bluuebunny/crossref_metadata_2025_split huggingface dataset:
EHR-ML: A generalisable pipeline for reproducible clinical outcomes using electronic health records
Authors: Ramakrishnaiah Yashpal , Macesic Nenad , Webb Geoffrey I. , Peleg Anton Y. , Tyagi Sonika 
Published: March 2024

ABSTRACTThe healthcare landscape is experiencing a transformation with the integration of Artificial Intelligence (AI) into traditional analytic workflows. However, this advancement encounters challenges due to variations in clinical practices, resulting in a crisis of generalisability. Addressing this issue, our proposed solution, EHR-ML, offers an open-source pipeline designed to empower researchers and clinicians. By leveraging institutional Electronic Health Record (EHR) data, EHR-ML facilitates predictive modelling, enabling the generation of clinical insights. EHR-ML stands out for its comprehensive analysis suite, guiding researchers through optimal study design, and its built-in flexibility allowing for construction of robust, customisable models. Notably, EHR-ML integrates a dedicated two-layered ensemble model utilising feature representation learning. Additionally, it includes a feature engineering mechanism to handle intricate temporal signals from physiological measurements. By seamlessly integrating with our quality assurance pipelines, this utility leverages its data standardization and anomaly handling capabilities.Benchmarking analyses demonstrate EHR-ML’s efficacy, particularly in predicting outcomes like inpatient mortality and the Intensive Care Unit (ICU) Length of Stay (LOS). Models built with EHR-ML outperformed conventional methods, showcasing its generalisability and versatility even in challenging scenarios such as high class-imbalance.We believe EHR-ML is a critical step towards democratising predictive modelling in health-care, enabling rapid hypothesis testing and facilitating the generation of biomedical knowledge. Widespread adoption of tools like EHR-ML will unlock the true potential of AI in healthcare, ultimately leading to improved patient care.
Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease
Authors: Wattacheril Julia , Kleinstein Sarah E. , Shea Patrick R. , Wilson Laura A. , Subramanian G. Mani , Myers Robert P. , Lefkowitch Jay , Behling Cynthia , Xanthakos Stavra A. , Goldstein David B. ,   the NASH Clinical Research Network
Published: March 2024

AbstractBackground and AimsNonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis.MethodsWhole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction.ResultsNo genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants inPNPLA3orTM6SF2was observed across phenotypes.ConclusionIn a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults:PNPLA3andTM6SF2,though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.
Revised Mechanism of Hydroxyurea Induced Cell Cycle Arrest and an Improved Alternative
Authors: Shaw Alisa E. , Whitted Jackson E. , Mihelich Mattias N. , Reitman Hannah J. , Timmerman Adam J. , Schauer Grant D. 
Published: March 2024

ABSTRACTReplication stress describes various types of endogenous and exogenous challenges to DNA replication in S-phase. Stress during this critical process results in helicase-polymerase decoupling at replication forks, triggering the S-phase checkpoint, which orchestrates global replication fork stalling and delayed entry into G2. The replication stressor most often used to induce the checkpoint response is hydroxyurea (HU), a chemotherapeutic agent. The primary mechanism of S-phase checkpoint activation by HU has thus far been considered to be a reduction of dNTP synthesis by inhibition of ribonucleotide reductase (RNR), leading to helicase-polymerase decoupling and subsequent activation of the checkpoint, mediated by the replisome associated effector kinase Mrc1. In contrast, we observe that HU causes cell cycle arrest in budding yeast independent of both the Mrc1-mediated replication checkpoint response and the Psk1-Mrc1 oxidative signaling pathway. We demonstrate a direct relationship between HU incubation and reactive oxygen species (ROS) production in yeast nuclei. We further observe that ROS strongly inhibits thein vitropolymerase activity of replicative polymerases (Pols), Pol α, Pol δ, and Pol ε, causing polymerase complex dissociation and subsequent loss of DNA substrate binding, likely through oxidation of their integral iron sulfur Fe-S clusters. Finally, we present “RNR-deg,” a genetically engineered alternative to HU in yeast with greatly increased specificity of RNR inhibition, allowing researchers to achieve fast, nontoxic, and more readily reversible checkpoint activation compared to HU, avoiding harmful ROS generation and associated downstream cellular effects that may confound interpretation of results.
Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection
Authors: El Moussaoui Majdouline , Bontems Sebastien , Meex Cecile , Hayette Marie-Pierre , Lejeune Marie , Hong Samuel L. , Dellicour Simon , Moutschen Michel , Cambisano Nadine , Renotte Nathalie , Bours Vincent , Darcis Gilles , Artesi Maria , Durkin Keith 
Published: March 2024

AbstractAccumulating evidence points to persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals as a source of genetically divergent, novel lineages, generally characterised by increased transmissibility and immune escape. While intrahost evolutionary dynamics of the virus in chronically infected patients have been previously reported, existing knowledge is primarily based on samples obtained from the nasopharyngeal compartment. In this study, we investigate the intrahost evolution and genetic diversity that accumulated during a prolonged SARS-CoV-2 infection with the Omicron sublineage BF.7, estimated to have persisted for over one year in an immunosuppressed patient. Based on the sequencing of eight viral genomes collected from the patient at six time points, we identified 86 intrahost single-nucleotide variants (iSNVs), two indels, and a 362 bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate (ETA), and bronchoalveolar (BAL) samples. Notably, while significant divergence was observed between NP and BAL samples, most of the iSNVs found in ETA samples were also detected in NP or BAL samples. This suggests that NP samples may not offer a comprehensive representation of the overall intrahost viral diversity. Nonsynonymous mutations were most frequent in the spike and envelope genes, along with loss-of-function mutations in ORF8, generated by a frameshift mutation and a large deletion detected in the BAL and NP samples, respectively. Using long-range PCR on SARS-CoV-2 samples sequenced as part of routine surveillance, we validated that similar deletions causing ORF8 loss of function can be carried by SARS-CoV-2 during acute infection. Our findings not only demonstrate that the Omicron sublineage BF.7 can further diverge from its already exceptionally mutated state but also highlight that patients chronically infected with SARS-CoV-2 can develop genetically specific viral populations across distinct anatomical compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections.
Nasopharyngeal metatranscriptomics reveals host-pathogen signatures of pediatric sinusitis
Authors: AbuMazen Nooran , Chu Vivian , Hunjan Manjot , Lobb Briallen , Lee Sojin , Kurs-Lasky Marcia , Williams John V. , MacDonald William , Johnson Monika , Hirota Jeremy A. , Shaikh Nader , Doxey Andrew C. 
Published: March 2024

AbstractAcute sinusitis (AS) is the fifth leading cause of antibiotic prescriptions in children. Distinguishing bacterial AS from common viral upper respiratory infections in children is crucial to prevent unnecessary antibiotic use but is challenging with current diagnostic methods. Despite its speed and cost, untargeted RNA sequencing of clinical samples from children with suspected AS has the potential to overcome several limitations of other methods. However, the utility of sequencing-based approaches in analysis of AS has not been fully explored. Here, we performed RNA-seq of nasopharyngeal samples from 221 children with clinically diagnosed AS to characterize their pathogen and host-response profiles. Results from RNA-seq were compared with those obtained using culture for three common bacterial pathogens and qRT-PCR for 12 respiratory viruses. Metatranscriptomic pathogen detection showed high concordance with culture or qRT-PCR, showing 87%/81% sensitivity (sens) / specificity (spec) for detecting bacteria, and 86%/92% (sens/spec) for viruses, respectively. We also detected an additional 22 pathogens not tested for in the clinical panel, and identified plausible pathogens in 11/19 (58%) of cases where no organism was detected by culture or qRT-PCR. We assembled genomes of 205 viruses across the samples including novel strains of coronaviruses, respiratory syncytial virus (RSV), and enterovirus D68. By analyzing host gene expression, we identified host-response signatures that distinguished bacterial and viral infections and correlated with pathogen abundance. Ultimately, our study demonstrates the potential of untargeted metatranscriptomics for in depth analysis of the etiology of AS, comprehensive host-response profiling, and using these together to work towards optimized patient care.One Sentence SummaryRNA-sequencing of nasopharyngeal samples enables pathogen-detection and host-response profiling in pediatric acute sinusitis.
The seroprevalence of SARS-CoV-2-specific antibodies in Australian children: a cross sectional study
Authors: Koirala Archana , McRae Jocelynne , Britton Philip N , Downes Marnie , Prasad Shayal A , Nicholson Suellen , Winkler Noni E , O’Sullivan Matthew V N , Gondalwala Fatima , Castellano Cecile , Carey Emma , Hendry Alexandra , Crawford Nigel , Wadia Ushma , Richmond Peter , Marshall Helen S , Clark Julia E , Francis Joshua R , Carr Jeremy , Bartlett Adam , McMullan Brendan , Skowno Justin , Hannah Donald , Davidson Andrew , von Ungern-Sternberg Britta S , Lee-Archer Paul , Burgoyne Laura L , Waugh Edith B , Carlin John B , Naing Zin , Kerly Nicole , McMinn Alissa , Hunter Guillian , Heath Christine , D’Angelo Natascha , Finucane Carolyn , Francis Laura A , Dougherty Sonia , Rawlinson William , Karapanagiotidis Theo , Cain Natalie , Brizuela Rianne , Blyth Christopher C , Wood Nicholas , Macartney Kristine 
Published: March 2024

AbstractBackgroundFollowing reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated.ObjectiveTo better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years.MethodsWe conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Parents or guardians of children and adolescents under 18 years provided written consent and participants aged 18-19 years provided their own consent. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. S and N seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework.ResultsBlood was collected from 2,046 participants (median age: 6.6 years). Adjusted seroprevalence of spike-antibody was 92.1 % (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence increased with age but was similar across geographic distribution and socioeconomic quintiles.ConclusionMost Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia.FundingAustralian Government Department of Health and Aged Care.
Effect of modified basic package of oral care on adolescents’ dental caries status in Copperbelt Province, Zambia; A Cluster Randomized Trial
Authors: Anthony Severine N , Mbawalla Hawa S , Kahabuka Febronia K , Siziya Seter , Åstrøm Anne N 
Published: March 2024

AbstractBackgroundDental caries remains the major oral health challenge affecting more than half of adolescents globally. Most of the disease remain untreated, therefore, negatively impacting adolescents’ general health, well-being, and quality of life. Basic Package of Oral Care (BPOC) is a potential solution to the challenge, however, evidence on its effectiveness is scarce. This study primarily assessed the effects of applying modified BPOC on dental caries prevalence and secondarily on knowledge and behaviors related to dental caries among adolescents in Copperbelt Province, Zambia.MethodsA parallel arms cluster randomized field trial (Reg-PACTR202210624926299) including 22 public secondary schools in Copperbelt province, Zambia, was carried out between January 2021 and March 2023. A pre-tested questionnaire was used to collect socio-demographics, knowledge and dental caries related behaviors data, while dental caries was assessed clinically using the caries assessment spectrum and treatment (CAST) at baseline and the follow-ups. The 1stand 2ndfollow ups were conducted at 18-and 24months after baseline respectively. The analysis was based on intention-to-treat protocol using generalized estimating equations (GEE) and results are reported as OR (95% CI).ResultsOut of 1,794 participants at baseline, 1,690 (94.2%) and 1,597 (89.0%) were seen at 1stand 2ndfollow ups respectively. A significant interaction (BPOC x time) for dental caries models at 18 months {OR (95%CI) = 1.3 (1.1, 1.6), p=0.003)} and 24 months {OR (95%CI) = 1.3 (1.1, 1.6), p=0.004)} was observed. Secondary outcomes with significant interactions included adequate knowledge models at 18 months {OR (95%CI) =1.5 (1.2,1.8), p<0.001} and 24 months {OR (95%CI) = 1.6 (1.3, 2.0), p<0.001} as well as use of fluoridated toothpaste twice or more per day at 18 months {OR (95%CI) = 1.6 (1.3, 2.1), p<0.001)} and 24 months {OR (95%CI) = 1.4 (1.2, 1.6), p<0.001)}. Subgroup analysis showed that the intervention group had better outcomes than the control group in terms of dental caries prevalence, adequate knowledge, use of fluoridated toothpaste twice or more per day, at 18- and 24 months.ConclusionThe modified BPOC was effective in reducing prevalence of dental caries, improving knowledge on dental caries, and the frequency of using fluoridated toothpaste among Zambian adolescents. Further studies need to be conducted in order to address other factors affecting oral health related behaviors such as the school and home environment, social and cultural factors.
Applying causal inference and Bayesian statistics to understanding vaccine safety signals — a simulation study
Authors: Tay Evelyn , Dymock Michael , Lopez Laura , Glover Catherine , Huang Yuanfei Anny , Shuvo Bakar K. , Snelling Thomas , Marsh Julie A. , Wu Yue 
Published: March 2024

AbstractCommunity perception of the safety of vaccines in the interest of public health influences vaccine uptake. Challenges for active vaccine safety monitoring include survey response rates, unbiased reporting and the balance between specificity and sensitivity of signal detection methods. To address these problems, we used causal DAGs and statistical methods to guide understanding of biological and behavioural factors which may influence vaccine safety signal detection. The DAGs informed the generation of scenarios in which these factors were varied. A posterior predictive analysis (PPA) signal detection method, based upon a Bayesian logistic model, was used to detect signals across the scenarios. In the high probability of severe reaction scenarios, true signals were generated where there was higher survey participation with more survey responder AEFI data available for analysis. In the low probability of severe reaction scenarios, false signals were generated when there was a strong influence of reaction severity on survey participation and reports of severe reactions. Low rates of survey participation reduce the amount of data available to inform the parameters of the statistical model, and therefore reduce the certainty regarding the value of these parameters. We obtained insights into the value of the causal DAG to account for survey non-response, to guide understanding of short-term vaccine safety, interpret the results of the PPA analysis under plausible scenarios, and review implications for future vaccine safety monitoring
Generative Adversarial Implicit Successor Representation
Authors: Choi Whan-Hyuk , Ha Sukyeon , Choi Hansol 
Published: March 2024

ABSTRACTWe propose a novel method to implicitly encode Successor Representations (SRs) using a Generative Adversarial Network (GAN). SRs are a method to encode states of the environment in terms of their predictive relationships with other states, which can be used to predict long-term future rewards. In standard explicit methods, the value of SR is found from an explicit map between future states after an action or to find an approximate function. Instead, our method encodes SR implicitly using a GAN. The distribution of samples generated by the GAN system approximates the successor representation. We also suggest an action decision procedure for the implicit encoding of SR. The system makes the decision using an analysis-by-synthesis procedure that it attempts to synthesize a sample that can explain the action decision constraints of the current and target states. Our system is different from the classical SR in several points. It can sample actual samples reflecting SR distribution, which is not easy for explicit models. It can also get around the issue of explicitly representing probabilities or successor representation values and doing math over them. We tested our system in a toy environment, where the agent could learn the implicit successor representation successfully and use it for action decisions.
Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies
Authors: Nazeen Sumaiya , Wang Xinyuan , Zielinski Dina , Lam Isabel , Hallacli Erinc , Xu Ping , Ethier Elizabeth , Strom Ronya , Zanella Camila A. , Nithianandam Vanitha , Ritter Dylan , Henderson Alexander , Saurat Nathalie , Afroz Jalwa , Nutter-Upham Andrew , Benyamini Hadar , Copty Joseph , Ravishankar Shyamsundar , Morrow Autumn , Mitchel Jonathan , Neavin Drew , Gupta Renuka , Farbehi Nona , Grundman Jennifer , Myers Richard H. , Scherzer Clemens R. , Trojanowski John Q. , Van Deerlin Vivianna M. , Cooper Antony A. , Lee Edward B. , Erlich Yaniv , Lindquist Susan , Peng Jian , Geschwind Daniel H , Powell Joseph , Studer Lorenz , Feany Mel B. , Sunyaev Shamil R. , Khurana Vikram 
Published: March 2024

ABSTRACTWhether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein (ɑS) and beta-amyloid (Aβ) cytotoxicity in yeast are enriched in risk factors for Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 ɑS/Aβ modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genesGBA1andLRRK2, rare variants AD genes (CD33,CR1andPSEN2) and Aβ toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated ɑS pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality ofPSEN2in both human cortical and dopaminergic neurons, andPSEN2mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology.PSEN2contributes to a common-risk signal in PD GWAS and regulates ɑS expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.