bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy
Authors: Gay Cynthia L , Hanley Patrick J , Falcinelli Shane D , Kuruc JoAnn D , Pedersen Susan M , Kirchherr Jennifer , Raines Samuel L M , Motta Cecilia M , Lazarski Chris , Chansky Pamela , Tanna Jay , Shibli Abeer , Datar Anushree , McCann Chase D , Sili Uluhan , Ke Ruian , Eron Joseph J , Archin Nancie , Goonetilleke Nilu , Bollard Catherine M , Margolis David M 
Published: February 2024

Abstract

Background
The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy.

Methods
Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400 mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy.

Results
VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention.

Conclusions
These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit.
Clinical Trials Registration. NCT03212989.
An integrated method for targeted Oxford Nanopore sequencing and automated bioinformatics for the simultaneous detection of bacteria, fungi, and ARG
Authors: Kuruwa Sanjana , Zade Amrutraj , Shah Sanchi , Moidu Rameez , Lad Shailesh , Chande Chhaya , Joshi Ameeta , Hirani Nilma , Nikam Chaitali , Bhattacharya Sanjay , Poojary Aruna , Kapoor Mahua , Kondabagil Kiran , Chatterjee Anirvan 
Published: February 2024

Abstract

Aims
The use of metagenomics for pathogen identification in clinical practice has been limited. Here we describe a workflow to encourage the clinical utility and potential of NGS for the screening of bacteria, fungi, and antimicrobial resistance genes (ARGs).

Methods and results
The method includes target enrichment, long-read sequencing, and automated bioinformatics. Evaluation of several tools and databases was undertaken across standard organisms (n = 12), clinical isolates (n = 114), and blood samples from patients with suspected bloodstream infections (n = 33). The strategy used could offset the presence of host background DNA, error rates of long-read sequencing, and provide accurate and reproducible detection of pathogens. Eleven targets could be successfully tested in a single assay. Organisms could be confidently identified considering ≥60% of best hits of a BLAST-based threshold of e-value 0.001 and a percent identity of &gt;80%. For ARGs, reads with percent identity of &gt;90% and &gt;60% overlap of the complete gene could be confidently annotated. A kappa of 0.83 was observed compared to standard diagnostic methods. Thus, a workflow for the direct-from-sample, on-site sequencing combined with automated genomics was demonstrated to be reproducible.

Conclusion
NGS-based technologies overcome several limitations of current day diagnostics. Highly sensitive and comprehensive methods of pathogen screening are the need of the hour. We developed a framework for reliable, on-site, screening of pathogens.
Co-occurrence of blaNDM-1 and blaOXA-23 in carbapenemase-producing Acinetobacter baumannii belonging to high-risk lineages isolated from burn patients in Tunisia
Authors: Raddaoui Anis , Mabrouk Aymen , Chebbi Yosra , Frigui Siwar , Salah Abbassi Mohamed , Achour Wafa , Thabet Lamia 
Published: February 2024

Abstract

Aims
Carbapenem-resistant Acinetobacter baumannii (CR-Ab) is an important cause of infections in burn patients. This study aimed to characterize the antimicrobial susceptibility pattern of CR-Ab isolated from burns in Burn Intensive Care Unit (BICU) of the Trauma and Burn Centre of Ben Arous, to determine the prevalence of β-lactamase-encoding genes and to search eventual genetic relatedness of CR-Ab strains.

Methods and Results
From 15 December 2016 to 2 April 2017, all nonduplicated CR-Ab isolated in burn patients in the BICU were screened by simplex Polymerase Chain Reaction (PCR) for the class A, B, C, and D β-lactamase genes. Sequencing was performed for NDM gene only. Genetic relatedness was determined by using pulsed field gel electrophoresis (PFGE) and by multilocus sequence typing. During the study period, 34 strains of CR-Ab were isolated in burns, mainly in blood culture (n = 14) and central vascular catheter (n = 10). CR-Ab strains were susceptible to colistin but resistant to amikacin (91%), ciprofloxacin (100%), rifampicin (97%), and trimethoprim-sulfamethoxazole (100%). All strains harbored blaOXA-51-like and blaOXA-23 genes, only or associated to blaGES (n = 26; 76%), blaADC (n = 20; 59%), blaPER-1 (n = 6; 18%) or/and blaNDM-1 (n = 3; 9%). PFGE identified 16 different clusters and revealed that most strains belonged to one major cluster A (n = 15; 44.1%). Among NDM-1 isolates, two were clonally related in PFGE and belonged to two single locus variant sequence type ST-6 and ST-85.

Conclusions
This is the first description of clonally related NDM-1 and OXA-23-producing A. baumannii strains in the largest Tunisian BICU associated with two single locus variant sequence types ST6 and ST85.
Estimation of racial and language disparities in pediatric emergency department triage using statistical modeling and natural language processing
Authors: Lee Seung-Yup (Joshua) , Alzeen Mohammed , Ahmed Abdulaziz 
Published: February 2024

Abstract

Objectives
The study aims to assess racial and language disparities in pediatric emergency department (ED) triage using analytical techniques and provide insights into the extent and nature of the disparities in the ED setting.

Materials and Methods
The study analyzed a cross-sectional dataset encompassing ED visits from January 2019 to April 2021. The study utilized analytical techniques, including K-mean clustering (KNN), multivariate adaptive regression splines (MARS), and natural language processing (NLP) embedding. NLP embedding and KNN were employed to handle the chief complaints and categorize them into clusters, while the MARS was used to identify significant interactions among the clinical features. The study also explored important variables, including age-adjusted vital signs. Multiple logistic regression models with varying specifications were developed to assess the robustness of analysis results.

Results
The study consistently found that non-White children, especially African American (AA) and Hispanic, were often under-triaged, with AA children having &gt;2 times higher odds of receiving lower acuity scores compared to White children. While the results are generally consistent, incorporating relevant variables modified the results for specific patient groups (eg, Asians).

Discussion
By employing a comprehensive analysis methodology, the study checked the robustness of the analysis results on racial and language disparities in pediatric ED triage. The study also recognized the significance of analytical techniques in assessing pediatric health conditions and analyzing disparities.

Conclusion
The study’s findings highlight the significant need for equal and fair assessment and treatment in the pediatric ED, regardless of their patients’ race and language.
Estimating a directed tree for extremes
Authors: Tran Ngoc Mai , Buck Johannes , Klüppelberg Claudia 
Published: February 2024

Abstract
We propose a new method to estimate a root-directed spanning tree from extreme data. Prominent example is a river network, to be discovered from extreme flow measured at a set of stations. Our new algorithm utilizes qualitative aspects of a max-linear Bayesian network, which has been designed for modelling causality in extremes. The algorithm estimates bivariate scores and returns a root-directed spanning tree. It performs extremely well on benchmark data and on new data. We prove that the new estimator is consistent under a max-linear Bayesian network model with noise. We also assess its strengths and limitations in a small simulation study.
Biogeographic Perspectives on Human Genetic Diversification
Authors: Hünemeier Tábita 
Published: February 2024

Abstract
Modern humans originated in Africa 300,000 yr ago, and before leaving their continent of origin, they underwent a process of intense diversification involving complex demographic dynamics. Upon exiting Africa, different populations emerged on the four other inhabited continents, shaped by the interplay of various evolutionary processes, such as migrations, founder effects, and natural selection. Within each region, continental populations, in turn, diversified and evolved almost independently for millennia. As a backdrop to this diversification, introgressions from archaic species contributed to establishing different patterns of genetic diversity in different geographic regions, reshaping our understanding of our species’ variability. With the increasing availability of genomic data, it has become possible to delineate the subcontinental human population structure precisely. However, the bias toward the genomic research focused on populations from the global North has limited our understanding of the real diversity of our species and the processes and events that guided different human groups throughout their evolutionary history. This perspective is part of a series of articles celebrating 40 yr since our journal, Molecular Biology and Evolution, was founded (Russo et al. 2024). The perspective is accompanied by virtual issues, a selection of papers on human diversification published by Genome Biology and Evolution and Molecular Biology and Evolution.
CRISPR-COPIES: an in silico platform for discovery of neutral integration sites for CRISPR/Cas-facilitated gene integration
Authors: Boob Aashutosh Girish , Zhu Zhixin , Intasian Pattarawan , Jain Manan , Petrov Vassily Andrew , Lane Stephan Thomas , Tan Shih-I , Xun Guanhua , Zhao Huimin 
Published: February 2024

Abstract
The CRISPR/Cas system has emerged as a powerful tool for genome editing in metabolic engineering and human gene therapy. However, locating the optimal site on the chromosome to integrate heterologous genes using the CRISPR/Cas system remains an open question. Selecting a suitable site for gene integration involves considering multiple complex criteria, including factors related to CRISPR/Cas-mediated integration, genetic stability, and gene expression. Consequently, identifying such sites on specific or different chromosomal locations typically requires extensive characterization efforts. To address these challenges, we have developed CRISPR-COPIES, a COmputational Pipeline for the Identification of CRISPR/Cas-facilitated intEgration Sites. This tool leverages ScaNN, a state-of-the-art model on the embedding-based nearest neighbor search for fast and accurate off-target search, and can identify genome-wide intergenic sites for most bacterial and fungal genomes within minutes. As a proof of concept, we utilized CRISPR-COPIES to characterize neutral integration sites in three diverse species: Saccharomyces cerevisiae, Cupriavidus necator, and HEK293T cells. In addition, we developed a user-friendly web interface for CRISPR-COPIES (https://biofoundry.web.illinois.edu/copies/). We anticipate that CRISPR-COPIES will serve as a valuable tool for targeted DNA integration and aid in the characterization of synthetic biology toolkits, enable rapid strain construction to produce valuable biochemicals, and support human gene and cell therapy applications.
Human CST complex restricts excessive PrimPol repriming upon UV induced replication stress by suppressing p21
Authors: Sang Pau Biak , Jaiswal Rishi K , Lyu Xinxing , Chai Weihang 
Published: February 2024

Abstract
DNA replication stress, caused by various endogenous and exogenous agents, halt or stall DNA replication progression. Cells have developed diverse mechanisms to tolerate and overcome replication stress, enabling them to continue replication. One effective strategy to overcome stalled replication involves skipping the DNA lesion using a specialized polymerase known as PrimPol, which reinitiates DNA synthesis downstream of the damage. However, the mechanism regulating PrimPol repriming is largely unclear. In this study, we observe that knockdown of STN1 or CTC1, components of the CTC1/STN1/TEN1 complex, leads to enhanced replication progression following UV exposure. We find that such increased replication is dependent on PrimPol, and PrimPol recruitment to stalled forks increases upon CST depletion. Moreover, we find that p21 is upregulated in STN1-depleted cells in a p53-independent manner, and p21 depletion restores normal replication rates caused by STN1 deficiency. We identify that p21 interacts with PrimPol, and STN1 depletion stimulates p21-PrimPol interaction and facilitates PrimPol recruitment to stalled forks. Our findings reveal a previously undescribed interplay between CST, PrimPol and p21 in promoting repriming in response to stalled replication, and shed light on the regulation of PrimPol repriming at stalled forks.
Transient states during the annealing of mismatched and bulged oligonucleotides
Authors: Todisco Marco , Ding Dian , Szostak Jack W 
Published: February 2024

Abstract
Oligonucleotide hybridization is crucial in various biological, prebiotic and nanotechnological processes, including gene regulation, non-enzymatic primer extension and DNA nanodevice assembly. Although extensive research has focused on the thermodynamics and kinetics of nucleic acid hybridization, the behavior of complex mixtures and the outcome of competition for target binding remain less well understood. In this study, we investigate the impact of mismatches and bulges in a 12 bp DNA or RNA duplex on its association (kon) and dissociation (koff) kinetics. We find that such defects have relatively small effects on the association kinetics, while the dissociation kinetics vary in a position-dependent manner by up to 6 orders of magnitude. Building upon this observation, we explored a competition scenario involving multiple oligonucleotides, and observed a transient low specificity of probe hybridization to fully versus partially complementary targets in solution. We characterize these long-lived metastable states and their evolution toward equilibrium, and show that sufficiently long-lived mis-paired duplexes can serve as substrates for prebiotically relevant chemical copying reactions. Our results suggest that transient low accuracy states may spontaneously emerge within all complex nucleic acid systems comprising a large enough number of competing strands, with potential repercussions for gene regulation in the realm of modern biology and the prebiotic preservation of genetic information.
A combinatorial approach for achieving CNS-selective RNAi
Authors: Ferguson Chantal M , Godinho Bruno M D C , Echeverria Dimas , Hassler Matthew , Vangjeli Lorenc , Sousa Jacquelyn , McHugh Nicholas , Alterman Julia , Hariharan Vignesh , Krishnamurthy Pranathi Meda , Watts Jonathan , Rogaev Eveny , Khvorova Anastasia 
Published: February 2024

Abstract
RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations.
The Impact of Three Alternate Nicotine-Delivery Products on Combusted Cigarette Use: A Randomized Controlled Trial
Authors: Piper Megan E , Schlam Tanya R , Donny Eric C , Kobinsky Kate , Matthews Julia , Piasecki Thomas M , Jorenby Douglas E 
Published: February 2024

Abstract

Introduction
Smoking cessation is a critical public health goal. This study examined the ability of e-cigarettes and very low nicotine cigarettes (VLNCs) to serve as cigarette substitutes and whether a substitution was supported by steady-state nicotine from a nicotine patch.

Aims and Methods
This mixed design experiment with study product (between-subjects) and patch (within-subjects) factors recruited adults smoking cigarettes daily and not motivated to quit (N = 160). Participants were randomized to 4 weeks of: (1) VLNCs; (2) e-cigarettes; or (3) no product. During two switch weeks, one with an active nicotine patch and one with a placebo patch (in a double-blind and counterbalanced fashion), participants were told to not smoke their usual cigarettes.

Results
During the switch weeks, participants in the VLNC (M = 2.88, SD = .65) and e-cigarette (M = 3.20, SD = .63) groups smoked fewer of their own cigarettes per day than did no product group participants who continued to smoke their own cigarettes (M = 5.48, SD = .63); the VLNC and e-cigarette groups did not differ. There was no main effect of patch on mean usual brand cigarettes smoked per day (P = .09), nor was there a product × patch interaction (P = .51). There was a product × age interaction (P = .03); smokers aged 60–74 smoked more of their own cigarettes if they were randomized to no product group.

Conclusions
VLNCs and e-cigarettes appear to reduce usual brand cigarettes smoked per day to a similar degree, regardless of patch condition. Behavioral factors, in addition to nicotine dependence, play an important role in sustaining smoking behavior and need to be addressed in smoking cessation treatment.

Implications
This study found that behavioral substitutes for cigarettes, whether or not they delivered nicotine, reduced the number of usual brand cigarettes smoked. Specifically, both e-cigarettes delivering nicotine and VLNCs equally reduce usual brand cigarettes smoked among adults who smoke daily and do not want to quit.
The Story of ECMO
Authors: Bartlett Robert H. 
Published: February 2024

Extracorporeal Circulation in Neonatal Respiratory Failure: A Prospective Randomized Study. By RH Bartlett, DW Roloff, RG Cornell, AF Andrews, PW Dillon, JB Zwischenberger. Pediatrics 1985; 76:479–87.
Extracorporeal membrane oxygenation (ECMO) is the use of mechanical devices to replace cardiac and pulmonary function in critical care. In the 1960s, laboratory research showed that extracorporeal circulation could be maintained for days using a membrane oxygenator. In the 1970s, the first clinical trials showed that ECMO could sustain life in severe cardiac and pulmonary failure for days or weeks, leading to organ recovery. From 1980 to 2000, ECMO became standard practice for neonatal and pediatric respiratory and cardiac failure. The critical clinical trial was a prospective randomized trial of ECMO in newborn respiratory failure, published in 1985. This is the classic article reviewed in this publication. This was the first use of a randomized, adaptive design trial to minimize the potential ethical dilemma inherent to clinical trials in which the endpoint is death. Other randomized trials followed, and ECMO is now standard practice for severe respiratory and cardiac failure in all age groups.
Incidence and Prevalence of Pain Medication Prescriptions in Pathologies with a Potential for Chronic Pain
Authors: Goudman Lisa , Moens Maarten , Pilitsis Julie G. 
Published: February 2024

Background
Heightened risks of dependence, addiction, anxiolytic effects, or prescription overdose death due to long-term use of pain medication have increased awareness about extended pain medication use in chronic pain populations. The goal of this study was to evaluate the incidence and prevalence of pain medication prescriptions from 2012 to 2022 in common pathologies with a potential for chronic pain.

Methods
A retrospective cohort study was conducted using electronic health records from TriNetX (Cambridge, Massachusetts) Global Collaborative Network. For 10 distinct cohorts (total n = 9,357,584 patients), pain medication prescriptions were extracted for five classes, namely nonsteroidal anti-inflammatory drug (NSAIDs) and acetaminophen, opioids, gabapentinoids, neuropathic mood agents, and muscle relaxants. Annual incidence and prevalence of each class of medication were evaluated for the past 11 yr.

Results
From 2012 to 2022, there was a significant increase in prescriptions of NSAIDs, except for patients with fibromyalgia, and persistent spinal pain syndrome (PSPS) type 2. Interestingly, over time, prescriptions of opioids in patients with complex regional pain syndrome, endometriosis, osteoarthritis, and PSPS type 2 increased, as did prescriptions of muscle relaxants for all cohorts except those with fibromyalgia. Incidence of prescriptions of neuropathic mood agents is high for patients with complex regional pain syndrome (both types) and PSPS type 2. Only for benzodiazepines did there seem to be a decline over the years, with a significantly decreased time trend in patients with complex regional pain syndrome type 1, fibromyalgia, and PSPS type 2.

Conclusions
During the last 11 yr, an increase in incidence of NSAIDs and acetaminophen, opioids, neuropathic agents, and muscle relaxants was observed. Only prescriptions of benzodiazepines significantly decreased over time in specific cohorts. Overall, patients with PSPS type 2 and complex regional pain syndrome (both types) consume a broad variety of pain medication classes.

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