bluuebunny/crossref_metadata_2025 huggingface dataset:
Aggregate-selective removal of pathological tau by clustering-activated degraders
Authors: Benn Jonathan , Cheng Shi , Keeling Sophie , Smith Annabel E. , Vaysburd Marina J. , Böken Dorothea , Miller Lauren V. C. , Katsinelos Taxiarchis , Franco Catarina , Dupré Elian , Danis Clément , Landrieu Isabelle , Buée Luc , Klenerman David , James Leo C. , McEwan William A.
Published: August 2024

Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif–containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein–tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer’s and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation.
Engineering of a hydroxysteroid dehydrogenase with simultaneous enhancement in activity and thermostability for efficient biosynthesis of ursodeoxycholic acid
Authors: Li Yuan , Li Shu-Fang , Zhang Lin , Xue Ya-Ping , Zheng Yu-Guo
Published: August 2024

Hydroxysteroid dehydrogenases (HSDHs) catalyze the oxidation/reduction of hydroxyl/keto groups of steroids with high regio- or stereoselectivity, playing an essential role in producing optically pure chemicals. In this work, a novel approach was developed to simultaneously improve the stability and activity of 7β-hydroxysteroid dehydrogenase (7β-HSDH) by combining B-factor analysis and computer-aided prediction. Several advantageous mutants were identified, and the most promising variant, S51Y/P202Y, exhibited 2.3-fold improvements in catalytic activity, 3.3-fold in half-life at 40°C, and 4.7-fold in catalytic efficiency (
k
cat
/K
m
), respectively. Structural modeling analysis showed that the shortened reversible oxidation reaction catalytic distance and the strengthened residue interactions compared to the wild type were attributed to the improved stability and activity of the obtained mutants. To synthesize ursodeoxycholic acid cost-effectively by mutant S51Y/P202Y, a NAD-kinase was employed to facilitate the substitution of nicotinamide adenine dinucleotide phosphate (NADP
+
) with nicotinamide adenine dinucleotide (NAD
+
) in the whole-cell catalysis system. The substrate 7-ketolithocholic acid (100 mM) was converted completely in 0.5 h, achieving a space-time yield of 1,887.3 g L
−1
d
−1
. This work provided a general target-oriented strategy for obtaining stable and highly active dehydrogenase for efficient biosynthesis.

IMPORTANCE

Hydroxysteroid dehydrogenases have emerged as indispensable tools in the synthesis of steroids, bile acids, and other steroid derivatives for the pharmaceutical and chemical industries. In this study, a novel approach was developed to simultaneously improve the stability and activity of a hydroxysteroid dehydrogenase by combining B-factor analysis and computer-aided prediction. This semi-rational method was demonstrated to be highly effective for enzyme engineering. In addition, NAD kinase was introduced to convert NAD
+
to NADP
+
for effective coenzyme regeneration in the whole-cell multienzyme-catalyzed system. This strategy reduces the significant economic costs associated with externally supplemented cofactors in NADP-dependent biosynthetic pathways.
VP3 protein of Senecavirus A promotes viral IRES-driven translation and attenuates innate immunity by specifically relocalizing hnRNPA2B1
Authors: Li Lu , Li Xinwei , Zhong Han , Li Mingyang , Wan Bo , He Wenrui , Zhang Yuhang , Du Yongkun , Chen Dongjie , Zhang Wei , Ji Pengchao , Jiang Dawei , Han Shichong
Published: August 2024

Viruses deploy sophisticated strategies to hijack the host’s translation machinery to favor viral protein synthesis and counteract innate cellular defenses. However, little is known about the mechanisms by which Senecavirus A (SVA) controls the host’s translation. Using a series of sophisticated molecular cell manipulation techniques, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was identified as an essential host factor involved in translation control in SVA-infected cells. It was also determined that the SVA structural protein, VP3, binds to and relocalizes hnRNPA2B1, which interferes with the host’s protein synthesis machinery to establish a cellular environment that facilitates viral propagation via a two-pronged strategy: first, hnRNPA2B1 serves as a potent internal ribosome entry site (IRES)
trans
-acting factor, which is selectively co-opted to promote viral IRES-driven translation by supporting the assembly of translation initiation complexes. Second, a strong repression of host cell translation occurs in the context of the VP3-hnRNPA2B1 interaction, resulting in attenuation of the interferons response. This is the first study to demonstrate the interaction between SVA VP3 and hnRNPA2B1, and to characterize their key roles in manipulating translation. This novel dual mechanism, which regulates selective mRNA translation and immune evasion of virus-infected cells, highlights the VP3-hnRNPA2B1 complex as a potential target for the development of modified antiviral or oncolytic reagents.

IMPORTANCE

Viral reproduction is contingent on viral protein synthesis, which relies entirely on the host's translation machinery. As such, viruses often need to control the cellular translational apparatus to favor viral protein production and avoid host innate defenses. Senecavirus A (SVA) is an important virus, both as an emerging pathogen in the pork industry and as a potential oncolytic virus for neuroendocrine cancers. Here, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was identified as a critical regulator of the translational landscape during SVA infection. This study supports a model whereby the VP3 protein of SVA efficiently subverts the host’s protein synthesis machinery through its ability to bind to and relocalize hnRNPA2B1, not only selectively promoting viral internal ribosome entry site-driven translation but also resulting in global translation shutdown and immune evasion. Together, these data provide new insights into how the complex interactions between translation machinery, SVA, and innate immunity contribute to the pathogenicity of the SVA.
Small archaea may form intimate partnerships to maximize their metabolic potential
Authors: Baker Brett J. , Sarno Natalie
Published: August 2024

DPANN archaea have characteristically small cells and unique genomes that were long overlooked in diversity surveys. Their reduced genomes often lack essential metabolic pathways, requiring symbiotic relationships with other archaeal and bacterial hosts for survival. Yet a long-standing question remains, what is the advantage of maintaining ultrasmall cells. A recent study by Zhang et al. examined genomes of DPANN archaea from marine oxygen deficient zones (ODZs) (I. H. Zhang, B. Borer, R. Zhao, S. Wilbert, et al., mBio 15:e02918-23, 2024,
https://doi.org/10.1128/mbio.02918-23
). Surprisingly, these genomes contain a broad array of metabolic pathways including genes predicted to be involved in nitrous oxide (N
2
O) reduction. However, N
2
O levels are likely too low in ODZs to make this metabolically feasible. Modeling co-localization of DPANN archaea (N
2
O consumers) with other larger cells (N
2
O producers) demonstrates that N
2
O uptake rates can be optimized by maximizing the producer-to-consumer size ratio and proximity of consumer cells to producers. This may explain why such a diversity of archaea maintain extremely small cell sizes.
Role of IgA1 protease-producing bacteria in SARS-CoV-2 infection and transmission: a hypothesis
Authors: Russell Michael W. , Kilian Mogens , Mestecky Jiri
Published: August 2024

Secretory (S) IgA antibodies against severe acute respiratory syndrome (SARS)-CoV-2 are induced in saliva and upper respiratory tract (URT) secretions by natural infection and may be critical in determining the outcome of initial infection. Secretory IgA1 (SIgA1) is the predominant isotype of antibodies in these secretions. Neutralization of SARS-CoV-2 is most effectively accomplished by polymeric antibodies such as SIgA. We hypothesize that cleavage of SIgA1 antibodies against SARS-CoV-2 by unique bacterial IgA1 proteases to univalent Fabα antibody fragments with diminished virus neutralizing activity would facilitate the descent of the virus into the lungs to cause serious disease and also enhance its airborne transmission to others. Recent studies of the nasopharyngeal microbiota of patients with SARS-CoV-2 infection have revealed significant increases in the proportions of IgA1 protease-producing bacteria in comparison with healthy subjects. Similar considerations might apply also to other respiratory viral infections including influenza, possibly explaining the original attribution of influenza to
Haemophilus influenzae
, which produces IgA1 protease.
Diagnosis and mitigation of the systemic impact of genome reduction in
Escherichia coli
DGF-298
Authors: Champie Antoine , Lachance Jean-Christophe , Sastry Anand , Matteau Dominick , Lloyd Colton J. , Grenier Frédéric , Lamoureux Cameron R. , Jeanneau Simon , Feist Adam M. , Jacques Pierre-Étienne , Palsson Bernhard O. , Rodrigue Sébastien
Published: August 2024

Microorganisms with simplified genomes represent interesting cell chassis for systems and synthetic biology. However, genome reduction can lead to undesired traits, such as decreased growth rate and metabolic imbalances. To investigate the impact of genome reduction on
Escherichia coli
strain DGF-298, a strain in which ~ 36% of the genome has been removed, we reconstructed a strain-specific metabolic model (
i
AC1061), investigated the regulation of gene expression using iModulon-based transcriptome analysis, and performed adaptive laboratory evolution to let the strain correct potential imbalances that arose during its simplification. The model notably predicted that the removal of all three key pathways for glycolaldehyde disposal in this microorganism would lead to a metabolic bottleneck through folate starvation. Glycolaldehyde is also known to cause self-generation of reactive oxygen species, as evidenced by the increased expression of oxidative stress resistance genes in the SoxS iModulon. The reintroduction of the
aldA
gene, responsible for one native glycolaldehyde disposal route, alleviated the constitutive oxidative stress response. Our results suggest that systems-level approaches and adaptive laboratory evolution have additive benefits when trying to repair and optimize genome-engineered strains.

IMPORTANCE

Genomic streamlining can be employed in model organisms to reduce complexity and enhance strain predictability. One of the most striking examples is the bacterial strain
Escherichia coli
DGF-298, notable for having over one-third of its genome deleted. However, such extensive genome modifications raise the question of how similar this simplified cell remains when compared with its parent, and what are the possible unintended consequences of this simplification. In this study, we used metabolic modeling along with iModulon-based transcriptomic analysis in different growth conditions to assess the impact of genome reduction on metabolism and gene regulation. We observed little impact of genomic reduction on the regulatory network of
E. coli
DGF-298 and identified a potential metabolic bottleneck leading to the constitutive activity of the SoxS iModulon. We then leveraged the model's predictions to successfully restore SoxS activity to the basal level.
Uncovering the roles of the scaffolding protein CsoS2 in mediating the assembly and shape of the α-carboxysome shell
Authors: Li Tianpei , Chen Taiyu , Chang Ping , Ge Xingwu , Chriscoli Vincent , Dykes Gregory F. , Wang Qiang , Liu Lu-Ning
Published: August 2024

Carboxysomes are proteinaceous organelles featuring icosahedral protein shells that enclose the carbon-fixing enzymes, ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco), along with carbonic anhydrase. The intrinsically disordered scaffolding protein CsoS2 plays a vital role in the construction of α-carboxysomes through bridging the shell and cargo enzymes. The N-terminal domain of CsoS2 binds Rubisco and facilitates Rubisco packaging within the α-carboxysome, whereas the C-terminal domain of CsoS2 (CsoS2-C) anchors to the shell and promotes shell assembly. However, the role of the middle region of CsoS2 (CsoS2-M) has remained elusive. Here, we conducted in-depth examinations on the function of CsoS2-M in the assembly of the α-carboxysome shell by generating a series of recombinant shell variants in the absence of cargos. Our results reveal that CsoS2-M assists CsoS2-C in the assembly of the α-carboxysome shell and plays an important role in shaping the α-carboxysome shell through enhancing the association of shell proteins on both the facet-facet interfaces and flat shell facets. Moreover, CsoS2-M is responsible for recruiting the C-terminal truncated isoform of CsoS2, CsoS2A, into α-carboxysomes, which is crucial for Rubisco encapsulation and packaging. This study not only deepens our knowledge of how the carboxysome shell is constructed and regulated but also lays the groundwork for engineering and repurposing carboxysome-based nanostructures for diverse biotechnological purposes.

IMPORTANCE

Carboxysomes are a paradigm of organelle-like structures in cyanobacteria and many proteobacteria. These nanoscale compartments enclose Rubisco and carbonic anhydrase within an icosahedral virus-like shell to improve CO
2
fixation, playing a vital role in the global carbon cycle. Understanding how the carboxysomes are formed is not only important for basic research studies but also holds promise for repurposing carboxysomes in bioengineering applications. In this study, we focuses on a specific scaffolding protein called CsoS2, which is involved in facilitating the assembly of α-type carboxysomes. By deciphering the functions of different parts of CsoS2, especially its middle region, we provide new insights into how CsoS2 drives the stepwise assembly of the carboxysome at the molecular level. This knowledge will guide the rational design and reprogramming of carboxysome nanostructures for many biotechnological applications.
Rubella virus assembly requirements and evolutionary relationships with novel rubiviruses
Authors: Das Pratyush Kumar , Kielian Margaret
Published: August 2024

Rubella virus (RuV) is an enveloped virus that usually causes mild disease in children, but can produce miscarriage or severe congenital birth defects. While in nature RuV only infects humans, the discovery of the related Ruhugu (RuhV) and Rustrela (RusV) viruses highlights the spillover potential of mammalian rubiviruses to humans. RuV buds into the Golgi, but its assembly and exit are not well understood. We identified a potential late domain motif
278
PPAY
281
at the C-terminus of the RuV E2 envelope protein. Such late domain motifs can promote virus budding by recruiting the cellular ESCRT machinery. An E2 Y281A mutation reduced infectious virus production by >3 logs and inhibited virus particle production. However, RuV was insensitive to inhibition by dominant-negative VPS4, and thus appeared ESCRT-independent. The E2 Y281A mutation did not significantly inhibit the production of the viral structural proteins capsid (Cp), E2, and E1, or dimerization, glycosylation, Golgi transport, and colocalization of E2 and E1. However, E2 Y281A significantly reduced glycoprotein-Cp colocalization and interaction, and inhibited Cp localization to the Golgi. Revertants of the E2 Y281A mutant contained an E2 281V substitution or the second site mutations [E2 N277I + Cp D215A]. These mutations promoted virus growth, particle production, E2/Cp colocalization and Cp-Golgi localization. Both the E2 substitutions 281V and 277I were found at the corresponding positions in the RuhV E2 protein. Taken together, our data identify a key interaction of the RuV E2 endodomain with the Cp during RuV biogenesis, and support the close evolutionary relationship between human and animal rubiviruses.

IMPORTANCE

Rubella virus (RuV) is an enveloped virus that only infects humans, where transplacental infection can cause miscarriage or congenital birth defects. We identified a potential late domain,
278
PPAY
281
, at the C terminus of the E2 envelope protein. However, rather than this domain recruiting the cellular ESCRT machinery as predicted, our data indicate that E2 Y281 promotes a critical interaction of the E2 endodomain with the capsid protein, leading to capsid's localization to the Golgi where virus budding occurs. Revertant analysis demonstrated that two substitutions on the E2 protein could partially rescue virus growth and Cp-Golgi localization. Both residues were found at the corresponding positions in Ruhugu virus E2, supporting the close evolutionary relationship between RuV and Ruhugu virus, a recently discovered rubivirus from bats.
From microbes to mind: germ-free models in neuropsychiatric research
Authors: Delgado-Ocaña Susana , Cuesta Santiago
Published: August 2024

The gut–microbiota–brain axis refers to the bidirectional communication system between the gut, its microbial community, and the brain. This interaction involves a complex interplay of neural pathways, chemical transmitters, and immunological mechanisms. Germ-free animal models have been extensively employed to investigate gut–microbiota–brain interactions, significantly contributing to our current understanding of the role of intestinal microbes in brain function. However, despite the many benefits, this absence of microbiota is not futile. Germ-free animals present physiological and neurodevelopmental alterations that can persist even after reconstitution with normal microbiota. Therefore, the main goal of this minireview is to discuss how some of the inherent limitations of this model can interfere with the conclusion obtained when using these animals to study the complex nature of neuropsychiatric disorders. Furthermore, we examine the inclusion and use of antibiotic-based treatments as an alternative in the research of gut–brain interactions.
Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates
Toxoplasma
dissemination
Authors: ten Hoeve Arne L. , Rodriguez Matias E. , Säflund Martin , Michel Valentine , Magimel Lucas , Ripoll Albert , Yu Tianxiong , Hakimi Mohamed-Ali , Saeij Jeroen P. J. , Ozata Deniz M. , Barragan Antonio
Published: August 2024

Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite
Toxoplasma gondii
. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II
T. gondii
lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 mitogen-activated protein kinase signaling pathways, respectively, with contributions by GRA16/18 and counter-regulation by effector TEEGR. Furthermore, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at the
Ccr7
gene locus in primary macrophages.
In vivo
, adoptively transferred macrophages infected with wild-type
T. gondii
outcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show that
T. gondii
, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors.

IMPORTANCE

Intracellular pathogens can hijack the cellular functions of infected host cells to their advantage, for example, for intracellular survival and dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasite
Toxoplasma gondii
actively invades the immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, acts on host cell signaling pathways to activate chemotaxis. Furthermore, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of GRA effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating how
T. gondii
can orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.
Whole genome sequences of
Yersinia pestis
strains of ancient phylogenetic branch 0.ANT5 isolated in the 21st century in the Tien-Shan in Kyrgyzstan
Authors: Balykova Alina N. , Katyshev Alexander D. , Eroshenko Galina A. , Kukleva Lyubov M. , Dzhaparova Aigul K. , Naryshkina Ekaterina A. , Oglodin Eugene G. , Berdiev Stalbek K. , Kutyrev Vladimir V.
Published: August 2024

We announce the whole genome hybrid sequences of 11 highly virulent
Yersinia pestis
strains of the ancient phylogenetic branch 0.ANT5, one of the closest to the strains of the First Plague Pandemic. Nine strains were isolated in 2013–2023 and two in 1953 and 1971 in the Tien Shan plague focus in Kyrgyzstan.
Complete genome sequence of
Vibrio cholerae
LK-18 isolated from tail-rotted
Procambarus clarkii
Authors: Yang Mingshu , Lv Jinxian , Li Kai , Lu Haojie , Wang Yongjie
Published: August 2024

Isolated from tail-rotted
Procambarus clarkii
, the pathogenic bacterium
Vibrio cholerae
LK-18 features two circular chromosomes: chromosome I (2,895,335 bp) and chromosome II (1,175,190 bp). The genome includes 3,522 open reading frames, 100 tRNA genes, and 31 rRNA genes, and it harbors the
Vibrio cholera
cytolysin and chitinase genes.
Challenging case of hypernatraemia in infancy
Authors: Hawton Katherine , Galloway Louise , Harmer Matthew , Kumaran Anitha , Kharbanda Mira , Platt Caroline , Candler Toby
Published: August 2024

A 1-month-old male infant presented unwell with a fever and shock. Blood tests showed hypernatraemia, hyperchloraemia and raised urea and creatinine. Initially, he was treated for dehydration secondary to sepsis. However, high urine output combined with low urine osmolality and high plasma osmolality was suggestive of a disorder of arginine vasopressin (AVP), previously called diabetes insipidus (DI). On further endocrine testing, thyroxine (T4) level was low with an inappropriately normal thyroid-stimulating hormone level with no other anterior pituitary hormone abnormalities, a normal MRI head and ophthalmological assessment. Desmopressin, a synthetic form of AVP, was commenced, however, there was an inadequate response despite dose escalation, leading to a diagnosis of AVP resistance (previously nephrogenic DI) rather than AVP deficiency (previously cranial DI). Copeptin, an AVP precursor peptide and surrogate marker, was significantly elevated. A renal tubulopathy genetic screen demonstrated a likely pathogenic hemizygous variant in the AVP receptor 2 gene, which has previously been associated with X-linked vasopressin resistance. This case demonstrates the challenge of differentiating between AVP deficiency and resistance in infancy and the value of copeptin and genetic testing in confirming diagnosis. We outline an approach to fluid management in AVP disorders.
Designing and validating a clinical decision support algorithm for diabetic nephroprotection in older patients
Authors: Alsalemi Noor , Sadowski Cheryl , Elftouh Naoual , Kilpatrick Kelley , Houle Sherilyn , Leclerc Simon , Fernandez Nicolas , Lafrance Jean-Philippe
Published: August 2024

Background

Older patients with diabetic kidney disease (DKD) often do not receive optimal pharmacological treatment. Current clinical practice guidelines (CPGs) do not incorporate the concept of personalised care. Clinical decision support (CDS) algorithms that consider both evidence and personalised care to improve patient outcomes can improve the care of older adults. The aim of this research is to design and validate a CDS algorithm for prescribing renin-angiotensin-aldosterone system inhibitors (RAASi) for older patients with diabetes.

Methods

The design of the CDS tool included the following phases: (1) gathering evidence from systematic reviews and meta-analyses of randomised clinical trials to determine the number needed to treat (NNT) and time-to-benefit (TTB) values applicable to our target population for use in the algorithm. (2) Building a list of potential cases that addressed different prescribing scenarios (starting, adding or switching to RAASi). (3) Reviewing relevant guidelines and extracting all recommendations related to prescribing RAASi for DKD. (4) Matching NNT and TTB with specific clinical cases. (5) Validating the CDS algorithm using Delphi technique.

Results

We created a CDS algorithm that covered 15 possible scenarios and we generated 36 personalised and nine general recommendations based on the calculated and matched NNT and TTB values and considering the patient’s life expectancy and functional capacity. The algorithm was validated by experts in three rounds of Delphi study.

Conclusion

We designed an evidence-informed CDS algorithm that integrates considerations often overlooked in CPGs. The next steps include testing the CDS algorithm in a clinical trial.
Workplace violence against female healthcare workers: a systematic review and meta-analysis
Authors: Ajuwa May-Elizabeth Pere-ere , Veyrier Clair-Antoine , Cousin Cabrolier Lorraine , Chassany Olivier , Marcellin Fabienne , Yaya Issifou , Duracinsky Martin
Published: August 2024

Background

Workplace violence (WPV) is highly prevalent in the health sector and remains a major occupational issue causing significant harm, ranging from bodily and psychological harm to death. Female healthcare workers (HCWs) are at high risk of WPV.

Objectives

Identify risk factors of WPV among different professional categories of female HCWs.

Data sources

PubMed, EMBASE and Web of Science, along with their references lists January 2010 and March 2022.

Eligibility criteria

English language observational studies focusing on WPV among HCWs evaluating the risk factors, impacts and consequences of WPV in female HCWs.

Method

Risk of bias was assessed for all studies by Joanna Briggs Institute critical appraisal checklists. We estimated the pooled prevalence of WPV and the associated 95% CI using a random-effects meta-analysis model. We then described the associated factors and effects of WPV.

Results

28 reviewed studies (24 quantitative, 4 qualitative and 1 mixed-method) from 20 countries were selected. From the available results of 16 studies, the pooled prevalence of WPV was estimated at 45.0% (95% CI 32% to 58%). Types of violence included verbal abuse, verbal threats, physical assaults, sexual harassment, mobbing, bullying and discrimination. Perpetrators were patients, patients’ relatives, colleagues and supervisors. Nurses were the most studied HCWs category. WPV was found to affect both mental and physical health. Age, marital status, lower occupational position, substance abuse, shorter work experience and low support at work were the main socio-demographic and organisational factors associated with higher risk of WPV.

Conclusion

WPV prevalence is high among female HCWs, warranting a multilevel intervention approach to address and mitigate its impact. This approach should include targeted policies and individual-level strategies to create a safer work environment and prevent adverse effects on both HCWs and the broader healthcare system. Further research is needed to better document WPV in categories of HCWs other than nurses.

PROSPERO registration number

CRD42022329574.
Addressing mental illness stigma in German higher education: study protocol for a mixed-methods evaluation of a psychosocial setting-based intervention
Authors: Nething Emily , Stoll Elena , Dobson Keith S. , Szeto Andrew C. H. , Tomczyk Samuel
Published: August 2024

Introduction

Mental illness stigma is associated with a range of negative consequences, such as reduced help-seeking for mental health problems. Since stigma affects individual, social, and structural aspects, multilevel interventions such as the Canadian programme The Working Mind have been proven to be the most effective. Given the solid evidence base for The Working Mind, it is our aim to implement and evaluate culturally adapted versions of the programme in German higher education, targeting students, employees and managers.

Methods and analysis

We will evaluate the programme with regard to its effect on mental illness stigma, openness to mental health problems, willingness to seek help, and positive mental health outcomes. Further, we will investigate the programme’s effectiveness dependent on gender and personal values, various mechanisms of change, and factors facilitating and hindering implementation. The study uses a sequential explanatory mixed-methods evaluation design (QUAN → qual) that consists of three steps: (1) quasi-experimental online survey with programme participants, (2) focus groups with programme participants, and (3) qualitative interviews with programme stakeholders. The quantitative data collected in step 1 will be analysed using 2×3 analysis of variances and a parallel multiple mediation analysis. The results will inform the qualitative data to be collected in steps 2 and 3, which will be analysed using qualitative content analysis.

Ethics and dissemination

The study was approved by the local Ethics Committee (Ethics Committee of University Medicine Greifswald; BB 098/23). Participants have to provide written consent before taking part in a focus group or interview. As for the online survey, participants have to give their consent by agreeing to an online data protection form before they can start completing the survey. We will publish central results and the anonymised data in an Open Access Journal. Further, the statistical code will be included as a supplement to the paper(s) documenting the results of the study.

Trial registration number

DRKS00033523.
Impact of time from discharge to readmission on outcomes: an observational study from the US National Readmission Database
Authors: Rachoin Jean-Sebastien , Hunter Krystal , Varallo Jennifer , Cerceo Elizabeth
Published: August 2024

Background

The Hospital Readmission Reduction Programme (HRRP) was created to decrease the number of hospital readmissions for acute myocardial infarction (AMI), chronic obstructive pulmonary disease (COPD), heart failure (HF), pneumonia (PNA), coronary artery bypass graft (CABG), elective total hip arthroplasty (THA) and total knee arthroplasty.

Objectives

To analyse the impact of the HRRP on readmission rates from 2010 to 2019 and how time to readmission impacted outcomes.

Design

Population-based retrospective study.

Setting

All patients included in the US National Readmission database from 2010 to 2019.

Patients

We recorded demographic and clinical variables.

Measurements

Using linear regression models, we analysed the association between readmission status and timing with death and length of stay (LOS) outcomes. We transformed LOS and charges into log-LOS and log-charges to normalise the data.

Results

There were 31 553 363 records included in the study. Of those, 4 593 228 (14.55%) were readmitted within 30 days. From 2010 to 2019, readmission rates for COPD (20.8%–19.8%), HF (24.9%–21.9%), PNA (16.4%–15.1%), AMI (15.6%–12.9%) and TKR (4.1%–3.4%) decreased whereas CABG (10.2%–10.6%) and THA (4.2%–5.8%) increased. Readmitted patients were at higher risk of mortality (6% vs 2.8%) and had higher LOS (3 (2–5) vs 4 (3–7)). Patients readmitted within 10 days had a mortality 6.4% higher than those readmitted in 11–20 days (5.4%) and 21–30 days (4.6%). Increased time from discharge to readmission was associated with a lower likelihood of mortality, like LOS.

Conclusion

Over the last 10 years, readmission rates decreased for most conditions included in the HRRP except CABG and THA. Patients readmitted shortly after discharge were at higher risk of death.
Examining self-described policy-relevant evidence base for policymaking: an evidence map of COVID-19 literature
Authors: Chukwu Emelda E , Woolaston Katie , Kaufer Ricardo , Bortolus Alejandro , Hewitt Chad L , Schwindt Evangelina , Sogbanmu Temitope O , Schwenkenbecher Anne , Rubin Hannah , Slanickova Helena , Schneider Mike D , Heesen Remco , Mitova Veli
Published: August 2024

Background

Evidence-based policymaking is a paradigm aimed at increasing the use of evidence by actors involved in policymaking processes. The COVID-19 pandemic highlighted a heavy reliance on emerging evidence for policymaking during emergencies.

Objective

This study describes the focus and types of evidence in journal articles self-described as relevant to policymaking using the COVID-19 pandemic as a case study, identifying gaps in evidence and highlighting author stated perceived biases specifically in evidence-based policy making.

Design

Evidence mapping.

Data sources

We systematically searched SCOPUS, PubMed and LexisNexis for literature identifying policy-relevant evidence available on the COVID-19 pandemic.

Eligibility criteria

The study included only peer-reviewed literature identified as ‘article’, ‘book chapter’, ‘review’ covering the period from January 2020 to December 2022. Inclusion criteria required that articles have an abstract, authorship attribution and are written in English.

Data extraction and synthesis

A minimum of two authors independently extracted and coded for every level and final outputs were compared for consistency.

Results

A total of 213 articles met the inclusion criteria and were reviewed in this study. Lead authorship affiliations were from 50 countries with 70% of the outputs from developed economies including USA (20.2%), UK (18.3%) and Australia (7.5%). The most common purpose of the articles was the presentation of research findings the authors considered of relevance to policy (60.1%), followed by work that examined the impact of policy (28.6%) or highlighted or supported a policy need (22.5%), while some papers had multiple stated purposes. The most common challenges in policymaking identified by the authors of the reviewed papers wereprocess failuresandpoor evidenceutilisation during policymaking.

Conclusions

The evidence map identified the need for an interdisciplinary policy approach involving relevant stakeholders and driven by quality research as a progressive step towards prevention of future public health crises/pandemics.
Association between biomass exposure and COPD occurrence in Fez, Morocco: results from the BOLD study
Authors: E L Harch Ibtissam , Garcia-Larsen Vanessa , Benmaamar Soumaya , Nejjari Chakib , E l Biaze Mohammed , Benjelloun Mohamed Chakib , Rhazi Karima E l
Published: August 2024

Objective

To investigate the association between biomass exposure and chronic obstructive pulmonary disease (COPD) in a representative sample of adults from the Moroccan population

Methods

A cross-sectional study was conducted in Fez as part of the Burden of Obstructive Lung Disease (BOLD) study, which included apparently healthy subjects aged 40 years and above. Biomass exposure was defined as self-report use of various biomass types for heating or cooking. The Wood Heating Exposure Index, and the Cooking Biomass Exposure Index were used to assess biomass exposure. Participants underwent post-bronchodilator spirometry and COPD was defined as having a forced expiratory volume in 1 s/forced vital capacity ratio <0.7. Descriptive, univariate and multivariable statistical analyses adjusting for potential confounders including age, sex, smoking, education level, Mokken scale (wealth index) and occupational dust exposure were performed for the general population and separately for men and women.

Results

A total of 760 subjects were included, comprising 350 men and 410 women. In the multivariable analyses, we found a statistically significant association between a higher Wood Heating Exposure Index and COPD in men (adjusted OR=3.8; 95% CI: 1.4 to 10.4). While for women, a high Cooking Biomass Exposure Index was the main factor potentially linked to the increased risk of COPD (adjusted OR=7.2; 95% CI: 1.7 to 30.0).

Conclusion

This study suggests that biomass exposure is a significant risk factor for COPD development in both men and women, independently of the smoking status which is known as its main risk factor.
Pharmacological and ethical comparisons of lung cancer medicine accessibility in Australia and New Zealand
Authors: Fenton Elizabeth , Ashton John
Published: August 2024

Gaps in funded cancer medicines between New Zealand and Australia can have significant implications for patients and their families. Pharmac, the New Zealand pharmaceutical funding agency, has been criticised for not funding enough cancer medicines, and a 2022 review identified ethical concerns about its utilitarian focus on efficiency. However, as the costs of new cancer medicines rise along with public and political pressure to fund them, questions about value for money remain critical for health systems worldwide. In this paper, we compare funding for cancer medicines in New Zealand and Australia, specifically medicines for non-small cell lung cancer. We argue that the ethical imperatives on funding agencies to get value for money and provide medicines for patients with cancer underscore the importance of transparent decision-making processes, including identifying and explaining intercountry differences in funded medicines.
POLG epilepsy presenting as new-onset refractory status epilepticus (NORSE) in pregnancy
Authors: Levee Viva , Sivaganesh Karthikeyan , Schaeffer Andrew , Karunaratne Kushan
Published: August 2024

A 21-year-old woman developed explosive new-onset refractory status epilepticus when 18 weeks pregnant. She had been previously well with no history of seizures and a normal developmental history. She had initially presented with focal impaired awareness seizures but subsequently developed status epilepticus requiring intensive care unit admission and was successfully treated with multiple anti-seizure medications. Once stabilised she was stepped down to the inpatient neurology ward and then transferred to the tertiary centre for a planned late termination of pregnancy, which was the patient’s choice. Following transfer, she again developed refractory status epilepticus, requiring intensive care readmission. Subsequent investigations identified a compound heterozygous POLG genetic mutation. We discuss the challenges in the acute clinical situation and important considerations in the diagnosis and management of POLG-related epilepsy.
Why non-human primates are needed in stroke preclinical research
Authors: Long Xiya , Zeng Jinsheng
Published: August 2024

Numerous seemingly promising cerebroprotectants previously validated in rodents almost all have failed in stroke clinical trials. The failure of clinical translation strikes an essential need to employ more ideal animal models in stroke research. Compared with the most commonly used rodent models of stroke, non-human primates (NHPs) are far more comparable to humans regarding brain anatomy, functionality and pathological features. The aim of this perspective was to summarise the advantages of NHPs stroke models over rodents, discuss the current limitations of NHPs models, and cast an outlook on the future development of NHPs in stroke preclinical research.
The role of dimensions in gravitating relativistic shear-free fluids
Authors: Gumede S. C. , Maharaj S. D. , Govinder K. S.
Published: August 2024

We study the dynamics of relativistic shear-free gravitating fluids in higher dimensions for both neutral and charged matter. We reduce the Einstein–Maxwell equations to a single second order nonlinear partial differential equation which contains two arbitrary functions. This generalizes the condition of pressure isotropy to higher dimensions; the new condition is functionally different from four dimensions. Our result in higher dimensions reduces to known results in four dimensions. The presence of higher dimensions affects the dynamics of relativistic fluids in general relativity. The dynamical behaviour of the gravitating fluid in higher dimensions is qualitatively different to the four dimensional case. Higher dimensions affect astrophysical and cosmological processes in gravitating shear-free fluids.
Extended B-Spline Collocation Method for Singularly Perturbed Time Delay Parabolic Differential-Difference Problems
Authors: Daba Imiru Takele , Kebede Nayilot Ejara , Gonfa Genanew Gofe
Published: August 2024

The paper presents a robust collocation B-spline numerical scheme for solving singularly perturbed time lag parabolic differential–difference problems. The method uses Taylor’s series expansion for the approximation of retarded terms, the [Formula: see text]-method (when [Formula: see text]) for time discretization, and the extended third-degree B-spline collocation method for spatial discretization in a piecewise uniform Shishkin mesh. The advantage of using an extended cubic B-spline rather than the classical third-degree B-spline method is that it introduces one additional free parameter to control the global shape parameter. The stability and uniform convergence of the proposed scheme are investigated. The method is first-order accurate in [Formula: see text] and almost second-order accurate in [Formula: see text], surpassing existing literature methods.
Triangle-free Graphs with Three Positive Eigenvalues
Authors: Duan Fang
Published: August 2024

A graph [Formula: see text] is called triangle-free if [Formula: see text] does not contain any triangle as its induced subgraph. Let [Formula: see text] be the set of triangle-free graphs of order [Formula: see text] each of which has three positive eigenvalues. In this paper, we find 20 specific graphs in [Formula: see text], each of which has nullity no more than 2, and we show that in terms of three graph transformations all the other graphs of [Formula: see text] can be constructed from these 20 specific graphs. Hence, we completely characterize the triangle-free graphs with exactly three positive eigenvalues.
External noise-induced stochastic resonance and stochastic transitions in p53-Mdm2 regulatory network
Authors: Jiang Cuicui , Dai Chenxi , Wang Kaifa
Published: August 2024

Because noise is an inevitable attribute in gene regulatory networks, a stochastic differential equations model is constructed to study the impact of external noise on p53-Mdm2 regulatory network. Near the Hopf bifurcation of the corresponding deterministic model, external noise can induce stochastic resonance. When three stable steady states coexist in the corresponding deterministic model, external noise can lead to stochastic transition. Therefore, external noise can not only expand the parameter range of p53 regulatory network oscillations, but also increase the amplitude of p53 regulatory network oscillations, and is closely related to the outcome of cell fate. These findings deepen our understanding of the impact of external noise on gene regulatory networks and may provide new perspectives for the treatment of related diseases.
Bifurcation in a single-species logistic model with addition Allee effect and fear effect-type feedback control
Authors: Zhu Qun , Li Zhong , Chen Fengde
Published: August 2024

In this paper, a single-species logistic model with both fear effect-type feedback control and additive Allee effect is developed and investigated using the new coronavirus as a feedback control variable. When the system introduces additive Allee effect and fear effect-type feedback control, more complicated dynamical behavior is obtained. The system can undergo transcritical bifurcation, saddle-node bifurcation, degenerate Hopf bifurcation and Bogdanov–Takens bifurcation. By numerical simulations, the system exhibits homoclinic bifurcation and saddle-node bifurcation of limit cycles as parameters are altered. Remarkably, it is the first time that two limit cycles have been discovered in a single-species logistic model with the Allee effect. Further, stronger Allee effect or stronger fear effect can lead to the extinction of the species population.
Finite determination for embeddings into Banach spaces: New proof, low distortion
Authors: Catrina Florin , Ostrovskii Mikhail I.
Published: August 2024

The main goal of this paper is to improve the result of M. I. Ostrovskii [Embeddability of locally finite metric spaces into Banach spaces is finitely determined, Proc. Amer. Math. Soc. 140 (2012) 2721–2730.] on the finite determination of bilipschitz and coarse embeddability of locally finite metric spaces into Banach spaces. There are two directions of the improvement: (1) Substantial decrease of distortion (from about [Formula: see text] to 3 + [Formula: see text]) is achieved by replacing the barycentric gluing by the logarithmic spiral gluing. This decrease in the distortion is particularly important when the finite determination is applied to construction of embeddings. (2) Simplification of the proof: a collection of tricks employed in M. I. Ostrovskii [Embeddability of locally finite metric spaces into Banach spaces is finitely determined, Proc. Amer. Math. Soc. 140 (2012) 2721–2730.] is no longer needed; in addition to the logarithmic spiral gluing we use only a version of the Brunel–Sucheston argument used to prove the existence of spreading models.
Adherence to Non-operative Clinical Quality Measures in Carpal Tunnel Syndrome
Authors: COOK Julia A. , CICHOCKI Meghan N. , TONG Yanlin , WANG Lu , CHUNG Kevin C.
Published: August 2024

Background: Clinical quality measures exist for non-operative management of carpal tunnel syndrome (CTS). Factors predicting adherence are unclear.

Methods: A retrospective cohort study of patients with chronic CTS using MarketScan Research Database (2015–2020) was conducted. Six logistic regression models were designed to study adherence to quality measures within 1 year after diagnosis.

Results: Of 782,717 patients identified, 514,073 (65.7%) were female with an average (SD) age of 51.4 (13.4) years. Only 88 patients (0.01%) met all quality measures. Greatest compliance observed with receipt of nerve conduction study (NCS; 283,959 [36.3%]), no prescription of medications (336,297 [43.0%]) and no laser therapy (772,979 [98.8%]); 294,305 patients (37.6%) received hand surgeon referral. Hand surgeon referral predicted higher likelihood of NCS and splinting (OR, 1.83; 95% CI: 1.81–1.84; OR, 2.53; 95% CI: 2.50–2.56) and medication over-prescription (OR, 1.05; 95% CI: 1.00–1.10). Females were more likely to be referred to a hand surgeon and be referred for splinting (OR 1.02; 95% CI: 1.01–1.03; OR 1.19; 95% CI: 1.18–1.21) but less likely to have no prescriptions or avoid laser therapy (OR 0.85, 95% CI: 0.84–0.85; OR 0.82, 95% CI: 0.79–0.86). Medicare recipients adhered less to quality measures compared to patients with fee-for-service insurance. As comorbidities increased, patients were less likely to receive hand surgeon referral and carpal tunnel release.

Conclusions: Findings suggest that hand surgery referrals increased adherence to quality measures. Females, Medicare recipients and multimorbid patients should be targeted for improved care. Future quality care efforts should incentivise adherence for Medicare beneficiaries and improve guideline recognition amongst physicians.

Level of Evidence: Level III (Therapeutic)