bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-Pandemic Landscape of the Oklahoma Public Health Workforce: A Case Study From the Region 6 Training Needs Assessment Survey, 2019
Authors: Reinschmidt Kerstin M. , Boyer Slate , Eberly Kristen , Shorter Charles F. , Dickens RD
Published: June 2024

Context:

The COVID-19 pandemic highlighted the need for a well-trained public health workforce prior to the public health crisis. Public health training centers regularly assess workforce needs and their pre-pandemic data play vital roles in guiding public health workforce development beyond the crisis.

Program:

In 2019, Oklahoma partners of the Region 6 South Central Public Health Training Center (R6SCPHTC) co-conducted an online survey of the public health workforce located in the Health Resources & Services Administration Region 6.

Implementation:

Between March and April, the R6SCPHTC collected 503 surveys, including 201 surveys from Oklahoma. Questions inquired about demographic and workforce characteristics, work contexts, training needs and interests, training access and logistics, and knowledge of R6SCPHTC online resources.

Evaluation:

Key findings included that two-thirds of the pre-pandemic Oklahoma public health workforce consisted of employees age 40 or older with few holding public health or medical degrees. The majority of respondents worked for health departments and Tribes, and almost half were frontline workers. Although at least half of the participants interested in training on public health activities and topics were familiar with them, confidence in their abilities related to these activities and topics was expressed by less than half. Qualitative data provided details on training needs addressed quantitatively and described new training areas. Survey participants expressed interest in diverse training delivery methods and technological devices. Most respondents were not familiar with the free trainings available through the R6SCPHTC.

Discussion:

Similar to the regional and national public health workforce, Oklahoma’s workforce needed training and support already before COVID-19. Time and resources need to be invested into the current and future workforce. While addressing priority public health skills and topics remains important, training on current and emerging topics is needed. Providing accessible trainings with expanded content will prepare Oklahoma’s public health workforce for the future.
HistoGWAS: An AI Framework for Automated and Interpretable Genetic Analysis of Tissue Phenotypes
Authors: Chaudhary Shubham , Voigts Almut , Bereket Michael , Albert Matthew L. , Schwamborn Kristina , Zeggini Eleftheria , Casale Francesco Paolo
Published: June 2024

Understanding how genetic variation affects tissue structure and function is crucial for deciphering disease mechanisms, yet comprehensive methods for genetic analysis of tissue histology are lacking. We address this gap with HistoGWAS, a framework integrating AI tools for representation learning and image generation with fast variance component models to enable scalable and interpretable genome-wide association studies of histological traits. HistoGWAS employs histology foundation models for automated trait characterization and generative models to visually interpret the genetic influences on these traits. Applied to eleven tissue types from the GTEx cohort, HistoGWAS identifies four genome-wide significant loci, which we linked to specific tissue histological and gene expression changes. A power analysis confirms the effectiveness of HistoGWAS in analyses of large-scale histological data, underscoring its potential to transform imaging genetic studies.
Sleep-Disordered Breathing Profiles in Patients with Cardiovascular Diseases: Kurume SDB-CVD Study
Authors: Shimozono Koutatsu , Adachi Hisashi , Nohara Shoichiro , Shibata Tatsuhiro , Sugiyama Yoichi , Ioji Tetsuya , Fukumoto Yoshihiro
Published: June 2024

Background

While evidence links sleep-disordered breathing (SDB) to various cardiovascular diseases (CVDs), comprehensive insights and detailed profiles of CVD patients with SDB remain scarce. This study aimed to examine the characteristics of CVD patients complicated by SDB.

Methods

This retrospective study enrolled all consecutive patients who underwent screening tests for SDB during hospitalization at Kurume University Hospital from January 2014 to December 2019. To explore the relationship between SDB severity and clinical data, we classified SDB severity into four groups and assessed its prevalence and severity across different CVDs, categorized by sex and age.

Results

A total of 5,765 patients were enrolled. Desaturation during sleep in SDB was significantly worse in terms of age, sex, daytime resting oxygen saturation (SpO2), systolic blood pressure (SBP), pulse pressure, body mass index (BMI), white blood cell count, hemoglobin A1c, serum creatinine, N-terminal Pro-B-type natriuretic peptide (NT-proBNP), cardiothoracic ratio on chest X-ray, and left ventricular ejection fraction (LVEF) on echocardiography (all p-values < 0.001, except for SBP p=0.002, and NT-proBNP p=0.004). Daytime SpO2and BMI strongly correlated across ages. Differences in renal function, diabetes control, and LVEF were notable between sex and ages. Analysis also showed the more prevalence and severity of SDB in coronary artery disease and heart failure, versus lower in pulmonary hypertension. Heatmaps of daytime SpO2 and BMI can effectively predict the severe SDB in patients with CVDs, suggesting the potential for efficient therapeutic interventions for SDB.

Conclusion

Coronary artery disease and heart failure were associated with a higher prevalence and a greater risk of moderate to severe SDB, typically in older patients. Notably, low SpO2during daytime and elevated BMI were indicative of SDB across all age categories for both sexes.
Convergent Acquisition of Glucomannan β-galactosyltransferases in Asterids and Rosids
Authors: Ishida Konan , Penner Matthew , Fukushima Kenji , Yoshimi Yoshihisa , Wilson Louis F.L. , Echevarría-Poza Alberto , Yu Li , Dupree Paul
Published: June 2024

β-Galactoglucomannan (β-GGM) is a primary cell wall polysaccharide in rosids and asterids. The β-GGM polymer has a backbone of repeating glucose and mannose, usually with mono- or di-galactosyl sidechains on the mannosyl residues. CELLULOSE SYNTHASE-LIKE 2 (CSLA2), MANNAN α-GALACTOSYLTRANSFERASE (MAGT), and MANNAN β-GALACTOSYLTRANSFERASE (MBGT) are required for β-GGM synthesis inArabidopsis thaliana. The single MBGT identified so far,AtMBGT1, lies in glycosyltransferase family 47A subclade VII, and was identified in Arabidopsis. However, despite the presence of β-GGM, an orthologous gene is absent in tomato (Solanum lycopersicum), a model asterid. In this study, we screened candidateMBGTgenes from the tomato genome, functionally tested the activities of encoded proteins, and identified the tomato MBGT (SlMBGT1) in GT47A-III. Interestingly therefore,AtMBGT1 andSlMBGT1 are located in different GT47A subclades. Further, phylogenetic and glucomannan structural analysis from different species raised the possibility that various asterids possess conserved MBGTs in GT47A-III, indicating that MBGT activity has been acquired convergently among asterids and rosids. Although functional convergence was observed, the acquired amino acid substitutions among the two MBGT groups were not shared, suggesting different evolutionary pathways to achieve the same biochemical outcome. The present study highlights the promiscuous emergence of donor and acceptor preference in GT47A enzymes, and suggests an adaptive advantage for eudicots to acquire β-GGM β-galactosylation.
Prenatal Exposure to the Genocide against the Tutsi in Rwanda is associated with DNA methylation at candidate genes in early adulthood: the role of trauma severity and postnatal adversity
Authors: Rivera Luisa Maria , Uwizeye Glorieuse , Stolrow Hannah , Christensen Brock , Rutherford Julienne , Thayer Zaneta
Published: June 2024

We investigated associations between prenatal genocidal trauma, including maternal rape, and postnatal adverse childhood experiences (ACEs) on DNA methylation of genes associated with the stress response. In a comparative cross-sectional study of 91 Rwandan young adults, categorized by prenatal exposure to genocide and maternal rape, genocide without rape, and unexposed controls, we analyzed DNA methylation from dried blood spots and assessed ACEs and mental health at age 24. Prenatal exposure to maternal rape was associated with DNA methylation changes inBDNFandSLC6A4, with the association inBDNFattenuated by ACEs exposure. Genocide exposure without rape was associated with methylation changes inPRDM8after adjusting for early adversity. Methylation inBDNFandSLC6A4correlated with mental health scores. These findings underscore the impact of prenatal and postnatal trauma on DNA methylation and mental health, emphasizing the need for continued support for survivors in the decades after conflict.
Evaluation of a flow cytometry-based surrogate assay (FlowSA) for the detection of SARS-CoV-2 in clinical samples
Authors: Upasani Vinit , Knoester Marjolein , Pantano Daniele , Gard Lili , Smit Jolanda M. , van der Gun Bernardina T.F. , Tami Adriana , Rodenhuis-Zybert Izabela A.
Published: June 2024

The current diagnostic methods for SARS-CoV-2 rely on quantitative RT-PCR. However, the presence of viral RNA in samples does not necessarily reflect the presence of an infectious virus. Therefore, the reliable detection of infectious SARS-CoV-2 in clinical samples is necessary to limit viral transmission. Here, we developed a flow cytometry-based surrogate assay (FlowSA), wherein the presence of infectious SARS-CoV-2 was detected using virus nucleocapsid-specific antibodies. We showed that FlowSA allows the detection of a wide range of viral titers of multiple SARS-CoV-2 variants. Furthermore, the assay was successfully used to detect infectious SARS-CoV-2 in nasopharyngeal swabs from SARS-CoV-2 positive individuals, including those with high Ct values. Notably, FlowSA identified the presence of infectious SARS-CoV-2 in biological specimens that scored negative for cytopathic effect (CPE) in cell culture and would otherwise be considered negative. We propose that FlowSA can be adopted as an alternative to conventional CPE methods for viral diagnostics.
Suspected Adverse Drug Reactions Associated with Leukotriene Receptor Antagonists Versus First Line Asthma Medications: A National Registry-Pharmacology Approach
Authors: Khan Mohammed , Hirsch Christine , Jones Alan M.
Published: June 2024

Aims

To determine the suspected adverse drug reaction (ADR) profile of leukotriene receptor antagonists (LTRAs: montelukast and zafirlukast) relative to first-line asthma medications short-acting beta agonists (SABA: salbutamol) and inhaled corticosteroid (ICH: beclomethasone) in the United Kingdom. To determine chemical and pharmacological rationale for the suspected ADR signals.

Methods

Properties of the asthma medications (pharmacokinetics and pharmacology) were datamined from the chemical database of bioactive molecules with drug-like properties, European molecular Biology laboratory (ChEMBL). Suspected ADR profiles of the asthma medications was curated from the Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card interactive drug analysis profiles (iDAP) and concatenated to the standardised prescribing levels (Open Prescribing) between 2018-2023.

Results

Total ADRs per 100,000Rx(P< .001) and psychiatric system organ class (SOC) ADRs (P< .001) reached statistical significance. Montelukast exhibited the greatest ADR rate at 15.64 per 100,000Rx. The low lipophilic ligand efficiency (LLE = 0.15) of montelukast relative to the controls may explain the promiscuity of interactions with off-target G-coupled protein receptors (GPCRs). This included the dopamine signalling axis, which in combination with bioaccumulation in the cerebrospinal fluid (CSF) to achieve Cmaxbeyond a typical dose can be ascribed to the psychiatric side effects observed. Cardiac ADRs did not reach statistical significance but inhibitory interaction of montelukast with the MAP kinase p38 alpha (a cardiac protective pathway) was identified as a potential rationale for montelukast withdrawal cardiac effects.

Conclusion

Relative to the controls, montelukast displays a range of suspected system organ class level ADRs. For psychiatric ADR, montelukast is statistically significant (P< .001). A mechanistic hypothesis is proposed based on polypharmacological interactions in combination with CSF levels attained. This work further supports the close monitoring of montelukast for neuropsychiatric side effects.
The GenoPred Pipeline: A Comprehensive and Scalable Pipeline for Polygenic Scoring
Authors: Pain Oliver , Al-Chalabi Ammar , Lewis Cathryn M.
Published: June 2024

Motivation

Polygenic scoring is a commonly used approach for estimating an individual’s likelihood of a given outcome. Polygenic scores are typically calculated using genetic effects derived from genome-wide association study (GWAS) summary statistics and individual-level genotype data for the target sample. Using a reference-standardised framework ensures the polygenic score can be reliably interpreted. Going from genotype to interpretable polygenic scores involves many steps and there are many methods available, limiting the accessibility of polygenic scores for research and clinical application. Additional challenges exist for studies in ancestrally diverse populations. We have implemented the leading polygenic scoring methodologies within an easy-to-use pipeline called GenoPred.

Results

Here we present the GenoPred pipeline, an easy-to-use, high-performance, reference-standardised and reproducible workflow for polygenic scoring. The pipeline requires just a few readily available inputs to get started, with configuration options available to cater for a range of use-cases. GenoPred implements a comprehensive set of analyses, including genotype and GWAS quality control, target sample ancestry inference, polygenic score file generation using a range of leading methods, and target sample scoring. GenoPred standardises the polygenic scoring process using reference genetic data, providing interpretable polygenic scores, and improving the transferability of results to external datasets. The pipeline is applicable to GWAS and target data from any population within the reference, facilitating studies of diverse ancestry. GenoPred is a Snakemake pipeline with associated Conda software environments, ensuring reproducibility. We apply the pipeline to UK Biobank data demonstrating the pipeline’s simplicity, efficiency, and performance. GenoPred is open-source software, that will continue to develop as polygenic scoring methodology develops.

Conclusions

The GenoPred pipeline provides a novel resource for polygenic scoring, integrating a range of complex processes within an easy-to-use framework. GenoPred widens access of the leading polygenic scoring methodology and their application to studies of diverse ancestry.
A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG
Authors: Dalton Hans M , Young Naomi J , Berman Alexys R , Evans Heather D , Peterson Sydney J , Patterson Kaylee A , Chow Clement Y
Published: June 2024

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We performed a drug repurposing screen on a model of DPAGT1-CDG in Drosophila ("DPAGT1 model") using 1,520 small molecules that are 98% FDA/EMA-approved. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor rescued the DPAGT1 model. Loss of both dopamine synthesis and recycling rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.
Visualization of Type IV-A1 CRISPR-mediated repression of gene expression and plasmid replication
Authors: Sanchez-Londono Mariana , Rust Selina , Hernández-Tamayo Rogelio , Gomes-Filho José Vicente , Thanbichler Martin , Randau Lennart
Published: June 2024

Type IV CRISPR-Cas effector complexes are often encoded on plasmids and are proposed to prevent the replication of competing plasmids. The Type IV-A1 CRISPR-Cas system ofPseudomonas oleovoransadditionally harbors a CRISPR RNA (crRNA) that tightly regulates the transcript levels of a chromosomal target and represents a natural CRISPR interference (CRISPRi) tool. This study investigates CRISPRi effects of this system using synthetic crRNAs against genome and plasmid sequences. Targeting of reporter genes revealed extended interference inP. oleovoransandEscherichia colicells producing recombinant CRISPR ribonucleoprotein (crRNP) complexes. RNA-Seq analyses of Type IV-A1 CRISPRi-induced transcriptome alterations demonstrated highly effective long-range down-regulation of histidine operon expression, whereas CRISPRi effects of dCas9 remained limited to the vicinity of its binding site. Single-molecule microscopy uncovered the localization dynamics of crRNP complexes. The tracks of fluorescently labeled crRNPs co-localized with regions of increased plasmid replication, supporting efficient plasmid targeting. These results identify mechanistic principles that facilitate the application of Type IV-A1 CRISPRi for the regulation of gene expression and plasmid replication.
In-host evolution ofYersinia enterocoliticaduring a chronic human infection
Authors: Cyril Savin , Pierre Lê-Bury , Julien Guglielmini , Thibaut Douché , Rodolphe Buzelé , Cécile Le Brun , Frédéric Bastides , Maud François , Béatrice Birmelé , Laura Guichard , Nicolas Cabanel , Laurent Dortet , Mariette Matondo , Olivier Dussurget , Elisabeth Carniel , Philippe Lanotte , Javier Pizarro-Cerdá
Published: June 2024

Following a pacemaker implantation, a 75-years-old patient suffered from five successive bacteremia episodes between in 1999 and 2013 despite long-term antibiotic treatment, with intermittent vegetation apparition on the device atrial lead. Four blood isolates, identified asYersinia enterocoliticabioserotype 4/O:3, were further genetically and phenotypically characterized. Phylogenetic reconstruction showed that the patient was chronically infected by the same strain, which evolved within the host for 14 years. Single-nucleotide polymorphism (SNP) analysis indicates that the last two isolates evolved in parallel and formed two independent lineages within the host. Pan-genome analysis and genome comparison showed that their common evolution was characterized by 41 small insertion/deletion events, loss of three large DNA fragments and mutations in 140 genes. A phylogenetic analysis by maximum likelihood identified two genes presenting a positive selection signal, suggesting that these mutations provided a survival advantage to bacteria during chronic infection. Quinolone resistance in the last two isolates was acquired through a so far undescribed deletion in thegyrAgene.

Mass-spectrometry analysis revealed a strong proteome remodeling in the last two isolates which was correlated with a truncation in the stringent response regulator DksA. A reduced carbon, energy and purine metabolism supports their severe growth defectsin vitro. 3rd-generation cephalosporin resistance of the last isolate was correlated with a truncation of OmpF, the main porin translocating antibiotics through the outer-membrane, as well as an increased production of BlaA and AmpC β-lactamases.

This is the first report of genetic and phenotypic changes associated to within-host adaptation of a pathogenicYersiniaspecies under antibiotic pressure.
Activation of NF-κB signaling by optogenetic clustering of IKKα and β
Authors: Fischer Alexandra A.M. , Grimm Merlin M. , Fliegauf Manfred , Grimbacher Bodo , Rahmann Sven , Weber Wilfried
Published: June 2024

A large percentage of proteins form higher-order structures in order to fulfill their function. These structures are crucial for the precise spatial and temporal regulation of the cellular signaling network. Investigation of this network requires sophisticated research tools, such as optogenetic tools, that allow dynamic control over the signaling molecules. Cryptochrome 2 and its variations are the best-characterized oligomerizing photoreceptors the optogenetics toolbox has to offer. Therefore, we utilized this switch and combined it with an eGFP-binding nanobody, to build a toolbox of optogenetic constructs that enables the oligomerization of any eGFP-tagged protein of interest. We further introduced the higher clustering variant Cry2oligand an intrinsically disordered region to create higher-order oligomers or phase-separated assemblies to investigate the impact of different oligomerization states on eGFP-tagged signaling molecules. We apply these constructs to cluster IKKα and IKKβ, which resemble the central signaling integrator of the NF-κB pathway, thereby engineer a potent, blue-light-inducible activator of NF-κB signaling.
Ankyrin-B is required for the establishment and maintenance of lens cytoarchitecture, mechanics, and clarity
Authors: Maddala Rupalatha , Allen Ariana , Skiba Nikolai P. , Rao Ponugoti Vasantha
Published: June 2024

Summary Statement

This study illustrates a vital role for ankyrin-B in lens architecture, growth and function through its involvement in membrane protein and spectrin-actin cytoskeletal organization and stability

The transparent ocular lens is essential for vision by focusing light onto the retina. Despite recognizing the importance of its unique cellular architecture and mechanical properties, the molecular mechanisms governing these attributes remain elusive. This study aims to elucidate the role of ankyrin-B (AnkB), a membrane scaffolding protein, in lens cytoarchitecture, growth and function using a conditional knockout (cKO) mouse model. AnkB cKO mouse has no defects in lens morphogenesis, but exhibited changes that supported a global role for AnkB in maintenance of lens clarity, size, cytoarchitecture, and stiffness. Notably, absence of AnkB led to nuclear cataract formation, evident from P16. AnkB cKO lens fibers exhibit progressive disruption in membrane organization of the spectrin-actin cytoskeleton, channel proteins, cell-cell adhesion, shape change, loss and degradation of several membrane proteins (e.g., NrCAM. N-cadherin and aquaporin-0) along with a disorganized plasma membrane and impaired ball-and-socket membrane interdigitations. Furthermore, absence of AnkB led to decreased lens stiffness. Collectively, these results illustrate the essential role for AnkB in lens architecture, growth and function through its involvement in membrane protein and cytoskeletal organization.
Development of inducible promoter and CRISPRi plasmids functional inRickettsia rickettsii
Authors: Nock Adam M. , Clark Tina R. , Hackstadt Ted
Published: June 2024

Rickettsia rickettsiiis an obligate intracellular, tick-borne bacterium that causes Rocky Mountain spotted fever. The demanding nature of cultivating these bacteria within host cells and the labor involved in obtaining clonal isolates has severely limited progress regarding the development of compatible genetic tools to study this pathogen. Conditional expression of genes which might be toxic or have an otherwise undesirable effect is the next logical goal to expand upon the constitutive expression plasmids generated thus far. We describe the construction of an inducible promoter system based on the tet-On system, leveraging design elements from the anhydrotetracycline inducible promoter system used forBorrelia burgdorferiand one of the few characterized rickettsial promoters for the outer membrane gene,rompB(sca5). The functionality of this promoter is demonstrated via fluorescence of induced mScarlet production and was then used to construct a generalized inducible expression vector forR. rickettsii. The development of a functional inducible promoter was then applied to the construction of a CRISPR interference plasmid as a means to reduce or essentially silence the transcription of targeted genes. We demonstrate the viability of a simplified, single vector CRISPRi system to disrupt gene expression inR. rickettsiitargeting the type IV secreted effectorrarP2and autotransporter peptidaserapLas examples.

IMPORTANCE

This work expands upon the genetic toolbox available forR. rickettsii. This is the first report of both an inducible promoter and CRISPRi system compatible withRickettsia, which may provide key instruments for the development of further tools. The development of an inducible promoter system allows for the overexpression of genes which might be toxic when expressed constitutively. The CRISPRi system enables the ability to knockdown genes with specificity, and critically, genes which may be essential and could not otherwise be knocked out. These developments may provide the foundation for unlocking genetic tools for other pathogens of the order Rickettsiales, such as theAnaplasma,Orientia, andEhrlichiafor which there are currently no inducible promoters or CRISPRi platforms.
DNA Nicks Drive Massive Expansions of (GAA)nRepeats
Authors: Li Liangzi , Scott W. Shem , Khristich Alexandra N. , Armenia Jillian F. , Mirkin Sergei M.
Published: June 2024

Over 50 hereditary degenerative disorders are caused by expansions of short tandem DNA repeats (STRs). (GAA)nrepeat expansions are responsible for Friedreich’s ataxia as well as late-onset cerebellar ataxias (LOCAs). Thus, the mechanisms of (GAA)nrepeat expansions attract broad scientific attention. To investigate the role of DNA nicks in this process, we utilized a CRISPR-Cas9 nickase system to introduce targeted nicks adjacent to the (GAA)nrepeat tract. We found that DNA nicks 5’ of the (GAA)100run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)nrepeats, recreating, for the first time in a model system, the expansion events that occur in human pedigrees. DNA nicks 3’ of the (GAA)100repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5’ strand nicks increase expansion frequency in non-dividing yeast cells, albeit to a lesser extent that in dividing cells.
Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors ofChikungunyansP2 Cysteine Protease with Anti-alphavirus Activity
Authors: Ghoshal Anirban , Asressu Kesatebrhan Haile , Hossain Mohammad Anwar , Brown Peter J. , Merten Eric M. , Sears John D. , Perveen Sumera , Pearce Kenneth H. , Popov Konstantin I. , Moorman Nathaniel J. , Heise Mark T. , Willson Timothy M.
Published: June 2024

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of1athat varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition ofChikungunya(CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog8dexhibited akinact/Kiratio >10,000 M-1s-1. 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like1a. The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.
Cost-effectiveness analysis of the geko™ device (an NMES technology) in managing venous leg ulcers in UK healthcare setting
Authors: Tuson Richard , Metry Andrew , Harding Keith
Published: June 2024

Objective

This study evaluates the cost-effectiveness of the geko device a neuromuscular electro-stimulator (NMES) technology with standard of care versus standard of care alone for venous leg ulcers treatment, from the UK National Health Service perspective over 12 months.

Setting

Research was conducted across NHS UK facilities, primarily within community services and outpatient leg ulcer clinics, encompassing a total of 51 patients.

Method

A partitioned survival model, based on a two-arm randomised controlled trial, assessed wound healing rates using Kaplan–Meier curves and parametric extrapolations over a 12-month time horizon. Costs were derived from UK reference costs the British National Formulary, and the Personal Social Services Research Unit (2021/22). The primary outcome measured was the incremental cost per quality-adjusted life-year gained. The geko device provides additional benefits by stimulating the lateral popliteal nerve, augmenting venous, arterial and microvascular flow.

Results

The addition of the geko device to standard of care significantly enhanced outcomes, increasing healing probability by 68% compared to standard of care. This integration would result in a cost saving of £774.14 per patient when compared to the standard of care alone across the NHS. Economic analyses indicate that integrating the geko device into standard of care protocols would reduce the overall NHS expenditure on venous leg ulcer wound management by as much as 15%. The approach also positively impacted health-related quality of life.

Conclusion

The geko™ device when used adjunctively with standard of care would be a cost-effective method for managing chronic venous leg ulcers within the NHS, improving healing rates and offering economic benefits.

Key messages

Enhanced Healing Rates

The addition of the geko™ device (an NMES technology) to standard of care significantly increases the probability of healing in patients with chronic venous leg ulcers.

Economic Advantage

Incorporating the geko device into standard of care would lead to a reduction in the overall costs of wound management in the NHS, potentially up to 15%.

Cost-Effectiveness

The combination of the geko device and standard of care demonstrates cost-effectiveness, offering a favourable balance between costs and quality-adjusted life years gained.

Improved Quality of Life

The use of the geko device in addition to standard of care impacts positively the health-related quality of life for patients.

Consistent Outcomes in Sensitivity Analysis

Sensitivity analyses support the cost dominance of the combined treatment approach, indicating robustness in various scenarios.

Policy Implications

These findings suggest that the integration of the geko device technology would be a viable policy option for enhancing venous leg ulcer treatment within the NHS.
Innovative COVID-19 Point-of-Care Diagnostics Suitable for Tuberculosis Diagnosis: A Scoping Review
Authors: Holtgrewe Lydia , Jain Sonal , Dekova Ralitza , Broger Tobias , Isaacs Chris , Nahid Payam , Cattamanchi Adithya , Denkinger Claudia M. , Yerlikaya Seda
Published: June 2024

Introduction

Rapid and accurate point-of-care (POC) tuberculosis (TB) diagnostics are a key priority to close the TB diagnostic gap of 3.1 million people without a diagnosis. Leveraging the recent surge in COVID-19 diagnostic innovation, we explored the potential adaptation of commercially available SARS-CoV-2 tests for TB diagnosis, aligning with World Health Organization (WHO) target product profiles (TPPs).

Methods

A scoping review was conducted following PRISMA-ScR guidelines to systematically map commercially available POC molecular and antigen SARS-CoV-2 diagnostic tests potentially meeting the TPPs for TB diagnostic tests for peripheral settings. Data were gathered from PubMed/MEDLINE, bioRxiv, and medRxiv, along with publicly accessible in vitro diagnostic test databases, and developer websites, up to November 23, 2022. Data on developer and test attributes, operational characteristics, pricing, and clinical performance were charted using standardized data extraction forms. Each identified test was evaluated using a standardized scorecard. A narrative synthesis of the charted data is presented.

Results

Our database search yielded 2,003 studies, from which 408 were considered eligible. Among these, we identified 58 commercialized diagnostic devices, including 17 near-POC antigen tests, one POC molecular test, 29 near-POC molecular tests, and 11 low-complexity molecular tests. We summarized the detailed characteristics, regulatory status, and clinical performance data of these tests. The LumiraDx (Roche, Switzerland) emerged as the highest- scoring near-POC antigen platform, while Visby (Visby, USA) was the highest-performing near-POC molecular platform. The Lucira Check-It (Pfizer, USA) was noted as the sole POC molecular test. The IdyllaTM(Biocartis, Switzerland) was identified as the leading low- complexity molecular test.

Discussion

We highlight a diverse landscape of commercially available diagnostic tests suitable for potential adaptation to TB POC testing. This work aims to bolster global TB initiatives by fostering stakeholder collaboration, leveraging COVID-19 diagnostic technologies for TB diagnosis, and uncovering new commercial avenues to tackle longstanding challenges in TB diagnosis.
Introducing the concept of the Widom line in the QCD phase diagram
Authors: Sordi G. , Tremblay A.-M. S.
Published: June 2024

Critical phenomena emerging from the critical end point of a first-order transition are ubiquitous in nature. Here we bring the concept of a supercritical crossover, the Widom line, initially developed in the context of fluids, into the interacting matter described by quantum chromodynamics (QCD). We show that the existence of the putative critical end point between hadron gas and quark-gluon plasma in the temperature versus chemical potential of the QCD phase diagram implies the existence of a Widom line emerging from it in the supercritical region. We survey the thermodynamic anomalies already identified in simplified theoretical models of QCD exhibiting a critical end point, to show that they can be interpreted in terms of a Widom line. Then we suggest possible directions where the Widom line concept could provide new light on the QCD phase diagram.

Published by the American Physical Society
2024
Do promoters cause financial distress in a bank?
Authors: Rastogi Shailesh , Kanoujiya Jagjeevan
Published: June 2024

Purpose

The study aims to explore the impact of ownership concentration (OC) on bank financial distress (FD). Furthermore, the bank’s financial stability levels determine the association between the two.

Design/methodology/approach

Bank data of 33 Indian commercial banks are procured for ten years (2013–2022). The panel data econometrics is applied for empirical estimations. The quantile regression approach is used to determine the association between OC and FD at different quantiles of the FD. Non-normalcy of the data is checked and ensured before applying the quantile regression.

Findings

Surprisingly, it is found that promoters have a nonlinear impact on the firm’s stability. The inverted U-shape result implies that as promoters cross a threshold level, the benefit of increasing promoters’ stake takes a beating and a further increase in promoters’ stakes adversely impacts the stability of the banks. Moreover, this threshold value increases while moving from low to high levels of stability in a quantile regression application.

Research limitations/implications

This study uses promoters as the proxy for OC. Other existing definitions of OC are not used in the study, which can further improve the robustness of the results. Additionally, the use of the type of ownership (private, public or foreign) is also not adopted in the present study. Both the limitations can be the study’s future scope on the topic.

Practical implications

The high OC is supposed to influence corporate governance adversely. Therefore, policymakers recommend low OC for better governance. However, the present study finds evidence that a higher OC (high threshold of OC as the stability increases) would be better for financial stability. This situation demands a trade-off between governance and financial stability regarding OC.

Originality/value

The authors do not observe any study having the nonlinear impact of OC on financial stability (opposite of FD). Moreover, the threshold of OC for the optimum level of financial stability increases as stability goes high. This evidence using quantile regression and finding the turning point using a quadratic equation is also not seen in the literature.
A systematic literature review of Japanese SMEs: trends, challenges and insights for future research and practice
Authors: Elbanna Said , Begum Fareed , Mauji Nasrina
Published: June 2024

Purpose

The distinctiveness of Japanese management practices offers invaluable insights for the strategic development and operational excellence of small and medium-sized enterprises (SMEs) worldwide. Recognizing this, the purpose of this study is to explore an extensive review of the literature on Japanese SMEs. The aim is to reveal previously explored research domains and to systematically categorize the unique factors contributing to the success and challenges of SMEs. This investigation not only illuminates the peculiarities of Japanese SMEs management but also sets the stage for applying these insights globally to SMEs across diverse industries.

Design/methodology/approach

Using a systematic review approach, 63 studies on Japanese SMEs from 1996 to 2021 were identified and analyzed.

Findings

This analysis identified six critical themes in Japanese SME management: nuanced firm management practices; forefront innovation and technology; internationalization; supportive government policies; commitment to corporate social responsibility and sustainable development; and vibrant entrepreneurship. The authors also spotlight challenges like navigating global competition and adapting to rapid technological changes. These insights, alongside noted methodological gaps in existing literature, suggest fertile grounds for future research and hold significant implications for SMEs globally.

Originality/value

The investigation of Japanese SMEs in this study highlights valuable insights for SMEs, policymakers and scholars, as it represents a rich and distinctive research phenomenon with various organizational, cultural, economic and political implications.
Enterprising spirit rejuvenated: entrepreneurship education in shaping company employees' career commitment and turnover intentions
Authors: Chang Yu-Yu , Chang Wei-Shiun , Fadhil Ahmad
Published: June 2024

Purpose

Entrepreneurship education is widely regarded as a fundamental means of fostering individuals' entrepreneurial intentions. In this paper, we delve into a distinctive empirical context: the integration of entrepreneurship education within Indonesia’s nationwide higher education system since 2010. Our goal is to investigate how prior participation in mandatory entrepreneurship training by company employees influences their inclination to leave their current employment and initiate a new business.

Design/methodology/approach

We employed structural equation modeling to analyze empirical data (n = 337) collected from full-time Indonesian employees in established companies.

Findings

Our findings indicate that previous engagement in entrepreneurship education predicts employees' entrepreneurial intentions, leading to reduced commitment to their current careers and an increased likelihood of having intentions to pursue new ventures. By comparing two groups of participants, our results suggest that government-mandated entrepreneurship education in Indonesia has a more substantial impact on employees' entrepreneurial intentions and turnover intentions.

Originality/value

This study, based on a unique sample from Indonesia, explores the entrepreneurial entry of organizational employees and the long-term effects of entrepreneurship education.
Effect of meal timing and frequency on lipid profile in adults: an overview of systematic reviews and meta-analyses
Authors: Yong Alene Sze Jing , Koo Rosamund Wei Xin , Ng Choon Ming , Lee Shaun Wen Huey , Teoh Siew Li
Published: June 2024

Purpose

Dyslipidaemia is an established risk factor for cardiovascular diseases. Calorie restriction and adopting a heart-healthy diet like the Mediterranean diet are the main dietary interventions for dyslipidaemia. Other dietary behaviours, such as changes in meal frequency and timing, are not included in the major dietary advice guidelines despite the potential correlation between eating patterns and lipid metabolism. This overview of systematic reviews and meta-analyses aims to summarise the effect of meal timing and frequency on lipid profile and make possible recommendations on which meal timing pattern is superior in reducing lipid levels.

Design/methodology/approach

According to the protocol published on PROSPERO (CRD42021248956), five databases were searched for systematic reviews and meta-analyses investigating the effects of meal timing and frequency on lipid profile in adults.

Findings

Five reviews were included, with two reviews on breakfast skipping and meal frequency, respectively, and one review on night-time eating. Increasing meal frequency while maintaining the total calorie intake was reported to reduce total cholesterol and low-density lipoprotein (LDL) levels with low- to moderate-quality evidence. There was a correlation between breakfast skipping and an undesirable increase in LDL levels with low-quality evidence. However, there needs to be more high-quality evidence to conclude the effect of dietary behaviours on blood lipid levels.

Originality/value

This overview provides a comprehensive summary of evidence examining the effects of meal timing and frequency on adult lipid profiles. The current low- or moderate-quality evidence could not support the recommendation of alteration of meal frequency as an alternative to conventional non-pharmacological treatments for dyslipidaemia.
Opinions of intensive care nurses on continuous renal replacement therapy: A qualitative study
Authors: Kılıç Gülşen , Eskigülek Yasemin , Erdoğan Bülent , Arpa Hilal , Erbaş Gizem , Baştürk Beyza
Published: June 2024

Introduction

This is a phenomenologically designed qualitative study conducted to explore and conceptualize the problems experienced by intensive care nurses caring for patients undergoing continuous renal replacement therapy.

Methods

Face‐to‐face, semi‐structured interviews were conducted with the participants. The interviews were transcribed verbatim, then thematic analysis was conducted.

Results

The study was conducted 12 intensive care nurses. As a result, 3 main and 6 sub‐themes were identified. The themes identified were changing routines, uncertainty in terms of patient benefit, and need for adaptation.

Conclusion

It was found that nurses experienced challenges in providing care to patients undergoing continuous renal replacement therapy, spent more effort to prevent complications, and lacked information on the subject. It is recommended to consider institutional and individual actions to meet the educational needs of nurses for implementing continuous renal replacement therapy.
Vismodegib in Gorlin‐Goltz syndrome: A systematic review
Authors: Palmeiro Ana Gusmão , Carvalho Mélissa , Gonçalves Castro Cristina , Pimentel Bernardo , Catorze Goreti
Published: June 2024

Treatment with Hedgehog Inhibitors in Gorlin‐Goltz syndrome (GGS) yields favourable objective clinical responses, yet secondary resistance and class‐related toxicity restrict treatment duration. This study aims to review current data on GGS patients undergoing vismodegib therapy, focusing on treatment duration, clinical outcomes and schedule modifications. A systematic search of the PubMed database was conducted for English articles from 1993 to 2023, identifying 31 papers suitable for inclusion. A total of 351 patients, with a mean age of 52 years, were analysed. The average treatment duration was 9.3 months for patients who discontinued treatment, and 25.1 months for those who continued vismodegib at the time this study was published. Vismodegib achieved a complete response rate of 44%. Treatment interruption predominantly occurred due to side effects (69.1%) and secondary resistance (9.1%). The use of alternative regimens, although not compromising efficacy, may enhance treatment compliance. Further investigations are warranted to ascertain the optimal treatment regimen and timeline for GGS patients. Schedule modifications offer promise in ameliorating side effects and facilitating long‐term treatment.
A pilot study of a brief and scalable psychosocial intervention for children and adolescents following disasters
Authors: Strauven Sarah , Dennison Meg J. , O'Donnell Meaghan L. , Cowlishaw Sean , Gibson Kari , Pedder David J. , Baur Jenelle , Nursey Jane , Cobham Vanessa E.
Published: June 2024

Objectives

Following disaster exposure, a significant proportion of children/adolescents will develop levels of post‐traumatic stress symptoms (PTSS) that do not meet diagnostic threshold for PTSD, but which cause ongoing distress. This paper describes the development and pilot testing of a brief, scalable, psychosocial intervention. SOLAR‐Kids/Teens has been designed to be delivered by non‐mental health professionals (‘coaches’) to children/adolescents experiencing moderate levels of PTSS following disasters.

Methods

An international collaboration of experts developed The Skills fOr Life Adjustment and Resilience (SOLAR) for Kids and Teens programs. The programs were piloted—using a pre‐post mixed methods design—with 10 children and adolescents (8–18 years), with the aims of examining the feasibility of the program's delivery model as well as the program's potential usefulness.

Results

The pilot data indicated that after 1 day of training and with ongoing supervision, the SOLAR program was safe and feasible for coaches to deliver to children/adolescents experiencing PTSS. Coaches reported increased knowledge (p = .001), confidence (p = .001) and skills (p = .006). The programs were acceptable to coaches, children/adolescents and parents. Parents and children/adolescents reported reductions in trauma and anxiety symptoms from pre‐ to post‐treatment, with moderate to large effect sizes.

Conclusions

The preliminary findings demonstrate that the SOLAR‐Kids/Teens program is feasible, acceptable and safe to be delivered by trained non‐mental health professionals to children and adolescents experiencing PTSS and anxiety following disaster exposure. Randomized controlled trials are required to evaluate the efficacy of the SOLAR‐Kids/Teens programs.