bluuebunny/crossref_metadata_2025 huggingface dataset:
The paradox of attraction: unveiling the dynamics of tourist motivation and impact perception at a dark heritage site through mixed-method approach
Authors: Dandotiya Ravi , Aggarwal Arun , Sharma Ishani
Published: May 2024

Purpose

The purpose of this study is to examine the relationships between tourists’ motivations, perception of tourism impacts, place attachment (PA) and loyalty toward Jallianwala Bagh, a dark heritage site in Punjab, India.

Design/methodology/approach

A mixed-method approach comprising qualitative and quantitative methods was used. Semi-structured interviews and the Delphi method helped generate a 34-item survey instrument. A sample size of 869 respondents was obtained, split into two subsets for exploratory factor analysis and confirmatory factor analysis.

Findings

Seven out of nine hypotheses were supported. Motivated tourists perceived higher positive tourism impacts but lower negative tourism impacts. Higher perceptions of positive tourism impacts increased both PA and loyalty to the destination. Surprisingly, the perception of negative tourism impacts did not significantly affect tourist loyalty, contrary to some previous research.

Practical implications

This study informs stakeholders about tourists’ cognitive and affective responses at a dark tourism site, aiding in the planning and development of sustainable tourism strategies.

Social implications

By understanding the tourists’ motivations and perceptions, stakeholders can manage tourism impacts more effectively, ensuring that tourists’ experiences align with sustainable practices.

Originality/value

This study enriches the understanding of the tourists’ complex interactions with dark heritage sites. It introduces a new angle by examining how motivations, PA and perceptions of tourism impacts influence tourist loyalty, especially in the context of dark tourism.
Triadic relationship of remittances, migration and labor force
Authors: Zhushi Genc , Qehaja Driton
Published: May 2024

Purpose

This study aims to investigate the relationship between Kosovo remittances, migration and labor force participation and seeks to uncover how migration and remittances, often considered separately, interact to shape labor market outcomes across gender, age and education groups.

Design/methodology/approach

To analyze the relationship between remittances, migration and labor force participation, this study leverages multivariate probit (mvprobit) to rectify the endogeneity issue intrinsic from remittances and migration. Utilizing this robust methodological approach allows us to circumvent the limitations traditionally associated with biprobit analysis. The research is grounded in empirical evidence from the Millennium Century Corporation survey in Kosovo.

Findings

The findings indicate that remittances and migration are pivotal determinants in shaping the contours of labor force participation, particularly influencing disparities across gender, age and educational attainment. Further, this study unearthed intriguing evidence suggesting the disincentivizing effect of remittances on labor force participation, alongside the potentially disruptive influence of prospective migration plans.

Originality/value

The novelty of this work lies not only in the context-specific insights it provides into the socio-economic fabric of Kosovo—an area that has hitherto received limited scholarly attention—but also in its methodological innovation. The simultaneous application of mvprobit technique provides a nuanced approach to tackle the inherent endogeneity issue, thereby pushing the methodological frontiers of the field.
Lesson studies in physical education – a scoping narrative
Authors: Marques Santinha Fernanda , Onofre Marcos , Martins Maria
Published: May 2024

Purpose

Lesson studies, a methodology originally developed in Japan, has been used in an increasing number of contexts, both in relation to initial teacher training and in the context of ongoing professional development. However, the research reported on the use of lesson studies in the training of physical education teachers is very limited. The aim of this review is to identify and analyze published studies on physical education lesson studies and to describe the advantages of using the methodology in the context of this discipline.

Design/methodology/approach

Exploratory searches were carried out in four multiple-search databases, and 14 publications were found. Information was collected about authors, year of publication, origin and type of study, purposes, concept of the lesson study, methodology and results.

Findings

The results of the different studies point in the same direction – potential of lesson studies in physical education in initial training and professional development; valuing collaborative work, contextualization and continuous nature; lesson studies as a significant experience; need to create conditions for teachers’ participation in lesson studies; need for further investigation.

Originality/value

The research reported on the use of lesson studies in the training of physical education teachers is very limited. This review is intended to cover all studies related to the theme of physical education lesson studies published in indexed journals.
Viewpoint: on the required level of consciousness for authentic allyship
Authors: Goltz Sonia
Published: May 2024

Purpose

In this JOCM Viewpoint article, the author reflects on the expectations of some minoritized group members that power holders and otherwise privileged group members should exhibit authentic allyship. Specifically, it is suggested that these expectations are unrealistic given both the challenges of being an ally and the absence in many power holders of the type of consciousness that enables effective allyship.

Design/methodology/approach

An analysis of the challenges inherent in allyship as well as the criticism that performative rather than authentic allyship frequently occurs is followed by a review of research on consciousness and the implications of the level of consciousness for generating effective ally behavior.

Findings

Different stages of consciousness generate different types of responses to the challenges of allyship, some being more effective than others. Reaching a certain stage of consciousness development may increase the likelihood that the ally will be able to hold space for the emotional well-being of the marginalized and the need for instrumental change, which are both necessary for effective allyship to occur. Without these, an individual’s allyship is likely to be absent or at the most performative. Allyship groups can be helpful in supporting this level of consciousness through their group norms.

Originality/value

This viewpoint challenges conventional assumptions that privileged members of society should engage in allyship and suggests only a subset will be able to make the commitment and exhibit the behaviors required of authentic allies.
Forecasting the potential of global marine shipping carbon emission under artificial intelligence based on a novel multivariate discrete grey model
Authors: Zeng Zirui , Xu Junwen , Zhou Shiwei , Zhao Yufeng , Shi Yansong
Published: May 2024

Purpose

To achieve sustainable development in shipping, accurately identifying the impact of artificial intelligence on shipping carbon emissions and predicting these emissions is of utmost importance.

Design/methodology/approach

A multivariable discrete grey prediction model (WFTDGM) based on weakening buffering operator is established. Furthermore, the optimal nonlinear parameters are determined by Grey Wolf optimization algorithm to improve the prediction performance, enhancing the model’s predictive performance. Subsequently, global data on artificial intelligence and shipping carbon emissions are employed to validate the effectiveness of our new model and chosen algorithm.

Findings

To demonstrate the applicability and robustness of the new model in predicting marine shipping carbon emissions, the new model is used to forecast global marine shipping carbon emissions. Additionally, a comparative analysis is conducted with five other models. The empirical findings indicate that the WFTDGM (1, N) model outperforms other comparative models in overall efficacy, with MAPE for both the training and test sets being less than 4%, specifically at 0.299% and 3.489% respectively. Furthermore, the out-of-sample forecasting results suggest an upward trajectory in global shipping carbon emissions over the subsequent four years. Currently, the application of artificial intelligence in mitigating shipping-related carbon emissions has not achieved the desired inhibitory impact.

Practical implications

This research not only deepens understanding of the mechanisms through which artificial intelligence influences shipping carbon emissions but also provides a scientific basis for developing effective emission reduction strategies in the shipping industry, thereby contributing significantly to green shipping and global carbon reduction efforts.

Originality/value

The multi-variable discrete grey prediction model developed in this paper effectively mitigates abnormal fluctuations in time series, serving as a valuable reference for promoting global green and low-carbon transitions and sustainable economic development. Furthermore, based on the findings of this paper, a grey prediction model with even higher predictive performance can be constructed by integrating it with other algorithms.
Driving ESG performance: CEO succession impact in European listed firms
Authors: Cambrea Domenico Rocco , Quarato Fabio , D'Allura Giorgia Maria , Paolone Francesco
Published: May 2024

Purpose

The purpose of the paper is to examine the effect of chief executive officer (CEO) succession on environmental, social and governance (ESG) performance and whether the characteristics of the incoming CEO, in terms of both gender and career horizon, are able to affect the relationship between CEO succession and ESG score.

Design/methodology/approach

The paper investigates a sample of European-listed companies between 2010 and 2021. Difference-in-difference and fixed-effects regressions are employed as the base empirical methodology. In addition, the robustness of the empirical findings is assessed by employing alternative methodologies and a different ESG proxy.

Findings

The empirical findings show the existence of a positive link between CEO succession and ESG performance and that this relationship is affected by two characteristics of the incoming CEO. Specifically, the empirical evidence indicates that the positive effect is magnified by the gender and the career horizon of the incoming CEO.

Originality/value

Considering the lack of research, this paper is the first one that opens a debate about the effects of CEO succession on corporate ESG performance in several European countries. By employing a unique sample of European listed firms, which has never been examined in other empirical research, this study highlights the importance of the demographic features of the incoming CEOs that should be taken into consideration during their selection process.
Association of dietary habits with non-communicable diseases: a qualitative review
Authors: Muraleedharan Manesh , P.A. Mounika , Chandak Alaka
Published: May 2024

Purpose

Kerala, a southern state in India, is acknowledged for its socio-economic reforms such as quality health care, gender parity, high literacy rate and more. However, recent trends show that the state has the highest incidence of various noncommunicable diseases in the country, including diabetes, hypertension and heart coronary artery disease. This research paper aims to examine the link between the Kerala population’s lifestyle, diet and genetic factors and its correlation with a heightened cardio-metabolic risk.

Design/methodology/approach

Using Dixon Wood’s interpretive synthesis, this qualitative literature review is systematically used by searching, gathering articles, theme building, comparing and criticising the evidence.

Findings

The result shows that only minimal evidence is available regarding the genetic makeup of the Kerala community, food patterns and its link to the high prevalence of non-communicable diseases (NCDs). However, limited and contradicting evidence and studies restricted to a particular region in the state demand more research on this domain.

Originality/value

It is vital to review the diet habits of Keralites due to the alarmingly high prevalence of NCDs. To the best of the authors’ knowledge, this is the first comprehensive review of the diet habits of Kerala and their link to NCDs.
Unraveling the origins of construction rework: a holistic bibliometric analysis and exploration of causative factors
Authors: Gumusburun Ayalp Gulden , Erdem Eda Nur
Published: May 2024

Purpose

Construction experts acknowledge the adverse effects of rework on project performance. However, the limited understanding of its underlying causes remains a significant challenge. Therefore, this study aimed to thoroughly investigate the sources of construction rework.

Design/methodology/approach

A mixed review using bibliometric analysis as a quantitative method and content analysis as a qualitative method was performed to understand the current knowledge in the field. The Web of Science (WoS) was selected for its comprehensive collection of major research articles and integrated analytical tools for generating representative data. The study involved an extensive bibliometric analysis of 107 journal articles on rework causes from 1991 to 2023. RStudio Bibliometrix, an R statistical programming package, was used to analyze rework origins. This method involved mapping the research landscape, identifying research gaps and analyzing emerging trends.

Findings

The causes of rework can be classified into three main clusters: human- and contractual-based rework causes, design-, quality- and project management-based rework causes and organizational-based rework causes.

Originality/value

Although several studies have addressed rework causes from various perspectives and methods, the topic has not been investigated holistically. This study is the first to leverage the quantitative and qualitative analytical capabilities of the RStudio Bibliometrix package. Innovative approaches, including the use of metrics, such as the h-index, thematic mapping and trend topic analysis, were employed for a comprehensive understanding of rework causes.
Strategic interventions for bridging the design-reality gap in property conferment rights: a case study of India’s ambitious initiative
Authors: Pandey Jitendra Kumar
Published: May 2024

Purpose

This research aims to assess how well the e-governance initiative aligns with its design expectations and on-ground realities for property management to redevelop Delhi, the mega-city of India. Additionally, the study proposes strategic interventions to address any gaps identified, aiming to improve the project’s effectiveness and success.

Design/methodology/approach

The research employs a singular exploratory case study methodology to scrutinise the e-governance initiative undertaken by the Government of India to confer property rights. Specifically, the study utilises a qualitative research approach known as design-reality gap (DRG) analysis. The study draws from primary and secondary sources using a mixed-methods data collection strategy. Primary data are gathered through a purposeful and snowball sampling method involving direct engagement with respondents, whilst secondary data are sourced from the project portal.

Findings

The investigation reveals a substantial disparity between the planning and execution phases of e-governance projects. This incongruity predominantly manifests in the domains of process, staffing and skills, as well as objectives and values. The study further finds that strategic collaboration amongst stakeholders and the sustainability of decisions are the most critical factors in ensuring the success of e-governance initiatives and bridging the DRG of e-governance projects.

Research limitations/implications

This research highlights the complex challenges faced by e-governance projects in technical, human and organisational aspects. The successful implementation and sustainability of these projects require effective strategies to overcome challenges, which management should proactively identify and act on. To improve services, beneficiaries should be encouraged to provide feedback and suggestions, as they play a crucial role in service enhancement. A dynamic feedback loop would be established by creating a two-way interaction between beneficiaries and service providers, leading to iterative service improvement. It is important to note that the study’s findings are more illustrative than conclusive due to the moderate sample size, reflecting its limitations.

Originality/value

The research contributes to the scholarly discourse on e-governance and policy implementation by comprehensively examining the alignment between conceptual design and real-world execution. It also introduces a normalised scale for the DRG framework, mapping its dimensions to deduce specific outcomes. This innovative approach enhances the research’s originality and value, offering insights applicable in both academic and practical domains.
Background food influences rate of encounter and efficacy of rodenticides in wild house mice
Authors: Brown Peter R. , Henry Steve , Hinds Lyn A. , Robinson Freya , Duncan Richard P. , Ruscoe Wendy A.
Published: May 2024

Baiting is widely used in wildlife management for various purposes, including lethal control, fertility control, disease and parasite control, and conditioned aversion programs for many invasive vertebrate species. The efficacy of baiting programs relies on the likelihood that target animals will encounter the bait, consume it and receive an appropriate dose of the active ingredient. However, there has been little focus on encounter rate of toxic baits combined with behavioural aversion, which are likely to be significant factors affecting efficacy.

Following optimal foraging theory, the likelihood of an animal encountering and consuming a toxic grain bait should increase in proportion to its availability relative to background food quantity if it is neither more or less detectable or palatable. Furthermore, the probability of consuming toxic baits might also be influenced by bait aversion following ingestion of a non‐lethal dose of toxin.

Using a model system of wild house mice (Mus musculus L.) in mouse‐proof enclosures in Australia, we manipulated background food, applied zinc phosphide (Zn3P2) baits and measured mouse mortality. When background food was scarce, mouse mortality was high, whereas an increasing abundance of background food led to reduced mortality. A scenario modelling random encounters and including bait aversion explained 78% of the variation in observed mortality outcomes and achieved a closer fit to the data than modelling random encounters alone. Mortality rates were predicted to be higher with a higher strength bait, which would overcome behavioural aversion.

Ensuring that animals locate and consume a lethal dose of toxic bait is a critical factor for successful bait delivery and efficacy. This is particularly significant in toxic baiting programs, where sublethal doses can make animals feel sick, leading to a negative association with the bait, and the development of aversion.

Synthesis and applications: Our findings explain why some toxic baiting programs might fail. To achieve successful control, efforts should be directed at reducing the availability of background food to increase the probability of encounter and uptake of toxic baits. It is important to measure and understand the role of background food on toxic baiting programs to explain variable outcomes and inform strategies for successful bait delivery.
The Human Body is the Collective Unconscious: Archetypal Images as Innate Embodied Metaphors
Authors: Goodwyn Erik
Published: May 2024

For a significant part of its history, archetype theory has been undermined by criticisms containing unexamined Cartesian assumptions. Such assumptions treat all cognition as disembodied, consisting of mere manipulation of abstract, inherently meaningless signs mimicked from verbal instruction or cultural learning. Since the 1980s, due to the results of many independent disciplines, however, this view is being replaced with one of embodied cognition. This shift has important consequences for archetype theory, allowing us to provide a non‐reductive biological anchor that explains many characteristics of the archetypal image.
To wear or not to wear, was that the question? Understanding citizen responses to COVID‐19 crisis management in social media across Europe
Authors: Liste Lucia , Johnson Victoria , Costa Sara , Karlsen André
Published: May 2024

This study aims to gain qualitative insights about and compare public responses to COVID‐19 crisis management during the different pandemic phases and across three countries—Norway, Sweden and Italy. To do so, we have carried out a qualitative content analysis of a selection of 2606 tweets containing the term ‘face mask’ in Italian, Norwegian, and Swedish published between March 1, 2020 and June 31, 2022. The article combines risk society theses with social practice theory as a lens through which to examine public responses to crisis management. Analyzing the data from Norway, Sweden, and Italy, this article discusses the extent to which individualism, reflexive modernization, and cosmopolitanism account for citizen responses to authority's crisis management efforts in each of the countries during the different phases of the pandemic. Findings highlight the crucial role of socio‐cultural contexts that shape citizen responses to crisis management over time, showcasing a spectrum of attitudes ranging from scepticism and critique to trust and compliance. This comparative analysis underscores the importance of considering the dynamic interplay between criticism and support, individualism and collectivism, as well as global and local experiences in understanding diverse and situated societal responses to crisis management during a global pandemic. The article also points to social media as a meaningful arena where individuals and groups share information and participate in discussions that shape collective views, thus having a significant role in shaping citizen responses to COVID‐19 crisis management and influencing decision‐making.
Tax Effort Levels across Non‐Special Category Indian States – A Stochastic Tax Frontier Analysis*
Authors: Singh Nirmal , Arora Nitin
Published: May 2024

This study aims to analyse the tax efforts of 17 non‐special category states of India over the period of 2000–01 to 2020–21. The stochastic estimation of the tax frontier identified per capita income and urbanisation as dominating factors determining tax revenue across Indian states. The implementation of a Goods and Services Tax is estimated to increase tax revenue significantly, whereas the pandemic shock resulted in a deterioration of the tax revenue. In addition, the sampled states have collectively secured a tax effort score of 0.832, ranging from 0.62 (Goa) to 0.92 (Karnataka). The empirics showed that Goa and West Bengal were the laggard states in terms of tax effort. Among the determinants of tax efficiency (effort), the variates ‘outstanding liabilities’ and ‘fiscal devolution from central government’ are found to be adversely affecting, while ‘social expenditure’ is predicted to have a stimulating impact on tax effort.
Liquid biopsy for molecular characterization of diffuse large B‐cell lymphoma and early assessment of minimal residual disease
Authors: Alcoceba Miguel , Stewart James P. , García‐Álvarez María , Díaz Luis G. , Jiménez Cristina , Medina Alejandro , Chillón M. Carmen , Gazdova Jana , Blanco Oscar , Díaz Francisco J. , Peñarrubia María J. , Fernández Silvia , Montes Carlos , Cabero Almudena , Caballero María D. , García‐Sanz Ramón , González Marcos , González David , Tamayo Pilar , Gutiérrez Norma C. , García‐Sancho Alejandro Martín , Sarasquete M. Eugenia
Published: May 2024

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next‐generation sequencing (NGS) approach (EuroClonality‐NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R‐CHOP‐treated diffuse large B‐cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high‐risk International Prognostic Index and a trend to shorter 2‐year progression‐free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5‐log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2‐year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2‐year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2‐year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality‐NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.
Evaluation of European LeukemiaNet 2022 risk classification in patients undergoing allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: Identification of a very poor prognosis genetic group
Authors: Jiménez‐Vicente Carlos , Charry Paola , Castaño‐Diez Sandra , Guijarro Francesca , López‐Guerra Mònica , Pérez‐Valencia Amanda Isabel , Martinez‐Roca Alexandra , Cortés‐Bullich Albert , Munárriz Daniel , Solano Maria Teresa , Rosiñol Laura , Carreras Enric , Urbano‐Ispizua Álvaro , Fernández‐Avilés Francesc , Martinez Carmen , Suárez‐Lledó María , Díaz‐Beyá Marina , Rovira Montserrat , Salas María Queralt , Esteve Jordi
Published: May 2024

European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo‐HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia‐free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse‐plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2‐year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo‐HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group.
Twice‐weekly induction with ixazomib–lenalidomide–dexamethasone (IRd) combination followed by extended IRd consolidation and lenalidomide maintenance in transplant‐eligible patients with newly diagnosed multiple myeloma: Results of the phase 2 study IFM2014‐03
Authors: Perrot Aurore , Roussel Murielle , Lauwers‐Cances Valerie , Hulin Cyrille , Leleu Xavier , Touzeau Cyrille , Facon Thierry , Mariette Clara , Schiano Jean‐Marc , Gay Julie , Montes Lydia , Ranta Dana , Huguet Amandine , Wuillème Soraya , Dejoie Thomas , Devlamynck Laure , Corre Jill , Avet‐Loiseau Hervé , Moreau Philippe , Attal Michel
Published: May 2024

Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014‐03 trial proposed an all‐oral triplet induction/consolidation regimen in transplant‐eligible NDMM patients, followed by lenalidomide maintenance. Induction consisted of three 21‐day cycles of ixazomib, lenalidomide and dexamethasone (IRd), before high‐dose Melphalan with transplant followed by eight 28‐day cycles of IRd consolidation before 13 cycles of lenalidomide maintenance. Forty‐six patients were enrolled and received at least one dose of therapy, and 39 entered the maintenance phase. The primary end‐point was stringent complete response after consolidation, and was achieved in nine patients (20.9%, 90% CI 11.4–33.7; p = 0.998). Ten patients (24.4%) had an undetectable minimal residual disease. The overall response rate was 95.7%. The 3‐year progression‐free survival was 66.3%. No unexpected toxicities were recorded, and only eight patients suspended from any study drug. Of note, 21 (45.7%) patients reported peripheral neuropathy (PN) (grades 1–2 with no serious adverse events). IRd induction and consolidation with transplant before lenalidomide maintenance shows lower response rates compared to other triplet therapies. It could be an alternative for patients who require an all‐oral regimen and/or with pre‐existent PN, especially if quadruplet regimens including anti‐CD38 antibody are not available.
Pronociceptive role of spinal Cav2.3 (R‐type) calcium channels in a mouse model of postoperative pain
Authors: Ferreira Marcella de Amorim , Lückemeyer Debora Denardin , Martins Fernanda , Schran Roberta Giusti , da Silva Ana Merian , Gambeta Eder , Zamponi Gerald W. , Ferreira Juliano
Published: May 2024

Background

More than 80% of patients may experience acute pain after a surgical procedure, and this is often refractory to pharmacological intervention. The identification of new targets to treat postoperative pain is necessary. There is an association of polymorphisms in the Cav2.3 gene with postoperative pain and opioid consumption. Our study aimed to identify Cav2.3 as a potential target to treat postoperative pain and to reduce opioid‐related side effects.

Experimental Approach

A plantar incision model was established in adult male and female C57BL/6 mice. Cav2.3 expression was detected by qPCR and suppressed by siRNA treatment. The antinociceptive efficacy and safety of a Cav2.3 blocker—alone or together with morphine—was also assessed after surgery.

Key Results

Paw incision in female and male mice caused acute nociception and increased Cav2.3 mRNA expression in the spinal cord but not in the incised tissue. Intrathecal treatment with siRNA against Cav2.3, but not with a scrambled siRNA, prevented the development of surgery‐induced nociception in both male and female mice, with female mice experiencing long‐lasting effects. High doses of i.t. SNX‐482, a Cav2.3 channel blocker, or morphine injected alone, reversed postoperative nociception but also induced side effects. A combination of lower doses of morphine and SNX‐482 mediated a long‐lasting reversal of postsurgical pain in female and male mice.

Conclusion

Our results demonstrate that Cav2.3 has a pronociceptive role in the induction of postoperative pain, indicating that it is a potential target for the development of therapeutic approaches for the treatment of postoperative pain.
Insulin‐degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver
Authors: Andres Marine , Hennuyer Nathalie , Zibar Khamis , Bicharel‐Leconte Marie , Duplan Isabelle , Enée Emmanuelle , Vallez Emmanuelle , Herledan Adrien , Loyens Anne , Staels Bart , Deprez Benoit , van Endert Peter , Deprez‐Poulain Rebecca , Lancel Steve
Published: May 2024

Background and Purpose

Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin‐degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo‐endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR.

Experimental Approach

We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress‐induced UPR and lipid accumulation in the liver.

Key Results

We found that IDE‐deficient mice display higher hepatic triglyceride content along with higher inositol‐requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress‐induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4μ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis.

Conclusion and Implications

These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases.
YTHDF3 phase separation regulates HSPA13‐dependent clear cell renal cell carcinoma development and immune evasion
Authors: Dai Chenyun , Cao Jianfu , Tang Yuangui , Jiang Yuxiao , Luo Chenghua , Zheng Junfang
Published: May 2024

Insufficient understanding about the immune evasion mechanism leads to the inability in predicting current immunotherapy effects in clear cell renal cell carcinoma (ccRCC) and sensitizing ccRCC to immunotherapy. RNA binding proteins (RBPs) can promote tumor progression and immune evasion. However, research on RBPs, particularly m6A reader YTHDF3, in ccRCC development and immune evasion is limited. In this study, we found that YTHDF3 level was downregulated in ccRCC and was an independent prognostic biomarker for ccRCC. Decreased YTHDF3 expression was correlated with the malignancy, immune evasion, and poor response to anti‐programmed death ligand 1 (PD‐L1)/CTLA‐4 in ccRCC. YTHDF3 overexpression restrained ccRCC cell malignancy, PD‐L1 expression, CD8+ T cell infiltration and activities in vivo, indicating its inhibitory role in ccRCC development and immune evasion. Mechanistically, YTHDF3 WT was found to have phase separation characteristics and suppress ccRCC malignancy and immune evasion. Whereas YTHDF3 mutant, which disrupted phase separation, abolished its function. YTHDF3 enhanced the degradation of its target mRNA HSPA13 by phase separation and recruiting DDX6, resulting in the downregulation of the downstream immune checkpoint PD‐L1. HSPA13 overexpression restored ccRCC malignancy and immune evasion suppressed by YTHDF3 overexpression. In all, our results identify a new model of YTHDF3 in regulating ccRCC progression and immune evasion through phase separation.
Quantitative systems pharmacology modeling of macrophage‐targeted therapy combined with PD‐L1 inhibition in advanced NSCLC
Authors: Wang Hanwen , Arulraj Theinmozhi , Anbari Samira , Popel Aleksander S.
Published: May 2024

Immune checkpoint inhibitors remained the standard‐of‐care treatment for advanced non‐small cell lung cancer (NSCLC) for the past decade. In unselected patients, anti‐PD‐(L)1 monotherapy achieved an overall response rate of about 20%. In this analysis, we developed a pharmacokinetic and pharmacodynamic module for our previously calibrated quantitative systems pharmacology model (QSP) to simulate the effectiveness of macrophage‐targeted therapies in combination with PD‐L1 inhibition in advanced NSCLC. By conducting in silico clinical trials, the model confirmed that anti‐CD47 treatment is not an optimal option of second‐ and later‐line treatment for advanced NSCLC resistant to PD‐(L)1 blockade. Furthermore, the model predicted that inhibition of macrophage recruitment, such as using CCR2 inhibitors, can potentially improve tumor size reduction when combined with anti‐PD‐(L)1 therapy, especially in patients who are likely to respond to anti‐PD‐(L)1 monotherapy and those with a high level of tumor‐associated macrophages. Here, we demonstrate the application of the QSP platform on predicting the effectiveness of novel drug combinations involving immune checkpoint inhibitors based on preclinical or early‐stage clinical trial data.
Rapid molecular profiling utilising minimal quantities of endobronchial ultrasound‐guided aspirates for the detection of Epidermal Growth Factor Receptor, KRAS, ALK, ROS1, RET, NTRK and MET gene alterations from patients with non‐small‐cell lung carcinomas on the Biocartis Idylla™ platform
Authors: Haragan Alexander , Lee Robert
Published: May 2024

Objectives

Comprehensive molecular analysis for patients with non‐small‐cell lung carcinoma (NSCLC) is essential for managing modern targeted therapies. This study sought to establish the feasibility of utilising real‐time PCR to perform rapid and comprehensive profiling on minimal amounts of endobronchial ultrasound‐guided (EBUS) aspirates as a fast, tissue‐sparing route of predictive profiling.

Methods

A volume of 500 μL of EBUS aspirate and fixative from patients with NSCLC was decanted, and 80 μL (<1% of total specimen received) was utilised for analysis. Biocartis Idylla™ cartridges for epidermal growth factor receptor (EGFR) mutations, KRAS mutations and a GeneFusion cartridge (ALK, ROS1, RET, NTRK1/2/3 rearrangements & MET 14 exon skipping) were analysed for each case to provide molecular data on the main clinically relevant targets as per UK guidelines.

Results

A total of 62 cases were included; all of which had successful DNA analysis (EGFR and KRAS cartridges). RNA analysis (GeneFusion cartridge) was successful for 42 of 51 (82%) with initial approach, with 11 of 11 (100%) achieving a successful result with modified protocol. In all, 23 KRAS mutations (37%), 5 EGFR mutations (8%) and 1 ROS fusion (2%) were identified. Average time from specimen receipt to molecular read‐out was 5 h.

Conclusion

Real‐time PCR utilising the Idylla™ platform is rapid, utilises minimal amounts of tissue and provides accurate results. We propose this is a useful ancillary method to utilise alongside next‐generation sequencing (NGS) in cases of urgent clinical requirement or EBUS aspirates with inadequate quantities of tissue for NGS.
Effects of biochar versus film mulching on soil hydrothermal properties and wheat crop performance in semi‐arid loess
Authors: Wang Huan , Fan Jun , Shao Ming'an , Wang Xi , Wang Jia , Hao Mingde
Published: May 2024

Film mulching and biochar have been applied as effective measures for increasing crop yields in arid and semi‐arid areas for many years. However, the effects of the temporal and spatial distributions of soil hydrothermal properties on crop yields are still unclear under film mulching and biochar addition. Thus, we conducted a field experiment with winter wheat on the Loess Plateau of China for two years (2020–2022) with three treatments: control, film mulching, and biochar. The results demonstrated that film mulching and biochar addition increased the average soil temperature in the 0–50 cm soil depth throughout the whole growth period and the influence depth exceeded 50 cm. Biochar addition only significantly increased soil temperature in the overwintering stage (p < 0.05). Film mulching increased the maximum and minimum temperatures in the 0–50 cm soil depth at seedling stage. Film mulching and biochar increased average ≥10°C accumulated soil temperature by increasing the ≥10°C accumulated soil temperature in the daytime and nighttime, and the number of days with a daily soil temperature ≥10°C during the whole growth period. Film mulching improved soil water storage in the 0–300 cm soil depth in each growth stage during both years, and also increased the wheat grain yield, aboveground biomass, and water use efficiency. Biochar addition increased the wheat grain yield and aboveground biomass of two years compared with control, but the increases were not significant (p > 0.05). In addition, correlation analysis showed that adequate temperatures in the 0–50 cm soil depth during the seedling and overwintering stages, and suitable soil moisture conditions in the 0–300 cm soil depth before sowing, jointing, and filling stages were important factors for increasing wheat grain yields under film mulching. In summary, film mulching mainly regulated the soil temperature in the 0–50 cm soil depth and moisture conditions in the 0–300 cm soil depth during different growth stages to increase grain yields. Film mulching has more obvious effects on moisture regulation, temperature regulation, and yield increases than biochar addition. Some environmentally friendly measures (such as conservation agriculture) with the same yield improving effect as mulching are also recommended to explore and promote in theLoess Plateau region.
Derivation of physically based soil hydraulic parameters in New Zealand by combining soil physics and hydropedology
Authors: Pollacco J. A. P. , Fernández‐Gálvez J. , Webb T. , Vickers S. , Robertson B. , McNeill S. , Lilburne L. , Rajanayaka C. , Chau H. W.
Published: May 2024

Field‐characterised soil morphological data (to 1 m depth) and modelled soil water release characteristics are recorded in the S‐map database for soils covering approximately 40% of New Zealand's soil area. This paper shows the development of the Smap‐Hydro database that estimates hydraulic parameters by synergising soil morphologic data recorded in S‐map and soil physics. The Smap‐Hydro parameters were derived using the bi‐modal Kosugi hydraulic function. The validity of the Smap‐Hydro parameters was tested by applying them within an uncalibrated physically based hydrological model (HyPix) and comparing results with soil water content, θ, measured with Aquaflex soil moisture probes (0–40 cm deep) at 24 sites across New Zealand. The HyPix model provided an excellent fit with observed soil water content for 25% of the sites, a good fit for 33% of the sites and a poor fit for 42% of the sites. Applying the model to all soils in the S‐map database required adjustments for the occurrence of rock fragments, hydraulic discontinuities caused by soil pans and required the addition of boundary conditions for water tables and the occurrence of impermeable rock. A discussion on how we can further synergise the development of pedotransfer functions with knowledge of soil physics is provided.
Recently acquired HCV infection in men who have sex with men in Germany in the direct‐acting antivirals era and during the COVID‐19 pandemic
Authors: Ingiliz Patrick , Lutz Thomas , Schewe Knud , Baumgarten Axel , Krznaric Ivanka , Mauss Stefan , Christensen Stefan , Bickel Markus , Schmidt Axel J. , Sabranski Michael , He Feng , Jain Sonia , Martin Nastasha K. , Rockstroh Jürgen K. , Boesecke Christoph
Published: May 2024

Introduction

Direct‐acting antivirals (DAAs) are key to eliminating hepatitis C virus (HCV). In men who have sex with men (MSM) with HIV co‐infection, recently acquired HCV infection is common. Sexual practices and reinfection rates may hamper micro‐elimination despite high treatment rates.

Methods

The cohort included MSM with recently acquired HCV infection from 2014 to 2021. The patients' demographic, clinical, behavioural, and laboratory data and treatment and reinfection outcomes were documented.

Results

A total of 237 men with recently acquired HCV infection were included: 216 (91%) had HIV. The median age was 46 years (interquartile range [IQR] 39–52), and the median CD4 count was 660/mm3 (IQR 527–835).

The annual incidence of recently acquired HCV remained between 0.28% and 0.43% but dropped to 0.02% in 2021 during the COVID pandemic, almost reaching micro‐elimination. The reinfection incidence was 15.5 per 100 patient‐years (95% confidence interval 12.6–18.8), and reinfection was associated with the use of crystal methamphetamine (p = 0.032) and ketamine (p = 0.042). In total, 31.3% had multiple reinfections, and four reinfections occurred in users of pre‐exposure prophylaxis.

Conclusions

High treatment and cure rates did not lead to HCV elimination. A change in sexual behaviour, potentially imposed by COVID‐19 restrictions, led to micro‐elimination in the NoCo cohort. As recently acquired HCV is prevalent in MSM with and without HIV, surveillance is necessary to consolidate elimination goals.
Post‐operative pain in non‐surgical root canal treatment after sealer‐based obturation versus warm vertical compaction: A randomized clinical trial
Authors: Alzoubi Fahad , Alajmi Samhan , Alkandari Abdullah , Alqahtani Saad , Alanezi Amer , Setzer Frank C.
Published: May 2024

Aim

Post‐operative pain may occur after non‐surgical root canal treatment (NSRCT). The root filling technique and choice of sealer may be contributing factors. This randomized controlled clinical trial compared post‐operative pain and analgesics intake after NSRCT using a sealer‐based obturation technique (SBO) with single‐cone gutta‐percha and calcium silicate sealer (CSS) versus a warm‐vertical compaction (WVC) technique with gutta‐percha and a resin‐based sealer (RBS).

Methodology

This study was designed as a parallel‐two arm, double‐blind, randomized superiority clinical trial registered at www.clinicaltrials.gov (NCT04753138). Patients referred for NSRCT fulfilling the inclusion criteria participated in this study. Pre‐operative periapical radiographs and CBCT scans were taken and numerical rating scale (NRS) pain scores were recorded. Upon completion of canal instrumentation, participants were randomly allocated to either Group SBO: SBO with CSS or Group WVC: Warm‐vertical compaction with RBS. Post‐operative pain and analgesics intake were recorded at 1, 3 and 7 days after endodontic treatment completion. Non‐parametric Mann–Whitney U and Friedman tests and a generalized estimating equation were used to assess differences in pain scores between the groups, within each treatment group at different time points and for correlations, respectively.

Results

The study included 195 participants (212 teeth). One participant declined to submit the NRS form. Therefore, 194 participants (211 teeth) were included in the final analysis (99.5% response rate). No statistically significant differences in post‐operative pain or analgesic intake existed between the two groups at any time point (p > .05). Age, pre‐operative pain, apical diagnosis and post‐operative analgesic intake were significantly related to post‐operative pain (p < .05).

Conclusions

Sealer‐based obturation technique with CSS was associated with similar post‐operative pain levels and analgesics intake as WVC with RBS. Regarding post‐operative pain, SBO with CSSs may be a suitable clinical alternative.