bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to treat severe Acinetobacter baumannii infections
Authors: Bouza Emilio , Muñoz Patricia , Burillo Almudena 
Published: November 2023

Purpose of review
To update the management of severe Acinetobacter baumannii infections (ABI), particularly those caused by multi-resistant isolates.

Recent findings
The in vitro activity of the various antimicrobial agents potentially helpful in treating ABI is highly variable and has progressively decreased for many of them, limiting current therapeutic options. The combination of more than one drug is still advisable in most circumstances. Ideally, two active first-line drugs should be used. Alternatively, a first-line and a second-line drug and, if this is not possible, two or more second-line drugs in combination. The emergence of new agents such as Cefiderocol, the combination of Sulbactam and Durlobactam, and the new Tetracyclines offer therapeutic options that need to be supported by clinical evidence.

Summary
The apparent limitations in treating infections caused by this bacterium, the rapid development of resistance, and the serious underlying situation in most cases invite the search for alternatives to antibiotic treatment, the most promising of which seems to be bacteriophage therapy.
Current viewpoint on the epidemiology of nonfermenting Gram-negative bacterial strains
Authors: Koulenti Despoina , Vandana Kalwaje Eswhara , Rello Jordi 
Published: November 2023

Purpose of reviewThis article aims to review the epidemiology of nonfermenting Gram-negative bacilli (NFGNB) based on recent literature reports, particularly, of the less common, but with emerging clinical significance species.Recent findingsThe reported frequency of multidrug-resistantAcinetobacter baumanniiandPseudomonas aeruginosais increasing, with very significant variability, however, between different countries. Apart from the major NFGNB, that is,A. baumanniiandP. aeruginosa, already recognized as of critical importance healthcare risks, several other NFGNB genera have been increasingly associated with diverse severe infections, such asStenotrophomonas maltophilia,Burkholderiaspp.,Elizabethkingiaspp.,Chryseobacteriumspp.,Achromobacterspp.,Alcaligenesspp.,Sphingomonasspp.,Shewanellaspp. andRalstoniaspp., among others.SummaryThe exploration of the epidemiology, as well as the pathogenic potential of the of the less frequent, but emerging and increasingly reported NFGNB, is crucial, not only for immunocompromised patients, but also for critically ill patients without overt immunosuppression. As we are heading fast towards a postantibiotic era, such information would contribute to the optimal antimicrobial management, that is, providing prompt, appropriate antimicrobial coverage when needed and, at the same time, avoiding overuse and/or inappropriate use of antimicrobial therapy. Also, it would help to better understand their transmission dynamics and to develop effective prevention strategies.
Analgesia Using Transcutaneous Electric Nerve Stimulation in Office Bladder Chemodenervation, a Randomized Controlled Trial
Authors: Hernandez-Aranda Diego , Panza Joseph , Eigg Marc , Greenstein Marc , Li Dongmei , O’Brien Jeanne , Warren Gareth , Doyle Paula Jaye 
Published: November 2023

Importance
Office bladder chemodenervation, performed via cystoscopy with intradetrusor onabotulinumtoxinA (BOTOX) injections, is a common treatment for overactive bladder/urge urinary incontinence. Transcutaneous electric nerve stimulation (TENS) has shown to provide analgesia during office hysteroscopy. Adjuvant analgesia using TENS during bladder chemodenervation has not been studied.

Objective
The primary outcome is a clinically significant (10-mm) difference in pain visual analog scale (VAS) measurements during injections for chemodenervation using active TENS compared with placebo TENS. We hypothesize that active TENS use will significantly change pain VAS scores. Secondary outcomes include 5-point pain Likert scale, satisfaction 10-point scale, and adverse events.

Study Design
This was a double-blind randomized control trial of men and women with urinary urge incontinence undergoing office chemodenervation performed in an academic and private setting. Participants were randomized into 2 groups: chemodenervation with active TENS or placebo TENS. Power calculation determined 100 patients would be required detect a difference of 10 mm on pain VAS.

Results
One hundred one (85 female and 16 male) participants were recruited. No differences were noted in the demographics. Participants in the active TENS group reported a difference of greater than 10 mm in pain VAS scores (48 ± 23 vs 31 ± 23, P = 0.01). Satisfaction index scores were high but no difference was noted between groups (8.6 vs 8.7, P = 0.68).

Conclusions
Most participants were eligible to use TENS units. Transcutaneous electric nerve stimulation is a safe and noninvasive adjuvant analgesia option for patients undergoing this procedure. Lower pain levels and high satisfaction rates suggest that this is an additional analgesic option during outpatient chemodenervation.
Intensive care unit readmission in injured older adults: Modifiable risk factors and implications
Authors: Agoubi Lauren L. , Reimel Beth Ann , Maine Rebecca G. , O'Connell Kathleen M. , Maier Ronald V. , McIntyre Lisa K. 
Published: November 2023

BACKGROUND
Prior evaluations of intensive care unit (ICU) readmission among injured older adults have inconsistently identified risk factors, with findings limited by use of subanalyses and small sample sizes. This study aimed to identify risk factors for and implications of ICU readmission in injured older adults.

METHODS
This retrospective, single-center cohort study was conducted at a high-volume Level 1 trauma center and included injured older adult patients (65 years or older) requiring at least one ICU admission during hospitalization between 2013 and 2018. Patients who died <48 hours of admission were excluded. Exposures included patient demographics and clinical factors. The primary outcome was ICU readmission. Multivariable regression was used to identify risk factors for ICU readmission.

RESULTS
A total of 6,691 injured adult trauma patients were admitted from 2013 to 2018, 55.4% (n = 3,709) of whom were admitted to the ICU after excluding early deaths. Of this cohort, 9.1% (n = 339) were readmitted to the ICU during hospitalization. Readmitted ICU patients had a higher median Injury Severity Score (21 [interquartile range, 14–26] vs. 16 [interquartile range, 10–24]), with similar mechanisms of injury between the two groups. Readmitted ICU patients had a significantly higher mortality (19.5%) compared with single ICU admission patients (9.9%) (p < 0.001) and higher rates of developing any complication, including delirium (61% vs. 30%, p < 0.001). On multivariable analysis, the factors associated with the highest risk of readmission were delirium (Relative Risk, 2.6; 95% confidence interval, 2.07–3.26) and aspiration (Relative Risk, 3.04; 95% confidence interval, 1.67–5.54). More patients in the single ICU admission cohort received comfort-focused care at the time of their death as compared with the ICU readmission cohort (93% vs. 85%, p = 0.035).

CONCLUSION
Readmission to the ICU is strongly associated with higher mortality for injured older adults. Efforts targeted at preventing respiratory complications and delirium in the geriatric trauma population may decrease the rates of ICU readmission and related mortality risk.

LEVEL OF EVIDENCE
Prognostic and Epidemiological; Level III.
Use of Low-Titer O-Positive Whole Blood in Female Trauma Patients: A Literature Review, Qualitative Multidisciplinary Analysis of Risk/Benefit, and Guidelines for Its Use as a Universal Product in Hemorrhagic Shock
Authors: Clements Thomas W , Van Gent Jan-Michael , Menon Neethu , Roberts Aaron , Sherwood Molly , Osborn Lesley , Hartwell Beth , Refuerzo Jerrie , Bai Yu , Cotton Bryan A 
Published: November 2023

BACKGROUND:
Whole blood transfusion is associated with benefits including improved survival, coagulopathy, and decreased transfusion requirements. The majority of whole blood transfusion is in the form of low-titer O-positive whole blood (LTOWB). Practice at many trauma centers withholds the use of LTOWB in women of childbearing potential due to concerns of alloimmunization. The purpose of this article is to review the evidence for LTOWB transfusion in female trauma patients and generate guidelines for its application.

STUDY DESIGN:
Literature and evidence for LTOWB transfusion in hemorrhagic shock are reviewed. The rates of alloimmunization and subsequent obstetrical outcomes are compared to the reported outcomes of LTOWB vs other resuscitation media. Literature regarding patient experiences and preferences in regards to the risk of alloimmunization is compared to current trauma practices.

RESULTS:
LTOWB has shown improved outcomes in both military and civilian settings. The overall risk of alloimmunization for Rhesus factor (Rh)− female patients in hemorrhagic shock exposed to Rh+ blood is low (3% to 20%). Fetal outcomes in Rh-sensitized patients are excellent compared to historical standards, and treatment options continue to expand. The majority of female patients surveyed on the risk of alloimmunization favor receiving Rh+ blood products to improve trauma outcomes. Obstetrical transfusion practices have incorporated LTOWB with excellent results.

CONCLUSIONS:
The use of whole blood resuscitation in trauma is associated with benefits in the resuscitation of severely injured patients. The rate at which severely injured, Rh-negative patients develop anti-D antibodies is low. Treatments for alloimmunized pregnancies have advanced, with excellent results. Fears of alloimmunization in female patients are likely overstated and may not warrant the withholding of whole blood resuscitation. The benefits of whole blood resuscitation likely outweigh the risks of alloimmunization.
Stochastic parabolic growth promotes coexistence and a relaxed error threshold in RNA-like replicator populations
Authors: Paczkó Mátyás , Szathmáry Eörs , Szilágyi András 
Published: November 2023

AbstractThe RNA world hypothesis proposes that during the early evolution of life, primordial genomes of the first self-propagating evolutionary units existed in the form of RNA-like polymers. Autonomous, non-enzymatic and sustained replication of such information carriers presents a problem, because product formation and hybridization between template and copy strands reduces replication speed. Kinetics of growth is then parabolic with the benefit of entailing competitive coexistence, thereby maintaining diversity. Here, we test the information-maintaining ability of parabolic growth in stochastic multispecies population models under the constraints of constant total population size and chemostat conditions. We find that large population sizes and small differences in the replication rates favor the stable coexistence of the vast majority of replicator species (“genes”), while the error-threshold problem is alleviated relative to exponential amplification. In addition, sequence properties (GC content) and the strength of resource competition mediated by the rate of resource inflow determine the number of coexisting variants, suggesting that fluctuations in building block availability favored repeated cycles of exploration and exploitation. Stochastic parabolic growth could thus have played a pivotal role in preserving viable sequences generated by random abiotic synthesis and providing diverse genetic raw material to the early evolution of functional ribozymes.
ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines
Authors: Lozinski Mathew , Bowden Nikola A. , Graves Moira C. , Fay Michael , Day Bryan W. , Stringer Brett W. , Tooney Paul A. 
Published: November 2023

AbstractGlioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines. We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment.MGMTpromoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.
Working Memory Gating in Obesity is Moderated by Striatal Dopaminergic Gene Variants
Authors: Herzog Nadine , Hartmann Hendrik , Janssen Lieneke Katharina , Kanyamibwa Arsene , Waltmann Maria , Kovacs Peter , Deserno Lorenz , Fallon Sean James , Villringer Arno , Horstmann Annette 
Published: November 2023

AbstractEveryday life requires an adaptive balance between distraction-resistant maintenance of information and the flexibility to update this information when needed. These opposing mechanisms are proposed to be balanced through a working memory gating mechanism. Prior research indicates that obesity may elevate the risk of working memory deficits, yet the underlying mechanisms remain elusive. Dopaminergic alterations have emerged as a potential mediator. However, current models suggest these alterations should only shift the balance in working memory tasks, not produce overall deficits. The empirical support for this notion is currently lacking, however. To address this gap, we pooled data from three studies (N = 320) where participants performed a working memory gating task. Higher BMI was associated with overall poorer working memory, irrespective of whether there was a need to maintain or update information. However, when participants, in addition to BMI level, were categorized based on certain putative dopamine-signaling characteristics (Single Nucleotide Polymorphisms; specifically, Taq1A and DARPP-32), distinct working memory gating effects emerged. These SNPs, primarily associated with striatal dopamine transmission, appear to be linked with differences in updating, specifically, among high-BMI individuals. Moreover, blood amino acid ratio, which indicates central dopamine synthesis capacity, combined with BMI, shifted the balance between distractor-resistant maintenance and updating. These findings suggest that both dopamine-dependent and dopamine-independent cognitive effects exist in obesity. Understanding these effects is crucial if we aim to modify maladaptive cognitive profiles in individuals with obesity.
Loss of ninein interferes with osteoclast formation and causes premature ossification
Authors: Gilbert Thierry , Barbier Merlin , Duployer Benjamin , Dufrançais Ophélie , Martet Laure-Elene , Dalbard Elisa , Segot Loelia , Tenailleau Christophe , Vérollet Christel , Bierkamp Christiane , Merdes Andreas 
Published: November 2023

AbstractNinein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the humannineingene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.
In silicoStudy of the Uncertainly SignificantVCPVariants reveal major Structural, Functional fluctuations leading to potential Disease-Based Associations
Authors: Das Tathagata , Roychowdhury Saileyee , Das Parimal 
Published: November 2023

AbstractValosin containing protein is involved in a plethora of crucial functions from proteostasis, stress granule clearance to genome maintenance and ubiquitination. Hence, mutations inVCPcan lead to a plethora of fatal diseases like Amyotrophic Lateral Sclerosis, Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1, Spastic paraplegia, Charcot-Marie-Tooth disease type 2Y, Dementia, and Osteitis Deformans to name a few. Studies onVCP’s disease phenotype relationship, structural, and functional modifications of the protein’s stability, conservation, molecular dynamics, and post-translational modifications haven’t been performed. Thisin silicostudy investigated the variants ofVCP(R95C, R95G, A160P, R191P, R191Q) which have conflicting interpretations of pathogenicity which are often depreciated and lack data. Additionally, this study screens the study cohort and the fatal diseases linked to all these variants. Interestingly through various computational tools and disease-based population studies, it was found that these variants are often found in patients linked with fatal diseases. The protein-protein interaction showedUFD1has a direct association withVCP. The physicochemical parameters showed that A160P had the highest fluctuations of all the variants.VCP’s protein secondary structure, molecular dynamics simulations of RMSD, RMSF, RoG, hydrogen bonds, and solvent accessibility were all comparatively impacted due to the changes caused by the variants. Box-plot and Principal component analysis of the MD simulations visualized the changes in the wild type of the protein. Research in wet labs and screening of patient cohorts is necessary to further characterize the diseases linked with these variants. This can potentially lead to the identification of biomarkers for fatal rare diseases.
Electric fields determine carbapenemase activity in class A β-lactamases
Authors: Jabeen Hira , Beer Michael , Spencer James , van der Kamp Marc W. , Bunzel H. Adrian , Mulholland Adrian J. 
Published: November 2023

ABSTRACTAntimicrobial resistance is a public health crisis. Limited understanding of the catalytic drivers in resistance-mediating enzymes such as β-lactamases hinders our ability to combat this crisis. Here, we dissect the catalytic contributions of active-site electric fields in class A β-lactamases. We studied the enzymatic hydrolysis of a carbapenem antibiotic by QM/MM molecular dynamics simulations and quantified active-site fields with a custom-made script. We discovered that the fields correlate well with activity and identified seven positions, some distal, that distinguish efficient carbapenemases. Electric-field analysis may help predict the activity of β-lactamases and guide antibiotic and enzyme design.Abstract FigureElectric field script:www.github.com/bunzela/FieldTools
DeepVASP-S: a deep-learning tool for explaining steric mechanism that controls binding specificity
Authors: Liu Yangying , Zhou Houliang , Chen Brian Y. 
Published: November 2023

AbstractDeepVASP-S is a computational tool that leverages the capabilities of convolutional neural networks (CNNs) to analyze steric aspects of protein-ligand interactions and predict amino acid contributions to binding specificity. This tool combines structural bioinformatics with machine learning to address the complex problem of understanding how specific amino acids contribute to the specificity of binding. Here, we use this tool to predict subclasses for Enolase and Serine Protease according to their binding specificity, and explain it through the underlying steric mechanism. The strength of DeepVASP-S lies in its ability to identify and highlight these specific regions, providing researchers with insights into the molecular determinants of protein function and interaction. Such information is extremely valuable for the field of drug design, as it enables the creation of more targeted and effective therapeutics with minimized side effects. The approach taken by DeepVASP-S represents a significant step forward in computational biochemistry, merging high-resolution 3D structural data with the predictive power of machine learning to unlock a deeper understanding of protein-ligand interactions.
The smooth-walled human RVOT contains trabeculations that cause conduction delay
Authors: Jensen Bjarke , Bosada Fernanda M. , Blok Michiel , Scholman Koen T , Efimov Igor R , Boukens Bastiaan J 
Published: November 2023

AbstractAimsThe right ventricular outflow tract (RVOT) is the outlet from the right ventricle and is the initiating substrate of life-threatening arrhythmias. While the luminal wall of the RVOT is often assumed to be without the complex trabecular meshwork that characterizes the right ventricular free wall, the anatomy of the RVOT is an understudied subject. Our aim was to investigate whether trabeculations occur in the RVOT and to assess whether this impacts electrical propagation.Methods & ResultsWe used high-resolution MRI and serial sectioning to reconstruct the macroscopic details of the human RVOT and identified cases exhibiting much trabeculation. The smooth lumen of the RVOT varied between 9% and 23% of the total RV anterior surface (N=11). Histological analysis on additional six hearts indicated that the RVOT compact layer is thinner when trabeculations are present. RNA sequencing of four human donor hearts revealed enrichment in the subendocardial region of 88 genes associated with cardiac conduction and trabeculations (P adjusted<0.05). Finally, we selected two human donor hearts showing trabeculations in the RVOT from which we generated wedge preparation and performed optical and electrical mapping. The trabecular regions demonstrated high degree of fractionation when compared to non-trabeculated regions, which coincided with delayed activation.ConclusionTrabeculations are found in the RVOT, and their extent varies among individuals. This impacts on the thickness of the compact wall in the RVOT, restricting the depth of tissue at which clinical interventions can be performed, as well as influencing electrical propagation and possible arrhythmogenicity.