bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of pyrazinamide resistance in Mycobacterium tuberculosis using structure-based machine-learning approaches
Authors: Carter Joshua J , Walker Timothy M , Walker A Sarah , Whitfield Michael G , Morlock Glenn P , Lynch Charlotte I , Adlard Dylan , Peto Timothy E A , Posey James E , Crook Derrick W , Fowler Philip W 
Published: March 2024

Abstract

Background
Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in pncA, encoding an enzyme that converts pyrazinamide into its active form.

Methods
We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features.

Results
The best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4027 samples harbouring 367 unique missense mutations in pncA derived from 24 231 clinical isolates.

Conclusions
This work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs.
Cryo-EM advances in GPCR structure determination
Authors: Shihoya Wataru , Iwama Aika , Sano Fumiya K , Nureki Osamu 
Published: March 2024

Abstract
G-protein-coupled receptors (GPCRs) constitute a prominent superfamily in humans and are categorized into six classes (A–F) that play indispensable roles in cellular communication and therapeutics. Nonetheless, their structural comprehension has been limited by challenges in high-resolution data acquisition. This review highlights the transformative impact of cryogenic electron microscopy (cryo-EM) on the structural determinations of GPCR–G-protein complexes. Specific technologies, such as nanobodies and mini-G-proteins, stabilize complexes and facilitate structural determination. We discuss the structural alterations upon receptor activation in different GPCR classes, revealing their diverse mechanisms. This review highlights the robust foundation for comprehending GPCR function and pave the way for future breakthroughs in drug discovery and therapeutic targeting.
Metabolic regulation of the host–fungus interaction: from biological principles to therapeutic opportunities
Authors: Silva-Gomes Rita , Caldeira Inês , Fernandes Raquel , Cunha Cristina , Carvalho Agostinho 
Published: March 2024

Abstract
Fungal infections present a significant global public health concern, impacting over 1 billion individuals worldwide and resulting in more than 3 million deaths annually. Despite considerable progress in recent years, the management of fungal infections remains challenging. The limited development of novel diagnostic and therapeutic approaches is largely attributed to our incomplete understanding of the pathogenetic mechanisms involved in these diseases. Recent research has highlighted the pivotal role of cellular metabolism in regulating the interaction between fungi and their hosts. In response to fungal infection, immune cells undergo complex metabolic adjustments to meet the energy demands necessary for an effective immune response. A comprehensive understanding of the metabolic circuits governing antifungal immunity, combined with the integration of individual host traits, holds the potential to inform novel medical interventions for fungal infections. This review explores recent insights into the immunometabolic regulation of host–fungal interactions and the infection outcome and discusses how the metabolic repurposing of immune cell function could be exploited in innovative and personalized therapeutic approaches.
Spatial Pattern Analysis using Closest Events (SPACE)—A Nearest Neighbor Point Pattern Analysis Framework for Assessing Spatial Relationships from Digital Images
Authors: Soltisz Andrew M , Craigmile Peter F , Veeraraghavan Rengasayee 
Published: March 2024

Abstract
The quantitative description of biological structures is a valuable yet difficult task in the life sciences. This is commonly accomplished by imaging samples using fluorescence microscopy and analyzing resulting images using Pearson's correlation or Manders’ co-occurrence intensity-based colocalization paradigms. Though conceptually and computationally simple, these approaches are critically flawed due to their reliance on signal overlap, sensitivity to cursory signal qualities, and inability to differentiate true and incidental colocalization. Point pattern analysis provides a framework for quantitative characterization of spatial relationships between spatial patterns using the distances between observations rather than their overlap, thus overcoming these issues. Here we introduce an image analysis tool called Spatial Pattern Analysis using Closest Events (SPACE) that leverages nearest neighbor-based point pattern analysis to characterize the spatial relationship of fluorescence microscopy signals from image data. The utility of SPACE is demonstrated by assessing the spatial association between mRNA and cell nuclei from confocal images of cardiac myocytes. Additionally, we use synthetic and empirical images to characterize the sensitivity of SPACE to image segmentation parameters and cursory image qualities such as signal abundance and image resolution. Ultimately, SPACE delivers performance superior to traditional colocalization methods and offers a valuable addition to the microscopist's toolbox.
Evolutionary and functional insights into the Ski2-like helicase family in Archaea: a comparison of Thermococcales ASH-Ski2 and Hel308 activities
Authors: Batista Manon , Langendijk-Genevaux Petra , Kwapisz Marta , Canal Isabelle , Phung Duy Khanh , Plassart Laura , Capeyrou Régine , Moalic Yann , Jebbar Mohamed , Flament Didier , Fichant Gwennaele , Bouvier Marie , Clouet-d’Orval Béatrice 
Published: March 2024

Abstract
RNA helicases perform essential housekeeping and regulatory functions in all domains of life by binding and unwinding RNA molecules. The Ski2-like proteins are primordial helicases that play an active role in eukaryotic RNA homeostasis pathways, with multiple homologs having specialized functions. The significance of the expansion and diversity of Ski2-like proteins in Archaea, the third domain of life, has not yet been established. Here, by studying the phylogenetic diversity of Ski2-like helicases among archaeal genomes and the enzymatic activities of those in Thermococcales, we provide further evidence of the function of this protein family in archaeal metabolism of nucleic acids. We show that, in the course of evolution, ASH-Ski2 and Hel308-Ski2, the two main groups of Ski2-like proteins, have diverged in their biological functions. Whereas Hel308 has been shown to mainly act on DNA, we show that ASH-Ski2, previously described to be associated with the 5′-3′ aRNase J exonuclease, acts on RNA by supporting an efficient annealing activity, but also an RNA unwinding with a 3′-5′ polarity. To gain insights into the function of Ski2, we also analyse the transcriptome of Thermococcus barophilus ΔASH-Ski2 mutant strain and provide evidence of the importance of ASH-Ski2 in cellular metabolism pathways related to translation.
Chest X-ray Features of HIV-Associated Pneumocystis Pneumonia (PCP) in Adults: A Systematic Review and Meta-analysis
Authors: Wills Nicola K , Adriaanse Marguerite , Erasmus Shandri , Wasserman Sean 
Published: March 2024

Abstract

Background
The performance of chest x-ray (CXR) features for Pneumocystis pneumonia (PCP) diagnosis has been evaluated in small studies. We conducted a systematic review and meta-analysis to describe CXR changes in adults with HIV-associated laboratory-confirmed PCP, comparing these with non-PCP respiratory disease.

Methods
We searched databases for studies reporting CXR changes in people &gt;15 years old with HIV and laboratory-confirmed PCP and those with non-PCP respiratory disease. CXR features were grouped using consensus terms. Proportions were pooled and odds ratios (ORs) generated using random-effects meta-analysis, with subgroup analyses by CD4 count, study period, radiology review method, and study region.

Results
Fifty-one studies (with 1821 PCP and 1052 non-PCP cases) were included. Interstitial infiltrate (59%; 95% CI, 52%–66%; 36 studies, n = 1380; I2 = 85%) and ground-glass opacification (48%; 95% CI, 15%–83%; 4 studies, n = 57; I2 = 86%) were common in PCP. Cystic lesions, central lymphadenopathy, and pneumothorax were infrequent. Pleural effusion was rare in PCP (0%; 95% CI, 0%–2%). Interstitial infiltrate (OR, 2.3; 95% CI, 1.4–3.9; I2 = 60%), interstitial–alveolar infiltrate (OR, 10.2; 95% CI, 3.2–32.4; I2 = 0%), and diffuse CXR changes (OR, 7.3; 95% CI, 2.7–20.2; I2 = 87%) were associated with PCP diagnosis. There was loss of association with alveolar infiltrate in African studies.

Conclusions
Diffuse CXR changes and interstitial–alveolar infiltrates indicate a higher likelihood of PCP. Pleural effusion, lymphadenopathy, and focal alveolar infiltrates suggest alternative causes. These findings could be incorporated into clinical algorithms to improve diagnosis of HIV-associated PCP.
Impact of the COVID-19 Pandemic on Candida auris Infections: A Retrospective Analysis in an Academic Medical Center in New York City
Authors: Schaefer Sarah , Walits Emily , Thaler Kalani , Patel Gopi 
Published: March 2024

Abstract

Background
Candida auris (C. auris), a multidrug-resistant fungus first described in Japan in 2009, has since spread rapidly around the world. More recently, cases of C. auris have increased substantially, which may have been affected by the strain the coronavirus disease 2019 (COVID-19) pandemic placed on health care resources. We describe the epidemiology of C. auris infection and colonization at a tertiary care hospital in New York City before, during, and after the peak of the COVID-19 pandemic and describe our approach to surveillance.

Methods
We performed a retrospective chart review for all incident cases of C. auris, defined as a patient without a known history of infection or colonization who had a positive surveillance or clinical culture detected at our institution from 2019 through 2022. Clinical and demographic data were collected using the electronic medical record.

Results
Sixty-four incident cases of C. auris were identified. Thirty-four of these were identified by surveillance and 30 by clinical culture. There was a statistically significant increase in the number of cases identified in 2022 compared with 2019, with incidence rates of 2.6 cases per 10 000 admissions in 2019 and 7.8 cases per 10 000 admissions in 2022 (p = .002), respectively.

Conclusions
The incidence of C. auris colonization or infection increased significantly at our institution during the COVID-19 pandemic, reflecting the potential impact the pandemic had on C. auris transmission. Targeted admission surveillance allows for the early identification of C. auris cases and can serve as a valuable tool to combat the increasing transmission of C. auris.
Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia
Authors: Wang Dao Sen , Phu Amy , McKee Kristen , Strasser Simone I , Sheils Sinead , Weltman Martin , Sellar Sue , Davis Joshua S , Young Mel , Braund Alicia , Farrell Geoffrey C , Blunn Anne , Harding Damian , Ralton Lucy , Muller Kate , Davison Scott A , Shaw David , Wood Marnie , Hajkowicz Krispin , Skolen Richard , Davies Jane , Tate-Baker Jaclyn , Doyle Adam , Tuma Rhoda , Hazeldine Simon , Lam Wendy , Edmiston Natalie , Zohrab Krista , Pratt William , Watson Belinda , Zekry Amany , Stephens Carlie , Clark Paul J , Day Melany , Park Gordon , Kim Hami , Wilson Mark , McGarity Bruce , Menzies Natalie , Russell Darren , Lam Thao , Boyd Peter , Kok Jen , George Jacob , Douglas Mark W 
Published: March 2024

Abstract

Background
Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported.

Methods
We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome.

Results
Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir.

Conclusions
In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.
Does attitudes toward own aging explain more variance in aging-related outcomes than chronological age and subjective age? A meta-analysis
Authors: Yang Huan , Shi Junqi , Zhao Xinyuan (Roy) , Pryor Christopher , Tian Mengwei 
Published: March 2024

Abstract
Significant research efforts have been devoted to explaining why and how aging impacts employees’ attitudes and behaviors. However, age itself has been subject to a range of conceptualizations and measurements, which has resulted in a fragmented literature. Chronological age (CA) captures biological differences, and subjective age (SA) captures people’s perceptions of their own chronological aging. Not surprisingly, these constructs have different effects on aging-related outcomes. More recently, a relatively newer construct, attitudes toward own aging (ATOA), has gained research traction. In this study, we synthesize the empirical evidence concerning ATOA, and we establish criterion-related and incremental validity of ATOA using meta-analytical techniques. We found that ATOA not only predicted health, cognitive function, well-being, and self-efficacy, but also provided additional explanatory power regarding these aging-related outcomes above and beyond CA and SA. The theoretical and practical implications of these studies are discussed.
Sustainability in Obstetrics and Gynecology
Authors: Wright Kelly N. , Melnyk Alexandra I. , Emont Jordan , Van Dis Jane 
Published: March 2024

ABSTRACT
The greatest threat to human health, otherwise known as the climate crisis, disproportionately affects women and pregnant people via exposure to air pollution, heat, extreme weather events, and toxic substances. These effects lead to increased mortality and morbidity in patient populations, but the overall role of the healthcare system and its contribution remains unknown to medical professionals. This review aims to educate clinicians on the effects of the climate crisis on health outcomes and how the current US healthcare system practices drive climate change. Solutions for decarbonizing operating rooms (ORs), neonatal intensive care units (and nurseries), and labor and delivery units are also addressed.
The impact on health can be categorized by the effect of heat (rising temperatures), air pollution, and toxic substances such as microplastics. These have variously been shown to impact fertility; rates of miscarriage, stillbirth, and preterm birth; and hypertensive disorders of pregnancy.
Notably, the healthcare industry contributes more carbon emissions than even global aviation, with the US healthcare industry producing 27% of the world’s healthcare carbon emissions through its energy and water usage, but also via the supply chain, its waste, and pharmaceuticals. Petroleum-based plastic single-use supplies (ie, gowns, instruments, drapes) in hospitals are also a major contributor to this crisis. Up to 95% of the environmental imprint of the healthcare supply chain stems from these single-use supplies. In addition, biohazard waste must be incinerated prior to landfill disposal, further adding to the environmental impact.
Evidence supports the immediate impact of systemic change in terms of decarbonizing healthcare. Replacing single-use instruments with sterilized reusable ones, for instance, has a major impact, such as replacing acrylic specula with stainless steel ones. Another study indicated lower rates of surgical site infections when single-use materials were unavailable in the OR. Beyond this, many single-use supplies are never utilized for patients and go directly to waste. In addition, over carbon dioxide, inhaled anesthetics such as desflurane have 2540 times the potential for global warming while lacking noticeable benefit over other anesthetics. Instead, intravenous anesthetic use can greatly decarbonizing surgeries due to the lower carbon footprint of these medications.
Finally, decreasing energy use in climate control measures within buildings can also impact the environment for the better. Powering down unused ORs saved one institution $33,000 annually. Powering down computers over weekends and on nights can also greatly reduce carbon emissions.
Evidence for the Role of Selection for Reproductively Advantageous Alleles in Human Aging
Authors: Long Erping , Zhang Jianzhi 
Published: March 2024

ABSTRACT
The antagonistic pleiotropy hypothesis is one of the leading theories in the evolutionary origin of aging. It states that mutations contributing to aging could be positively selected for if they are advantageous early in life and promote earlier reproduction or more offspring. The evidence supporting the antagonistic pleiotropy hypothesis in humans is mixed and lacks unambiguous genome-wide support. The UK Biobank contains the genotypes and various phenotypes of 500,000 participants, offering an opportunity to test the antagonistic pleiotropy hypothesis in humans.
This analysis aimed to use the UK Biobank to determine whether genetic variants influencing reproduction are likely to affect lifespan, whether pleiotropy between reproduction and lifespan are largely antagonistic, and whether pleiotropic mutations promoting reproduction but causing aging are favored by natural selection. In addition, potential molecular mechanisms linking reproduction to aging were investigated. Genetic correlation between 2 phenotypic traits was defined as the proportion of variance that the 2 traits share due to genetic causes and is a measure of the contribution of pleiotropy to the covariation of the traits. Four reproductive traits were focused on negative age at first birth, negative age at first sex, number of children fathers, and age at menopause, with larger values of these traits corresponding to higher reproduction. Two life span traits were examined: father's age at death and mother's age at death.
Data were available for a total of 276,406 UK Biobank participants, and 583 genetic variants were reported to be associated with at least 1 reproductive trait. A strong, negative genetic correlation was observed between the 3 reproductive traits and 2 life span traits, supporting the antagonistic pleiotropy hypothesis. Individuals ranked in the top third in polygenic score (PGS) for the 3 reproductive traits had a significantly lower probability of survival to age 76 (SV76) than that of individuals ranked in the bottom third. Compared with randomly selected polymorphisms, those impacting reproduction were 5 times more likely to affect life span and 7.5 times more likely to affect life span antagonistically. Among individuals with the same number of children ever born, SV76 was negatively correlated with the PGS for each of the 4 reproductive traits. In this study, the evidence shows a strong negative genetic correlation between reproduction and parental life span, as well as between parental reproduction and parental life span. This supports the antagonistic pleiotropy hypothesis of aging in humans.
Problem Opioid Use Among US Military Veterans: Prevalence, Correlates, and Psychiatric Characteristics
Authors: Na Peter J. , Petrakis Ismene L. , Krystal John H. , Pietrzak Robert H. 
Published: March 2024

Objective
Problem opioid use (POU) is a serious public health crisis in the United States. However, little research has examined the prevalence, correlates, and psychiatric characteristics of POU in vulnerable segments of the population, such as US military veterans.

Methods
Data were analyzed from the National Health and Resilience in Veterans Study, which surveyed a nationally representative sample of 2441 US veterans. Multivariable logistic regression models were conducted to identify correlates and psychiatric correlates of POU (defined as a positive screen on the Tobacco, Alcohol, Prescription Medication, and Other Substance Use Tool).

Results
A total 3.0% (95% confidence interval, 2.0%–4.5%) of US veterans screened positive for POU. Black, non-Hispanic race/ethnicity (odds ratio [OR], 3.83), lifetime alcohol use disorder (OR, 3.38), major depressive disorder (MDD; OR, 2.52), greater number of medical conditions (OR, 1.15), and disability in instrumental activities of daily living (IADL); OR, 1.86) were independently associated with POU. A significant interaction between IADL disability and MDD was observed (OR, 10.73)—among veterans with IADL disability, those with MDD had more than 6-fold greater POU than those without MDD (20.6% vs 3.2%). Furthermore, POU was associated with 2- to 3-folds greater odds of current generalized anxiety disorder and current posttraumatic stress disorder, and lifetime suicide attempt.

Conclusions
POU affects 3.0% of US veterans and is associated with Black race/ethnicity, lifetime physical and mental health morbidities, as well as current psychiatric disorders and lifetime suicide attempts. Results underscore the importance of assessing physical and mental health disorders in veterans at-risk for POU and addressing co-occurring psychiatric disorders associated with POU in this population.