bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bias due to coarsening of time intervals in the inference for the effectiveness of colorectal cancer screening
Authors: Karmakar Bikram , Zauber Ann G , Hahn Anne I , Lau Yan Kwan , Doubeni Chyke A , Joffe Marshall M 
Published: July 2024

Abstract

Background
Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale.

Development
This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency.

Application
First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations.

Conclusions
The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.
Substrate Interactions and Free-Swimming Dynamics in the Crayfish Escape Response
Authors: de Pablo L X , Carleton A , Modarres-Sadeghi Y , Clotfelter E D 
Published: July 2024

Synopsis
The caridoid or “tail flip” escape behavior of decapod crustaceans is a model system in neurobiology, but many aspects of its biomechanics are not well understood. To understand how the freshwater virile crayfish Faxonius virilis interacts with the substrate during the tail flip, we studied tail-flip hydrodynamics and force generation for free-moving animals standing on substrate, as well as tethered animals held at different distances from the substrate. We found no significant differences in force generation when distance from substrate was varied. Particle image velocimetry revealed that vortex formation was similar at all distances, but there were notable differences in interactions between shed vortices and substrate at different distances. Negative vorticity (clockwise flow of water) was observed in tethered animals interacting with the substrate but was largely absent in free-swimming animals. We found no evidence of ground effects enhancing tail flip performance in either tethered or free-swimming individuals, as peak force generation occurred before vortex shedding. This study contributes to our understanding of the crayfish escape response and highlights the need for more work that incorporates free-swimming animals and complex environments in the study of crustacean biomechanics.
A microbiological and genomic perspective of globally collected Escherichia coli from adults hospitalized with invasive E. coli disease
Authors: Arconada Nuin Enya , Vilken Tuba , Xavier Basil Britto , Doua Joachim , Morrow Brian , Geurtsen Jeroen , Go Oscar , Spiessens Bart , Sarnecki Michal , Poolman Jan , Bonten Marc , Ekkelenkamp Miquel , Lammens Christine , Goossens Herman , Glupczynski Youri , Van Puyvelde Sandra ,   COMBACTE-NET Consortium/EXPECT Study Group, Leten Gert , Van Mieghem Sofie , Violette Madison , Munshi Sonal , Aitabi Moussa , Azzini Anna Maria , Righi Elda , Salerno Nicola Duccio , Cascio Giuliana Lo , Cremonini Eleonora , Pascual Álvaro , Espíndola Reinaldo , Palomo Virginia , Barraud Olivier , Walker Sarah V , Akai Naomi , Kimura Risa , Lakatos Louis , De Blacam Killian , Thaden Joshua , Ruffin Felicia , Dagher Michael 
Published: July 2024

Abstract

Objectives
Escherichia coli can cause infections in the urinary tract and in normally sterile body sites leading to invasive E. coli disease (IED), including bacteraemia and sepsis, with older populations at increased risk. We aimed to estimate the theoretical coverage rate by the ExPEC4V and 9V vaccine candidates. In addition, we aimed at better understanding the diversity of E. coli isolates, including their genetic and phenotypic antimicrobial resistance (AMR), sequence types (STs), O-serotypes and the bacterial population structure.

Methods
Blood and urine culture E. coli isolates (n = 304) were collected from hospitalized patients ≥60 years (n = 238) with IED during a multicentric, observational study across three continents. All isolates were tested for antimicrobial susceptibility, O-serotyped, whole-genome sequenced and bioinformatically analysed.

Results
A large diversity of STs and of O-serotypes were identified across all centres, with O25b-ST131, O6-ST73 and O1-ST95 being the most prevalent types. A total of 45.4% and 64.7% of all isolates were found to have an O-serotype covered by the ExPEC4V and ExPEC9V vaccine candidates, respectively. The overall frequency of MDR was 37.4% and ST131 was predominant among MDR isolates. Low in-patient genetic variability was observed in cases where multiple isolates were collected from the same patient.

Conclusions
Our results highlight the predominance of MDR O25b-ST131 E. coli isolates across diverse geographic areas. These findings provide further baseline data on the theoretical coverage of novel vaccines targeting E. coli associated with IED in older adults and their associated AMR levels.
Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division
Authors: Glen Karl A , Lamont Iain L 
Published: July 2024

Abstract

Background
β-lactam antibiotics, which inhibit penicillin-binding protein 3 (PBP3) that is required for cell division, play a key role in treating P. aeruginosa infections. Some sequence variations in PBP3 have been associated with β-lactam resistance but the effects of variations on antibiotic susceptibility and on cell division have not been quantified. Antibiotic efflux can also reduce susceptibility.

Objectives
To quantify the effects of PBP3 variations on β-lactam susceptibility and cell morphology in P. aeruginosa.

Methods
Nineteen PBP3 variants were expressed from a plasmid in the reference strain P. aeruginosa PAO1 and genome engineering was used to construct five mutants expressing PBP3 variants from the chromosome. The effects of the variations on β-lactam minimum inhibitory concentration (MIC) and cell morphology were measured.

Results
Some PBP3 variations reduced susceptibility to a variety of β-lactam antibiotics including meropenem, ceftazidime, cefepime and ticarcillin with different variations affecting different antibiotics. None of the tested variations reduced susceptibility to imipenem or piperacillin. Antibiotic susceptibility was further reduced when PBP3 variants were expressed in mutant bacteria overexpressing the MexAB-OprM efflux pump, with some variations conferring clinical levels of resistance. Some PBP3 variations, and sub-MIC levels of β-lactams, reduced bacterial growth rates and inhibited cell division, causing elongated cells.

Conclusions
PBP3 variations in P. aeruginosa can increase the MIC of multiple β-lactam antibiotics, although not imipenem or piperacillin. PBP3 variations, or the presence of sub-lethal levels of β-lactams, result in elongated cells indicating that variations reduce the activity of PBP3 and may reduce bacterial fitness.
The use of fosfomycin in infections caused by multidrug-resistant pathogens, especially pneumonia in children: a five-year retrospective single-centre experience
Authors: Dizi Işık Aylin , Akkoç Gülşen , Ergenç Zeynep , Yılmaz Seyhan , Aslan Tuncay Sevgi , Parlak Burcu , Canizci Erdemli Pınar , Büyüktaş Aytaç Didem , Abacı Çapar M Çağla , Öcal Demir Sevliya , Kepenekli Eda 
Published: July 2024

Abstract

Background
Fosfomycin is gaining increasing attention for its activity against MDR or XDR pathogens. Currently, IV fosfomycin is a potential option for treating various infections, including urinary tract infections, pneumonia and skin infections when first-line treatments fail.

Objectives
To evaluate the demographic, clinical, microbiological and treatment modality of children received IV fosfomycin to treat infections caused by MDR pathogens since there are few data on the use of fosfomycin in children.

Methods
This study was conducted retrospectively with patients under 18 years of age who were treated with IV fosfomycin for at least 72 h due to infections caused by MDR pathogens between January 2019 and October 2023 at Marmara University Pendik Training and Research Hospital, İstanbul, Türkiye. Data on demographic and clinical features, microbiological findings, treatment modalities and side effects were evaluated.

Results
Twenty-five children, for a total of 32 cases of infection episodes, with a mean age of 11.4 ± 3.92 years who received IV fosfomycin were included. The most frequent comorbidity was chronic pulmonary diseases, and the most common infection needed for IV fosfomycin was MDR Pseudomonas aeruginosa pneumonia. In all cases, fosfomycin was administered in combination with other antibiotics, mainly meropenem–colistin (68.7%) or meropenem (15.6%). Twenty-two (71.9%) cases had favourable clinical responses at the end of therapy.

Conclusions
Our results suggest that IV fosfomycin may be an effective treatment option for MDR pathogens in the paediatric population. Nevertheless, careful stewardship is necessary to maintain efficacy and reduce antimicrobial resistance selection risk.
Epidemiology of carbapenem-resistant Klebsiella pneumoniae in China and the evolving trends of predominant clone ST11: a multicentre, genome-based study
Authors: Shi Qiucheng , Ruan Zhi , Zhang Ping , Hu Huangdu , Han Xinhong , Wang Zhengan , Lou Tao , Quan Jingjing , Lan Wei , Weng Rui , Zhao Dongdong , Du Xiaoxing , Yu Yunsong , Jiang Yan 
Published: July 2024

Abstract

Objectives
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major nosocomial infectious pathogen with rapidly increasing prevalence. The genomic epidemiological characteristics of CRKP nationwide, especially the evolving trends within the predominant clones, should be evaluated clearly.

Methods
We collected 3415 K. pneumoniae strains from 28 hospitals across China. Antimicrobial susceptibility testing and WGS were performed. Subsequent genomic analyses, including sequence typing, K-locus (KL) identification, antimicrobial resistance gene screening, and virulence score assessment were performed. The phylogenetic relationship of clonal group 11 was determined based on core-genome analysis, and the presence of the pLVPK-like virulence plasmid in ST11 isolates was confirmed using plasmid core-gene analysis. Additionally, the trends of the ST11 lineage with different KL types on a global scale were investigated using Beast2.

Results
Of the K. pneumoniae strains, 708 were identified as CRKP isolates (20.7%), of which 97.7% were MDR. ST11 was the predominant clone, and KPC-2 was the prevalent carbapenemase in China, although the prevalence of specific clones and carbapenemases varied by geographic region. Among ST11 isolates, KL47 and KL64 were the predominant KL types, and KL64 gradually replaced KL47, with a higher percentage of KL64 isolates harbouring the pLVPK-like plasmid. Global genome data showed a significant increase in the effective population size of KL64 over the last 5 years.

Conclusions
The prevalence of CRKP was very high in certain regions in China. The increasing convergence of virulence and resistance, particularly in ST11-KL64 isolates, should be given more attention and further investigation.
Defining optimal sulbactam regimens for treatment of Acinetobacter baumannii pneumonia and impact of blaOXA-23 on efficacy
Authors: Abouelhassan Yasmeen , Nicolau David P , Abdelraouf Kamilia 
Published: July 2024

Abstract

Objectives
We evaluated the efficacies of human-simulated regimens (HSRs) of two clinically utilized sulbactam regimens: 1 g q6h 0.5 h infusion (maximum FDA-approved dosage) and 3 g q8h 4 h infusion (high-dose, prolonged-infusion regimen), against Acinetobacter baumannii in a translational murine model.

Methods
Thirty-two clinical A. baumannii isolates were investigated, of which 16 were sulbactam resistant (MIC ≥ 16 mg/L), 6 were sulbactam intermediate (MIC = 8 mg/L) and 10 were sulbactam susceptible (MIC ≤ 4 mg/L). Efficacies of the two sulbactam HSRs were assessed in the neutropenic murine pneumonia model. Changes in log10 cfu/lungs at 24 h compared with 0 h controls were measured, and efficacy was defined as achieving 1 log kill relative to baseline. WGS of the isolates and bioinformatics analysis were performed to explore potential associations between the genomic backgrounds and the in vivo responses.

Results
Eleven isolates harboured blaOXA-23, of which 10 were sulbactam resistant, 1 was sulbactam intermediate while none was sulbactam susceptible. Both sulbactam HSRs achieved &gt;1 log kill against sulbactam-susceptible isolates. Against sulbactam-intermediate and sulbactam-resistant isolates, lack of efficacy correlated with the presence of the blaOXA-23 gene; sulbactam 1 g HSR and 3 g HSR did not show efficacy against 11/11 and 9/11 blaOXA-23-positive isolates, respectively, while efficacy was observed against all 11 blaOXA-23-negative sulbactam-intermediate and sulbactam-resistant isolates (i.e. harbouring other resistance genes).

Conclusions
A sulbactam high-dose prolonged-infusion regimen provides comparable activity to the standard dose against isolates currently considered sulbactam susceptible. However, the activity against isolates with intermediate and resistant susceptibility could be predicted by the detection of blaOXA-23. Enhancing detection capabilities of common diagnostic modalities to include OXA-23 can improve patient outcome.
Clinical, pharmacological, and qualitative characterization of drug–drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa
Authors: Kiiza Daniel , Rostami-Hochaghan Danial , Alhassan Yussif , Seden Kay , Reynolds Helen , Kaboggoza Julian P , Taegtmeyer Miriam , Chen Tao , Challenger Elizabeth , Malaba Thokozile , Wang Duolao , Else Laura , Hern Faye , Sharp Jo , Neary Megan , Dilly Penchala Sujan , Waitt Catriona , Orrell Catherine , Colbers Angela , Myer Landon , Owen Andrew , Rannard Steve , Khoo Saye , Lamorde Mohammed 
Published: July 2024

Abstract

Background
We investigated the impact of Drug–Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs.

Methods
Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure.

Results
The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%–13.9%) and iron (4%–6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (−21%; P = 0.0271) and C24 (−53%; P = 0.0028).

Conclusions
The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
Extraction of sleep information from clinical notes of Alzheimer’s disease patients using natural language processing
Authors: Sivarajkumar Sonish , Tam Thomas Yu Chow , Mohammad Haneef Ahamed , Viggiano Samuel , Oniani David , Visweswaran Shyam , Wang Yanshan 
Published: July 2024

Abstract

Objectives
Alzheimer’s disease (AD) is the most common form of dementia in the United States. Sleep is one of the lifestyle-related factors that has been shown critical for optimal cognitive function in old age. However, there is a lack of research studying the association between sleep and AD incidence. A major bottleneck for conducting such research is that the traditional way to acquire sleep information is time-consuming, inefficient, non-scalable, and limited to patients’ subjective experience. We aim to automate the extraction of specific sleep-related patterns, such as snoring, napping, poor sleep quality, daytime sleepiness, night wakings, other sleep problems, and sleep duration, from clinical notes of AD patients. These sleep patterns are hypothesized to play a role in the incidence of AD, providing insight into the relationship between sleep and AD onset and progression.

Materials and Methods
A gold standard dataset is created from manual annotation of 570 randomly sampled clinical note documents from the adSLEEP, a corpus of 192 000 de-identified clinical notes of 7266 AD patients retrieved from the University of Pittsburgh Medical Center (UPMC). We developed a rule-based natural language processing (NLP) algorithm, machine learning models, and large language model (LLM)-based NLP algorithms to automate the extraction of sleep-related concepts, including snoring, napping, sleep problem, bad sleep quality, daytime sleepiness, night wakings, and sleep duration, from the gold standard dataset.

Results
The annotated dataset of 482 patients comprised a predominantly White (89.2%), older adult population with an average age of 84.7 years, where females represented 64.1%, and a vast majority were non-Hispanic or Latino (94.6%). Rule-based NLP algorithm achieved the best performance of F1 across all sleep-related concepts. In terms of positive predictive value (PPV), the rule-based NLP algorithm achieved the highest PPV scores for daytime sleepiness (1.00) and sleep duration (1.00), while the machine learning models had the highest PPV for napping (0.95) and bad sleep quality (0.86), and LLAMA2 with finetuning had the highest PPV for night wakings (0.93) and sleep problem (0.89).

Discussion
Although sleep information is infrequently documented in the clinical notes, the proposed rule-based NLP algorithm and LLM-based NLP algorithms still achieved promising results. In comparison, the machine learning-based approaches did not achieve good results, which is due to the small size of sleep information in the training data.

Conclusion
The results show that the rule-based NLP algorithm consistently achieved the best performance for all sleep concepts. This study focused on the clinical notes of patients with AD but could be extended to general sleep information extraction for other diseases.
Unveiling Impurities: A Comprehensive RP-HPLC Method for Accurate Atorvastatin Impurity Analysis in Pharmaceuticals Using an Accuracy Profile Approach
Authors: El Kacemi Mounir , El Orche Aimen , El Bourakadi Khadija , Benchekroun Yassine Hameda , Echerfaoui Fouad , Karrouchi Khalid , Bouatia Mustapha , El Karbane Miloud 
Published: July 2024

Abstract

Background
Accurate determination of active pharmaceutical ingredients and impurities is essential for ensuring the safety and effectiveness of medications. This study focuses on the validation of a high-performance liquid chromatography (HPLC) method for quantifying atorvastatin and its impurities, addressing a critical aspect of pharmaceutical analysis.

Objective
The primary objective is to conduct a comprehensive validation study for the HPLC method, covering specificity assessment, response function establishment, and a detailed analysis of precision, trueness, and tolerance intervals. The emphasis is on demonstrating the method’s precision, accuracy, and stability-indicating capabilities across various concentrations and compounds.

Methods
The HPLC method is validated through rigorous assessments, including specificity, response function establishment, and analyses of precision, trueness, and tolerance intervals. Induced degradation experiments are conducted to explore atorvastatin’s behavior under extreme conditions. Insights into the compound’s synthesis and degradation pathways are provided through a proposed mechanism for intramolecular esterification.

Results
The results affirm the precision, accuracy, and stability-indicating capabilities of the validated HPLC method. The method effectively differentiates between atorvastatin and its impurities, showcasing its suitability for pharmaceutical quality control.

Conclusions
The validated HPLC method emerges as a robust and reliable tool for atorvastatin analysis, contributing significantly to pharmaceutical research and quality control. Its application ensures the safety and efficacy of medications, reinforcing its role in pharmaceutical analysis.

Highlights
This study not only validates a crucial HPLC method for atorvastatin analysis but also provides insights into the compound’s behavior under extreme conditions and its synthesis and degradation pathways. The validated method serves as a cornerstone in pharmaceutical research and quality control, ensuring medication safety and efficacy.