bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication
Authors: Hooijberg Femke , Layegh Zohra , Leeuw Maureen , Boekel Laura , van den Berg Stefan P.H. , Ruwaard Jill , Bastida Carla , Huitema Alwin D.R. , Pel Sara , Elkayam Ori , de Vries Annick , Nurmohamed Mike , Rispens Theo , Dorlo Thomas P.C. , Wolbink Gertjan 
Published: January 2024

Background:
Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure–response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients.

Methods:
A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4–6 mg/L after 20 weeks of dose tapering.

Results:
Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4–6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups.

Conclusions:
This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.
Development, Validation, and Clinical Application of an Ultra–High-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for the Determination of 10 Antituberculosis Drugs in Human Serum
Authors: Fan Xudong , Guo Suhang , Zhang Ruoying , Cai Qingshan , Lang Yazhen , Huang Jinpeng , Chen Yuanyuan , Zhang Ying , Xu Yingying , Chen Meng , Yang Gaoyi , Cai Xinjun 
Published: January 2024

Introduction:
Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra–high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum.

Methods:
Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode.

Results:
Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R2) >0.9954 for each curve. The accuracy (85.0%–114.7%) and precision (intraday: 0.27%–9.32%; interday: 0.20%–7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%–115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis.

Conclusions:
A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.
Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy
Authors: Ma Bingsuo , Yang Kun , Li Xinping , Su Ning , Yu Ting , Zou Yan , Xu Xingmeng , Wang Fei , Cheng Jingdong , Yan Zijun , Chen Tong , Zhang Liangming 
Published: January 2024

Background:
The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing.

Methods:
The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR.

Results:
The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes (P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV.

Conclusions:
Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.
Clinical efficacy of intratympanic steroid injection for treating idiopathic sudden sensorineural hearing loss
Authors: Kuo Liang-Kuan , Wu Jiunn-Liang , Li Yi-Lu , Hsu Heng-Jui 
Published: January 2024

Background:
Idiopathic sudden sensorineural hearing loss (ISSNHL) is an emergency that causes permanent hearing loss if timely treatment is not provided. However, the evidence supporting the effect of intratympanic steroid injection (ITSI) starting time on hearing outcome is limited.

Methods:
We retrospectively enrolled 582 patients with ISSNHL who were treated with ITSIs and reviewed their clinical and audiological variables. The relationship between ITSI starting time and hearing recovery was analyzed.

Results:
The mean starting time of ITSI was 13.17 ± 16.53 days. The overall hearing recovery rate was 55.15% (recovery = mean hearing level gain of ≥10 dB). The recovery rates were 79.2%, 67.4%, 50%, 36.6%, and 17.8% for the ITSI starting times of 1 to 3, 4 to 7, 8 to 14, 15 to 28, and ≥29 days, respectively. A multivariate analysis revealed that ITST starting time (odds ratio [OR] = 0.94, 95% CI, 0.92-0.96, p < 0.001) and salvage therapy (OR = 0.55, 95% CI, 0.35-0.86, p = 0.009) were independent poor prognostic factors for patients with ISSNHL.

Conclusion:
Earlier ITSI treatment is associated with a higher hearing recovery rate. Comorbidities and post-ITSI complications were nonsignificant independent risk factors.
What Are the Predictors of Post-traumatic Stress Disorder Among Road Traffic Accident Survivors
Authors: Sabahi Zahra , Hasani Parham , Salehi-Pourmehr Hanieh , Beheshti Rasa , Sadeghi-Bazargani Homayoun 
Published: January 2024

Abstract
Traffic accidents put tremendous burdens on the psychosocial aspects of communities. Post-traumatic stress disorder (PTSD), after an accident, is one of the most prevalent and incapacitating psychiatric conditions worldwide. In this systematic review, we aimed to investigate the predictors of PTSD in traffic accident victims. Primary search was conducted in November 2021 and updated in 2023. Studies were excluded if they used any analysis except regression for predictors. Cumulatively, primary and update searches retrieved 10,392 articles from databases, and of these, 87 studies were systematically reviewed. The predictors were categorized into sociodemographics, pretrauma, peritrauma, and post-trauma factors. The PTSD assessment time varied between 2 weeks and 3 years. Being a woman, having depression and having a history of road traffic accidents pretraumatically, peritraumatic dissociative experiences, acute stress disorder diagnosis, rumination, higher injury severity, and involvement in litigation or compensation after the trauma were significant predictors of PTSD.
Thyroglossal Duct Cyst Infection Caused by Neisseria gonorrhoeae: An Unusual Complication of Pharyngeal Gonorrhea
Authors: Roberts Abigail , Johnson Stephanie , Lee B. Craig 
Published: January 2024

Abstract

Neisseria gonorrhoeae is a human obligate pathogen whose clinical expression of disease ranges from localized genital infection to involvement of extragenital sites such as the conjunctiva and throat. We describe the second case of a thyroglossal duct abscess due to N. gonorrhoeae, an uncommon complication of pharyngeal gonococcal infection. The fortuitous occurrence in the same individual of these 2 conditions that both exhibit an occult clinical presentation likely accounts for rarity of this infection. We discuss the pertinent gonococcal and host factors that underlie the clinical manifestations of this infection. A particular focus is the fundamental role that the binding of the gonococcal opacity-associated protein to the ubiquitous human carcinoembryonic cell adhesion molecule plays in the pathogenesis of pharyngeal gonorrhea.
Reference-free Structural Variant Detection in Microbiomes via Long-read Coassembly Graphs
Authors: Curry Kristen D. , Yu Feiqiao Brian , Vance Summer E. , Segarra Santiago , Bhaya Devaki , Chikhi Rayan , Rocha Eduardo P.C. , Treangen Todd J. 
Published: January 2024

AbstractBacterial genome dynamics are vital for understanding the mechanisms underlying microbial adaptation, growth, and their broader impact on host phenotype. Structural variants (SVs), genomic alterations of 10 base pairs or more, play a pivotal role in driving evolutionary processes and maintaining genomic heterogeneity within bacterial populations. While SV detection in isolate genomes is relatively straightforward, metagenomes present broader challenges due to absence of clear reference genomes and presence of mixed strains. In response, our proposed method rhea, forgoes reference genomes and metagenome-assembled genomes (MAGs) by encompassing a single metagenome coassembly graph constructed from all samples in a series. The log fold change in graph coverage between subsequent samples is then calculated to call SVs that are thriving or declining throughout the series. We show rhea to outperform existing methods for SV and horizontal gene transfer (HGT) detection in two simulated mock metagenomes, which is particularly noticeable as the simulated reads diverge from reference genomes and an increase in strain diversity is incorporated. We additionally demonstrate use cases for rhea on series metagenomic data of environmental and fermented food microbiomes to detect specific sequence alterations between subsequent time and temperature samples, suggesting host advantage. Our innovative approach leverages raw read patterns rather than references or MAGs to include all sequencing reads in analysis, and thus provide versatility in studying SVs across diverse and poorly characterized microbial communities for more comprehensive insights into microbial genome dynamics.
NEAR: Neural Embeddings for Amino acid Relationships
Authors: Olson Daniel , Colligan Thomas , Demekas Daphne , Roddy Jack W. , Youens-Clark Ken , Wheeler Travis J. 
Published: January 2024

AbstractProtein language models (PLMs) have recently demonstrated potential to supplant classical protein database search methods based on sequence alignment, but are slower than common alignment-based tools and appear to be prone to a high rate of false labeling. Here, we present NEAR, a method based on neural representation learning that is designed to improve both speed and accuracy of search for likely homologs in a large protein sequence database. NEAR’s ResNet embedding model is trained using contrastive learning guided by trusted sequence alignments. It computes per-residue embeddings for target and query protein sequences, and identifies alignment candidates with a pipeline consisting of residue-level k-NN search and a simple neighbor aggregation scheme. Tests on a benchmark consisting of trusted remote homologs and randomly shuffled decoy sequences reveal that NEAR substantially improves accuracy relative to state-of-the-art PLMs, with lower memory requirements and faster embedding and search speed. While these results suggest that the NEAR model may be useful for standalone homology detection with increased sensitivity over standard alignment-based methods, in this manuscript we focus on a more straightforward analysis of the model’s value as a high-speed pre-filter for sensitive annotation. In that context, NEAR is at least 5x faster than the pre-filter currently used in the widely-used profile hidden Markov model (pHMM) search tool HMMER3, and also outperforms the pre-filter used in our fast pHMM tool, nail.
Acute toxicity effects of pesticides on beneficial organisms – Dispelling myths for a more sustainable use of chemicals in agricultural environments
Authors: Mata Luis , Knapp Rosemary A. , McDougall Robert , Overton Kathy , Hoffmann Ary A. , Umina Paul A. 
Published: January 2024

AbstractAgricultural practitioners, researchers and policymakers are increasingly advocating for integrated pest management (IPM) to reduce pesticide use while preserving crop productivity and profitability. Selective pesticides, putatively designed to act on pests while minimising impacts on off-target organisms, have emerged as one such option – yet evidence of whether these compounds control pests without adversely affecting natural enemies and other beneficial species (henceforth beneficials) remains scarce. At present, the selection of pesticides compatible with IPM often considers a single (or a limited number of) widely distributed beneficial species, without considering undesired effects on co-occurring beneficials. In this study, we conducted standardised laboratory bioassays to assess the acute toxicity effects of 20 chemicals on 15 beneficial species at multiple exposure timepoints, with the specific aims to: (1) identify common and diverging patterns in acute toxicity responses of tested beneficials; (2) determine if the effect of pesticides on beetles, wasps and mites is consistent across species within these groups; and (3) assess the impact of mortality assessment timepoints on International Organisation for Biological Control (IOBC) toxicity classifications. Our work demonstrates that in most cases, chemical toxicities cannot be generalised across a range of beneficial insects and mites providing biological control, a finding that was found even when comparing impacts among closely related species of beetles, wasps and mites. Additionally, we show that toxicity impacts increase with exposure length, pointing to limitations of IOBC protocols. This work challenges the notion that chemical toxicities can be adequately tested on a limited number of ‘representative’ species; instead it highlights the need for careful consideration and testing on a range of regionally and seasonally relevant beneficial species.
MEDIATOR SUBUNIT 25 modulates ERFVII-controlled hypoxia responses in Arabidopsis
Authors: Schippers Jos H.M. , von Bongartz Kira , Laritzki Lisa , Frohn Stephanie , Frings Stephanie , Renziehausen Tilo , Augstein Frauke , Winkels Katharina , Sprangers Katrien , Sasidharan Rashmi , Vertommen Didier , Breusegem Frank Van , Hartman Sjon , Beemster Gerrit T. S. , Mhamdi Amna , van Dongen Joost T. , Schmidt-Schippers Romy R. 
Published: January 2024

AbstractFlooding impairs plant growth through oxygen deprivation, which activates plant survival and acclimation responses. Low-oxygen responses are generally associated with activation of group VII ETHYLENE-RESPONSE FACTOR (ERFVII) transcription factors. However, mechanism and molecular components by which ERFVII factors initiate gene expression are not fully elucidated. Here, we show that the Mediator complex subunitAtMED25 is recruited by RELATED TO APETALA 2.2 (RAP2.2) and RAP2.12 to coordinate gene expression during hypoxia inArabidopsis thaliana.. Themed25mutants display reduced low-oxygen stress tolerance.AtMED25 associates with several ERFVII-controlled hypoxia core genes and its loss impairs transcription under hypoxia due to decreasing RNA polymerase II recruitment. Protein complex pulldown assays demonstrate that the Mediator complex built aroundAtMED25 is adjusted under low-oxygen conditions. Moreover, during hypoxia, no functional cooperation betweenAtMED25 and the two subunitsAtMED8 andAtMED16 occurs, contrasting previous observations made for other conditions. In addition,AtMED25 function under hypoxia is independent from ethylene signalling. Finally, a functional conservation at the molecular level was found for the MED25-ERFVII module betweenArabidopsis thalianaand the monocotOryza sativa, pointing to a potentially universal role of MED25 in enabling ERFVII-dependent transcript responses to hypoxia in plants.
Combining machine learning algorithms and single-cell data to study the pathogenesis of Alzheimer’s disease
Authors: Cui Wei , Zhang Liang , Zheng Fang-Rui , Li Xi Huang , Xie Gui-Lin 
Published: January 2024

AbstractExtracting valuable insights from high-throughput biological data of Alzheimer’s disease to enhance understanding of its pathogenesis is becoming increasingly important. We engaged in a comprehensive collection and assessment of Alzheimer’s microarray datasets GSE5281 and GSE122063 and single-cell data from GSE157827 from the NCBI GEO database. The datasets were selected based on stringent screening criteria: a P-value of less than 0.05 and an absolute log fold change (|logFC|) greater than 1. Our methodology involved utilizing machine learning algorithms, efficiently identified characteristic genes. This was followed by an in-depth immune cell infiltration analysis of these genes, gene set enrichment analysis (GSEA) to elucidate differential pathways, and exploration of regulatory networks. Subsequently, we applied the Connectivity Map (cMap) approach for drug prediction and undertook single-cell expression analysis. The outcomes revealed that the top four characteristic genes, selected based on their accuracy, exhibited a profound correlation with the Alzheimer’s disease (AD) group in terms of immune infiltration levels and pathways. These genes also showed significant associations with multiple AD-related genes, enhancing the potential pathogenic mechanisms through regulatory network analysis and single-cell expression profiling. Identified three subpopulations of astrocytes in late-stage of AD Prefrontal cortex dataset. Discovering dysregulation of the expression of the AD disease-related pathway maf/nrf2 in these cell subpopulations Ultimately, we identified a potential therapeutic drug score, offering promising avenues for future Alzheimer’s disease treatment strategies.
Efficient parameter estimation for ODE models of cellular processes using semi-quantitative data
Authors: Dorešić Domagoj , Grein Stephan , Hasenauer Jan 
Published: January 2024

AbstractQuantitative dynamical models facilitate the understanding of biological processes and the prediction of their dynamics. The parameters of these models are commonly estimated from experimental data. Yet, experimental data generated from different techniques do not provide direct information about the state of the system but a non-linear (monotonic) transformation of it. For such semi-quantitative data, when this transformation is unknown, it is not apparent how the model simulations and the experimental data can be compared. Here, we propose a versatile spline-based approach for the integration of a broad spectrum of semi-quantitative data into parameter estimation. We derive analytical formulas for the gradients of the hierarchical objective function and show that this substantially increases the estimation efficiency. Subsequently, we demonstrate that the method allows for the reliable discovery of unknown measurement transformations. Furthermore, we show that this approach can significantly improve the parameter inference based on semi-quantitative data in comparison to available methods. Modelers can easily apply our method by using our implementation in the open-source Python Parameter EStimation TOolbox (pyPESTO).
Induction of common beanOVATE Family Protein 7(PvOFP7) promotes resistance to common bacterial blight
Authors: Gaudin Charlotte , Preveaux Anne , Aubineau Nathan , Le Goff Damien , Jacques Marie-Agnès , Chen Nicolas W.G. 
Published: January 2024

ABSTRACTCommon bacterial blight of bean (CBB) is a devastating seed-transmitted disease caused byXanthomonas phaseolipv.phaseoliandXanthomonas citripv.fuscanson common bean (Phaseolus vulgarisL.). The genes responsible for CBB resistance are largely unknown. moreover, the lack of reproducible and universal transformation protocol limits the study and improvement of genetic traits in common bean. We producedX. phaseolipv.phaseolistrains expressing artificially-designed Transcription-Activator Like Effectors (dTALEs) to target 14 candidate genes and performedin plantaassays in a susceptible common bean genotype to analyse if the transcriptional induction of these genes could confer resistance to CBB. Induction ofPvOFP7,PvAP2-ERF71andPvExpansinA17resulted in CBB symptom reduction. In particular,PvOFP7induction led to strong symptom reduction, linked to reduced bacterial growthin plantaat early colonisation stages. RNA-Seq analysis revealed up-regulation of cell wall formation and primary metabolism, and major down-regulation of Heat Shock Proteins. Our results demonstrate that PvOFP7 is contributes to CBB resistance, and underline the usefulness of dTALEs for highlighting genes of quantitative activity.