Obj. 2: The cost-utility analysis over a 3-month time horizon will combine economic and clinical variables (estimated through quality-adjusted life years) using a Societal perspective. The results of the cost-utility analysis will be reported using an ICER. Obj. 3: The ICER will be estimated using a hybrid decision tree (0-3 months post-visit) and Markov model (3-24 months post-visit); the analysis will be conducted from a Societal perspective over a two-year time horizon.ConclusionThis study will help to determine which model of care is most efficient for the management of individuals who come to the ED with minor musculoskeletal disorders. The increased involvement of various health professionals in the management of patients in the ED paves the way for the development of new avenues of practice and more efficient organization of services.
The crystal structure of a simian Foamy Virus receptor binding domain provides clues about entry into host cells
Authors: Fernández Ignacio , Dynesen Lasse Toftdal , Coquin Youna , Pederzoli Riccardo , Brun Delphine , Haouz Ahmed , Gessain Antoine , Rey Felix A. , Buseyne Florence , Backovic Marija 
Published: October 2022

AbstractThe surface envelope glycoprotein (Env) of all retroviruses mediates virus binding to cells and fusion of the viral and cellular membranes. A structure-function relationship for the HIV Env that belongs to the Orthoretrovirus subfamily has been well established. Structural information is however largely missing for the Env of Foamy viruses (FVs), the second retroviral subfamily. FV Envs lack sequence similarity with their HIV counterpart. We present the X-ray structure of the receptor binding domain (RBD) of a simian FV Env at 2.6 Å resolution, revealing two subdomains and an unprecedented fold. We have generated a model for the organization of the RBDs within the trimeric Env which indicates that the upper subdomain is important for stabilization of the full-length Env, and have demonstrated that residues K342, R343, R359 and R369 in the lower subdomain play key roles in the interaction of the RBD and viral particles with heparan sulfate.
SARS-CoV-2 infection alkalinizes the ERGIC and lysosomes through the viroporin activity of the viral envelope protein
Authors: Wang Wen-An , Sureda Amado Carreras , Demaurex Nicolas 
Published: October 2022

AbstractThe coronavirus SARS-CoV-2, the agent of the deadly COVID-19 pandemic, is an enveloped virus propagating within the endocytic and secretory organelles of host mammalian cells. Enveloped viruses modify the ionic homeostasis of organelles to render their intra-luminal milieu permissive for viral entry, replication, and egress. Here, we show that infection of Vero E6 cells with the delta variant of the SARS-CoV-2 alkalinizes the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) as well as lysosomes, mimicking the effect of inhibitors of vacuolar proton ATPases. We further show the envelope protein of SARS-CoV-2 accumulates in the ERGIC when expressed in mammalian cells and selectively dissipates the ERGIC pH. This viroporin effect is not associated with acute cellular toxicity but is prevented by mutations within the channel pore of E. We conclude that the envelope protein acts as a proton channel in the ERGIC to mitigate the acidity of this intermediate compartment. The altered pH homeostasis of the ERGIC likely contributes to the virus fitness and pathogenicity, making the E channel an attractive drug target for the treatment of COVID-19.
Phloem anatomy restricts root system architecture development: theoretical clues from in silico experiments
Authors: Zhou Xiao-Ran , Schnepf Andrea , Vanderborght Jan , Leitner Daniel , Vereecken Harry , Lobet Guillaume 
Published: October 2022

AbstractPlant growth and development involve the integration of numerous processes, influenced by both endogenous and exogenous factors. At any given time during a plant’s life cycle, the plant architecture is a readout of this continuous integration. However, untangling the individual factors and processes involved in the plant development and quantifying their influence on the plant developmental process is experimentally challenging.Here we used a combination of computational plant models to help understand experimental findings about how local phloem anatomical features influence the root system architecture. In particular, we simulated the mutual interplay between the root system architecture development and the carbohydrate distribution to provide a plausible mechanistic explanation for several experimental results.Our in silico study highlighted the strong influence of local phloem hydraulics on the root growth rates, growth duration and final length. The model result showed that a higher phloem resistivity leads to shorter roots due to the reduced flow of carbon within the root system. This effect was due to local properties of individual roots, and not linked to any of the pleiotropic effects at the root system level.Our results open the door to a better representation of growth processes in plant computational models.
Deep generative modeling of sample-level heterogeneity in single-cell genomics
Authors: Boyeau Pierre , Hong Justin , Gayoso Adam , Kim Martin , McFaline-Figueroa José L. , Jordan Michael I. , Azizi Elham , Ergen Can , Yosef Nir 
Published: October 2022

AbstractThe field of single-cell genomics is now observing a marked increase in the prevalence of cohort-level studies that include hundreds of samples and feature complex designs. These data have tremendous potential for discovering how sample or tissue-level phenotypes relate to cellular and molecular composition. However, current analyses are based on simplified representations of these data by averaging information across cells. We present MrVI, a deep generative model designed to realize the potential of cohort studies at the single-cell level. MrVI tackles two fundamental and intertwined problems: stratifying samples into groups and evaluating the cellular and molecular differences between groups, both without requiringa priorigrouping of cells into types or states. Due to its single-cell perspective, MrVI is able to detect clinically relevant stratifications of patients in COVID-19 and inflammatory bowel disease (IBD) cohorts that are only manifested in certain cellular subsets, thus enabling new discoveries that would otherwise be overlooked. Similarly, we demonstrate that MrVI can de-novo identify groups of small molecules with similar biochemical properties and evaluate their effects on cellular composition and gene expression in large-scale perturbation studies. MrVI is available as open source atscvi-tools.org.
CHRONO participates in multi-modal repression of circadian transcriptional complexes
Authors: Crosby Priya , Goularte Nicolette F. , Sharma Diksha , Chen Eefei , Parico Gian Carlo G. , Philpott Jon M. , Harold Rachel , Gustafson Chelsea L. , Partch Carrie L. 
Published: October 2022

AbstractThe mammalian protein CHRONO is a rhythmically expressed repressor of the circadian transcriptional activator complex CLOCK:BMAL1, and was proposed to be a novel component of the circadian clock. However, lack of specific mechanistic understanding of the activity and function of CHRONO meant that its role within the circadian machinery was opaque. Here we fill this knowledge gap, confirming an evolutionarily conserved minimal repressive domain (MRD) of CHRONO that interacts with specific regions in the BMAL1 C-terminal transactivation domain (TAD) to repress CLOCK:BMAL1 activity. Notably, this binding region overlaps with the binding site for the repressor CRY and coactivators CBP/p300, with CHRONO capable of competing with both of these classical regulators of BMAL1 for TAD binding, highlighting CHRONO as a direct regulator of BMAL1 function.Additionally, we investigate the interaction between CHRONO and the major circadian repressor, PERIOD2 (PER2). We show that CHRONO reduces PER2 stability through interaction between the CHRONO C-terminus and the Casein Kinase 1 (CK1)-binding domain of PER2. This results in competition between CHRONO and CK1 for binding at this site on PER2, with CHRONO binding inhibiting CK1 phosphorylation of PER2 at the stabilising S662 residue. Taken together, these data show a more substantive and complex role for CHRONO in molecular circadian timekeeping than previously posited, suggesting that CHRONO acts to fine-tune cellular timekeeping by modulating multiple protein-protein interactions that are critical for maintenance of circadian rhythmicity.
Rapid inactivation of vaccinia, a surrogate virus for monkeypox and smallpox, using ultraviolet-C disinfection
Authors: Koutras Carolina , Wade Richard L. 
Published: October 2022

AbstractHuman monkeypox is an emerging health threat that has the potential to cause serious sequelae. Ultraviolet-C (UV-C) disinfection is a physical process that triggers microbial inactivation through irreversible DNA damage. A high-output mobile UV-C unit was evaluated against vaccinia, a monkeypox surrogate, for antimicrobial efficacy. In under 7 minutes, a single UV-C cycle had a virucidal efficacy of ≥ 99.996 % in a 200 sq feet area. UV-C technology is a promising strategy for infection prevention and control in the post-COVID era.
Genetic architecture of cardiac dynamic flow volumes
Authors: Gomes Bruna , Singh Aditya , O’Sullivan Jack W , Amar David , Kostur Mykhailo , Haddad Francois , Salerno Michael , Parikh Victoria N. , Meder Benjamin , Ashley Euan A. 
Published: October 2022

AbstractCardiac blood flow is a critical determinant of human health. However, definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep learning system to extract cardiac flow and volumes from phase contrast cardiac magnetic resonance imaging. A mixed linear model applied to 37,967 individuals from the UK Biobank reveals novel genome-wide significant associations across cardiac dynamic flow volumes including aortic forward velocity, total left ventricular stroke volume, forward left ventricular flow and aortic regurgitation fraction. Mendelian randomization using CAUSE reveals a causal role for aortic root size in aortic valve regurgitation. The most significant contributing variants (near ELN, FBN1 and ULK4) are implicated in connective tissue and blood pressure pathways. DeepFlow cardiac flow phenotyping at scale, combined with population-level genotyping data in the UK Biobank, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function in the general population.