bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of Cognitive Health Services in Large Systems of Care: Highlights From Coordinated Specialty Care for First Episode Psychosis
Authors: Saperstein Alice M , Bello Iruma , Nossel Ilana , Dixon Lisa B , Medalia Alice
Published: March 2024

Background and Hypothesis

With increasing recognition of the importance of cognitive health for recovery in people with psychosis, questions arise as to how to implement cognitive health services in large systems of care. This paper describes the implementation of cognitive health services in OnTrackNY (OTNY), a network of clinics delivering a Coordinated Specialty Care treatment model for early psychosis, with the goal of documenting the processes, challenges, and useful adaptations.

Study Design

In 2018, OTNY piloted a Cognitive Health Toolkit for implementation across 18 affiliated clinics. The toolkit intended to identify the cognitive health needs of individuals early in the course of psychosis and to integrate cognitive health into the vocabulary of wellness and recovery. Implementation involved creating mechanisms for staff training and support to, in turn, help participants improve how they use cognitive skills in daily life.

Study Results

The toolkit was disseminated to all 28 OTNY programs throughout New York state by 2023. When simple assessment and decision-making tools were embedded in routine care practices, the majority of participants identified that improving memory, attention, and critical thinking skills would be helpful. Consistently, about 70% of those asked wanted to learn more about how to better their cognitive health.

Conclusions

Cognitive health services can be implemented in large systems of care that provide a multi-level system of implementation supports. Organizational facilitators of implementation include a training program to educate about cognitive health and the delivery of cognitive health interventions, and embedded quality assurance monitoring and improvement activities.
Trichloroethylene metabolite modulates DNA methylation-dependent gene expression in Th1-polarized CD4+ T cells from autoimmune-prone mice
Authors: Choudhury Samrat Roy , Byrum Stephanie D , Blossom Sarah J
Published: March 2024

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant associated with CD4+ T-cell activation and autoimmune disease. Prior studies showed that exposure to TCE in the drinking water of autoimmune-prone mice expanded effector/memory CD4+ T cells with an interferon-γ (IFN-γ)-secreting Th1-like phenotype. However, very little is known how TCE exposure skews CD4+ T cells towards this pro-inflammatory Th1 subset. As observed previously, TCE exposure was associated with hypermethylation of regions of the genome related to transcriptional repression in purified effector/memory CD4 T cells. We hypothesized that TCE modulates transcriptional and/or epigenetic programming of CD4+ T cells as they differentiate from a naive to effector phenotype. In the current study, purified naive CD4 T cells from both male and female autoimmune-prone MRL/MpJ mice were activated ex vivo and polarized towards a Th1 subset for 4 days in the presence or absence of the oxidative metabolite of TCE, trichloroacetaldehyde hydrate (TCAH) in vitro. An RNA-seq assessment and reduced representation bisulfite sequencing for DNA methylation were conducted on Th1 cells or activated, non-polarized cells. The results demonstrated TCAH’s ability to regulate key genes involved in the immune response and autoimmunity, including Ifng, by altering the level of DNA methylation at the gene promoter. Intriguing sex differences were observed and for the most part, the effects were more robust in females compared to males. In conclusion, TCE via TCAH epigenetically regulates gene expression in CD4+ T cells. These results may have implications for mechanistic understanding or future therapeutics for autoimmunity.
Organophosphate ester flame retardants and plasticizers affect the phenotype and function of HepG2 liver cells
Authors: Yu Dongwei , Hales Barbara F , Robaire Bernard
Published: March 2024

Exposure to the organophosphate esters (OPEs), used as flame retardants and plasticizers, is associated with a variety of adverse health effects including an increase in the incidence of fatty liver diseases. The goal of this study was to investigate the effects of six OPEs, all detected in Canadian house dust, on the phenotype and function of HepG2 liver cells. We used high-content imaging to investigate the effects of these OPEs on cell survival, mitochondria, oxidative stress, lipid droplets, and lysosomes. Effects on the autophagy/lipophagy pathway were evaluated using confocal microscopy. The triaryl OPEs (isopropylated triphenylphosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) were more cytotoxic than non-triaryl OPEs (tris(2-butoxyethyl) phosphate [TBOEP], tris(1-chloro-2-propyl) phosphate [TCIPP], and tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]). Exposure to most OPEs increased total mitochondria, reduced reactive oxygen species, and increased total lipid droplet areas and lysosomal intensity. Potency ranking was done using the lowest benchmark concentration/administered equivalent dose method and toxicological prioritization index analyses to integrate all phenotypic endpoints. IPPP, TBOEP, and TPHP ranked as the most potent OPEs, whereas TMPP, TCIPP, and TDCIPP were relatively less bioactive. Confocal microscopic analysis demonstrated that IPPP reduced the colocalization of lipid droplets (PLIN2), lysosomes (LAMP1), and autophagosomes (p62), disrupting autophagy. In contrast, TBOEP rescued cells from bafilomycin A1-induced inhibition of autophagy and/or increased autophagic flux. Together, these data demonstrate that OPEs have adverse effects on HepG2 cells. Further, OPE-induced dysregulation of autophagy may contribute to the association between OPE exposure and adverse effects on liver lipid homeostasis.
Chimeric antigen receptors: “CARs” in the fast lane for rheumatology
Authors: Johnson Nathan M. , Koumpouras Fotios
Published: March 2024

Purpose of review

Recent advances in hematology-oncology have pioneered cell-mediated elimination of pathologic B-cell populations employing chimeric antigen receptor (CAR) T cells. In this review, we discuss recent adoption of CAR-T treatment for severe refractory autoimmune disease. We highlight unique aspects of the autoimmune model and review current clinical data regarding treatment of rheumatologic disease.

Recent findings

To date, several CAR-Ts are FDA approved for Multiple Myeloma and B-cell malignancies and have demonstrated extraordinary clinical responses in refractory disease. Realizing the central role of B-cells in certain autoimmune diseases, CAR-T is now being explored for achieving drug-free remission induction, and potentially cure, of several rheumatologic diseases. The largest experience to date in the field of autoimmunity, building off the University Hospital Erlangen groups’ earlier success treating a single patient with CD19-CAR in severe refractory SLE, Mackensen et al. enrolled five patients in a compassionate use program. Following autologous CD19-CAR T infusion, they demonstrated drug-free clinical and laboratory remission for at least 12 months in all five patients, with reconstitution of B cells expressing a naïve phenotype.

CAR-T treatment has shown striking drug-free responses in severe lupus and other autoimmune diseases, creating a need for further exploration and development.
Digital pathology and spatial omics in steatohepatitis: Clinical applications and discovery potentials
Authors: Meroueh Chady , Warasnhe Khaled , Tizhoosh Hamid R. , Shah Vijay H. , Ibrahim Samar H.
Published: March 2024

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction–associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.
Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset
Authors: Quiroga-Garza Manuel E. , Ruiz-Lozano Raul E. , Rodriguez-Gutierrez Luis A. , Khodor Ali , Ma Symon , Komai Seitaro , Mohamed-Noriega Karim , Perez Victor L.
Published: March 2024

The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a “time zero,” meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a “time zero” allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the “time zero” concept in the study of oGVHD.
Evaluating appropriateness of 18F-fluciclovine PET/CT relative to standard of care imaging guidelines and the impact of ADT on positivity: a prospective study in 62 Veterans Administration patients at a single institution
Authors: Green Aileen , Temsah Peter , Goldfarb Leonard , Sanfolippo Kristen , Knoche Eric , Muzaffar Razi , Osman Medhat M.
Published: March 2024

Background

According to the National Comprehensive Cancer Network Guidelines, 18F-fluciclovine PET/CT is considered appropriate after negative standard of care (SOC) imaging.

Objective

To prospectively compare 18F-fluciclovine to SOC imaging, investigate whether it should be done when SOC imaging is (+), and evaluate its detection rate in patients receiving androgen deprivation therapy.

Methods

We recruited 57 prostate cancer patients with biochemical recurrence with 18F-fluciclovine PET/CT and SOC imaging within 30 days. Prostate-specific antigen (PSA) level, Gleason score (GS), history of radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT) were reviewed.

Results

The 57 patients had a median PSA of 2.6 and average GS of 7.4; 27 (47.4%) had RP, 28 (49.1%) had RT, 1 (1.75%) had HT and 1 (1.75%) observation only. 18F-fluciclovine identified disease recurrence in 45/57 patients (78.9%), including oligometastasis in 18/45 (40%). SOC imaging identified recurrent disease in 12/57 patients (21.1%) while 18F-fluciclvoine identified additional sites of disease in 11/12 (91.7%). The (+) 18F-fluciclovine studies had a median PSA 2.6 ng/ml compared to 6.0 ng/ml in the (+) SOC studies.

Conclusion

18F-fluciclovine was superior to SOC imaging for lesion detection, identification of oligometastasis and identification of additional sites of disease.
Botulinum toxin therapy for management of phantom and residual limb pain following amputation: A systematic review
Authors: Frengopoulos Courtney , Neferu Ramona , Pasquali Matthew , Viana Ricardo , Miller Tom , Payne Michael
Published: March 2024

Chronic pain following amputation is debilitating. Due to its mechanisms in modulating muscle contraction and pain, botulinum toxin has been investigated as a treatment option for phantom limb pain (PLP) and residual limb pain (RLP). The objective of this study was to determine the efficacy of botulinum toxin injection in the management of PLP and RLP following major limb amputation using a systematic review of the literature. The databases Medline, CINAHL, EMBASE, Scopus, Web of Science, and Cochrane were searched from inception through October 30, 2023. The search identified 50 articles; 37 underwent full-text review, and 11 were included in the final review. Eighty-nine individuals with pain were investigated by the included studies; 53 had RLP and 63 had PLP. There was significant variation in botulinum toxin type, injection method, and dosage. Twenty-one (53.9%) and 27 (64.3%) participants had improvement in PLP and RLP following botulinum toxin injection, respectively. Therefore, there is potential for use of botulinum toxin for the treatment of PLP and RLP. However, due to the minimal number of studies, small sample sizes, and heterogenous methodologies, our ability to conclude with certainty the efficacy of botulinum toxin injection on the treatment of PLP and RLP following amputation is limited.
Diagnostic Performance of central nervous system infections in patients with neurosurgical intensive care using metagenomic next-generation sequencing: A Prospective Observational Study
Authors: Tian Ying , Duan Yuqing , Gao Ran , Gao Wei , Xu Shanshan , Wang Shuya , Li Fangqiang , Fang Fang , Su Rui , Chen Yuqing , Xu Ningyuan , Li Wei , Zhang Linlin , Zhou Jian-Xin
Published: March 2024

Background

Identifying the causative pathogens of central nervous system infections (CNSIs) is crucial, but the low detection rate of traditional culture methods in cerebrospinal fluid (CSF) has made the pathogenic diagnosis of CNSIs a longstanding challenge. Patients with CNSIs after neurosurgery often overlap with inflammatory and bleeding. Metagenomic next generation sequencing (mNGS) has shown some benefits in pathogen detection. This study aimed to investigate the diagnostic performance of mNGS in the etiological diagnosis of CNSIs in patients after neurosurgery.

Methods

In this prospective observational study, we enrolled patients with suspected CNSIs after neurosurgical operations who were admitted to the intensive care unit of Beijing Tiantan Hospital. All enrolled patients' CSF was tested using mNGS and pathogen culture. According to comprehensive clinical diagnosis, the enrolled patients were divided into CNSIs group and non-CNSIs group to compare the diagnostic efficiency of mNGS and pathogen culture.

Results

From December 2021 to March 2023, 139 patients were enrolled while 66 in CNSIs group and 73 in non-CNSIs. The mNGS exceeded culture in the variety and quantity of pathogens detected. The mNGS outperformed traditional pathogen culture in terms of positive percent agreement (63.63%), accuracy (82.01%), and negative predictive value (75.00%), with statistically significant differences (P < 0.05) for traditional pathogen culture. The mNGS also detected bacterial spectrum and antimicrobial resistance genes.

Conclusions

Metagenomics has the potential to assist in the diagnosis of patients with CNSIs who have a negative culture.
DEVELOPMENT AND VALIDATION OF A NOMOGRAM FOR PREDICTING 28-DAY IN-HOSPITAL MORTALITY IN SEPSIS PATIENTS BASED ON AN OPTIMIZED ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II SCORE
Authors: Yuan Yamin , Meng Yanfei , Li Yihui , Zhou Jinquan , Wang Jiaqi , Jiang Yujing , Ma Li
Published: March 2024

Purpose: The objective of this study is to establish a nomogram that correlates optimized Acute Physiology and Chronic Health Evaluation II (APACHE II) score with sepsis-related indicators, aiming to provide a robust model for early prediction of sepsis prognosis in clinical practice and serve as a valuable reference for improved diagnosis and treatment strategies. Methods: This retrospective study extracted sepsis patients meeting the inclusion criteria from the MIMIC-IV database to form the training group. An optimized APACHE II score integrated with relevant indicators was developed using a nomogram for predicting the prognosis of sepsis patients. External validation was conducted using data from the intensive care unit at Lanzhou University Second Hospital. Results: The study enrolled 1805 patients in the training cohort and 203 patients in the validation cohort. A multifactor analysis was conducted to identify factors affecting patient mortality within 28 days, resulting in the development of an optimized score by simplifying evaluation indicators from APACHE II score. The results showed that the optimized score (area under the ROC curve [AUC] = 0.715) had a higher area under receiver operating characteristic curve than Sequential Organ Failure Assessment score (AUC = 0.637) but slightly lower than APACHE II score (AUC = 0.720). Significant indicators identified through multifactor analysis included platelet count, total bilirubin level, albumin level, prothrombin time, activated partial thromboplastin time, mechanical ventilation use and renal replacement therapy use. These seven indicators were combined with optimized score to construct a nomogram based on these seven indicators. The nomogram demonstrated good clinical predictive value in both training cohort (AUC = 0.803) and validation cohort (AUC = 0.750). Calibration curves and decision curve analyses also confirmed its good predictive ability, surpassing the APACHE II score and Sequential Organ Failure Assessment score in identifying high-risk patients. Conclusions: The nomogram was established in this study using the MIMIC-IV database and validated with external data, demonstrating its robust discriminability, calibration, and clinical practicability for predicting 28-day mortality in sepsis patients. These findings aim to provide substantial support for clinicians’ decision making.
REDUCED CX43 EXPRESSION INDUCES AUTOPHAGY THROUGH ACTIVATION OF THE AMPK-MTOR-ULK1 SIGNALING PATHWAY IN THE COMMON BILE DUCT LIGATION RAT HEART
Authors: Wang Xiaoyu , Liao Pingping , Dong He , Liu Aijie , Wang Qian , Yang Han , Xu Xiaolin , Chai Dongyue , Zhu Lin , Lyu Lin
Published: March 2024

Backgrounds: This study aimed to investigate the relationship between Cx43 expression and autophagy mediated by the AMPK-mTOR-Ulk1 signaling pathway in jaundice heart. Methods: In this study, a jaundice model was established in common bile duct ligation (CBDL) rats. Cardiac injury was assessed using various methods including myocardial injury indicators, echocardiography, transmission electron microscopy, hematoxylin and eosin staining, Masson staining, immunohistochemical analyses, and immunofluorescence staining. We investigated the regulatory relationship between Cx43, autophagy, and the AMPK-mTOR-ULK pathway in vivo by administering autophagy agonists (Rapa), autophagy inhibitors (3-MA), and Cx43 inhibitors (Gap 26). In vitro, we observed the relationship between autophagy and the AMPK-mTOR-ULK1 pathway in cells by exposing them to the AMPK inhibitor Compound C and the AMPK activator AICAR. Results: We found that CBDL induced autophagy through the AMPK-mTOR-ULK pathway, leading to the inhibition of myocardial dysfunction. Rapamycin pretreatment with CBDL3d exhibited a protective effect against myocardial injury and promoted autophagy. In contrast, 3-MA had no impact. Pretreatment with rapamycin at CBDL2w enhanced autophagy and aggravated cardiac injury; however, inhibition of autophagy using 3-MA attenuated cardiac injury. Cell viability was enhanced by AMPK inhibitors and inhibited by AMPK agonists. In addition, we observed that increased autophagy led to decreased Cx43 expression, which negatively affected cardiac function. Conclusions: CBDL induces myocardial injury in rats and activates autophagy through the AMPK-mTOR-ULK pathway, resulting in decreased Cx43 protein levels. A moderate increase in early autophagy in CBDL can improve cardiac injury, while late inhibition of autophagy can reduce myocardial injury.
Frailty Changes After Liver Transplantation. Results From a Spanish Multicenter Prospective Cohort Study
Authors: Puchades Lorena , Herreras Julia , Cebrià i Iranzo Maria Àngels , Reyes Érick , Crespo Gonzalo , Rodríguez-Perálvarez Manuel , Cortés Luis , Serrano Trinidad , Fernández-Yunquera Ainhoa , Montalvá Eva , Berenguer Marina
Published: March 2024

Introduction.

Until now, there has been limited evidence, primarily from US cohorts, focusing on frailty as a patient-oriented outcome after liver transplantation (LT). Our study aimed to explore the relationship between pre- and post-LT frailty in a multicenter European cohort of outpatients with cirrhosis undergoing LT.

Methods.

We conducted a prospective analysis of data from 180 LT recipients recruited between 2018 and 2020 from 5 Spanish centers. Participants underwent objective and subjective frailty assessments using the Liver Frailty Index (LFI) and the Subjective Clinician Assessment (SCA) pretransplant and at 3- and/or 6-mo posttransplant.

Results.

The median pretransplant LFI was 3.9, showing minimal change at 3 mo (3.8; P = 0.331) and improvement at 6-mo post-LT (3.6; P = 0.001). Conversely, the SCA significantly improved early post-LT: at 3 mo, poor SCA decreased from 11% to 1%, and good SCA increased from 54% to 89% (P < 0.001), remaining stable between 3- and 6-mo post-LT. Multivariable analysis revealed that each 0.1 increase in pretransplant LFI correlated with a reduced probability of being robust at 3-mo (odds ratio [OR] = 0.75; P < 0.001) and 6-mo post-LT (OR = 0.74; P < 0.001). There was poor concordance between SCA and LFI, with SCA underestimating frailty both pre- and post-LT (Kappa < 0.20).

Conclusion.

In our European cohort, incomplete improvement of physical frailty was observed, with <20% achieving robust physical condition within 6-mo post-LT. The pretransplant LFI strongly predicted posttransplant frailty. As the SCA tends to overestimate physical function, we recommend using both subjective and objective tools for frailty assessment in LT candidates and recipients.
Reducing Blood Culture Contamination Rates: Introduction of a Combined Education and Skin Antisepsis Intervention
Authors: Mullane Niamh , O'Mara Niall , Coffey Darragh , Connolly Aine , O'Callaghan Isabelle , Kelly Deborah , Broderick Deirdre , Hickey Caitriona
Published: March 2024

Background
Blood culture contamination (BCC) is an important quality concern in clinical microbiology as it can lead to unnecessary antimicrobial therapy in patients and increased workload for laboratory scientists. The Clinical Laboratory and Standards Institute recommend BCC rates to be <3% and recently updated guidelines have set a new goal of 1%. The aim of this project was to design and implement interventions to reduce BCC rates at our institution.
Methods
We introduced a combined education and skin antisepsis intervention in a large Model 4 academic teaching hospital in the South of Ireland. BD ChloraPrep™ skin antisepsis applicators (2% chlorhexidine gluconate/70% isopropyl alcohol), licensed for use for blood culture collection, were introduced, replacing Clinell® (2% chlorhexidine gluconate/70% isopropyl alcohol) wipes. In addition, a multimodal education programme was designed and delivered. This consisted of a video demonstrating the recommended blood culture collection technique using the new applicators as well as simulation training for all interns. The video was uploaded to the intranet as an educational resource available to all staff.
Results
The interventions were implemented in July 2022 and BCC rates pre- and post-intervention were calculated. The average BCC rate for the 12 months preceding the intervention (July 2021-July 2022) was 2.56% with highest rates in the emergency department. This compared to an average rate of 2.2% in the 12 months post-intervention (July 2022-July 2023). In comparing the two rates the reduction in BCC rates between the two periods was not statistically significant (p=0.30).
Conclusion
Overall BCC rates reduced but the difference between the two periods did not reach statistical significance. The resource intensive nature of providing regular and timely feedback of contamination rates and the larger impact of in–person education and training over virtual modalities may explain the modest reduction. Further investments in these areas, particularly in the emergency department will be necessary to further reduce rates in line with new recommendations.
Phenotypic Characterization of Carbapenem-Resistant Enterobacteriaceae in Presumptive Tuberculosis Patient across One Health Interface
Authors: OJO Abidemi Esther , Ojo Olugbenga , ADEBAJO SEUN , Oloyede Adejare , Ajibola Abiola , adebanjo omolade , ojo David
Published: March 2024

Introduction

Globally, Nigeria remains one of the 30 countries highly burdened with tuberculosis (TB), TB/Human immunodeficiency virus and multidrug-resistant TB (MDR-TB).

Objective

This study aimed to characterize carbapenem-resistant Enterobacteriaceae (CRE) in presumptive tuberculosis patients across one health interface.

Methods

Sixty-six sputum samples from presumptive tuberculosis patients, fecal samples of animals loitering the hospital and environmental soil samples were collected and characterized. Isolated Enterobacteriaceae were screened for multidrug resistance and characterized for carbapenemase production.

Result

Fifty-seven enterobacteriaceae were isolated from 66 samples of sputum, fecal and soil samples. The frequency of occurrence of Klebsiella pneumoniae was 66.7% and 100% in sputum and fecal samples, respectively, while 60% of the soil sample was Proteus mirabilis. Multidrug resistance was exhibited, with ceftizidime showing the highest resistance of 100%, augumentin (95.7%), and nitrofurantoin (59.6%) in sputum samples. Animal and fecal samples showed similar resistance patterns to antibiotics with gentamicin, cefixime augementin and nitrofurantin. Majority (70.2%) were carbapenemase-producing Enterobacteriaceae, while only 34% were producing metallo-beta lactamase from sputum samples. Conclusions: The interconnectivity and frequency of CRE occurrence was found to be high in this study across the three pillars of One Health.
HIV-DRIVES: HIV Drug Resistance Identification, Variant Evaluation, & Surveillance Pipeline
Authors: Kanyerezi Stephen , Sserwadda Ivan , Ssemaganda Aloysius , Seruyange Julius , Ayitewala Alisen , Oundo Hellen Rosette , Tenywa Wilson , Kagurusi Brian A. , Tusabe Godwin , Were Stacy , Ssewanyana Isaac , Nabadda Susan , Namaganda Maria Magdalene , Mboowa Gerald
Published: March 2024

The global prevalence of resistance to antiviral drugs combined with antiretroviral therapy (cART) emphasizes the need for continuous monitoring to better understand the dynamics of drug-resistant mutations to guide treatment optimization and patient management as well as check the spread of resistant viral strains. We have recently, integrated next-generation sequencing (NGS) into routine HIV drug resistance (HIVDR) monitoring, with key challenges in the bioinformatic analysis and interpretation of the complex data generated while ensuring data security and privacy of patient information. To address these challenges, here, we present HIV-DRIVES (HIV Drug Resistance Identification, Variant Evaluation, and Surveillance), an NGS-HIVDR bioinformatics pipeline that has been developed and validated using Illumina short-reads, FASTA, and Sanger ab1.seq files.
Neural dynamics express syntax in the time domain during natural story listening
Authors: Coopmans Cas W. , de Hoop Helen , Tezcan Filiz , Hagoort Peter , Martin Andrea E.
Published: March 2024

Studies of perception have long shown that the brain adds information to its sensory analysis of the physical environment. A touchstone example for humans is language use: to comprehend a physical signal like speech, the brain must add linguistic knowledge, including syntax. Yet, syntactic rules and representations are atemporal (i.e., abstract and not bound by time), so they must be translated into time-varying signals for speech comprehension and production. Here, we test three different models of the temporal spell-out of syntactic structure against brain activity of people listening to Dutch stories: an integratory bottom-up parser, a predictive top-down parser, and a mildly predictive left-corner parser. These models build exactly the same structure but differ in when syntactic information is added by the brain – this difference is captured in the (temporal distribution of the) complexity metric ‘incremental node count’. Using temporal response function models with both acoustic and information-theoretic control predictors, node counts were regressed against source-reconstructed delta-band activity acquired with magnetoencephalography. Neural dynamics in left frontal and temporal regions most strongly reflect node counts derived by the top-down method, which postulates syntax early in time, suggesting that predictive structure building is an important component of Dutch sentence comprehension. The absence of strong effects of the left-corner model further suggests that its mildly predictive strategy does not represent Dutch language comprehension well, in contrast to what has been found for English. Understanding when the brain projects its knowledge of syntax onto speech, and whether this is done in language-specific ways, will inform and constrain the development of mechanistic models of syntactic-structure building in the brain.
Reduced PaxillinB localization to cell-substrate adhesions promotes cell migration inDictyostelium
Authors: Morales Julio C. Fierro , Redfearn Chandler , Titus Margaret A. , Roh-Johnson Minna
Published: March 2024

Many cells adhere to extracellular matrix for efficient cell migration. This adhesion is mediated by focal adhesions, a protein complex linking the extracellular matrix to the intracellular cytoskeleton. Focal adhesions have been studied extensively in mesenchymal cells, but recent research in physiological contexts and amoeboid cells suggest focal adhesion regulation differs from the mesenchymal focal adhesion paradigm. We usedDictyostelium discoideumto uncover new mechanisms of focal adhesion regulation, asDictyosteliumare amoeboid cells that form focal adhesion-like structures for migration. We show that PaxillinB, theDictyosteliumhomologue of Paxillin, localizes to dynamic focal adhesion-like structures duringDictyosteliummigration. Unexpectedly, reduced PaxillinB recruitment to these structures increasesDictyosteliumcell migration. Quantitative analysis of focal adhesion size and dynamics show that lack of PaxillinB recruitment to focal adhesions does not alter focal adhesion size, but rather increases focal adhesion turnover. These findings are in direct contrast to Paxillin function at focal adhesions during mesenchymal migration, challenging the established focal adhesion model.

Short Summary

Fierro Morales et al. show that the role of PaxillinB in focal adhesion-based migration differs from the canonical mesenchymal focal adhesion paradigm.
Senolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitness
Authors: Eskiocak Onur , Chowdhury Saria , Shah Vyom , Nnuji-John Emmanuella , Chung Charlie , Boyer Jacob A. , Harris Alexander S. , Habel Jill , Sadelain Michel , Beyaz Semir , Amor Corina
Published: March 2024

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature of the aging process, little is known about thein vivoeffects of senescent cells on intestinal fitness. Here, we identify the accumulation of senescent cells in the aging gut and, by harnessing senolytic CAR T cells to eliminate them, we uncover their detrimental impact on epithelial integrity and overall intestinal homeostasis in natural aging, injury and colitis. Ablation of intestinal senescent cells with senolytic CAR T cellsin vivoorin vitrois sufficient to promote the regenerative potential of aged ISCs. This intervention improves epithelial integrity and mucosal immune function. Overall, these results highlight the ability of senolytic CAR T cells to rejuvenate the intestinal niche and demonstrate the potential of targeted cell therapies to promote tissue regeneration in aging organisms.
Floor Sitting Rising in Adults with and without Disability: A Scoping Review Protocol
Authors: Alomar Jehan Abdulmohsen , Li Haoyu , Fisher Keri , King Miriam , Quinn Lori
Published: March 2024

Background

Getting down to the floor and rising to a standing position (Floor Sitting-Rising | FSR) is a fundamental task for independent living and participation across the lifespan. Multiple studies have reported activity limitations in FSR among adults and individuals with musculoskeletal and neurological impairments. However, few studies have investigated FSR assessments and the body structures and functions contributing to FSR performance.

Objectives

To describe assessments that measure FSR in adulthood, including their psychometric properties, and to determine if impairments in body structures and functions contribute to limitations in FSR performance in adults with orthopedic or neurological disability.

Design

Google Scholar, Pubmed, CINHAL (Medline), and Rehab Measures will be searched for studies that report the full FSR transition. Studies must be original research in the adult population.

Result

We will categorize studies based on aims, study type, population characteristics, and abilities. We will narratively synthesize results, discuss potential personal and environmental factors influencing FSR, and identify the gaps in the literature to inform future research directions.

Conclusion

This review of FSR assessments will provide recommendations for methods to evaluate FSR and its movement strategies and consider impairments that may influence performance.
Insights into Parental Behavior: Self-Medication Patterns with antibiotics for Child Health
Authors: Kumar Shishir , Agrawal Shivani , Yasmin Tajwar , Sinha Setu
Published: March 2024

Objectives

The alarming trend of self-medication with antibiotics in children, exacerbated by factors such as easy access to medications and insufficient awareness of the consequences, presents a critical health concern. This study aims to understand the behavior of parents on self medicating their children with antibiotics.

Methods

A cross-sectional study was done in the community under UHTC of IGIMS, Patna among 173 parents having children <12 years of age for a period of 12 months. Participants were selected through simple random sampling and were interviewed using a questionnaire developed by the authors. Data were compared using logistic regression and presented with odd ratios and confidence intervals.

Result

Prevalence of self medication was 31.8% in this study. Higher prevalence was seen among mothers, parents between 30-39 years, graduates (p = 0.001), having family income 20000-40000, housewives and those who do not have Ayushman card. Mothers, parents ≥40 years, having Secondary/ Higher secondary education, not having Ayushman card and those having child’s age of 7-9 years normally stop giving antibiotics when their child start feeling better. Whereas postgraduates parents (p = 0.000) and participants having family member in medical field were seen keeping antibiotic stock at home for later use. 39.9% parents could identify antibiotics correctly. Majority of the parents wait for 1-2 days before starting antibiotic. Most common reason for self medication was minor illness followed by previous experience with similar symptoms.

Conclusion

Lack of essential knowledge about medicines among parents is a serious matter particularly when children are concerned. Interventions targeted at improving awareness about antibiotic misuse, resistance and adverse effects amongst parents involved in self-medication need to be implemented on large scale.
Leveraging Real-World Evidence to Define Severe RSV Lower Respiratory Tract Disease in Adults
Authors: Panozzo Catherine A. , Walsh Edward E. , Yang Zhen , Wilson Eleanor , Goswami Jaya , Stoszek Sonia K. , Loback Adrianna , Ng Tony , Francis Beverly M. , Simorellis Alana K. , Huang Wenmei , Li Linwei , Vislay-Wade Rebecca , Zheng Zhe , Anderson Evan J. , August Allison , Chen Grace , Falsey Ann R.
Published: March 2024

This study analyzed previously published data in hospital and community cohorts of adults with respiratory syncytial virus (RSV)–associated symptoms. Shortness of breath (dyspnea) alone, and in combination with certain other lower respiratory tract disease signs/symptoms, was a leading symptomatic indicator for severe RSV outcomes.
Respiratory syncytial virus vaccination strategies for older Canadian adults: a cost-utility analysis
Authors: Tuite Ashleigh R. , Simmons Alison E. , Rudd Monica , Cernat Alexandra , Gebretekle Gebremedhin B. , Yeung Man Wah , Killikelly April , Siu Winnie , Buchan Sarah A. , Brousseau Nicholas , Tunis Matthew
Published: March 2024

Background

Vaccines against respiratory syncytial virus (RSV) have the potential to reduce disease burden and costs in Canadians, but the cost-effectiveness of RSV vaccination programs for older adults is unknown. We evaluated the cost-effectiveness of different adult age cutoffs for RSV vaccination programs, with or without a focus on people with higher disease risk due to chronic medical conditions (CMCs).

Methods

We developed a static individual-based model of medically-attended RSV disease to evaluate the cost-utility of alternate age-, medical risk-, and age-plus medical risk-based vaccination policies. The model followed a multi-age cohort of 100,000 people aged 50 years and older over a three-year period. Vaccine characteristics were based on RSV vaccines authorized in Canada as of March 2024. We calculated incremental cost-effectiveness ratios (ICERs) in 2023 Canadian dollars per quality-adjust life year (QALY) from the health system and societal perspectives, discounted at 1.5%.

Results

Although all vaccination strategies averted medically-attended RSV disease, strategies focused on adults with CMCs were more likely to be cost-effective than age-based strategies. A program focused on vaccinating adults aged 70 years and older with one or more CMCs was optimal for a cost-effectiveness threshold of $50,000 per QALY. Results were sensitive to assumptions about vaccine price, but approaches based on medical risk remained optimal compared to age-based strategies even when vaccine prices were low. Findings were robust to a range of alternate assumptions.

Interpretation

Based on available data, RSV vaccination programs in some groups of older Canadians with underlying medical conditions are expected to be cost-effective.
Development and content validation of a questionnaire identifying patients’ functional priorities and abilities after hip or knee arthroplasty
Authors: Karimijashni Motahareh , Westby Marie , Ramsay Tim , Beaulé Paul E. , Poitras Stéphane
Published: March 2024

Background

To develop a self-report questionnaire evaluating functional priorities after hip or knee arthroplasty and evaluate patients’ understanding of its items and conceptual relevance.

Methods

A self-report questionnaire was first developed based on the International Classification of Functioning, Disability, and Health (ICF) core set for osteoarthritis (OA). In the second stage, two research physiotherapists thoroughly reviewed and refined the questionnaire, and another physiotherapist conducted cognitive think-aloud interviews with 18 patients to assess the face and content validity of the questionnaire.

Results

All categories and corresponding activities of ICF core set for OA were used to develop the questionnaire. Several questionnaire issues were identified and addressed. Most challenges were related to comprehension, followed by item ordering and visual elements. Patients identified ambiguous wording which we subsequently simplified. Ten activities of the core set were excluded due to lack of face validity, two activities were added, and four activities were modified.

Conclusion and implication

The findings suggest that the ICF core set for OA needs to be adjusted for patients undergoing hip or knee arthroplasty and highlight the feasibility of applying a modified core set to assess functional priorities after hip or knee arthroplasty.
Improved diagnosis of COVID-19 vaccine-associated myocarditis with cardiac scarring identified by cardiac magnetic resonance imaging
Authors: Warren Josephine , Cheng Daryl , Crawford Nigel W , Jones Bryn , Ng Rui Lun , Alafaci Annette , Stub Dion , Lew Philip , Taylor Andrew
Published: March 2024

Background

Myocarditis is a rare but potentially serious complication of COVID-19 vaccination. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging can identify cardiac scar, which may improve diagnostic accuracy and prognostication.

Objectives

To define the incidence of long-term LGE post COVID-19 vaccine-associated myocarditis (C-VAM) and to establish the additive role of CMR in the diagnostic work-up.

Methods

Patients with Brighton Collaboration Criteria Level 1 (definite) or Level 2 (probable) C-VAM were prospectively recruited from the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC) database to undergo CMR at least 12 months after diagnosis. As there were limited patients with access to baseline CMR, prior CMR results were not included in the initial case definition. The presence of LGE on follow-up CMR was then integrated into the diagnostic algorithm and the reclassification rate (definite vs. probable) was calculated.

Results

Sixty-seven patients with C-VAM (mean age 30 ± 13 years, 72% male) underwent CMR evaluation. Median time from vaccination to CMR was 548 (range 398-603) days. Twenty patients (30%) had persistent LGE, most frequently found in the basal inferolateral segment (n = 11). At diagnosis, nine patients (13%) were classified as definite and 58 (87%) as probable myocarditis. With integration of CMR LGE data, 16 patients (28%) were reclassified from probable to definite myocarditis.

Conclusion

Persistent LGE on CMR occurs in one third of patients with C-VAM. Without CMR at diagnosis, almost one third of patients are misclassified as probable rather than definite myocarditis.
A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults
Authors: Shawer Heba , Cheng Chew W , Hemmings Karen E , Aldawsari Abeer M , Revilla-González Gonzalo , Stocco Fabio , Shi Jian , Beech David J , Bailey Marc A
Published: March 2024

Background

Pathological remodelling of native vascular smooth muscle cells (VSMC) within the arterial wall is a key contributor to vascular disease. A driver of this remodelling is platelet-derived growth factor BB (PDGF-BB) and its signalling via activation of the calcium ion channel, ORAI1. Here, we investigated if there are associations ofORAI1polymorphisms with human cardiovascular disease.

Methods and results

We conducted candidate gene association analysis and revealed that a missenseORAI1variant (rs3741596, S218G) associates with an increased risk of hospital-diagnosed peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block in White British UK Biobank participants. Rs3741596 is also associated with higher circulating platelet counts and reduced total triglyceride levels. Functional analysis of the effects of rs3741596 S218G variant on ORAI1 channel function, via introduction of the S218G ORAI1 variant in HEK293 cells using CRISPR/Cas9 and investigation of its effects on SOCE, showed significantly enhanced SOCE compared to wild type cells, suggesting that the S218G variant enhances ORAI1 function.

Conclusions

Our results reveal an association between anORAI1missense variant and occlusive vascular diseases. These findings provide a novel insight into the role of ORAI1 in vascular remodelling and highlight its potential as a treatment target for vascular pathologies.
Deep Learning Model Utilization for Mortality Prediction in Mechanically Ventilated ICU Patients
Authors: Ashrafi Negin , Liu Yiming , Xu Xin , Wang Yingqi , Zhao Zhiyuan , Pishgar Maryam
Published: March 2024

Background

The requirement for mechanical ventilation has increased in recent years. Patients in the intensive care unit (ICU) who undergo mechanical ventilation often experience serious illness, contributing to a high risk of mortality. Predicting mortality for mechanically ventilated ICU patients helps physicians implement targeted treatments to mitigate risk.

Methods

We extracted medical information of patients with invasive mechanical ventilation during ICU admission from the Medical Information Mart for Intensive Care III (MIMIC-III) dataset. This information includes demographics, disease severity, diagnosis, and laboratory test results. Patients who met the inclusion criteria were randomly divided into the training set (n=11,549, 70%), the test set (n=2,475, 15%), and the validation set (n=2,475, 15%). The Synthetic Minority Over-sampling Technique (SMOTE) was utilized to resolve the imbalanced dataset. After literature research, clinical expertise and an ablation study, we selected 12 variables which is fewer than the 66 features in the best existing literature. We proposed a deep learning model to predict the ICU mortality of mechanically ventilated patients, and established 7 baseline machine learning (ML) models for comparison, including K-nearest Neighbors (KNN), Logistic Regression, Decision Tree, Random Forest, Bagging, XGBoost, and Support Vector Machine (SVM). Area under the Receiver Operating Characteristic Curve (AUROC) was used as an evaluation metric for model performance.

Results

Using 16,499 mechanically ventilated patients from the MIMIC-III database, the Neural Network model outperformed existing literature by 7.06%. It achieved an AUROC score of 0.879 (95% Confidence Interval (CI) [0.861-0.896]), an accuracy of 0.859 on the test set, and was well-calibrated with a Brier score of 0.0974, significantly exceeding previous best results.

Conclusions

The proposed model demonstrated an exceptional ability to predict ICU mortality among mechanically ventilated patients. The SHAP analysis showed respiratory failure is a significant indicator of mortality prediction compared to other related respiratory dysfunction diseases. We also incorporated mechanical ventilation duration variable for the first time in our prediction model. We observed that patients with higher mortality rates tended to have longer mechanical ventilation times. This highlights the model’s potential in guiding clinical decisions by indicating that longer mechanical ventilation may not necessarily enhance patient survival chances.