bluuebunny/crossref_metadata_2025 huggingface dataset:
Disturbed sleep after lung transplantation is associated with worse patient-reported outcomes and chronic lung allograft dysfunction
Authors: Prather Aric A. , Gao Ying , Betancourt Legna , Kordahl Rose C , Sriram Anya , Huang Chiung-Yu , Hays Steven R , Kukreja Jasleen , Calabrese Daniel R. , Venado Aida , Kapse Bhavya , Greenland John R , Singer Jonathan P
Published: October 2023

Many lung transplant recipients fail to derive the expected improvements in functioning, HRQL, or long-term survival. Sleep may represent an important, albeit rarely examined, factor influencing lung transplant outcomes.

Within a larger cohort study, 141 lung transplant recipients completed the Medical Outcomes Study (MOS) Sleep Scale along with a broader survey of patient-reported outcome (PRO) measures and frailty assessment. MOS Sleep yields the Sleep Problems Index (SPI); we also derived an insomnia-specific subscale. Potential perioperative predictors of disturbed sleep and time to chronic lung allograft dysfunction (CLAD) and death were derived from medical records. We investigated associations between perioperative predictors on SPI and Insomnia and associations between SPI and Insomnia on PROs and frailty by linear regressions, adjusting for age, sex, and lung function. We evaluated the associations between SPI and Insomnia on time to CLAD and death using Cox models, adjusting for age, sex, and transplant indication.

Post-transplant hospital length of stay >30 days was associated with worse sleep by SPI and insomnia (SPI: p=0.01; Insomnia p=0.02). Worse sleep by SPI and insomnia was associated with worse depression, cognitive function, HRQL, physical disability, health utilities, and Fried Frailty Phenotype frailty (all p<0.01). Those in the worst quartile of SPI and insomnia exhibited increased risk of CLAD (HR 2.18; 95%CI: 1.22—3.89; p=0.01 for SPI and HR 1.96; 95%CI 1.09—3.53; p=0.03 for insomnia). Worsening in SPI but not insomnia was also associated with mortality (HR: 1.29; 95%CI: 1.05—1.58; p=0.01).

Poor sleep after lung transplant may be a novel predictor of patient reported outcomes, frailty, CLAD, and death with potentially important screening and treatment implications.
Rapid enzymatic detection of Shigatoxin-producingE. coliusing fluorescence-labeled oligonucleotide substrates
Authors: Ramming Isabell , Lang Christina , Hauf Samuel , Krüger Maren , Worbs Sylvia , Peukert Carsten , Fruth Angelika , Dorner Brigitte G. , Brönstrup Mark , Flieger Antje
Published: October 2023

Shigatoxin-producingE. coli(STEC) are important human pathogens causing disease ranging from diarrhea to severe hemolytic uremic syndrome. As STEC are transmitted via animals, food, and water, and may produce large outbreaks, their timely and qualified detection including isolate recovery is of high importance, but challenging and labor-intense. Thus, the availability of an easy-to-perform rapid test would be a tremendous advance. Since the common feature and major virulence factor of otherwise multifaceted STEC is the Shiga toxin (Stx), we developed a detection method for Stx, specifically for its catalytic RNA-N-glycosidase activity targeting the Sarcin Ricin Loop (SRL) of 28S ribosomal RNA. To this end, synthetic ssDNA substrates mimicking the SRL were designed and linked to a fluorophore and quencher pair, which conferred a fluorescence signal after cleavage by Stx. Optimal results using bacterial culture supernatants or single colonies were achieved for substrateStxSense 4following 30 to 60 minutes incubation. Importantly, different Stx1 and Stx2 subtypes, diverse STEC serotypes, andShigellawere detected. In conclusion, the assay offers rapid and facile detection of STEC based on a real-time readout for Stx activity. Therefore, it may improve STEC risk evaluation, therapy decisions, outbreak and source detection, and simplify research for antimicrobials.
Modeling the impact of prioritizing first or second vaccine doses during the 2022 mpox outbreak
Authors: Clay Patrick A. , Pollock Emily D. , Saldarriaga Enrique M. , Pathela Preeti , Macaraig Michelle , Zucker Jane R. , Crouch Bindy , Kracalik Ian , Aral Sevgi O. , Spicknall Ian H.
Published: October 2023

Background

Early in the 2022 mpox outbreak, vaccine doses and administrative capacity were limited. The US recommendation was to administer two doses of the JYNNEOS® vaccine 4 weeks apart. However, because of the limited vaccine supply and high demand, New York City (NYC) prioritized administration of first doses to reach a larger portion of the impacted population as quickly as possible. We estimated mpox cases averted compared to strategies that prioritized 2-dose vaccination for a smaller portion of the population.

Methods

We fit a dynamic network transmission model to incident mpox cases reported by NYC, as well as to first and second vaccine doses administered from May 2022 through March 2023. Model output consisted of predicted cases over time when vaccine doses were administered with the ‘first-dose priority’ strategy, compared with counterfactual simulations where individuals were either pre-allocated full courses of the vaccine (‘second-dose priority’ strategy), or not pre-allocated doses, but where doses were administered to those eligible for a second dose ahead of those waiting for a first dose (‘intermediate’ strategy).

Results

We estimate that NYC’s ‘first-dose priority’ strategy averted 81% [IQR:75%–86] of potential mpox cases. Their ‘first-dose priority’ strategy was more effective than alternatives, averting 3.0% [IQR:1.2%–4.5%] more cases than the ‘intermediate’ strategy, and 9.5% [IQR:7.7%–12%] more cases than the ‘second-dose priority’ strategy.

Conclusions

A focus on widespread, 1 dose vaccination during future mpox outbreaks can reduce cases and limit transmission in scenarios of limited vaccine supply, limited vaccine administration capacity, or increased demand.
Native, addict, innovator: young teachers' digital competence in the post-COVID-19 instructional era
Authors: Jogezai Nazir Ahmed , Baloch Fozia Ahmed
Published: October 2023

Purpose

The COVID-19 pandemic, in addition to posing challenges, has also created opportunities for greater digital integration than ever. However, the scale and efficacy of digital integration are contingent on the digital competence (DC) of teachers. In the same way, how well teachers learn and teach online may depend on how willing they are to try new ways of digitizing learning or being innovative. This study aimed to ascertain if teachers' digital nativeness, digital addiction and innovative work behavior had an impact on their DC.

Design/methodology/approach

The study used a quantitative research method, whereby data were collected from 276 schools, colleges and university teachers. The researchers employed structural equation modeling (SEM) using SmartPLS to analyze the data.

Findings

The results illuminate the literature regarding DC and the predictive capability of teachers' digital nativeness, digital addiction and innovative work behavior, which can contribute to paving the way for digitizing teaching and learning in the post-COVID-19 era.

Research limitations/implications

The study has significant implications for meaningful learner engagement by explaining the importance of teachers' digital competencies and how they could be approached conceptually to better understand the factors associated with teachers' DC. The differences in DC between digital natives and digital emigrants remain one of the limitations that future research may address.

Practical implications

The results have policy level and practical implications for organizations to consider the value of young teachers in the integration of digital resources. It is also critical to encourage teachers' innovative behavior in the digitization of teaching by creating a supportive organizational environment.

Originality/value

The study remains valuable in the post-COVID-19 era, where educational institutes are revisiting the prospect of online learning as a parallel to in-person teaching. The results remain innovative and genuine and have not been explored in previous research, in particular in the post-COVID-19 era. The involvement of teachers from schools, colleges and universities makes the results more general, which all of them can equally benefit from.
Promoting shared leadership in Lean Six Sigma project teams: toward a three-way interaction model
Authors: Wu Qiong , Zhou Qiwei , Cormican Kathryn
Published: October 2023

Purpose

Shared leadership is an effective mechanism for managing project teams. Its performance-enhancing benefits have been demonstrated in many studies. Nonetheless, there is an obvious silence about how to promote shared leadership in Lean Six Sigma (LSS) project teams. To address this deficit, the purposes of this study are to investigate the influence of shared leadership on LSS project success and to explore how team psychological safety, project task complexity and project task interdependence influence shared leadership.

Design/methodology/approach

A multi-source, time-lagged survey design with a four-month interval was conducted. To do this, the authors collected data from 71 project teams (comprising 71 project managers and 352 project members) using LSS approaches in the manufacturing and service industries.

Findings

The findings show that shared leadership positively influences LSS project success. The authors also found that team psychological safety fosters the development of shared leadership and, more importantly, these effects are stronger when the tasks are more complex and more interdependent.

Practical implications

These findings advance our understanding of the factors that enable shared leadership and equip LSS project managers with practical techniques to improve shared leadership for the success of their projects.

Originality/value

This study extends the theory of shared leadership to the context of LSS project management and is among the first, to the best of the authors’ knowledge, to theoretically propose and empirically validate how to promote shared leadership in LSS project teams.
Does central bank credibility from professional forecasters and consumers affect the interest rate and its expectations?
Authors: de Mendonça Helder Ferreira , de Lima Cristiane Nascimento
Published: October 2023

Purpose

This paper aims to contribute to the analysis concerning how inflation forecasts from different economic agents (professional forecasters and consumers) lead to varying levels of central bank credibility and how it affects the monetary policy interest rate and its expectations.

Design/methodology/approach

Based on the Brazilian economy data from June 2007 to May 2022, the authors provide evidence that is useful for search mechanisms that improve the conduct of monetary policy through the management of inflation expectations. The authors perform several ordinary least squares and generalized method of moments regressions inspired by the Taylor rule principle. In brief, the benchmark model considers that the monetary policy interest rate and its expectations respond to departures of inflation expectations to the target (a proxy for central bank credibility) and the level of economic activity.

Findings

The main result of the analysis is that inflation expectations from professional forecasters and consumers imply different perceptions of central bank credibility that affect the monetary policy interest rate and expectations for horizons until one year ahead.

Originality/value

The novelty that the authors bring from the analysis is that the authors calculate central bank credibility by taking into account the “public beliefs” of different economic agents. Furthermore, the authors analyze the effect of central bank credibility from professional forecasters and consumers on the monetary policy interest rate and its expectations.
Modelling thermal sensitivity in the full phenological distribution: A new approach applied to the spring arboreal caterpillar peak
Authors: Macphie Kirsty H. , Samplonius Jelmer M. , Pick Joel L. , Hadfield Jarrod D. , Phillimore Albert B.
Published: October 2023

Advances in spring phenology are among the clearest biological responses to climate warming. There has been much interest in how climate impacts on phenology because the timings of key events have implications for species interactions, nutrient cycling and ecosystem services. To date most work has focused on only one aspect of population phenology, the effects of temperature on the average timing. In comparison, effects of temperature on the abundance of individuals and their seasonal spread are understudied, despite their potential to have profound impacts on species interactions.

Here we develop a new method that directly estimates the effect of spring temperatures on the timing, height and width of the phenological distribution and apply it to temperate forest caterpillars, a guild that has been the focus of much research on phenology and trophic mismatch.

We find that warmer spring conditions advance the timing of the phenological distribution of abundance by −4.96 days °C−1 and increase its height by 34% °C−1 but have no significant effect on the duration of the distribution. An increase in the maximum density of arboreal caterpillars with rising temperatures has implications for understanding climate impacts on forest food chains, both in terms of herbivory pressure and the resources available to secondary consumers.

The new method we have developed allows the thermal sensitivity in the full phenological distribution to be modelled directly from raw data, providing a flexible approach that has broad applicability within global change research.

Read the free Plain Language Summary for this article on the Journal blog.
Regulation of ferroptosis‐related genes in CD8+ NKT cells and classical monocytes may affect the immunotherapy response after combined treatment in triple negative breast cancer
Authors: Liu Zheming , He Songjiang , Huang Zhou , Liu Jiahui , Gong Yiping , Yao Yi , Zhang Xue
Published: October 2023

Background

Drug resistance has led to the failure of immunotherapy in triple negative breast cancer patients. Here we aimed to explore the mechanisms of drug resistance in patients in order to enhance their response to immunotherapy.

Methods

We downloaded publicly available single‐cell RNA‐sequencing data of peripheral blood mononuclear cells from patients after treatment to investigate the possible mechanisms of drug resistance. The publicly available TCGA transcriptomic data and somatic mutation data were used for further validation. In this study, a series of bioinformatics and machine learning methods were employed.

Results

We identified the vital roles of CD8+ NKT cells and classical monocytes in the immunotherapy response of triple‐negative breast cancer patients. The proportion of these cell types was significantly increased in group partial response. We also found that downregulation of ferroptosis‐related genes regulates the immune pathway. The analysis of scRNA data and TCGA transcriptomic data presented that DUSP1 may play a crucial role in immunotherapy resistance.

Conclusion

Overall, the composition of the tumor microenvironment affects the immunotherapy response of patients, and DUSP1 may be a potential target for overcoming drug resistance.
Letter: Exploring the clinical utility of ammonia in critically ill patients with cirrhosis: More to do?
Authors: Dong Jia‐Jia , Zhang Qiong‐Ying , Cai Yi‐Jing
Published: October 2023

LINKED CONTENT

This article is linked to Cardoso et al papers. To view these articles, visit https://doi.org/10.1111/apt.17650 and https://doi.org/10.1111/apt.17725
Letter: Exploring the clinical utility of ammonia in critically ill patients with cirrhosis: More to do? Authors' reply
Authors: Cardoso Filipe S. , Kim Minjee , Pereira Rui , Bagulho Luís , Fidalgo Pedro , Pawlowski Anna , Wunderink Richard , Germano Nuno , Bagshaw Sean M. , Abraldes Juan G. , Karvellas Constantine J.
Published: October 2023

LINKED CONTENT

This article is linked to Cardoso et al papers. To view these articles, visithttps://doi.org/10.1111/apt.17650andhttps://doi.org/10.1111/apt.17698
Review: Systematic review and metasynthesis of qualitative literature on young people's experiences of going to A&E/emergency departments for mental health support
Authors: Cadorna Gianna , Vera San Juan Norha , Staples Heather , Johnson Sonia , Appleton Rebecca
Published: October 2023

Background

There has been an increase in children and young people attending emergency departments for mental health reasons, including self‐harm. Patients often report having poor experiences when attending emergency departments for mental health support. However, there has yet to be a review exploring the experiences of young people. Our aim in this study was to synthesise qualitative literature on young people's experiences of going to emergency departments for mental health support.

Methods

A systematic review and metasynthesis were conducted. Five databases and grey literature were searched for relevant studies. Five articles met study criteria and were analysed using an iterative process of thematic synthesis.

Results

The synthesis yielded four overarching themes: (a) emergency departments' inability to meet the mental health needs of young people, (b) emergency departments exacerbating patient distress, (c) patients feeling like a burden or undeserving of treatment and (d) consequences of poor emergency department experiences.

Conclusions

These findings (based on a still very limited literature) highlight the role that emergency departments have in relation to being a key point of contact with young people who self‐harm. To properly engage with patients, emergency departments need to have the resources to provide compassionate care and follow clinical guidelines regarding assessments.
Agreement between self‐reported and objectively assessed physical activity among out‐of‐hospital cardiac arrest survivors
Authors: Heimburg Katarina , Lilja Gisela , Blennow Nordström Erik , Friberg Hans , Gregersen Oestergaard Lisa , Grejs Anders M. , Keeble Thomas R. , Mion Marco , Nielsen Niklas , Rylander Christian , Segerström Magnus , Thomsen Ida Katrine , Ullén Susann , Undén Johan , Wise Matthew P. , Cronberg Tobias , Tornberg Åsa B.
Published: October 2023

Background

Low level of physical activity is a risk factor for new cardiac events in out‐of‐hospital cardiac arrest (OHCA) survivors. Physical activity can be assessed by self‐reporting or objectively by accelerometery.

Aim

To investigate the agreement between self‐reported and objectively assessed physical activity among OHCA survivors

Hypothesis

Self‐reported levels of physical activity will show moderate agreement with objectively assessed levels of physical activity.

Method

Cross‐sectional study including OHCA survivors in Sweden, Denmark, and the United Kingdom. Two questions about moderate and vigorous intensity physical activity during the last week were used as self‐reports. Moderate and vigorous intensity physical activity were objectively assessed with accelerometers (ActiGraph GT3X‐BT) worn upon the right hip for 7 consecutive days.

Results

Forty‐nine of 106 OHCA survivors answered the two questions for self‐reporting and had 7 valid days of accelerometer assessment. More physically active days were registered by self‐report compared with accelerometery for both moderate intensity (median 5 [3:7] vs. 3 [0:5] days; p < 0.001) and vigorous intensity (1 [0:3] vs. 0 [0:0] days; p < 0.001). Correlations between self‐reported and accelerometer assessed physical activity were sufficient (moderate intensity: rs = 0.336, p = 0.018; vigorous intensity: rs = 0.375, p = 0.008), and agreements were fair and none to slight (moderate intensity: k = 0.269, p = 0.001; vigorous intensity: k = 0.148, p = 0.015). The categorization of self‐reported versus objectively assessed physical activity showed that 26% versus 65% had a low level of physical activity.

Conclusion

OHCA survivors reported more physically active days compared with the results of the accelerometer assessment and correlated sufficiently and agreed fairly and none to slightly.
Using repeated measures to study the contribution of alcohol consumption and smoking to the social gradient in all‐cause mortality: Results from the Stockholm Public Health Cohort
Authors: Berg Lisa , Landberg Jonas , Thern Emelie
Published: October 2023

Introduction

The social gradient in consumption behaviours has been suggested to partly explain health inequalities. The majority of previous studies have only included baseline measurements and not considered potential changes in behaviours over time. The study aimed to investigate the contribution of alcohol consumption and smoking to the social gradient in mortality and to assess whether the use of repeated measurements results in larger attenuations of the main association compared to using single baseline assessments.

Methods

Longitudinal survey data from the population‐based Stockholm Public Health Cohort from 2006 to 2014 was linked to register data on mortality until 2018 for 13,688 individuals and analysed through Cox regression.

Results

Low socioeconomic position (SEP) was associated with increased mortality compared with high SEP; hazard ratios 1.56 (95% CI 1.30–1.88) for occupational status and 1.77 (95% CI 1.49–2.11) for education, after adjustment for demographic characteristics. Using repeated measurements, alcohol consumption and smoking explained 44% of the association between occupational status and all‐cause mortality. Comparing repeated and baseline measures, the percentage attenuation due to alcohol consumption increased from 11% to 18%, whereas it remained similar for smoking (25–23%).

Discussion and Conclusions

Smoking and alcohol consumption explained a large part of the association between SEP and mortality. Comparing results from time‐fixed and time‐varying models, there was an increase in overall percentage attenuation that was mainly due to the increased proportion explained by alcohol consumption. Repeated measurements provide a better estimation of the contribution of alcohol consumption, but not smoking, for the association between SEP and mortality.
Patterns of anti‐CGRP mAbs use and variation of triptan consumption following treatment initiation: A descriptive drug utilization study in the Tuscany region, Italy
Authors: Hyeraci Giulia , Paoletti Olga , Iannone Luigi Francesco , Gini Rosa , De Cesaris Francesco , Geppetti Pierangelo , Roberto Giuseppe
Published: October 2023

Objective

To describe the pattern of anti‐calcitonin gene–related peptide monoclonal antibodies (anti‐CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation.

Background

Given the recent commercialization of anti‐CGRP mAbs as migraine preventive medications, real‐world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited.

Methods

A retrospective, descriptive, cohort study on the real‐world utilization of anti‐CGRP mAbs was performed using the population‐based regional administrative database of Tuscany. Patients with ≥1 anti‐CGRP mAb dispensing (namely erenumab, galcanezumab, fremanezumab) between April 1, 2019, and September 30, 2021, were identified. The first dispensing was the cohort entry (CE). New users (NUs) were patients with no anti‐CGRP mAb dispensing before CE. Kaplan–Meier (KM) curves were plotted to describe the cumulative probability of remaining with the initial anti‐CGRP mAb during a 15‐month follow‐up period as a measure of treatment persistence. Among NUs with ≥2 triptan dispensings during the 6 months before CE (i.e., baseline), the mean monthly number of triptan dosage units dispensed was measured in five consecutive follow‐up time windows (months 1–3, 4–6, 7–9, 10–12, 13–15) and the difference from the baseline was calculated.

Results

A total of 624 NUs (erenumab = 295, galcanezumab = 223, fremanezumab = 106) were identified, of whom 188 (78%) were women. Mean age was 49.2 years (standard deviation [SD] = 12.6). The survival to discontinuation at 6, 12, and 15 months was about 69%, 48%, and 6%, respectively. The survival to switch was about 6% at 15 months. The observed variation of triptan consumption at 3/6/9/12/15 months and the corresponding SD was −4.4 [8.2]/−5.2 [9.0]/−5.5 [9.2]/−5.4 [9.2]/−4.5 [10.0], respectively.

Conclusion

Patient demographics reflect the place of these medications in therapy. Overall, findings seem to indicate a favorable tolerability and effectiveness profile. Further studies are warranted to better establish the long‐term comparative effectiveness, safety, and cost effectiveness of anti‐CGRP mAbs compared to other preventive medications.
A HYBRID ANALYSIS OF THE FRENCH PRONOUN EN*
Authors: Hvidsten Eirik
Published: October 2023

This paper puts forward a novel account of the clitic pronoun en in French. It is shown that previous analyses cannot account for the rich nominal structure involved in en‐pronominalization, in particular structures with stranded DP‐internal remnants. The analysis proposed sees en‐pronominalization as a hybrid between pronominalization and ellipsis, which includes DP‐internal focus movement for the stranded remnants. It will be argued that en itself is best analyzed as being derived from an nP within the DP, even when it seemingly pronominalizes the entire DP. Following Cinque (2010), the analysis presented here also assumes that only modifiers of the indirect kind can be stranded by en‐pronominalization.
Residual Stresses in Surgical Growing Rods
Authors: Croonenborghs Maïté , Ismail Karim , Mousny Maryline , Delannay Laurent , Everaerts Joris , Korsunsky Alexander M. , Jacques Pascal J. , Pardoen Thomas
Published: October 2023

The treatment of early onset scoliosis using surgical growing rods suffers from high failure rate. Fatigue resistance can be improved by inducing compressive residual stresses within the near surface region. An in-depth investigation of the residual stresses profile evolution is performed through the sequence of material processing steps followed by surgeons handling operations, in connection to material properties. The final goal is to guide further improvements of growing rod lifetime. Residual stress evaluation was carried out on Ti-6Al-4V rods using digital image correlation applied to microbeam ring-core milling by focused ion beam. This provided experimental stress profiles in shot-peened rods before and after bending and demonstrated that compressive residual stresses are maintained at both concave and convex rod sides. A finite element model using different core and skin conditions was validated by comparison to experiments. The combination of an initial shot peening profile associated with a significant level of backstress was found to primarily control the generation of compressive stresses at the rod surface after bending. Guidelines to promote larger compressive stresses at the surface were formulated based on a parametric analysis. The analysis revealed the first order impact of the initial yield strength, kinematic hardening parameters and intensity of the shot peening operation, while the bending angle and the depth of shot peening stresses were found to be of minor importance. Materials exhibiting large kinematic hardening and low yield strength should be selected in order to induce compressive residual stresses at key fatigue initiation site.
A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion
Authors: Li Jie , Krause Gregory J. , Gui Qi , Kaushik Susmita , Rona Gergely , Zhang Qingyue , Liang Feng-Xia , Dhabaria Avantika , Anerillas Carlos , Martindale Jennifer L. , Vasilyev Nikita , Askenazi Manor , Ueberheide Beatrix , Nudler Evgeny , Gorospe Myriam , Cuervo Ana Maria , Pagano Michele
Published: October 2023

Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr
131
, allowing its interaction with V
1
subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between autophagy and unconventional secretion in a manner dependent on cellular nutrient status.
Proteasome activity is required for reovirus entry into cells
Authors: Abad Andrew T. , McNamara Andrew J. , Danthi Pranav
Published: October 2023

Since viruses have limited coding capacity in their genomes, they use host cell machinery to complete virtually every stage of their replication cycle. Mammalian orthoreovirus (reovirus) is comprised of two concentric protein shells, the inner core and the outer capsid. Following attachment to its receptor, reovirus enters the cell by receptor-mediated endocytosis. Within endosomes, reovirus utilizes host acid-dependent proteases to process the viral outer capsid. Specifically, the outer capsid protein σ3 is degraded, and μ1 is cleaved to form the disassembly intermediate infectious subvirion particles (ISVPs). ISVPs undergo additional conformational changes into ISVP*s that release small peptides, which mediate the penetration of endosomal membranes. Membrane penetration allows for delivery of the remaining viral core into the cytoplasm for subsequent gene expression. Here, we describe that proteasomes control an entry step of reovirus particles. We show that chemically inhibiting the proteasome blocks infection at a stage following ISVP formation but prior to transcriptional activation of cores. Specifically, inhibition of the proteasome prevents conformational changes in μ1 characteristic of ISVP-to-ISVP* conversion. In the absence of these conformational changes, cores are unable to be delivered and become transcriptionally active, thereby blocking viral replication. This work highlights a previously unknown way in which reovirus relies on host factors for successful replication.

IMPORTANCE

Due to their limited genetic capacity, viruses are reliant on multiple host systems to replicate successfully. Mammalian orthoreovirus (reovirus) is commonly used as a model system for understanding host-virus interactions. In this study, we identify that the proteasome system, which is critical for cellular protein turnover, affects reovirus entry. Inhibition of the proteasome using a chemical inhibitor blocks reovirus uncoating. Blocking these events reduces subsequent replication of the virus. This work identifies that additional host factors control reovirus entry.
Silencing essential gene expression in
Mycobacterium abscessus
during infection
Authors: Boudehen Yves-Marie , Tasrini Yara , Aguilera-Correa John Jairo , Alcaraz Matthéo , Kremer Laurent
Published: October 2023

Mycobacterium abscessus
is a multi-drug-resistant non-tuberculous mycobacterial species causing tuberculosis-like lung infections. The functional characterization of the extensive repertoire of genes encoding virulence factors and drug targets has been largely restricted by the lack of powerful genetic tools. In this study, we evaluated the performances of a Tet-OFF system, previously optimized for
M. tuberculosis
and
M. smegmatis
. Fluorescence reporter
M. abscessus
strains were developed where mCherry was under the control of the Tet-OFF regulatory system on an integrative plasmid. The addition of anhydrotetracycline (ATc) correlated with a decrease in fluorescence intensity not only in solid and broth medium but also in colony biofilms, for both smooth and rough variants of
M. abscessus
. Next, unmarked
mmpL3
conditional knockdown mutants were engineered in both smooth and rough
M. abscessus
. Biochemical studies indicated that the addition of ATc was associated with a dose-dependent decrease in (i) the production of the MmpL3 protein, (ii) the biosynthesis of trehalose dimycolate and mycolylated arabinogalactan, (iii) bacterial viability on agar and liquid medium as well as in biofilms. Importantly, intravenous injection of ATc in zebrafish embryos infected with the rough
mmpL3
conditional mutant impeded bacterial growth and correlated with a significant gain in embryo survival. These results suggest that
mmpL3
is essential for
M. abscessus
growth
in vitro
and in the infected host, thus validating MmpL3 as an attractive drug target. Together, this study demonstrates the potential of ATc-dependent repression to modulate the expression of
M. abscessus
genes in the infected host.

IMPORTANCE

Mycobacterium abscessus
represents the most common rapidly growing mycobacterial pathogen in cystic fibrosis and is extremely difficult to eradicate. Essential genes are required for growth, often participate in pathogenesis, and encode valid drug targets for further chemotherapeutic developments. However, assessing the function of essential genes in
M. abscessus
remains challenging due to the limited spectrum of efficient genetic tools. Herein, we generated a Tet-OFF-based system allowing to knock down the expression of
mmpL3
, encoding the mycolic acid transporter in mycobacteria. Using this conditional mutant, we confirm the essentiality of
mmpL3
in planktonic cultures, in biofilms, and during infection in zebrafish embryos. Thus, in this study, we developed a robust and reliable method to silence the expression of any
M. abscessus
gene during host infection.
Role of Antimicrobial Peptides in Immunity of Parasitic Leeches
Authors: Kaygorodova I. A.
Published: October 2023

The review summarizes the current state of knowledge about leech immunity, with emphasis on the special role of antimicrobial peptides (AMPs), and highlights the wide variety of primary AMP structures, which seem to correlate with a variety of life strategies and the ecology of ectoparasites. Antimicrobial proteins and AMPs are a diverse class of natural molecules that are produced in all living organisms in response to an attack by a pathogen and are essential components of the immune system. AMPs can have a wide range of antibiotic activities against foreign and opportunistic bacteria, fungi, and viruses. AMPs play an important role in selection of colonizing bacterial symbionts, thus helping multicellular organisms to cope with certain environmental problems. AMPs are especially important for invertebrates, which lack an adaptive immune system. Although many AMPs are similar in physicochemical properties (a total length from 10 to 100 amino acids, a positive total charge, or a high cysteine content), their immunomodulatory activities are specific for each AMP type.
Polygenic risk score predicts risk of primary sclerosing cholangitis in inflammatory bowel disease
Authors: Wang Ming-Hsi , Friton Jessica J , Raffals Laura E , Leighton Jonathan A , Pasha Shabana F , Picco Michael F , Monroe Kelly , Nix Billy D , Newberry Rodney D , Faubion William A
Published: October 2023

Background

Forty distinct primary sclerosing cholangitis (PSC) genomic loci have been identified through multiancestry meta-analyses. The polygenic risk score (PRS) could serve as a promising tool to discover unique disease behaviour, like PSC, underlying inflammatory bowel disease (IBD).

Aim

To test whether PRS indicates PSC risk in patients with IBD.

Materials and methods

Mayo Clinic and Washington University at St Louis IBD cohorts were used to test our hypothesis. PRS was modelled through the published PSC loci and weighted with their corresponding effect size. Logistic regression was applied to predict the PSC risk.

Results

In total, 63 (5.6%) among 1130 patients with IBD of European ancestry had PSC. Among 381 ulcerative colitis (UC), 12% had PSC; in contrast to 1.4% in 761 Crohn disease (CD). Compared with IBD alone, IBD-PSC had significantly higher PRS (PSC risk: 3.0% at the lowest PRS quartile vs 7.2% at the highest PRS quartile, Ptrend=.03). In IBD subphenotypes subgroup analysis, multivariate analysis shows that UC-PSC is associated with more extensive UC disease (OR, 5.60; p=0.002) and younger age at diagnosis (p=0.02). In CD, multivariate analysis suggests that CD-PSC is associated with colorectal cancer (OR, 50; p=0.005).

Conclusions

We found evidence that patients with IBD with PSC presented with a clinical course difference from that of patients with IBD alone. PRS can influence PSC risk in patients with IBD. Once validated in an independent cohort, this may help identify patients with the highest likelihood of developing PSC.
Cardiovascular health: an important component of cancer survivorship
Authors: Cleary Siobhan , Rosen Stuart D , Gilbert Duncan C , Langley Ruth E
Published: October 2023

Advances in the detection and treatment of cancer have translated into improved cancer survival rates and a growing population of cancer survivors. These include those living with cancer and individuals free of the disease following treatment. Epidemiological studies demonstrate that cancer survivors are at an increased risk of cardiovascular disease (CVD), with cardiovascular (CV) mortality overtaking cancer mortality in some tumour types. Cancer and CVD share common aetiological risk factors, for example, age, tobacco use and obesity, as well as a shared inflammatory pathogenesis. The CV risks of mediastinal radiotherapy and chemotherapy, first observed in the 1970s with anthracyclines, have long been appreciated. More recently, targeted anticancer therapeutics (human epidermal growth factor receptor-2 targeted therpies, vascular endothelial growth factor inhibitors, second/third-generation BCR-ABL inhibitors, multiple myeloma therapies and combination RAF and MEK inhibitors in particular) as well as immunotherapies have added to the burden of treatment-related CV toxicity. Additionally, cancer therapy may indirectly impact on CV health by decreasing physical activity, increasing weight gain and accelerating the ageing process. Improving overall health outcomes by considering cardiological prevention and management in cancer survivorship is an area of increasing interest. CV risk factor assessment and management are recommended post-cancer treatment in accordance with primary prevention guidelines. The European Society of Cardiology 2022 guidelines also recommend enhanced surveillance after cancer treatments with a moderate to high risk of CV consequences. The aim of this article is to provide an overview of the interconnections between cancer and CVD, review current survivorship recommendations, and highlight key areas of ongoing and future research.
Effectiveness of an artificial intelligence clinical assistant decision support system to improve the incidence of hospital-associated venous thromboembolism: a prospective, randomised controlled study
Authors: Huang Xiaoyan , Zhou Shuai , Ma Xudong , Jiang Songyi , Xu Yuanyuan , You Yi , Qu Jieming , Shang Hanbing , Lu Yong
Published: October 2023

Background

Thromboprophylaxis has been determined to be safe, effective and cost-effective for hospitalised patients at venous thromboembolism (VTE) risk. However, Chinese medical institutions have not yet fully used or improperly used thromboprophylaxis. The effectiveness of information technology applied to thromboprophylaxis in hospitalised patients has been proved in many retrospective studies, lacking of prospective research evidence.

Methods

All hospitalised patients aged >18 years not discharged within 24 hours from 1 September 2020 to 31 May 2021 were prospectively enrolled. Patients were randomly assigned to the control (9890 patients) or intervention group (9895 patients). The control group implemented conventional VTE prevention programmes; the intervention group implemented an Artificial Intelligence Clinical Assistant Decision Support System (AI-CDSS) on the basis of conventional prevention. Intergroup demographics, disease status, hospital length of stay (LOS), VTE risk assessment and VTE prophylaxis were compared using the χ2test, Fisher’s exact test, t-test or Wilcoxon rank-sum test. Univariate and multivariate logistic regressions were used to explore the risk factor of VTE.

Results

The control and intervention groups had similar baseline characteristics. The mean age was 58.32±15.41 years, and mean LOS was 7.82±7.07 days. In total, 5027 (25.40%) and 2707 (13.67%) patients were assessed as having intermediate-to-high VTE risk and high bleeding risk, respectively. The incidence of hospital-associated VTE (HA-VTE) was 0.38%, of which 86.84% had deep vein thrombosis. Compared with the control group, the incidence of HA-VTE decreased by 46.00%, mechanical prophylaxis rate increased by 24.00% and intensity of drug use increased by 9.72% in the intervention group. However, AI-CDSS use did not increase the number of clinical diagnostic tests, prophylaxis rate or appropriate prophylaxis rate.

Conclusions

Thromboprophylaxis is inadequate in hospitalised patients with VTE risk. The role of AI-CDSS in VTE risk management is unknown and needs further in-depth study.

Trial registration number

ChiCTR2000035452.
Intellectual disability syndrome associated with a homozygous founder variant in
SGSM3
in Ashkenazi Jews
Authors: Birnbaum Rivka , Ezer Shlomit , Lotan Nava Shaul , Eilat Avital , Sternlicht Keren , Benyamini Lilach , Reish Orit , Falik-Zaccai Tzipora , Ben-Gad Gali , Rod Raya , Segel Reeval , Kim Katherine , Burton Barabra , Keegan Catherine E , Wagner Mallory , Henderson Lindsay B , Mor Nofar , Barel Ortal , Hirsch Yoel , Meiner Vardiella , Elpeleg Orly , Harel Tamar , Mor-Shakad Hagar
Published: October 2023

Background

Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.

Methods

Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals.

Results

We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in
SGSM3
gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature.

Conclusions

An Ashkenazi Jewish homozygous founder variant in
SGSM3
was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.
Longitudinal associations of cardiovascular health and vascular events with incident dementia
Authors: Ou Ya-Nan , Kuo Kevin , Yang Liu , Zhang Ya-Ru , Huang Shu-Yi , Chen Shi-Dong , Deng Yue-Ting , Guo Yu , Zhang Rui-Qi , Wu Bang-Sheng , Tan Lan , Dong Qiang , Feng Jian-Feng , Cheng Wei , Yu Jin-Tai
Published: October 2023

Introduction

Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: (1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment and (2) examine the associations between cardiovascular diseases and the risk of dementia.

Methods

A total of 432 079 dementia-free individuals at baseline from UK Biobank were included. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all-cause dementia (ACD) and its major components, Alzheimer’s disease (AD) and vascular dementia (VaD).

Results

During a median follow-up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high-risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischaemic heart disease (ACD: HR=1.354; AD: HR=1.269; VaD: HR=1.768), atrioventricular block (ACD: HR=1.562; AD: HR=1.556; VaD: HR=2.069), heart failure (ACD: HR=1.639; AD: HR=1.543; VaD: HR=2.141) and hypotension (ACD: HR=2.912; AD: HR=2.361; VaD: HR=3.315) were observed. Several distinctions were also found, with atrial fibrillation, cerebral infarction, and haemorrhage only associated with greater risks of ACD and VaD.

Discussion

By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive ‘mapping’ that may untangle the long-standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation.
Catch as catch can: markets, availability, and fishery closures drive distinct responses among the U.S. West Coast coastal pelagic species fleet segments
Authors: Quezada Felipe J. , Tommasi Desiree , Frawley Timothy H. , Muhling Barbara , Kaplan Isaac , Stohs Stephen
Published: October 2023

Fishers often target multiple species. More diverse harvest portfolios may reduce income risk, increasing resilience to climate-driven changes in target species’ spatial distributions and availability. Moreover, different effects can be observed across vessels in response to the same shocks and stressors, as fishers are heterogeneous. Evaluation of climate risk across different vessel groups within a particular fishery requires consideration of heterogeneous climate impacts on the availability of multiple target species and how such changes may impact substitution behavior. Here we analyze how historical climate-driven changes in forage species distribution and the closure of the Pacific sardine fishery affected landings per vessel of three coastal pelagic species (CPS): Pacific sardine ( Sardinops sagax), market squid ( Doryteuthis opalescens), and northern anchovy ( Engraulis mordax) targeted by the U.S. West Coast CPS fleet from 2000 to 2020. Using cluster analysis, we grouped vessels into different fleet segments and estimated heterogeneous responses by fleet segment and port area. Our results show that considering heterogeneity is essential in the development of equitable and effective adaptation policies designed to mitigate the impact of changes on species availability in these fisheries.