bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Consequences of Occult Free Valproate Toxicity in Critically Ill Adult Patients: A Multicenter Retrospective Cohort Study
Authors: Webb Andrew J , Gagnon David J , Brown Caitlin S , Riker Richard R , Lopez Natasha D , Goodberlet Melanie Z , Schontz Michael J , Marino Kaylee K , Uljon Sacha N , Zafar Sahar F. , Rosenthal Eric S 
Published: May 2024

AbstractBackground and ObjectivesValproate has wide pharmacokinetic variability and a narrow therapeutic index. Its protein binding is unpredictable, particularly among critically ill patients who may experience unexpectedly elevated free concentrations. We sought to identify the clinical consequences and determinants of occult free valproate toxicity in critically ill adults.MethodsWe conducted a multicenter retrospective cohort study of adult patients admitted to an intensive care unit (ICU) who were receiving valproate and had concurrent total and free valproate concentrations measured. We examined whether valproate concentrations were independently associated with adverse drug effects (ADEs) including thrombocytopenia, hepatotoxicity, hyperammonemia, and pancreatic injury. Determinants of occult toxicity were also identified using logistic mixed-effects models, adjusting for age, weight, albumin, propofol and aspirin use, and blood urea nitrogen (BUN). Occult toxicity was defined as a free valproate concentration that was discordant with total concentration (e.g., supratherapeutic free concentration associated with therapeutic total concentration).Results311 unique patients (mean age 58 [±17] years, 36% female, 31% non-white, and 29% on valproate prior to admission) with 550 concurrent free and total valproate concentration pairs met inclusion criteria. The median (IQR) total valproate concentration was 46 mcg/mL (34-63) and the median free valproate concentration was 17 mcg/ml (11-23); median free fraction was 35% (25-63%). Eighty-four percent of total valproate concentrations represented occult free toxicity; a therapeutic total with a supratherapeutic free valproate concentration was the most common pattern (32% of concentration pairs). Each 2.5 mcg/mL increase in free valproate concentration was associated with thrombocytopenia (adjusted unit odds 1.15, 95% CI 1.05-1.26) and hepatotoxicity (adjusted unit odds 1.11, 95% CI 1.05-1.18). Albumin concentration (adjusted odds; aOR 0.17, 95% CI 0.08-0.36), BUN (aOR 1.36, 95% CI 1.09-1.70), and propofol exposure (aOR 3.06, 95% CI 1.38-6.79) were associated with occult toxicity.ConclusionFree valproate concentrations should be measured in critically ill patients because it is associated with ADEs and is often underrepresented by total concentrations. Most critically ill patients are at risk, especially those with hypoalbuminemia, uremia, and lipid exposure.
Exploring Multilevel Determinants of Stillbirth: A Comprehensive Analysis Across Sub-Saharan African Countries
Authors: Adeleye Khadijat , Ogungbe Oluwabunmi , Yeboah-Kordieh Yvette , Gresh Ashley , Iradukunda Favorite 
Published: May 2024

ABSTRACTBackgroundStillbirths and associated outcomes remain a significant concern in Sub-Saharan Africa (SSA), with approximately 44% of global stillbirths.MethodsUsing Demographic and Health Surveys (DHS) data, this study examined determinants of stillbirth among women in 29 SSA countries. Our cross-sectional analysis included a weighted sample of women 15-49 years of age who had given birth or experienced stillbirth. We used bivariate analyses and multilevel logistic regression approaches.FindingsStillbirth prevalence was 319·06/1000 live births. Among individual-level factors, risk increased with age. Higher maternal education levels were significantly associated with decreased stillbirth risk. Single women had significantly lower odds of stillbirth compared to those who no longer lived together/separated from their partner. Contextually, women with a job had an increased risk compared to women without a job, and living in a rural residential area was a significant factor.InterpretationThe complex interplay of individual-level factors and contextual factors influences stillbirth outcomes in SSA. Cross-sector holistic approaches to maternal and neonatal health are needed to address the multifaceted determinants of stillbirths.FundingThere was no funding for the study.Evidence before the studyThe prevalence of stillbirth is higher in SSA compared to other regions. Factors influencing stillbirth are complex and include individual, household, and community-level factors. We searched PubMed and Medline with no language restrictions using the search terms (“stillbirth” AND “determinant” AND “Sub-Saharan Africa”). By 2023, no studies were published on the determinants of stillbirth in Sub-Saharan Africa. Earlier studies were conducted in the context of other countries without using the calendar method to calculate stillbirth or the national demographic dataset.Added value of this studyThe relative importance of risk factors for stillbirth in different SSA countries.Protective effect of household leadership dynamics on reducing stillbirth odds in SSA.Implications of all the available evidenceFocused interventions to reduce stillbirths, such as promoting female household leadership and equity.Improving access to education and maternal health literacy.Public health initiatives to prioritize social and familial support for pregnant women to create environments conducive to positive pregnancy outcomes.Clinicians could promote pregnancy spacing and family planning to promote optimal maternal and child health, especially among women with higher parity.Healthcare policies for more investment and strengthening of maternal and child care services.
The Congenital Heart Initiative: Results from a Patient-Centered Registry for Adults with Congenital Heart Disease
Authors: Leezer Scott , Messmer Mindi , Agarwal Anushree , Phillippi Ruth , Jackson Jamie L. , Roeder Mark , Marlin Aliza , Peyser Noah , Pletcher Mark J. , Krasuski Richard , Lewis Matthew , Reardon Leigh , Saidi Arwa , Kanter Ronald , Sandhu Satinder , Young Thomas , Jacobsen Roni , Ruckdeschel Emily , Lubert Adam , Singh Simran , Zaidi Ali , Halpern Dan H. , Mathews Anita , Mehta Rittal , Carton Thomas , John Anitha S. 
Published: May 2024

AbstractBackgroundIn the United States, there are over 1.5 million adults living with congenital heart disease (CHD). The Congenital Heart Initiative (CHI) is a digital, online patient empowered registry that was created to advance multicenter research and improve clinical care by gathering patient-reported outcomes (PROs) in adults with CHD.MethodsAfter a two year design process, the CHI was created and launched nationally on December 7, 2020 using a human centered design approach. Demographics and validated survey tools on quality of life, mental health, physical activity and health care utilization were collected at baseline and every 4 months. Data were collected virtually and stored on Health Insurance Portability and Accountability Act (HIPAA)–compliant cloud-based servers with restricted access.ResultsBy December 31, 2023, the CHI had enrolled 4558 participants (56% female) with an average age of 39 years ± 14, representing all 50 states. Approximately 88% of participants have completed at least one e-Visit as of December 31, 2023. The most prevalent CHD anatomy included tetralogy of Fallot (883, 22%), transposition of great arteries (452, 11%), and coarctation of the aorta (429, 11%). Approximately 88% of participants reported at least one co-morbidity, with arrhythmia (1310, 29%) and mood disorder (1339, 29%) as the most common cardiac and non-cardiac co-morbidity, respectively. Among female participants, 45% (n=1147) reported having had a pregnancy with 38% (n=967) resulting in biological children. Participants with complex CHD were less likely to meet recommended physical activity guidelines (X2(2, n = 917) = 15.9, p < 0.001), a factor that was more pronounced amongst female participants. Overall health-related quality of life was rated as good or better by 84% of participants with no difference by CHD complexity.ConclusionCHI is the largest ongoing registry of adults living with congenital heart disease in the US and includes patients with a wide variety of CHD subtypes. Many patients report mood disorders, but most report good or very good health-reported quality of life. The CHI is poised to facilitate multicenter research with the goal of improving clinical outcomes for all adults with CHD.
Comparative evaluation of machine learning models versus TIMI score in ST-segment-elevation myocardial infarction patients
Authors: Gupta Mohit D , Goyal Dixit , Kunal Shekhar , Shetty Manu Kumar , MP Girish , Batra Vishal , Bansal Ankit , Mishra Prashant , Shukla Mansavi , Gupta Aarti , Kohli Vanshika , Chadha Akul , Fatima Arisha , Muduli Subrat , Gupta Anubha , Yusuf Jamal 
Published: May 2024

AbstractBackgroundRisk stratification is an integral component of ST-segment-elevation myocardial infarction (STEMI) management practices. This study aimed to derive a machine learning (ML) model for risk stratification and identification of factors associated with in-hospital and 30-day mortality in patients with STEMI and compare it with traditional TIMI score.MethodsThis was a single center prospective study wherein subjects >18 years with STEMI (n=1700) were enrolled. Patients were divided into two groups: training (n=1360) and validation dataset (n=340). Six ML algorithms (Extra Tree, Random Forest, Multiple Perceptron, CatBoost, Logistic Regression and XGBoost) were used to train and tune the ML model and to determine the predictors of worse outcomes using feature selection. Additionally, the performance of ML models both for in-hospital and 30-day outcomes was compared to that of TIMI score.ResultsOf the 1700 patients, 168 (9.88%) had in-hospital mortality while 30-day mortality was reported in 210 (12.35%) subjects. In terms of in-hospital mortality, Random Forest ML model (sensitivity: 80%; specificity: 74%; AUC: 80.83%) outperformed the TIMI score (sensitivity: 70%; specificity: 64%; AUC:70.7%). Similarly, Random Forest ML model (sensitivity: 81.63%; specificity: 78.35%; AUC: 78.29%) had better performance as compared to TIMI score (sensitivity: 63.26%; specificity: 63.91%; AUC: 63.59%) for 30-day mortality. Key predictors for worse outcomes at 30-days included mitral regurgitation on presentation, smoking, cardiogenic shock, diabetes, ventricular septal rupture, Killip class, age, female gender, low blood pressure and low ejection fraction.ConclusionsML model outperformed the traditional regression based TIMI score as a risk stratification tool in patients with STEMI.
Hydrocarbon-degrading microbial populations in permanently cold deep-sea sediments in the NW Atlantic
Authors: Adebayo Oyeboade , Bhatnagar Srijak , Webb Jamie , Campbell Calvin , Fowler Martin , MacAdam Natasha M. , Macdonald Adam , Li Carmen , Hubert Casey R.J. 
Published: May 2024

AbstractPermanently cold deep-sea sediments (2500-3500 m water depth) with or without indications of thermogenic hydrocarbon seepage were exposed to naphtha to examine the presence and potential of aerobic hydrocarbon-degrading microbial populations. Monitoring these microcosms for volatile hydrocarbons by GC-MS revealed sediments withoutin situhydrocarbons responded more rapidly to naphtha amendment than hydrocarbon seep sediments overall, but seep sediments removed BTEX compounds more readily. Naphtha-driven aerobic respiration was more evident in surface sediment (0-20 cmbsf) than deeper anoxic layers (>130 cmbsf) that responded less rapidly. In all cases, enrichment of Gammaproteobacteria included lineages ofOleispira,Pseudomonas, andAlteromonasknown to be associated with marine oil spills. On the other hand, taxa known to be prevalentin situand diagnostic for thermogenic hydrocarbon seepage in deep sea sediment did not respond to naphtha amendment. This suggests a limited role for seep-associated populations in the context of oil spill biodegradation.
Large-scale estimation of bacterial and archaeal DNA prevalence in metagenomes reveals biome-specific patterns
Authors: Eisenhofer Raphael , Alberdi Antton , Woodcroft Ben J. 
Published: May 2024

AbstractMetagenomes often contain many reads derived from eukaryotes. However, there is usually no reliable method for estimating the prevalence of non-microbial reads in a metagenome, forcing many analysis techniques to make the often-faulty assumption that all reads are microbial. For instance, the success of metagenome-assembled genome (MAG) recovery efforts is assessed by the number of reads mapped to recovered MAGs, a procedure which will underestimate the true fidelity if eukaryotic reads are present. Here we present “SingleM microbial_fraction” (SMF), a scalable algorithm that robustly estimates the number of bacterial and archaeal reads in a metagenome, and the average microbial genome size. SMF does not use eukaryotic reference genome data and can be applied to any Illumina metagenome. Based on SMF, we propose the “Domain-Adjusted Mapping Rate” (DAMR) as an improved metric to assess microbial genome recovery from metagenomes. We benchmark SMF on simulated and real data, and demonstrate how DAMRs can guide genome recovery. Applying SMF to 136,284 publicly available metagenomes, we report substantial variation in microbial fractions and biome-specific patterns of microbial abundance, providing insights into how microorganisms and eukaryotes are distributed across Earth. Finally, we show that substantial amounts of human host DNA sequence data have been deposited in public metagenome repositories, possibly counter to ethical directives that mandate screening of these reads prior to release. As the adoption of metagenomic sequencing continues to grow, we foresee SMF being a valuable tool for the appraisal of genome recovery efforts, and the recovery of global patterns of microorganism distribution.
Comprehensive Proteomic Analysis of HCoV-OC43 Virions and Virus-Modulated Extracellular Vesicles
Authors: Joharinia Negar , Bonneil Éric , Grandvaux Nathalie , Thibault Pierre , Lippé Roger 
Published: May 2024

AbstractViruses are obligate parasites that depend on the cellular machinery for their propagation. Several viruses also incorporate cellular proteins that facilitate viral spread. Defining these cellular proteins is critical to decipher viral life cycles and delineate novel therapeutic strategies. While numerous studies have explored the importance of host proteins in coronavirus spread, information about their presence in mature virions is limited. In this study, we developed a protocol to highly enrich mature HCoV-OC43 virions and characterize them by proteomics. Recognizing that cells release extracellular vesicles whose content is modulated by viruses, and given our ability to separate virions from these vesicles, we also analyzed their protein content in both uninfected and infected cells. We uncovered 69 unique cellular proteins associated with virions including 31 high confidence hits. These proteins primarily regulate RNA metabolism, enzymatic activities, vesicular transport, cell adhesion, metabolite interconversion and translation. We further discovered that the virus had a profound impact on exosome composition, incorporating 47 novel cellular proteins (11 high confidence) and excluding 92 others (61 high confidence) in virus-associated extracellular vesicles compared to uninfected cells. Moreover, a dsiRNA screen revealed that 11 of 18 select targets significantly impacted viral yields, including proteins found in virions or extracellular vesicles. Overall, this study provides new and important insights into the incorporation of numerous host proteins into HCoV-OC43 virions, their biological significance and the ability of the virus to modulate extracellular vesicles.ImportanceIn recent years, coronaviruses have dominated global attention, making it crucial to develop methods to control them and prevent future pandemics. Besides viral proteins, host proteins play a significant role in viral propagation and offer potential therapeutic targets. Targeting host proteins is advantageous because they are less likely to mutate and develop resistance compared to viral proteins, a common issue with many antiviral treatments. In this study, we examined the protein content of the less virulent biosafety level 2 HCoV-OC43 virus as a stand-in for the more virulent SARS-CoV-2. Our findings reveal that several cellular proteins incorporated into the virion regulate viral spread. Additionally, we report that the virus extensively modulates the content of extracellular vesicles, enhancing viral dissemination. This underscores the critical interplay between the virus, host proteins, and extracellular vesicles.
Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles
Authors: Zheng Xu , Yu Shi , Zhou Yanqiu , Yu Kuai , Gao Yuhui , Chen Mengdan , Duan Dong , Li Yunyi , Cui Xiaoxian , Mou Jiabin , Yang Yuying , Wang Xun , Chen Min , Jiu Yaming , Zhao Jincun , Meng Guangxun 
Published: May 2024

AbstractInnate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including pro-inflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably,in vivoinfection experiments in mice confirms that IL-1β significantly restricted SARS-CoV-2 spreading in the lung epithelia. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.
Fungal pathogens exposed – genomic and phenotypic insights intoCandida aurisand its relatives of theCandida haemuloniispecies complex
Authors: de Jong Auke W. , Boden Sander , Zandijk Annemarie , Kortsinoglou Alexandra M. , Gerrits van den Ende Bert , Francisco Elaine C. , Nefeli Podimata Konstantina , Kouvelis Vassili N. , Zhou Miaomiao , Hagen Ferry 
Published: May 2024

AbstractCandida aurisshowed the world the ability of fungi to rapidly emerge as an urgent threat to public health. Close relatives of theCandida haemuloniicomplex exhibit also a similar multi-drug resistant nature and are increasingly reported as nosocomial pathogens. Here, we analyze both complete genomes assemblies and extensive phenotypic data for the fiveC. aurisclades and pathogenic and non-pathogenic species related to theC. haemuloniispecies complex. First, we resolved the phylogeny of the species complex. Next, comparingC. auristo its pathogenic and non-pathogenic relatives we identified a pathogenic potential for the wholeC. haemuloniispecies complex by shared gene content and phenotypic traits linked to drug resistance and virulence.In vivovirulence assays using theGalleria mellonellafungal infection model show thatC. aurisstrains are significantly more virulent than any of the sibling species in theC. haemuloniicomplex. Phenotypic analysis links the increased virulence ofC. auristo a more stress resistant phenotype compared to its siblings.
A noncanonical GTPase signaling mechanism controls exit from mitosis in budding yeast
Authors: Zhou Xiaoxue , Weng Shannon Y. , Bell Stephen P. , Amon Angelika 
Published: May 2024

ABSTRACTIn the budding yeastSaccharomyces cerevisiae, exit from mitosis is coupled to spindle position to ensure successful genome partitioning between mother and daughter cell. This coupling occurs through a GTPase signaling cascade known as the mitotic exit network (MEN). The MEN senses spindle position via a Ras-like GTPase Tem1 which localizes to the spindle pole bodies (SPBs, yeast equivalent of centrosomes) during anaphase and signals to its effector protein kinase Cdc15. How Tem1 couples the status of spindle position to MEN activation is not fully understood. Here, we show that Cdc15 has a relatively weak preference for Tem1GTPand Tem1’s nucleotide state does not change upon MEN activation. Instead, we find that Tem1’s nucleotide cycle establishes a localization-based concentration difference in the cell where only Tem1GTPis recruited to the SPB, and spindle position regulates the MEN by controlling Tem1 localization. SPB localization of Tem1 primarily functions to promote Tem1-Cdc15 interaction for MEN activation by increasing the effective concentration of Tem1. Consistent with this model, we demonstrate that artificially tethering Tem1 to the SPB or concentrating Tem1 in the cytoplasm with genetically encoded multimeric nanoparticles could bypass the requirement of Tem1GTPand correct spindle position for MEN activation. This localization/concentration-based GTPase signaling mechanism for Tem1 differs from the canonical Ras-like GTPase signaling paradigm and is likely relevant to other localization-based signaling scenarios.
Spike protein of the SARS-CoV-2 omicron variant interacts with actin
Authors: Fujimoto Ai , Kawai Haruki , Kawamura Rintaro , Kitamura Akira 
Published: May 2024

AbstractThe omicron variant of SARS-CoV-2 is responsible for the COVID-19 pandemic, serving as a significant origin for the variants still being detected today. It affects the spike protein that most vaccines used to target when the Omicron strain was discovered. Here, we demonstrate that the receptor binding domain (RBD) of the Omicron variant of SARS-CoV-2 exhibits an increased affinity for human angiotensin-converting enzyme type 2 (hACE2) as a viral cell receptor compared to the prototype RBD. We also identified that β- and γ-actin are Omicron-specific binding partners of RBD. Protein complex predictions suggested that many of the Omicron-specific amino acid substitutions might be involved in the affinity of RBD and actin. Accordingly, we highlight the intriguing observation that proteins expected to localize to different cellular compartments exhibit strong binding.
Changes in pain, mood, and functional connectivity following cryo-auriculotherapy in adults with chronic refractory low back pain: An open-label preliminary study
Authors: Vogt Keith M. , Khan Abdurrehman , Alter Benedict J , Emerick Trent D. , Ibinson James W. , Wasan Ajay D. , Sadhasivam Senthilkumar , Chelly Jacques E. 
Published: May 2024

AbstractIntroductionThis report describes the effects of auriculotherapy (AT) using cryogenic needles in a small cohort of chronic low back pain patients.MethodsThe effects of AT on pain, mood, and functioning were recorded in 10 patients with chronic back pain before and after cryogenic AT using patient-reported outcome instruments: Brief Pain Inventory (BPI), Patient Health Questionnaire (PHQ-9), General Anxiety Disorder (GAD-7), and Patient-Reported Outcomes Measurement Information System (PROMIS-29). In addition, resting-state MRI data collected before and 5-7 days after AT treatment were analyzed for changes in functional connectivity in 4 patients.ResultsGAD-7 scores decreased from 10.0 to 7.7 (95% confidence interval of difference= 0.2 – 4.4, p=0.036). Other patient-reported outcomes showed non-significant differences in this pilot cohort. Significant functional MRI connectivity changes were observed in 4 patients, suggesting that AT affected areas of the brain involved in pain processing.ConclusionCryogenic AT is a technique that may reduce the psychological burden of low back pain, but further study is needed. Preliminary functional connectivity changes support the concept that the effect of AT is centrally mediated.