bluuebunny/crossref_metadata_2025 huggingface dataset:
A new combined finite-discrete element method for stability analysis of soil-rock mixture slopes
Authors: Deng Penghai , Liu Quansheng , Lu Haifeng
Published: September 2024

Purpose

The purpose of this paper is to propose a new combined finite-discrete element method (FDEM) to analyze the mechanical properties, failure behavior and slope stability of soil rock mixtures (SRM), in which the rocks within the SRM model have shape randomness, size randomness and spatial distribution randomness.

Design/methodology/approach

Based on the modeling method of heterogeneous rocks, the SRM numerical model can be built and by adjusting the boundary between soil and rock, an SRM numerical model with any rock content can be obtained. The reliability and robustness of the new modeling method can be verified by uniaxial compression simulation. In addition, this paper investigates the effects of rock topology, rock content, slope height and slope inclination on the stability of SRM slopes.

Findings

Investigations of the influences of rock content, slope height and slope inclination of SRM slopes showed that the slope height had little effect on the failure mode. The influences of rock content and slope inclination on the slope failure mode were significant. With increasing rock content and slope dip angle, SRM slopes gradually transitioned from a single shear failure mode to a multi-shear fracture failure mode, and shear fractures showed irregular and bifurcated characteristics in which the cut-off values of rock content and slope inclination were 20% and 80°, respectively.

Originality/value

This paper proposed a new modeling method for SRMs based on FDEM, with rocks having random shapes, sizes and spatial distributions.
Casson-Williamson ternary hybrid nanofluid flow over a yawed cylinder with the impacts of multiple slips
Authors: Patil Prabhugouda Mallanagouda , Goudar Bharath , Momoniat Ebrahim
Published: September 2024

Purpose

Many industries use non-Newtonian ternary hybrid nanofluids (THNF) because of how well they control rheological and heat transport. This being the case, this paper aims to numerically study the Casson-Williamson THNF flow over a yawed cylinder, considering the effects of several slips and an inclined magnetic field. The THNF comprises Al2O3-TiO2-SiO2 nanoparticles because they improve heat transmission due to large thermal conductivity.

Design/methodology/approach

Applying suitable nonsimilarity variables transforms the coupled highly dimensional nonlinear partial differential equations (PDEs) into a system of nondimensional PDEs. To accomplish the goal of achieving the solution, an implicit finite difference approach is used in conjunction with Quasilinearization. With the assistance of a script written in MATLAB, the numerical results and the graphical representation of those solutions were ascertained.

Findings

As the Casson parameter

β increases, there is an improvement in the velocity profiles in both chord and span orientations, while the gradients

Re1/2Cf, Re1/2C¯f reduce for the same variations of

β. The velocities of Casson THNF are greater than those of Casson-Williamson THNF. Approximately, a 202% and a 32% ascension are remarked in the magnitudes of

Re1/2Cf and

Re1/2C¯f for Casson-Williamson THNF than the Casson THNF only. When velocity slip attribute

S1 jumps to 1 from 0.5, magnitude of both

F(ξ,η) and

Re1/2Cf fell down and it is reflected to be 396% at

ξ=1,

Wi=1 and

β=1. An augmentation in thermal jump results in advanced fluid temperature and lower

Re−1/2Nu. In particular, about 159% of down drift is detected when

S2 taking 1.

Originality/value

There is no existing research on the effects of Casson-Williamson THNF flow over a yawed cylinder with multiple slips and an angled magnetic field, according to the literature.
A modified fuzzy PFMEA model for risk-centric Six Sigma assessment under the paradigm of Quality 4.0
Authors: Kar Anwesa , Rai Rajiv Nandan
Published: September 2024

Purpose

The purpose of the study is to examine how risk factors contribute to the occurrence of defects in a process. By analyzing these risk factors in relation to process quality, the study aims to help organizations prioritize their resources and efforts toward addressing the most significant risks. These challenges, integrated with the emerging concept of Quality 4.0, necessitate a comprehensive risk assessment technique.

Design/methodology/approach

Fuzzy logic integrated with an analytic network process is used in the process failure mode and effects analysis for conducting risk identification and assessment under uncertainty. Through a mathematical model, the linkage of risk with Six Sigma is established and, finally, a value–risk matrix is developed for illustrating and analysing risk impact on process quality.

Findings

A case study on fused filament fabrication demonstrates the proposed methodology’s applicability. The results show its effectiveness in assessing risk factors’ impact on Six Sigma metrics: defects per million opportunities/sigma level.

Practical implications

By integrating qualitative assessments and leveraging available data, this approach enables a more comprehensive understanding of risks and their utilization for an organization’s quality improvement initiatives.

Originality/value

This approach establishes a risk-centric Six Sigma assessment method in accordance with the requirement of ISO 9001:2015 and in the context of Quality 4.0.
Comparing human and synthetic data in service research: using augmented language models to study service failures and recoveries
Authors: Bickley Steven J. , Chan Ho Fai , Dao Bang , Torgler Benno , Tran Son , Zimbatu Alexandra
Published: September 2024

Purpose

This study aims to explore Augmented Language Models (ALMs) for synthetic data generation in services marketing and research. It evaluates ALMs' potential in mirroring human responses and behaviors in service scenarios through comparative analysis with five empirical studies.

Design/methodology/approach

The study uses ALM-based agents to conduct a comparative analysis, leveraging SurveyLM (Bickley et al., 2023) to generate synthetic responses to the scenario-based experiment in Söderlund and Oikarinen (2018) and four more recent studies from the Journal of Services Marketing. The main focus was to assess the alignment of ALM responses with original study manipulations and hypotheses.

Findings

Overall, our comparative analysis reveals both strengths and limitations of using synthetic agents to mimic human-based participants in services research. Specifically, the model struggled with scenarios requiring high levels of visual context, such as those involving images or physical settings, as in the Dootson et al. (2023) and Srivastava et al. (2022) studies. Conversely, studies like Tariq et al. (2023) showed better alignment, highlighting the model's effectiveness in more textually driven scenarios.

Originality/value

To the best of the authors’ knowledge, this research is among the first to systematically use ALMs in services marketing, providing new methods and insights for using synthetic data in service research. It underscores the challenges and potential of interpreting ALM versus human responses, marking a significant step in exploring AI capabilities in empirical research.
Is sustainability reporting a way forward? Evidence from banking industry
Authors: Gupta Mayank
Published: September 2024

Purpose

This paper aims to examine the influence of sustainability reporting on bank performance. Furthermore, this study investigates the impact of the country’s economic development, financial system and crisis in moderating sustainability reporting and bank performance relationship.

Design/methodology/approach

The sample consists of 400 listed banks from 19 countries over the 2009–2022 period. Panel fixed-effect regression is applied, and System Generalized Method of Moments is used as robustness to address endogeneity concerns. The results are robust and survive several sensitivity tests.

Findings

The results, aligning with legitimacy and agency theories, suggest a negative relationship between sustainability reporting and bank performance. Based on further classifications, results suggest the negative (positive) impact of country’s financial system (economic development) in moderating the sustainability reporting and bank performance nexus. Finally, this study documents the positive influence of sustainability reporting on bank performance during the crisis period. Overall, the findings fail to support the reduced information asymmetry accruing from higher sustainability disclosures in developing and bank-based economies.

Practical implications

This study has important implications for regulators, policymakers and other stakeholders, especially in light of recent banking scandals that have deteriorated stakeholders' faith in financial institutions' reporting quality.

Originality/value

This study extends the scant literature on sustainability reporting in banking from a cost-benefit vantage point. Furthermore, to the best of the author’s knowledge, no previous research has examined the moderating role of the country’s financial structure and crisis in sustainability reporting and bank performance relationship.
Impact of organisational facilitators and perceived HR effectiveness on acceptance of AI-augmented HRM: an integrated TAM and TPB perspective
Authors: Prikshat Verma , Kumar Sanjeev , Patel Parth , Varma Arup
Published: September 2024

Purpose

Drawing on the integrative perspective of the technology acceptance model (TAM) and theory of planned behaviour (TPB) and extending it further by examining the role of organisational facilitators and perceived HR effectiveness in this integrative perspective, we examine HR professionals’ AI-augmented HRM (HRM(AI)) acceptance in this research.

Design/methodology/approach

The data (N=375) were collected from HR professionals working in different organisations in India. Structural equation modelling (SEM) was employed to analyse the data.

Findings

The results of the study suggest that along with organisational facilitator antecedents to the relevant components of both TAM and TPB, perceived HR effectiveness also enhanced the HRM(AI) acceptance levels of HR professionals.

Practical implications

The research findings are expected to contribute to the understanding of the factors that influence the acceptance of AI-augmented HRM in organizations. The results may also help organisations to identify the facilitators that can enhance the adoption and implementation of AI-augmented HRM by HR professionals. Finally, the study provides a composite TAM-TPB theoretical framework that can guide future research on the acceptance of AI-augmented HRM.

Originality/value

To the best of our knowledge, this is one of the first attempts to factor in the effect of contextual factors (i.e. organisational facilitators and perceived HR effectiveness) in the TAM and TPB equations.
The role of digitalization along new product development processes: the case of a servitized firm
Authors: Messina Mariastella , Leotta Antonio
Published: September 2024

Purpose

This paper aims to address the challenge raised in the literature regarding whether and how digitalization supports a servitized new product development (NPD) process, considering the customer’s involvement from the early stage of the process.

Design/methodology/approach

Pragmatic constructivism (PC) has been adopted for conceptualizing the NPD process as the construction of a new reality. PC is the method theory used for interpreting the field evidence drawn from a qualitative case study carried out at a multinational company operating in the semiconductor industry.

Findings

This study shows how digitalization supports the alignment to the overarching topoi of the company servitization strategy by enabling the integration and merging of different organizational topoi during the NPD process.

Research limitations/implications

This study is confined to a single-case study and context.

Practical implications

The results of this study are relevant for managers involved in the stage-gate product development of manufacturing companies, informing them on how the use of digital tools enables or hinders the progression of product development projects.

Originality/value

This paper contributes to the servitization literature by offering field evidence that demonstrates the importance for manufacturing firms of acquiring customer feedback from an early NPD phase. Another contribution is related to the literature on the role of digitalization in NPD processes, describing how digital tools give support during the different phases of the NPD process.
Market concentration and implicit taxes: analyzing Brazilian firms
Authors: Lopo Martinez Antonio , da Silva Raimundo , Sarlo Neto Alfredo
Published: September 2024

Purpose

This study aims to explore the interplay between market concentration and implicit tax burdens in Brazil, offering a fresh perspective on the conventional belief of perfect competition.

Design/methodology/approach

Data was sourced from Brazilian firms on the B3 stock exchange between 2011 and 2021. Multiple linear regression techniques were employed to analyze the relation of explicit tax rates to firms’ pre- and post-tax returns.

Findings

Dominant firms in the market tend to bear a lower implicit tax burden and have the capacity to extend tax incentive benefits to shareholders.

Research limitations/implications

The findings highlight Brazil’s intricate corporate tax fabric, particularly regarding implicit taxes. They provide a foundation for deeper inquiries into how market dominance, taxation policies, and corporate strategies converge.

Practical implications

Regulators and business leaders can harness this knowledge to recalibrate tax strategies and market regulations. Specifically, a closer examination of the dynamics that permit reduced implicit tax implications in monopolized markets is essential for equity.

Social implications

Companies with pronounced market concentration can mitigate their implicit tax burdens, potentially offloading them to consumers and suppliers. This points to potential inequities in current tax structures.

Originality/value

This research unveils nuanced insights into Brazil’s multifaceted interrelations between corporate influence, taxation strategies, and market forces.
Rapid investment casting of nanotechnology-enhanced aluminum alloy 6061
Authors: Chi Yitian , Murali Narayanan , Li Xiaochun
Published: September 2024

Purpose

High-performance wrought aluminum alloys, particularly AA6061, are pivotal in industries like automotive and aerospace due to their exceptional strength and good response to heat treatments. Investment casting offers precision manufacturing for these alloys, because casting AA6061 poses challenges like hot cracking and severe shrinkage during solidification. This study aims to address these issues, enabling crack-free investment casting of AA6061, thereby unlocking the full potential of investment casting for high-performance aluminum alloy components.

Design/methodology/approach

Nanotechnology is used to enhance the investment casting process, incorporating a small volume fraction of nanoparticles into the alloy melt. The focus is on widely used aluminum alloy 6061, utilizing rapid investment casting (RIC) for both pure AA6061 and nanotechnology-enhanced AA6061. Microstructural characterization involved X-ray diffraction, optical microscopy, scanning electron microscopy, differential scanning calorimetry and energy dispersive X-ray spectroscopy. Mechanical properties were evaluated through microhardness and tensile testing.

Findings

The study reveals the success of nanotechnology-enabled investment casting in traditionally challenging wrought aluminum alloys like AA6061. Achieving crack-free casting, enhanced grain morphology and superior mechanical properties, because the nanoparticles control grain sizes and phase growth, overcoming traditional challenges associated with low cooling rates. This breakthrough underscores nanotechnology's transformative impact on the mechanical integrity and casting quality of high-performance aluminum alloys.

Originality/value

This research contributes originality and value by successfully addressing the struggles in investment casting AA6061. The novel nano-treating approach overcomes solidification defects, showcasing the potential of integrating nanotechnology into rapid investment casting. By mitigating challenges in casting high-performance aluminum alloys, this study paves the way for advancements in manufacturing crack-free, high-quality aluminum alloy components, emphasizing nanotechnology's transformative role in precision casting.
Predicted short‐term mesoscavenger release gives way to apex‐scavenger dominance
Authors: Donohue J. G. , Piiroinen P. T. , Kane A.
Published: September 2024

Vultures play a crucial role in scavenging communities as apex scavengers. Scavenging communities in turn are a key component of terrestrial ecosystems, ensuring that dead biomass is removed quickly and efficiently. Anthropogenic disturbances, particularly mass poisonings, have caused crashes in vulture populations in Africa and Asia.

We ask if vultures can re‐establish themselves in a scavenging community from a point of near extirpation. To allow for maximum knowledge transfer across ecosystems, we focus on an ecosystem that is otherwise considered pristine.

We chose Kruger National Park (KNP), a well‐documented African scavenging community, as our focal ecosystem and parameterised a mathematical model of scavenging‐community dynamics using field data from the park. We predicted the upper limit of vulture population size in an ecosystem like KNP. We then analysed vultures' path to recovery, using this empirically parameterised scavenging‐community model. We used perturbation methods to determine how parameter values that may be specific to KNP influence our predictions.

Comparisons of predicted vulture carrying capacity with recent population estimates suggest that the cumulative effect of human activities on vulture abundance is larger than previously believed. Our analysis shows that vulture populations can reach their carrying capacity approximately five decades after a poisoning event that would almost extirpate the population. Over shorter time scales, we predict a decade of enhanced mammal abundance (i.e. mesoscavenger release) before the mammals are excluded from the scavenging community. In our study system, jackals and hyenas are the mammalian groups predicted to benefit from the absence of vultures. However, neither group removes biomass as efficiently as vultures and animal carcasses are predicted to accumulate in the ecosystem while the vulture population recovers.

In our framework, the carrying capacity for vulture populations is determined by carcass availability. As evidence for an alternative regulating factor is lacking, we conclude that present‐day vulture population densities are orders of magnitude below their upper limits. Our results therefore suggest that with a recovery plan in place, the long‐term prospects for vulture species and the associated ecosystems are positive.
Predicting yolk testosterone allocation using ecological contexts and species‐specific traits
Authors: James Anna O. , Bentz Alexandra B.
Published: September 2024

The prenatal transfer of testosterone (T) from mother to offspring is an important source of phenotypic plasticity. In birds, exposure to ecologically relevant stimuli, such as social competition or an attractive mate, can cause females to deposit more T into their egg yolks. Exposure to elevated yolk T can modify the expression of several fitness‐related traits in offspring (e.g. growth, immune function, secondary sex traits and behaviour). Despite some of these changes being potentially adaptive, not all studies find that yolk T levels change in response to ecologically relevant stimuli. This heterogeneity is currently unexplained, limiting our ability to predict inter‐generational responses to ecological change.

Here, we performed a systematic literature search and found 119 observations across 39 wild species that measured inter‐female variation in yolk T allocation in response to various stimuli. We used boosted regression trees, a form of machine learning, to examine whether species‐specific traits or variation in study‐level variables could explain variation in yolk T allocation (i.e. statistically significant vs. non‐significant responses).

We found that both species‐specific traits and study‐level variables are important predictors of significant changes in yolk T levels. Geographic range (latitude and longitude), evolutionary distinctiveness, longevity, egg mass relative to female mass, sociality, migration status and time to fledge were among the top 10 most influential predictors of the 48 examined. We also found that studies measuring or manipulating social stimuli (e.g. competition and breeding density) or breeding date were more likely to detect changes in yolk T allocation compared with studies examining other ecological contexts.

Overall, these data provide several testable hypotheses concerning yolk T allocation and its adaptive value across species and contexts. Additionally, these findings can help us predict how ecological changes will affect hormonal responses in females that can shape future generations.
The Economic Competence of the Labour Party in Historical Perspective
Authors: Telesca Giuseppe
Published: September 2024

The theme of the relationship between Labour Party and economic competence resurfaced in February 2024 when Keir Starmer decided to scale down its £28 billion green investment pledge. This work explores the historical and structural reasons why the economic competence issue has tended to be ‘owned’ by the Tories. It highlights that the definition of economic competence has often coincided with an emphasis on monetary stability and balancing government budgets with relatively low levels of taxation from the late 1970s onwards. The Exchange Rate Mechanism (ERM) crisis in the 1990s led to a partial redefinition of economic competence, now built around a political economy of ‘constrained discretion’ and ‘credible Keynesianism’. The 2007–8 global financial crisis gave the Conservative Party the opportunity to regain its reputation for competence by arguing that the crisis had been the consequence of excessive public spending. The Labour Party's decision to sacrifice its biggest single policy pledge on the altar of financial probity heralds the difficulties that the new Labour government will face when attempting to reconcile the need for an active and strategic state with its stance on fiscal rectitude.
Is it possible to obtain substitutes for human milk oligosaccharides from bovine milk, goat milk, or other mammal milks?
Authors: Jiang Yishan , Sun Tianrui , Lin Yihan , Liu Manshun , Wang Xin
Published: September 2024

Considering the current level of chemical and biological synthesis technology, it was a sensible selection to obtain milk oligosaccharides (MOs) from other mammals as the potential substitute for human MOs (HMOs) that possessed various structural features in the infant formula. Through a comprehensive analysis of the content, structure, and function of MOs in six distinct varieties of mammal milk, it has been shown that goat milk was the most suitable material for the preparation as a human milk substitute. Goat MOs (GMOs) had a relatively high content and diverse structural features compared to those found in other mammalian milks. The concentration of GMOs in colostrum ranged from 60 to 350 mg/L, whereas in mature milk, it ranged from 200 to 24,00 mg/L. The acidic oligosaccharides in goat milk have attracted considerable attention due to their closeness in acidic content and structural diversity with HMOs. Simultaneously, it was discovered that some structures, like N‐glycolylneuraminic acid, were found to have a certain content in GMOs and served essential functional properties. Moreover, studies focused on the extraction of MOs from goat milk indicated that the production of GMOs on an industrial scale was viable. Furthermore, it is imperative to do further study on GMOs to enhance the preparation process, discover of new MOs structures and bioactivity evaluation, which will contribute to the development of both the commercial production of MOs and the goat milk industry.
Overview of cardiac toxicity from radiation therapy
Authors: Chin Vicky , Finnegan Robert N , Keall Paul , Otton James , Delaney Geoff P , Vinod Shalini K
Published: September 2024

Radiotherapy is an essential part of treatment for many patients with thoracic cancers. However, proximity of the heart to tumour targets can lead to cardiac side effects, with studies demonstrating link between cardiac radiation dose and adverse outcomes. Although reducing cardiac dose can reduce associated risks, most cardiac constraint recommendations in clinical use are generally based on dose to the whole heart, as dose assessment at cardiac substructure levels on individual patients has been limited historically. Furthermore, estimation of an individual's cardiac risk is complex and multifactorial, which includes radiation dose alongside baseline risk factors, and the impact of systemic therapies. This review gives an overview of the epidemiological impact of cancer and cardiac disease, risk factors contributing to radiation‐related cardiotoxicity, the evidence for cardiac side effects and future directions in cardiotoxicity research. A better understanding of the interactions between risk factors, balancing treatment benefit versus toxicity and the ongoing management of cardiac risk is essential for optimal clinical care. The emerging field of cardio‐oncology is thus a multidisciplinary collaborative effort to enable better understanding of cardiac risks and outcomes for better‐informed patient management decisions.
Metamorphic P‐T‐t Evolution of Granulite in the Yishui Area: New Insights into the Tectonic Evolution of the Eastern Block, North China Craton
Authors: CHEN Ziyuan , YUAN Mingkao , ZHONG Zhenyu , LI Tianqi , WANG Guodong , XIAO Lingling
Published: September 2024

The Yishui complex, located in the western Shandong area of the North China Craton, is representative of the Archean crystalline basement of the North China Craton to explore the early tectonic‐thermal evolution history of the Earth. Detailed petrography, mineral chemistry, metamorphic evolution and zircon U‐Pb dating are presented for felsic granulite and two‐pyroxene granulite from the Yishui complex to contribute to new insights into the Neoarchean tectonic evolution of the North China Craton. Three mineral assemblages are recognized for these granulite samples, including the prograde (M1), peak (M2) and retrograde (M3) mineral assemblages. Conventional geothermobarometry and phase equilibrium modeling yield P‐T conditions of 6.5–10.9 kbar/718–839°C for the peak metamorphism, which define a medium‐pressure granulite‐facies metamorphism occurred at middle to lower crust. Anticlockwise P‐T paths with near‐isobaric cooling (IBC) retrograde segments were reconstructed. Zircon LA‐ICP‐MS U‐Pb dating suggests that the protolith of the felsic granulite was emplaced at 2541 ± 7 Ma and the subsequent medium‐pressure granulite‐facies metamorphism occurred at 2518–2494 Ma. A two‐stage mantle plume related crustal‐scale sagduction geodynamic regime is proposed in the western Shandong terrane in the Neoarchean.
UN Resolution 1325/2000 (women, peace and security): Its impact in Europe
Authors: Duran y Lalaguna Paloma
Published: September 2024

This article aims first, to decipher the content of UN Resolution 1325 and the obligations it entails; second, to systematize actions carried out by the EU; and third, to propose some conclusions. Security Council Resolution 1325 (2000) marked the beginning of political decisions taking into account the impact of conflict on women and girls. Member States have developed national action plans to integrate Resolution 1325 into their policies and programs and the EU has approved some plans and decisions but there is still a long way to go, especially to ensure impact and implementation.
Is the Transcription Factor NANOG Involved in Placental Aging?
Authors: Farladansky‐Gershnabel Sivan , Silber Michal , Biron‐Shental Tal , Kovo Michal , Kidron Debora , Weisz Avivit , Zitman‐Gal Tali
Published: September 2024

Problem

Accelerated placental aging is linked to abnormal fetal growth, preeclampsia (PE), and preterm birth (PTB). NANOG, a transcription factor, is known for its role in cellular reprogramming, self‐renewal, and clonogenic growth. Its expression is regulated by Kruppel‐like factor 4 (KLF4), which functions as both a transcriptional activator and repressor. This study evaluated the KLF4‐NANOG pathway in placental samples from normal pregnancies (NP) as well as those with PE, fetal growth restriction (FGR), and PTB.

Method of Study

Placental samples from NP pregnancies and those with PE, FGR, and PTB were analyzed for NANOG and KLF4 expression using western blotting and immunohistochemistry.

Results

NANOG protein expression was significantly increased in placentas from PE, FGR, and PTB compared to NP (fold changes vs. NP: PE 2.48 ± 0.3, p = 0.002; FGR 1.64 ± 0.16, p = 0.03; PTB 6.03 ± 3.35, p = 0.01). Similarly, KLF4 protein expression was elevated in PE, FGR, and PTB placentas compared to NP (fold changes vs. NP: PE 5.78 ± 0.73, p = 0.001; FGR 2.61 ± 0.43, p = 0.02; PTB 11.42 ± 2.76, p = 0.0006). Immunohistochemistry revealed strong NANOG staining in the syncytiotrophoblast tissue of PE, FGR, and PTB samples, especially in extravillous trophoblasts, compared to NP placentas.

Conclusions

The elevated expression of NANOG and KLF4 in abnormal placental tissues suggests their potential role as markers of enhanced placental aging and dysfunction. These findings underscore the importance of the KLF4‐NANOG pathway in the pathology of PE, FGR, and PTB, providing a basis for future research into therapeutic targets for these conditions.
Review article: Recommendations for detection, assessment and management of suspected drug‐induced liver injury during clinical trials in oncology patients
Authors: Fettiplace Anna , Marcinak John , Merz Michael , Zhang Hui‐Talia , Kikuchi Luciana , Regev Arie , Palmer Melissa , Rockey Don , Fontana Robert , Hayashi Paul H. , Tillmann Hans L. , Di Bisceglie Adrian M. , Lewis James H.
Published: September 2024

Background

Drug‐induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre‐treatment or on‐study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co‐morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients.

Aims

The goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials.

Methods

This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions.

Results

This review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose‐modification is provided.

Conclusions

This review brings together evidence‐based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.
“I Forgot My Numbers and the Machine Swallowed It Up”: Adults With Learning Disabilities Share Their Perspectives on the Shift to a Cashless Society
Authors: Watts Paul , Hoskin Janet , Upadhyay Radhika , Tapley Emma , Kwiatkowska Gosia
Published: September 2024

Introduction

This paper examines the experiences of people with learning disabilities in the United Kingdom as society transitions towards cashless transactions and services. It is a significant study because it highlights the need to understand their digital financial experiences.

Methods

This study employed an inclusive, interpretivist approach, focusing on participatory methods. Reflexive thematic analysis was used to analyse data from focus groups including 40 people with learning disabilities across 3 day services. This original study included co‐researchers with lived experience of learning disabilities who assisted in data collection and analysis.

Results

Four key themes emerged: heterogeneity of preferences for cash versus digital payments; the urgent need for support and training in digital financial literacy; balancing safeguarding and fostering independence; and accessibility challenges in physical and online banking environments.

Conclusions

The shift to a cashless society poses significant challenges for people with learning disabilities, requiring tailored support and training in digital finance. Financial institutions should be cognisant of these needs, suggesting that systemic changes are required for improved financial inclusion. The study highlights the importance of including people with learning disabilities in the design of digital financial tools and policies, to support their financial autonomy and independence.
Selective modulation of epileptic tissue by an adenosine A3 receptor‐activating drug
Authors: Ghosh Anwesha , Ribeiro‐Rodrigues Leonor , Ruffolo Gabriele , Alfano Veronica , Domingos Cátia , Rei Nádia , Tosh Dilip K. , Rombo Diogo M. , Morais Tatiana P. , Valente Cláudia A. , Xapelli Sara , Bordadágua Beatriz , Rainha‐Campos Alexandre , Bentes Carla , Aronica Eleonora , Diógenes Maria José , Vaz Sandra H. , Ribeiro Joaquim A. , Palma Eleonora , Jacobson Kenneth A. , Sebastião Ana M.
Published: September 2024

Background and Purpose

Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R‐selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A1R and/or through a disease‐specific mechanism, we assessed the effect of MRS5474 on the hippocampus.

Experimental Approach

Excitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A3 receptor (A3R) density in human tissue were assessed by Western blot.

Key Results

MRS5474 (50–500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT‐1)‐mediated γ‐aminobutyric acid (GABA) uptake, an action not blocked by an A1R antagonist but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration‐dependent potentiation of GABA‐evoked currents in oocytes micro‐transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non‐epileptic tissue, an action blocked by an A3R antagonist.

Conclusion and Implications

We identified a drug that activates A3R and has selective actions on epileptic hippocampal tissue. This underscores A3R as a promising target for the development of antiseizure medications.
Vortioxetine reduces the development of pain‐related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down‐regulation
Authors: Tomić Maja , Nastić Katarina , Dinić Miroslav , Brdarić Emilija , Kotur‐Stevuljević Jelena , Pecikoza Uroš , Pavićević David , Micov Ana , Milenković Danijela , Jovanović Aleksandar , Stepanović‐Petrović Radica
Published: September 2024

Background and Purpose

Vortioxetine, a multimodal‐acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.

Experimental Approach

In the monoiodoacetate (MIA)‐induced rat model of knee OA, pain‐related behaviour was assessed in weight‐bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain‐related mediators (Ngf, Il‐1β, Tnf‐α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol.

Key Results

Vortioxetine and duloxetine dose dependently reduced weight‐bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA‐injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA‐injected knees to the level in sham‐injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain‐related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up‐regulated in MIA‐injected rats. This effect was male‐specific.

Conclusion and Implications

Vortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain‐related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex‐specific pattern.
Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation
Authors: Portelli Michael A. , Ketelaar Maria E. , Bates Stewart , Csomor Eszter , Shaw Dominick , Emsley Jonas , Brightling Christopher , Hall Ian , Affleck Karen , Edwards Matthew , Nawijn Martijn C. , Koppelman Gerard H. , Van Oosterhout Antoon J. , Sayers Ian
Published: September 2024

Introduction

The interleukin‐33/interleukin‐1 receptor‐like‐1 (IL‐33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.

Method

In a project funded by GSK plc, which has developed an IL‐33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa‐beta (NF‐κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic‐generated IL‐33 isoforms (0.001–50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin‐8 (IL‐8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL‐33112–270 (50 ng/mL) and induced IL‐8 mRNA expression measured.

Results

HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33‐driven signalling, with minimal signalling after IL‐33 activation in other protective haplotypes. All IL‐33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395–270 and IL33106–270 had the greatest effect and the IL33113–270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.

Conclusions

Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395–270 and IL33106–270 may be more amenable to IL33/IL1RL1 targeting.
Use of autologous micrografts associated with xenogeneic anorganic bone in vertical bone augmentation procedures with Barbell Technique®
Authors: Cosmo Luiz Antonio Mazzucchelli , Coutinho Reginaldo Machado , de Macedo Luís Guilherme Scavone , Aloise Antonio Carlos , Jayme Sérgio Jorge , Zeferino João Pedro Grandini , Graziano Antonio , Martinez Elizabeth Ferreira , Moy Peter Karyen , Pelegrine André Antonio
Published: September 2024

Introduction

Bidirectional vertical ridge augmentation in the posterior maxilla is very challenging.

Purpose

To evaluate the regenerative potential of micrografts, derived from periosteum or bone tissue, added to an anorganic xenograft in vertical reconstruction of the posterior maxilla, by a prospective, controlled study.

Materials and methods

After clinical selection and the analysis of CBCT scans, 24 posterior maxillary sites, in 19 patients, were treated by using Barbell Technique®. Sites requiring both inlay and onlay reconstruction were enrolled in the study. In the Control Group (CG, n = 8), a xenograft was used in the inlay site and for the onlay site, a 1:1 mix of xenograft and an autograft was used. In Test Group 1 (TG1, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from periosteum. In Test Group 2 (TG2, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from bone. Six months after the procedures, CBCT scans were obtained, and bone biopsy samples were harvested during implant placement surgery. The bone specimens were analyzed histomorphometrically, by measuring the percentages of vital mineralized tissue (VMT), non vital mineralized tissue (NVMT) and non mineralized tissue (NMT). Immunohistochemically, the levels of VEGF were categorized by a score approach.

Results

Histomorphometric analysis revealed, for the inlay grafts, no significant difference among the groups for VMT, NVMT and NMT. However, for onlay grafts, CG achieved a higher amount of VMT in comparison with TG2, and the opposite occurred for NMT values. In this regard, no statistical difference was observed between CG and TG1. Concerning immunohistochemistry, the VEGF values for CG and TG1 were slightly higher than those obtained by TG2 for both inlay and onlay grafts, but without statistical significance. CBCT analysis showed a similar level of gain for all groups, for both inlay and onlay bone augmentation sites. Clinically, one implant (in CG) within a total of 50 implants installed, had early failure and was replaced after 3 months. All patients received implant supported prosthesis.

Conclusion

This study indicated that the clinical use of micrograft derived from periosteum may have some potential to increase bone formation in onlay reconstructions, unlike the micrograft derived from bone tissue.
Comparison of surface micro‐roughness and adaptation of titanium and cobalt chrome implant abutment fabricated by selective laser melting and conventional techniques
Authors: Albaijan Refal , Vohra Fahim , Alnassar Talal M. , Robaian Ali , Alnafaiy Sarah M. , Murayshed Mohammed S. , Alnasser Abdullah H. , Alshehri Abdullah , Gufran Khalid
Published: September 2024

Purpose

The objective of this study was to assess the surface micro‐roughness and abutment adaptation of selective laser melting (SLM) implant abutments in comparison to cast and machined implant abutments.

Methods

Forty abutment specimens were divided equally into four groups according to the fabrication technique as follows (n = 10), Machined Ti alloy abutments (Control), Cast CoCr abutments, SLM‐CoCr abutments, and SLM‐Ti alloy abutments. Forty internal connection implants (Ø 4.0 ×10 mm, Superline™, Dentium Co., Seoul, Korea) were mounted in clear acrylic resin. Fabricated abutments were assessed for surface micro‐roughness using a 3D optical noncontact surface microscope. Vertical and horizontal adaptation of the abutment with implant interface was assessed by using Bruker micro‐CT. Data was assessed using analysis of variance and Tukey post hoc comparison tests for all the variables except vertical misfit was assessed using Kruskal–Wallis test. Pearson correlation was used to assess dependence between independent variable (surface roughness) and dependent variables (Horizontal misfit and vertical misfit).

Results

SLM‐Ti abutments showed significantly rougher surface (p < 0.05) among the study groups. While SLM‐CoCr abutments were smoother than Cast abutments with mean Ra of 1.30 ± 0.11 and 1.58 ± 0.17 μm, respectively (p < 0.05). For abutment adaptation, SLM‐Ti abutments showed the highest horizontal misfit among the groups (p < 0.05). While, SLM‐CoCr abutments (29.24 ± 11.11 μm) showed comparable (p > 0.05) horizontal misfit results with Cast (26.08 ± 3.93 μm) and machined (26.45 ± 7.33 μm) abutments. Comparable (p > 0.05) vertical misfit values between Cast CoCr (487.01 ± 40.34 μm), SLM‐CoCr (358.38 ± 114.93 μm) and SLM‐Ti (299.85 ± 172.88 μm) abutments were observed. A positive correlation was found between the surface roughness of the mating surfaces and abutment adaptation.

Conclusion

SLM CoCr abutments exhibited low roughness and comparable abutment adaptation (vertically and horizontally) than cast (control) abutments. Therefore, SLM CoCr abutments should be clinically investigated as potential implant abutments for clinical use.