bluuebunny/crossref_metadata_2025 huggingface dataset:
Business model innovation canvas: a visual business model innovation model
Authors: Jin Yuran , Ji Shoufeng , Liu Li , Wang Wei
Published: June 2021

Purpose

More and more enterprises have realized the importance of business model innovation. However, the model tools for it are still scarce. There is a clear research gap in this academic field. Therefore, the aim of this study is to put forward a visual business model innovation model.

Design/methodology/approach

The scientific literature clustering paradigm of grounded theory is used to design business model innovation theory model (BMITM). BMITM and the business model innovation options traced back from 870 labels in the grounded process are integrated into a unified framework to build the business model innovation canvas (BMIC).

Findings

BMIC composed of three levels and seven modules is successfully developed. 145 business model innovation options are designed in BMIC. How to use BMIC is explained in detail. Through the analysis of innovation hotspots, the potential business model innovation directions can be found. A new business model of clothing enterprises using 3D printing is innovated with BMIC as an example.

Research limitations/implications

Compared with the previous tools, BMIC owns a clearer business model innovation framework and provides a problem-oriented business model innovation process and mechanism.

Practical implications

BMIC provides a systematic business model innovation solution set and roadmap for business model innovation practitioners.

Originality/value

BMIC, a new tool for business model innovation is put forward for the first time. “Mass Selection Customization-Centralized Manufacturing” designed with BMIC for the clothing enterprises using 3D printing is put forward for the first time.
Estimating competitiveness of Greek food and beverage industry: a comparison between Greek flour milling industry and Greek food and beverage industry
Authors: Konstantinidis Christos , Aggelopoulos Stamatis , Tsiouni Maria , Rizopoulou Evanthia
Published: June 2021

Purpose

The objective of this study is to estimate the competitiveness for both the Greek food and beverage industry as a whole and the flour and milling industry, justifying the certain economic factors and the way which these factors affect on it.

Design/methodology/approach

The Greek food and beverage firms which published their balance sheets for the studying period were studied. According to the existing literature two equations were created and estimated as a simultaneous equations system.

Findings

Summarizing the results both for the whole food and beverage industry and the flour milling industry are observed significant similarities on how certain economics factors such as profitability, market share, sustainable growth, age and operating costs affect on competitiveness as measured in this work. This may happen due to the high degree of concentration but also in the special characteristics which present both the Greek food and beverage industry and the flour milling sector.

Research limitations/implications

The fact that this work referred only in Greek firms can be a limitation of this research, in spite of that it can provide useful and safe conclusions for the Greek food manufacturing industry.

Practical implications

The provision of proposals for increasing firm competitiveness to managers as well as to policymakers.

Social implications

The importance of food and beverage industry for the Greek economy as well as that the flour milling industry holds an important position in the Greek food and beverage industry makes the study of the competitiveness for both of them to be important from both an academic and research perspective.

Originality/value

The Greek food and beverage industry is the strength of Greek manufacturing and at the same time an important lever for the development of the entire Greek economy. The high quality products it produces and the organized promotion of its products in international markets are elements that give it an advantage and stimulate its competitiveness. The flour milling industry is one of the sectors in which there is intense competition and whose presence in terms of sales, turnover, employment and gross value is particularly important, so a simultaneous study of these cases is very important.
A meta-analysis of consumer innovation resistance: is there a cultural invariance?
Authors: Leong Lai-Ying , Hew Teck-Soon , Ooi Keng-Boon , Lin Binshan
Published: June 2021

Purpose

In the literature of industrial management, the focus is normally given on examining the factors that contribute to product innovation acceptance. The advocates of “pro-innovation bias” assume that consumers are open to new products and are willing to accept an innovative product. However, there is a high failure rate of technological innovations and most of the technological innovations were rejected due to users' resistance. Since the inception of innovation resistance theory (IRT), the number of studies that used IRT has gained much attention from scholars. However, the findings from these studies from various contexts are inconsistent, lack universality, and a clear understanding of technological innovation barriers. The study aims to determine whether the IRT theory is indeed valid and whether IRT is culturally invariant from the Eastern and Western cultures.

Design/methodology/approach

A meta-analysis based on a random-effects model and studies drawn from 24 countries and/or regions with a consolidated sample size of 10,463 was conducted. Cultural invariance was identified based on subgroup analysis. Moderator analysis was performed by applying the weighted linear regression.

Findings

The results reveal that tradition is the strongest barrier followed by the value, risk, image and usage barrier. Interestingly, there is a cultural invariance in IRT from the Eastern and Western cultures. Besides, there are significant moderating effects due to the temporal factor.

Originality/value

The study has contributed useful theoretical and managerial implications in advancing the product innovation literature.
Making sense of the internet of things: a critical review of internet of things definitions between 2005 and 2019
Authors: Goumagias Nikolaos , Whalley Jason , Dilaver Ozge , Cunningham James
Published: June 2021

Purpose

This paper aims to study the evolution of definitions of internet of things (IoT) through time, critically assess the knowledge these definitions contain and facilitate sensemaking by providing those unfamiliar with IoT with a theoretical definition and an extended framework.

Design/methodology/approach

164 articles published between 2005 and 2019 are collected using snowball sampling. Further, 100 unique definitions are identified in the sample. Definitions are examined using content analysis and applying a theoretical framework of five knowledge dimensions.

Findings

In declarative/relational dimensions of knowledge, increasing levels of agreement are observed in the sample. Sources of tautological reasoning are identified. In conditional and causal dimensions, definitions of IoT remain underdeveloped. In the former, potential limitations of IoT related to resource scarcity, privacy and security are overlooked. In the latter, three main loci of agreement are identified.

Research limitations/implications

This study does not cover all published definitions of IoT. Some narratives may be omitted by our selection criteria and process.

Practical implications

This study supports sensemaking of IoT. Main loci of agreement in definitions of IoT are identified. Avenues for further clarification and consensus are explored. A new framework that can facilitate further investigation and agreement is introduced.

Originality/value

This is, to the authors’ knowledge, the first study that examines the historical evolution of definitions of IoT vis-à-vis its technological features. This study introduces an updated framework to critically assess and compare definitions, identify ambiguities and resolve conflicts among different interpretations. The framework can be used to compare past and future definitions and help actors unfamiliar with IoT to make sense of it in a way to reduce adoption costs. It can also support researchers in studying early discussions of IoT.
Theoretical aspects of insider trading regulation in Zimbabwe
Authors: Chitimira Howard
Published: June 2021

Purpose

Insider trading is treated as a punishable offence in many jurisdictions and countries. In relation to this, various theories were developed to justify and enhance the regulation of insider trading in such jurisdictions and countries. For instance, regulatory bodies and the relevant courts in jurisdictions such as the Commonwealth and the European Union as well as in countries such as the USA and the UK have to date developed and consistently applied theories such as the classical theory, misappropriation theory, fiduciary theory, unified theory and equal access theory in their quest to detect, prevent and combat insider trading activities. For the purposes of this article, the aforesaid theories are discussed so as to recommend possible measures that could be adopted by the policy makers to effectively curb insider trading activities in the Zimbabwean financial markets. It is against this background that some theoretical aspects of the insider trading regulation as adopted by the Zimbabwean policymakers, regulatory bodies and the relevant courts are scrutinised in this paper. This is done to, inter alia, investigate possible flaws and the rationale for such direct and indirect application of certain insider trading theorem in Zimbabwe. Thereafter, some recommendations in respect thereof are provided.

Design/methodology/approach

A qualitative research methodology is used in the entire paper.

Findings

It is hoped that the recommendations in the paper will be used by the relevant policymakers to enhance the curbing of insider trading in Zimbabwe.

Research limitations/implications

The paper does not use an empirical research.

Practical implications

It is hoped that the recommendations in this paper will be used by the relevant policymakers to enhance the curbing of insider trading in Zimbabwe.

Social implications

It is hoped that the recommendations in this paper will be used by the relevant policymakers to enhance the curbing of insider trading in Zimbabwe.

Originality/value

This paper is original research on the theoretical aspects of the regulation of insider trading in Zimbabwe.
Depression and association with diet diversity score among adolescent (14-19) students of Jimma town high school, Jimma, southwest Ethiopia
Authors: Tsehay Mekonnen , Girma Shimelis , Mamaru Almaz , Abera Mubarek
Published: June 2021

Purpose

Dietary patterns are important for the physical and psychological development of adolescents. The purpose of this study is to determine magnitude and severity of depression and its relation with diet diversity score (DDS) among adolescent high school students.

Design/methodology/approach

A cross-sectional study was conducted among 546 adolescents selected from schools using multistage sampling technique. Dietary intakes were assessed using a 24-h dietary recall, and depression severity and prevalence were assessed by PHQ-9A. A structured questionnaire was used to collect data. Linear regression analysis was used, and unstandardized beta (ß) coefficients with 95% confidence intervals (CI) were computed to determine the association of depression and its severity with dietary diversity score.

Findings

In all, 546 questionnaires were filled completely and consistently making a response rate of 97.3%. The dietary diversity score in 97 (17.8%) of the adolescents were between 1 and 3 (low dietary diversity score) but 259 (47.4%) scored greater than 6 (high dietary diversity score). Chi-square test revealed that with a decrease in DDS from highest to lowest level, the percentage of moderate to severe and severe depression slightly increased (3.4%). In addition, the percentage of moderate to severe and severe depression who consumed meat, fish and milk and dairy products slightly increased (3% and 3.2%). Multivariate adjusted regression analysis demonstrated that dietary diversity score was found to be inversely associated with depression severity and prevalence.

Originality/value

It was found that linear association between diet diversity and depression severity, and prevalence after adjustment for relevant con-founders. The study provided epidemiological evidence of a robust association of dietary pattern with depression symptoms' severity and prevalence in adolescents.
Impacts of winter heating on the population mobility of northern China's prefectural cities: evidence from a regression discontinuity design
Authors: Cai Haiya , Nan Yongqing , Zhao Yongliang , Xiao Haoran
Published: June 2021

Purpose

The purpose of this study is to regard winter heating as a quasi-natural experiment to identify the possible causal effects of winter heating on population mobility. However, there are scant research studies examining the effect of atmospheric quality on population mobility. There also exists some relevant research studies on the relationship between population mobility and environmental degradation (Lu et al., 2018; Reis et al., 2018; Shen et al., 2018), and these studies exist still some deficiencies.

Design/methodology/approach

The notorious atmospheric quality problems caused by coal-fired heating in winter of northern China have an aroused widespread concern. However, the quantitative study on the effects on population mobility of winter heating is still rare. In this study, the authors regard the winter heating as a quasi-natural experiment, based on the of daily panel data of 58 cities of Tencent location Big Data in China from August 13 to December 30 in 2016 and August 16 to December 30 in 2017, and examine the impacts of winter heating on population mobility by utilizing a regression discontinuity method.

Findings

The findings are as follows, in general, winter heating significantly aggravates regional population mobility, but the impacts on population mobility among different cities are heterogeneous. Specifically, the effects of winter heating on population mobility is greater for cities with relatively good air quality, and the effects is also more obvious for big and medium-sized cities than that in small cities. In addition, different robustness tests, including continuity test, different bandwidth tests and alternative empirical model, are adopted to ensure the reliability of the conclusion. Finally, the authors put forward corresponding policy suggestions from the three dimensions of government, enterprises and residents.

Originality/value

First, regarding winter heating as a quasi-natural experiment, a regression discontinuity design method is introduced to investigate the relationship between winter heating and population mobility, which is helpful to avoid the estimation error caused by endogeneity. Second, the authors use the passenger travel “big data” based on the website of Tencent Location Big Data, which can effectively capture the daily characteristics of China's population mobility. Third, this study discusses the population mobility from the perspective of winter heating and researches population mobility before and after winter heating, which is helpful in enriching the research on population mobility.
My meaning is my engagement: exploring the mediating role of meaning between servant leadership and work engagement
Authors: Khan Muhammad Mumtaz , Mubarik Muhammad Shujaat , Ahmed Syed Saad , Islam Tahir , Khan Essa , Rehman Asif , Sohail Farhan
Published: June 2021

Purpose

The purpose of the study is to ascertain the mediating role of meaning between servant leadership and work engagement. The study also explores the relationship between servant leadership and work engagement.

Design/methodology/approach

The data were collected from 704 service sector employees working in Pakistan through survey design. The data analysis was done through structural equation modeling using PLS-Smart and hierarchical regression using SPSS.

Findings

The results revealed that servant leadership was related to meaning and work engagement. Moreover, meaning was found to be related to work engagement. Finally, meaning was found to mediate the relationship between servant leadership and work engagement.

Originality/value

The research has ascertained the previously unexplored mediating role of meaning between servant leadership and work engagement.
Environmental effects of ISO 9001 and ISO 14001 management system implementation in SSCM
Authors: Zimon Dominik , Madzík Peter , Dellana Scott , Sroufe Robert , Ikram Muhammad , Lysenko-Ryba Kateryna
Published: June 2021

Purpose

Comprehensive management systems such as ISO 9001 or ISO 14001 are designed to help organizations improve processes, ensure customer satisfaction, efficient information flow, efficient use of resources and many other prosperous management areas. These systems can also bring unintended direct and indirect effects on organizations. In this study, the authors examine the environmental effects that the implementation of these management systems cause.

Design/methodology/approach

A survey-based methodology was used for this study, with textile organizations in three countries – Poland, Slovakia and the Czech Republic. The research focused on four areas related to environmental effects. The first area was the level of improvement of the organizations' environmental performance, which was examined by the methods of descriptive statistics. The second area was analyzing differences in environmental effects concerning the implementation of the systems using inferential statistics. The third area was the analysis of latent links between individual effects using factor analysis.

Findings

This study's insights shed some light on the benefits of implementing more, not fewer systems with benefits to organizations and entire industries with new possibilities for economic growth that do not have to come at the expense of the environment.

Originality/value

Organizations implementing management systems can realize dynamic benefits across a supply chain and within a manufacturing organization. Here the authors see an opportunity for ISO systems as a stepping stone to a more sustainable textile manufacturing economy.
Framing the visitor experience in sacred places
Authors: Bideci Mujde , Bideci Caglar
Published: June 2021

Purpose

The purpose of this study is to explore the dimensional structure of visitor experience in a sacred place based on the framing process.

Design/methodology/approach

Mix-method research was conducted in Turkey–Virgin Mary House which featured a sacred and popular tourist destination. Qualitative research, including interviews and expert panels, was used to create a set of knowledge for further analysis. Quantitative research, including two field studies comprising 842 participants, was used to validate the framing of visitor experiences in a sacred place providing reliability and construct validity.

Findings

The six dimensions were found within three framing axes of religious, environmental and organizational: inner experience; religious experience; physical environment; history; tour organization and service experience.

Originality/value

Current studies on visitor experience in a sacred place have mainly focused on emotions, motivations or physical dimensions. By synthesising the framing process and theoretical approaches, this study contributes to the literature by analysing the unique characteristics of visitors' experiences in sacred places, regardless of their religious identities.
Investigating stakeholder awareness of the sustainable development goals and tourism stakeholder collaboration: the case of North Cyprus
Authors: Özgit Hale , Zhandildina Dana
Published: June 2021

Purpose

The aim of the study is to consider the extent to which the 17 sustainable development goals (SDGs) agreed by United Nations member states contribute to sustainable tourism and to relevant targets in North Cyprus. The study also investigates how tourism stakeholders in North Cyprus understand and implement the UN’s SDGs.

Design/methodology/approach

A qualitative study with structured questions was used to investigate awareness of the UN SDGs and collaboration between 19 tourism stakeholders from different sectors (tour guides, hotels, travel agencies, restaurants and government) in North Cyprus.

Findings

The results of the study reveal that not all of the SDGs have been embraced in North Cyprus, and that there is lack of understanding about the goals and about the need for collaboration among the different tourism stakeholders in North Cyprus.

Practical implications

This study reveals many shortcomings in implementing sustainable tourism in North Cyprus. It would seem that only issues that affect financial performance are prioritised. At present, tourism stakeholders in North Cyprus do not collaborate and do not believe that collaboration would, in any way, influence the sustainability of tourism in the region or benefit them financially. Given this finding, stakeholder collaboration needs to be enhanced in support of tourism sustainability in North Cyprus, and in this, the government needs to act as a catalyst.

Originality/value

Many developing countries are trying to improve living conditions and, at the same time, protect the environment by implementing sustainable development initiatives. The most common initiatives include the creation of protected areas for tourism development. In this context, sustainable development targets for island economies such as North Cyprus are important.
Seismic erratic noise attenuation using unsupervised anomaly detection
Authors: Jeong Woodon , Almubarak Mohammed S. , Tsingas Constantinos
Published: June 2021

This study introduces a new attribute to identify seismic erratic noise, i.e. outlier, in the context of unsupervised anomaly detection and is defined as local outlier probabilities. The local outlier probabilities calculate scores of degrees of isolation, i.e. outlier‐ness, for each object in a data set, which represents how far an object is deviated from its surrounding objects. Since the local outlier probabilities combines a density‐based outlier detection method with a statistically oriented scheme, its scoring system provides regularized outlier‐ness, which is an outlier probability, to be used for making a binary decision to do inclusion or exclusion of an object; such a decision only requires a simple and straightforward threshold on a probability. Based on the binary decision that flags outliers versus non‐outliers, local outlier probabilities‐denoising workflows are developed by combining multiple steps to complete an application of the local outlier probabilities to attenuate seismic erratic noise. Higher stability and improved robustness in the detection and rejection of seismic erratic noise have been achieved by implementing moving windows and decision tree‐based processes. To avoid loss of useful signal energy, signal enhancement applications are additionally suggested. Numerical experiments on synthetic data investigate the applicability of the proposed algorithms to seismic erratic noise attenuation. Field data examples demonstrate the feasibility of a local outlier probabilities‐denoising application as an effective tool in seismic denoising portfolio.
Bridging preference‐based instrumental variable studies and cluster‐randomized encouragement experiments: Study design, noncompliance, and average cluster effect ratio
Authors: Zhang Bo , Heng Siyu , MacKay Emily J. , Ye Ting
Published: June 2021

Instrumental variable (IV) methods are widely used in medical research to draw causal conclusions when the treatment and outcome are confounded by unmeasured confounding variables. One important feature of such studies is that the IV is often applied at the cluster level, for example, hospitals' or physicians' preference for a certain treatment where each hospital or physician naturally defines a cluster. This paper proposes to embed such observational IV data into a cluster‐randomized encouragement experiment using nonbipartite matching. Potential outcomes and causal assumptions underpinning the design are formalized and examined. Testing procedures for two commonly used estimands, Fisher's sharp null hypothesis and the pooled effect ratio (PER), are extended to the current setting. We then introduce a novel cluster‐heterogeneous proportional treatment effect model and the relevant estimand: the average cluster effect ratio. This new estimand is advantageous over the structural parameter in a constant proportional treatment effect model in that it allows treatment heterogeneity, and is advantageous over the PER estimand in that it does not suffer from Simpson's paradox. We develop an asymptotically valid randomization‐based testing procedure for this new estimand based on solving a mixed‐integer quadratically constrained optimization problem. The proposed design and inferential methods are applied to a study of the effect of using transesophageal echocardiography during coronary artery bypass graft surgery on patients' 30‐day mortality rate. R package ivdesign implements the proposed method.
Spatial correlation structures for detections of individuals in spatial capture–recapture models
Authors: Stevenson Ben C. , Fewster Rachel M. , Sharma Koustubh
Published: June 2021

Spatial capture–recapture (SCR) models are commonly used to estimate animal density from surveys on which detectors passively detect animals without physical capture, for example, using camera traps, hair snares, or microphones. An individual is more likely to be recorded by detectors close to its activity center, the centroid of its movement throughout the survey. Existing models to account for this spatial heterogeneity in detection probabilities rely on an assumption of independence between detection records at different detectors conditional on the animals' activity centers, which are treated as latent variables. In this paper, we show that this conditional independence assumption may be violated due to the way animals move around the survey region and encounter detectors, such that additional spatial correlation is almost inevitable. We highlight the links between the well‐studied issue of unmodeled temporal heterogeneity in nonspatial capture–recapture and this variety of unmodeled spatial heterogeneity in SCR, showing that the latter causes predictable bias in the same way as the former. We address this by introducing a latent detection field into the model, and illustrate the resulting approach with a simulation study and an application to a camera‐trap survey of snow leopards Panthera uncia. Our method is a unifying model for several existing SCR approaches, with special cases including standard SCR, models that account for nonspatial individual heterogeneity, and models with overdispersed detection counts.
The transition from salt diapir to weld and thrust: Examples from the Northern Flinders Ranges in South Australia
Authors: Vidal‐Royo Oskar , Rowan Mark G. , Ferrer Oriol , Fischer Mark P. , Fiduk J. Carl , Canova David P. , Hearon Thomas E. , Giles Katherine A.
Published: June 2021

The interactions between salt diapirs, thrust welds and thrusts in contractional belts are poorly understood due to, first, the inability of seismic data to distinguish between thrusts and welds or resolve associated sub‐resolution deformation, and second, the paucity of good field examples. The Warraweena area in the Northern Flinders Ranges of South Australia contains examples of Neoproterozoic to Early Cambrian squeezed diapirs linked by steep reverse faults formed during the Delamerian Orogeny. Benefiting from good field exposures, we use geological mapping, cross‐section construction and conceptual structural models to assess the three‐dimensional geometry and evolution of the structures, the lateral transition from diapirs to linking faults and the variability of associated meso‐ and small‐scale deformation. Three discrete diapirs consist of narrow outcrops of Callanna Group megabreccia (Willouran in age) up to 5‐km long. Their diapiric origin is confirmed by local development of caprock, steepening of flanking strata in composite halokinetic sequences and reworked diapir and roof debris in adjacent strata. The surrounding rocks display only background levels of small‐scale deformation. In contrast, the linking faults show no evidence of precursor diapirism, have fault‐related anticlines up to 100s of m in wavelength in their hanging walls, and an associated increase in small‐scale deformation (i.e. millimetre to metre scale folds, fractures and shear fabrics). The transitions from diapirs to faults occur within less than 200 m as short thrust welds at the diapir terminations. The exposed structures are analogous to those found on the subsurface of other salt basins such as the Gulf of Mexico and the South Atlantic conjugate margins. The results of this work can aid geoscientists evaluating three‐way traps against squeezed diapirs, welds or faults, and can help them to predict the style and abundance of both halokinetic and small‐scale structures that are below seismic resolution.
The gut microbiota associated with high‐Gleason prostate cancer
Authors: Matsushita Makoto , Fujita Kazutoshi , Motooka Daisuke , Hatano Koji , Fukae Shota , Kawamura Norihiko , Tomiyama Eisuke , Hayashi Yujiro , Banno Eri , Takao Tetsuya , Takada Shingo , Yachida Shinichi , Uemura Hirotsugu , Nakamura Shota , Nonomura Norio
Published: June 2021

We have found that intestinal bacteria and their metabolites, short‐chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analyzed the gut microbiota profiles of men with suspected PCa. One hundred and fifty‐two Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: a discovery cohort (114 samples) and a test cohort (38 samples). The gut microbiota was compared between two groups, a high‐risk group (men with Grade group 2 or higher PCa) and a negative + low‐risk group (men with negative biopsy or Grade group 1 PCa), using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFA‐producing bacteria, were significantly increased in high‐risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression detected high‐risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve [AUC] = 0.85 vs 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs 0.67). The specific bacterial taxa were associated with high‐risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high‐risk PCa and could contribute to the carcinogenesis of PCa.
Phytochemical library screening reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non–small cell lung cancer
Authors: He Dan‐Hua , Chen Yu‐Fei , Zhou Yi‐Le , Zhang Shi‐Bing , Hong Ming , Yu Xianjun , Wei Su‐Fen , Fan Xiang‐Zhen , Li Si‐Yi , Wang Qi , Lu Yongzhi , Liu Yong‐Qiang
Published: June 2021

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome‐dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant‐derived Skp2 inhibitor, betulinic acid (BA), via high‐throughput structure‐based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2‐SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H‐bonds with residue Lys145, decreases its stability by disrupting Skp1‐Skp2 interactions, thereby inhibiting the Skp2‐SCF E3 ligase and promoting the accumulation of its substrates; that is, E‐cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2‐SCF E3 ligase and upregulating p27 and E‐cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.
Synthesis andin vitroanticancer activities of seleniumN‐heterocyclic carbene compounds
Authors: Huang Sheng , Sheng Xinyu , Bian Mianli , Yang Zhibin , Lu Yunlong , Liu Wukun
Published: June 2021

Fourteen novel seleniumN‐heterocyclic carbene (Se‐NHC) compounds derived from 4,5‐diarylimidazole were designed, synthesized, and evaluated as antiproliferative agents. Most of them were more effective toward A2780 ovarian cancer cells than HepG2 hepatocellular carcinoma cells. Among them, the most active compound2bwas about fourfold more active than the positive control ebselen against A2780 cells. In addition, this compound displayed twofold higher cytotoxicity to A2780 cells than to IOSE80 normal ovarian epithelial cells. Further studies revealed that2bcould induce reactive oxygen species production, damage mitochondrial membrane potential, block the cells in the G0/G1 phase, and finally promote A2780 cell apoptosis.
Sarcoidosis of the ear, nose and throat: A review of the literature
Authors: Cereceda‐Monteoliva Nicholas , Rouhani Maral J. , Maughan Elizabeth F , Rotman Anthony , Orban Nara , Al Yaghchi Chadwan , Sandhu Guri
Published: June 2021

Objectives

Sarcoidosis is a multisystemic inflammatory disease with extrathoracic manifestations, most commonly affecting the young and middle‐aged, female and Black populations. Diagnosis usually requires evidence of non‐caseating granulomata and, when treated, prognosis is usually favourable. We aim to establish the incidence, clinical features and optimal treatment of ENT manifestations of this disease.

Design

We performed a PubMed literature review to determine the evidence base supporting this.

Results

ENT manifestations are present in 5%‐15% of patients with sarcoidosis, often as a presenting feature, and require vigilance for swift recognition and coordinated additional treatment specific to the organ. Laryngeal sarcoidosis presents with difficulty in breathing, dysphonia and cough, and may be treated by speech and language therapy (SLT) or intralesional injection, dilatation or tissue reduction. Nasal disease presents with crusting, rhinitis, nasal obstruction and anosmia, usually without sinus involvement. It is treated by topical nasal or intralesional treatments but may also require endoscopic sinus surgery, laser treatment or even nasal reconstruction. Otological disease is uncommon but includes audiovestibular symptoms, both sensorineural and conductive hearing loss, and skin lesions.

Conclusions

The consequences of ENT manifestations of sarcoidosis can be uncomfortable, disabling and even life‐threatening. Effective management strategies require good diagnostic skills and use of specific therapies combined with established treatments such as corticosteroids. Comparisons of treatment outcomes are needed to establish best practice in this area.
Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome
Authors: Eudy‐Byrne Rena , Zane Nicole , Adeniyi‐Jones Susan C. , Gastonguay Marc R. , Ruiz‐Garcia Ana , Kaushal Gagan , Kraft Walter K.
Published: June 2021

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC50) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.
Hydrogen sulfide donor protects against mechanical ventilation‐induced atrophy and contractile dysfunction in the rat diaphragm
Authors: Ichinoseki‐Sekine Noriko , Smuder Ashley J. , Morton Aaron B. , Hinkley James M. , Mor Huertas Andres , Powers Scott K.
Published: June 2021

Mechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life‐saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as “ventilator‐induced diaphragm dysfunction” (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H2S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H2S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV‐induced fiber atrophy and contractile dysfunction. H2S prevents MV‐induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV‐induced activation of the proteases, calpain, and caspase‐3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H2S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H2S has therapeutic potential to protect against MV‐induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator‐induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H2S) donors protect skeletal muscle against ischemia‐reperfusion‐induced injury. Nonetheless, it is unknown if treatment with a H2S donor can protect against VIDD.

WHAT QUESTION DID THIS STUDY ADDRESS?

Can treatment with an H2S donor protect against VIDD?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides the first evidence that treatment with a H2S donor protects against VIDD.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These new findings provide the basis for further exploration of H2S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.
Pharmacogenomic‐based personalized medicine: Multistakeholder perspectives on implementational drivers and barriers in the Canadian healthcare system
Authors: Subasri Mathushan , Barrett David , Sibalija Jovana , Bitacola Lisa , Kim Richard B.
Published: June 2021

Pharmacogenomics (PGx)‐based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug‐disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London‐based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed‐method qualitative model, key stakeholders, and patients from LHSC’s PGx‐based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system‐level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.
Dietary approaches for atherosclerotic cardiovascular disease prevention in cerebral palsy
Authors: Iyer Jessica R , Razavi Alexander C
Published: June 2021

This commentary is on the original article by Brown et al. on pages 1221–1228 of this issue.
Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship
Authors: Karkucinska‐Wieckowska Agnieszka , Simoes Ines C. M. , Kalinowski Piotr , Lebiedzinska‐Arciszewska Magdalena , Zieniewicz Krzysztof , Milkiewicz Piotr , Górska‐Ponikowska Magdalena , Pinton Paolo , Malik Afshan N. , Krawczyk Marcin , Oliveira Paulo J. , Wieckowski Mariusz R.
Published: June 2021

According to the ‘multiple‐hit’ hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro‐oxidative (nitroso‐oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.
Predictive factors for a severe course of COVID‐19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival
Authors: Jakubíková Michala , Týblová Michaela , Tesař Adam , Horáková Magda , Vlažná Daniela , Ryšánková Irena , Nováková Iveta , Dolečková Kristýna , Dušek Pavel , Piťha Jiří , Voháňka Stanislav , Bednařík Josef
Published: June 2021

Background and purpose

Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID‐19) mainly due to respiratory muscle weakness, older age and long‐term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID‐19 in MG patients and risk of MG exacerbation during COVID‐19.

Methods

We evaluated clinical features and outcomes after COVID‐19 in 93 MG patients.

Results

Thirty‐five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID‐19. Higher forced vital capacity (FVC) values tested before COVID‐19 were shown to be protective against severe infection (95% CI 0.934–0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047–1.232). Long‐term chronic corticosteroid treatment worsened the course of COVID‐19 in MG patients (95% CI 1.784–111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448–2.935), mycophenolate mofetil (95% CI 0.91–12.515) and ciclosporin (95% CI 0.029–2.212) did not influence the course of COVID‐19. MG patients treated with rituximab had a high risk of death caused by COVID‐19 (95% CI 3.216–383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885–10.87).

Conclusions

As the most important predictors of severe COVID‐19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long‐term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.