bluuebunny/crossref_metadata_2025 huggingface dataset:
Marketing strategies for highly volatile emerging markets: an empirical study from Pakistani cellular industry
Authors: Javed Ammar , Khan Zia
Published: November 2020

Purpose

This study aims to highlight important marketing strategies within the context of a highly competitive emerging market with few points of difference because of service homogeneity. Drawing upon the social identity and self-expansion theories, this research explores the role of corporate social responsibility (CSR) and discounts and packages offers (DPO) as determinants of purchase intentions. The understudied mediating role of brand love is investigated in the CSR–purchase intentions and DPO–purchase intentions relationships, with relationship age as a moderating variable for the two relationships.

Design/methodology/approach

Data from 359 valid responses from customers of cellular service firms in Pakistan were analyzed using partial least squares-based structural equation modeling.

Findings

The findings show that brand love partially (albeit a weaker relationship) mediates the CSR–purchase intentions relationship. Brand love also partially (albeit a stronger relationship) mediates the DPO–purchase intentions relationship. The moderating role of relationship age is not established.

Practical implications

Cellular firms in emerging markets experience high volatility. Therefore, understanding of the volatile behavior alongside devising strategies is of the utmost importance. This research shows that customers continue their business with the firms they love. Interestingly, the non-significance of relationship age as a moderator for both CSR–purchase intentions and DPO–purchase intentions indicates that garnering customers' purchase intentions with respect to relationship age will be very difficult for cellular firms under fierce competition. CSR and DPO should be strategically used to increase brand love to boost purchase intentions.

Originality/value

This study makes two important contributions to the literature of emerging markets. The first contribution of this research is the proposal and validation of brand love as a mediating variable in CSR–purchase intentions and DPO–purchase intentions relationships. Evaluation of the moderating role of relationship age in CSR–purchase intentions and DPO–purchase intentions relationships is the second contribution.
Pathways to improving financial inclusion through mobile money: a fuzzy set qualitative comparative analysis
Authors: Senyo PK , Osabutey Ellis L.C. , Seny Kan Konan A.
Published: November 2020

Purpose

The purpose of this study is to investigate and explain pathways through which mobile money can improve financial inclusion.

Design/methodology/approach

The study used 294 survey responses from mobile money users in Ghana. The data were analysed using fuzzy set qualitative comparative analysis (fsQCA).

Findings

The findings reveal four pathways for improving financial inclusion through mobile money. In addition, the study identified three distinct user topologies as well as their associated pathways through which mobile money can be used to improve financial inclusion.

Practical implications

Managers and financial service organisations need to design products and services to align with different pathways and user topologies to improve financial inclusion through mobile money. Moreover, they need to take into account people’s diverse social and economic backgrounds.

Originality/value

The study makes theoretical and empirical contributions by unpacking pathways through which mobile money can improve financial inclusion. In addition, this study reveals three distinct user topologies, being ease-of-use, behavioural intention and coverage-price-service driven and associated pathways through which mobile money can improve financial inclusion. These pathways and user topologies are important to tailor mobile money services and financial inclusion policies. Lastly, this study is arguably the first to utilise the unified theory of acceptance and use of technology (UTAUT) in fsQCA to extend the mobile money literature.
A moderated-mediated examination of the relations among strategic planning, organizational learning, slack and firm performance
Authors: Rau Devaki , Flores Luis , Simha Aditya
Published: November 2020

Purpose

Planning is a perennially popular management tool with an ambiguous relationship to learning and performance. The purpose of this study attempts to resolve this ambiguity. The authors suggest that the critical question is not whether firms need learning for planning to influence performance, but when different firms experience different performance outcomes. The authors propose firms will benefit from strategic planning only when they learn from planning and have the resources to act on their learning.

Design/methodology/approach

The authors collected data from a survey of 293 individuals from 191 publicly listed US firms.

Findings

Organizational learning mediates the relations between strategic planning and organizational performance. This mediated relationship is positively moderated by high levels of human resource slack and moderate to high levels of financial slack.

Research limitations/implications

The study provides evidence for previous theoretical arguments on the planning–learning relationship while extending this research by finding a complicated moderating effect of slack. The study also adds to the existing debate on optimal slack levels by suggesting that having bundles of slack resources may matter more than having uniformly high or low levels of slack. A cross-sectional study means the authors cannot infer causation.

Practical implications

While strategic planning is a common practice, companies may vary in their planning methodologies, influencing the outcomes of planning. Firms seeking to benefit from planning need to have both the mechanisms to learn from planning and slack to deploy these mechanisms.

Originality/value

These findings clarify the planning–learning–performance relationship while challenging the assumption of an average effect of planning on performance across firms.
Environmental, social and corporate governance framework for corporate disclosure: a multicriteria dimension analysis approach
Authors: Zopounidis Constantin , Garefalakis Alexandros , Lemonakis Christos , Passas Ioannis
Published: November 2020

Purpose

The purpose of this paper is to provide to the Board of Directors and CEOs of a firm to be aware of and accountable for the information they provide to the public. As long as the quality of the companies’ public information is high, it will be able to retain its investors as well as to obtain new ones more easily.

Design/methodology/approach

This paper introduces a Multi-Criteria Decision Aid (MCDA) tool with the use of the PROMETHEE II method to formulate an alternative aggregate ESG quality approach. We conduct comparisons in a sectorial and regional based perspective during different exam periods before and after the implementation of International Financial Reporting Standards (IFRS), in an attempt to provide a robust framework for corporate disclosure reporting.

Findings

The findings are of particular interest to both scholars and decision-makers, including providers of corporate governance indices and rating agencies. The innovation of this paper lies among others in using the MCDA method with the ESG framework, which proposes a combination of qualitative and quantitative criteria, enabling experienced and/or not experienced analysts to avoid manipulating techniques in business information.

Research limitations/implications

The sample of companies based on the US and Europe companies incorporating only large-sized ones.

Practical implications

Findings are of particular interest to both scholars and decision-makers including providers of corporate governance indices and rating agencies.

Social implications

Better understanding features pay key importance for increasing the “quality” information in firms financial statements, especially after the use of IFRS in reporting standards.

Originality/value

The authors proceed to analysis using a multiple perspective use that is decomposed into the following options: (a) Time-period oriented option, (b) Regional-oriented option and (c) Sectoral-oriented option respectively.
Longitudinal dynamics and behavioural correlates of telomeres in male wire‐tailed manakins
Authors: Vernasco Ben J. , Dakin Roslyn , Majer Ariana D. , Haussmann Mark F. , Brandt Ryder T. , Moore Ignacio T.
Published: November 2020

Building on the predictions of state‐dependent life‐history theory, telomeres are hypothesized to either correlate with or function as an adaptive, proximate mediator of an individual's behaviour and life‐history strategy. To further understand the relationship between telomeres, behaviour and life‐history strategies, we measured male behaviour, telomere lengths and telomere dynamics in a free‐living population of known‐age, male wire‐tailed manakins Pipra filicauda.

Male wire‐tailed manakins perform coordinated displays with other males at leks and these displays form the basis of long‐term coalition partnerships. Males exhibit consistent individual differences in the number of social partners within their social network and the frequency of social interactions. Male sociality is also positively correlated with both social rise and reproductive success.

We measured male behaviour using a telemetry‐based, proximity datalogging system and blood telomere lengths were quantified using qPCR. We examined the relationships between telomere length, telomere dynamics, social status, and male behaviour. We also quantified the repeatability of telomere lengths, examined age‐related changes in telomere length, and tested for instances of telomere elongation that exceed residual error in telomere length.

Telomere length was found to be highly repeatable. More social males exhibited shorter telomeres and higher rates of telomere attrition. Telomeres did not significantly vary with age within or between individuals in either of the male social classes. Two out of 25 individuals exhibited patterns telomere elongation that exceeded residual error in telomere measurements.

Here we show that telomeres consistently vary between male wire‐tailed manakins and these differences are related to variation in male social behaviour. In this relatively long‐lived species, telomeres appear to be flexible traits that can increase or decrease in length. Overall, this study provides observational support for the hypothesis that telomeres act as a molecular marker that relates to behaviour in a state‐dependent manner. We also provide insight into the molecular consequences of individual variation in male social behaviour.

A free Plain Language Summary can be found within the Supporting Information of this article.
Increased burning in a warming climate reduces carbon uptake in the Greater Yellowstone Ecosystem despite productivity gains
Authors: Henne Paul D. , Hawbaker Todd J. , Scheller Robert M. , Zhao Feng , He Hong S. , Xu Wenru , Zhu Zhiliang
Published: November 2020

The effects of changing climate and disturbance on mountain forest carbon (C) stocks vary with tree species distributions and over elevational gradients. Warming can not only increase C uptake by stimulating productivity at high elevations but also enhance C release by increasing respiration and the frequency, intensity and size of wildfires.

To understand the consequences of climate change for temperate mountain forests, we simulated interactions among climate, wildfire, tree species and their combined effects on regional C stocks in forests of the Greater Yellowstone Ecosystem, USA (GYE) with the LANDIS‐II landscape change model. Simulations used historical climate and future potential climate represented by downscaled projections from five general circulation models (GCMs) that bracket the range of variability under the representative concentration pathway (RCP) 8.5 emissions scenario.

Total ecosystem C increased by 67% through 2100 in simulations with historical climate, and by 38%–69% with GCM climate. Differences in C uptake among GCMs resulted primarily from variation in area burned, not productivity. Warming increased productivity by extending the growing season, especially near upper tree line, but did not offset biomass losses to fire. By 2100, simulated area burned increased by 27%–215% under GCM climate, with the largest increases after 2050. With warming >3°C in mean annual temperature, the increased frequency of large fires reduced live C stocks by 4%–36% relative to the control, historical climate scenario. However, relative losses in total C were delayed under GCMs with large increases in summer precipitation and buffered by C retained in soils and the wood of fire‐killed trees. Increasing fire size limited seed dispersal, and reductions in soil moisture limited seedling establishment; both effects will likely constrain long‐term forest regeneration and C uptake.

Synthesis. Forests in the GYE can maintain a C sink through the mid‐century in a warming climate but continued warming may cause the loss of forest area, live above‐ground biomass and, ultimately, ecosystem C. Future changes in C stocks in similar forests throughout western North America will depend on regional thresholds for extensive wildfire and forest regeneration and therefore, changes may occur earlier in drier regions.
Estimated direct costs of non‐small cell lung cancer by stage at diagnosis and disease management phase: A whole‐disease model
Authors: Buja Alessandra , Rivera Michele , De Polo Anna , Brino Eugenio di , Marchetti Marco , Scioni Manuela , Pasello Giulia , Bortolami Alberto , Rebba Vincenzo , Schiavon Marco , Calabrese Fiorella , Mandoliti Giovanni , Baldo Vincenzo , Conte PierFranco
Published: November 2020

Background

Non‐small cell lung cancer (NSCLC) is the first cause of cancer‐related death among men and the second among women worldwide. It also poses an economic threat to the sustainability of healthcare services. This study estimated the direct costs of care for patients with NSCLC by stage at diagnosis, and management phase of pathway recommended in local and international guidelines.

Methods

Based on the most up‐to‐date guidelines, we developed a very detailed “whole‐disease” model listing the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of each stage of NSCLC. We assigned a cost to each procedure, and obtained an estimate of the total and average per‐patient costs of each stage of the disease and phase of its management.

Results

The mean expected cost of a patient with NSCLC is 21,328 € (95% C.I. −20 897−22 322). This cost is 16 291 € in stage I, 19530 € in stage II, 21938 € in stage III, 22175 € in stage IV, and 28 711 € for a Pancoast tumor. In the early stages of the disease, the main cost is incurred by surgery, whereas in the more advanced stages radiotherapy, medical therapy, treatment for progressions, and supportive care become variously more important.

Conclusions

An estimation of the direct costs of care for NSCLC is fundamental in order to predict the burden of new oncological therapies and treatments on healthcare services, and thus orient the decisions of policy‐makers regarding the allocation of resources.

Key points

Significant findings of the study

The high costs of surgery make the early stages of the disease no less expensive than the advanced stages.

What this study adds

An estimation of the direct costs of care is fundamental in order to orient the decisions of policy‐makers regarding the allocation of resources.
Impact of the generation of EGFR‐TKIs administered as prior therapy on the efficacy of osimertinib in patients with non‐small cell lung cancer harboring EGFR T790M mutation
Authors: Miyashita Yosuke , Ko Ryo , Shimada Naoko , Mitsuishi Yoichiro , Miura Keita , Matsumoto Naohisa , Asao Tetsuhiko , Shukuya Takehito , Shibayama Rina , Koyama Ryo , Takahashi Kazuhisa
Published: November 2020

Background

There are few studies that directly compare the effects of osimertinib on patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation between the generation of prior EGFR tyrosine kinase inhibitors (TKIs).

Methods

We retrospectively reviewed clinical data from the medical records of consecutive patients with advanced NSCLC who had developed resistance to first‐ or second‐generation EGFR‐TKIs due to EGFR T790M mutation and were subsequently treated with osimertinib at Juntendo University Hospital. In patients with available tumor samples, target amplicon sequencing analyses were performed to explore the genetic biomarkers.

Results

A total of 38 patients with NSCLC harboring EGFR T790M mutation were treated with osimertinib. Eight patients were classified into group A (afatinib followed by osimertinib) and 30 patients were classified into group B (first‐generation EGFR‐TKI followed by osimertinib). Progression‐free survival (PFS) was significantly longer in group A than in group B (median PFS; not reached vs. 11.0 months, P = 0.018). Fourteen patients had available tissue samples collected before osimertinib treatment for target sequencing. In group A we found no additional mutations, other than EGFR T790M mutation. On the other hand, there were three samples in which other mutations emerged, in addition to EGFR T790M mutation, in group B.

Conclusions

PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs. Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment.

Key points

Significant findings of the study:

PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs.

What this study adds:

Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment.
Industry momentum: an exchange‐traded funds approach
Authors: Vanstone Bruce , Hahn Tobias , Earea Dean
Published: November 2020

Price momentum is a well‐documented anomaly in many of the world’s equity markets, and refers to the excess returns due to buying (selling) past winner (loser) stocks. Industry momentum refers to the excess returns due to buying (selling) stocks from past winner (loser) industries, and has been demonstrated to be more profitable than individual stock momentum in the United States. We investigate whether industry momentum can be captured by investing with sector exchange‐traded funds (ETFs). The performance of sector ETF‐based industry momentum is very different to stock momentum, and the strong performance of an unexpected group of sector ETF momentum portfolios remains robust after controlling for risk.
Applying a complex systems perspective to alcohol consumption and the prevention of alcohol‐related harms in the 21st century: a scoping review
Authors: McGill Elizabeth , Petticrew Mark , Marks Dalya , McGrath Michael , Rinaldi Chiara , Egan Matt
Published: November 2020

Background and Aims

A complex systems perspective has been advocated to explore multi‐faceted factors influencing public health issues, including alcohol consumption and associated harms. This scoping review aimed to identify studies that applied a complex systems perspective to alcohol consumption and the prevention of alcohol‐related harms in order to summarize their characteristics and identify evidence gaps.

Methods

Studies published between January 2000 and September 2020 in English were located by searching for terms synonymous with ‘complex systems’ and ‘alcohol’ in the Scopus, MEDLINE, Web of Science and Embase databases, and through handsearching and reference screening of included studies. Data were extracted on each study's aim, country, population, alcohol topic, system levels, funding, theory, methods, data sources, time‐frames, system modifications and type of findings produced.

Results

Eighty‐seven individual studies and three systematic reviews were identified, the majority of which were conducted in the United States or Australia in the general population, university students or adolescents. Studies explored types and patterns of consumption behaviour and the local environments in which alcohol is consumed. Most studies focused on individual and local interactions and influences, with fewer examples exploring the relationships between these and regional, national and international subsystems. The body of literature is methodologically diverse and includes theory‐led approaches, dynamic simulation models and social network analyses. The systematic reviews focused on primary network studies.

Conclusions

The use of a complex systems perspective has provided a variety of ways of conceptualizing and analyzing alcohol use and harm prevention efforts, but its focus ultimately has remained on predominantly individual‐ and/or local‐level systems. A complex systems perspective represents an opportunity to address this gap by also considering the vertical dimensions that constrain, shape and influence alcohol consumption and related harms, but the literature to date has not fully captured this potential.
Socio‐economic distribution of e‐cigarette use among recent former regular smokers and current smokers at ages 25–26 in England
Authors: Gagné Thierry , Brown Jamie
Published: November 2020

Background and aims

E‐cigarettes may potentially help young adult smokers to quit smoking, yet little is known about differences among socio‐economic groups. We examined associations between key socio‐economic characteristics and e‐cigarette use among recent former smokers and current smokers in a sample of young adults in England.

Design, setting, participants and measurements

We used data on 346 recent former regular (daily for 12+ months) smokers and 1913 current smokers from the ages 25–26 wave of the Next Steps cohort study (2015–2016). In multinomial logistic regression, we estimated relative risk ratios (RRR) of e‐cigarette use (never, former, non‐daily, daily) by educational attainment, social class [using the National Statistics Socio‐economic classification (NS‐SEC)] and employment status [full‐time, part‐time, unemployed and other ‘inactivity’ (e.g. stay‐at‐home parents and permanantly disabled)], adjusting for sex.

Findings

Among recent former regular smokers, there were no patterns of association between socio‐economic characteristics and e‐cigarette use. Among current smokers: (1) compared with higher occupation (NS‐SEC I/II), intermediate occupation (NS‐SEC III/IV) was positively associated with non‐daily e‐cigarette use [RRR = 1.77, 95% confidence interval (CI) = 1.03–3.03]; (2) compared with full‐time employment, unemployment was negatively associated with non‐daily and daily e‐cigarette use (RRR = 0.38, 95% CI = 0.18–0.81; RRR = 0.12, 95% CI = 0.02–0.56) and other economic inactivity was negatively associated with daily e‐cigarette use (RRR = 0.39, 95% CI = 0.16–0.93).

Conclusions

Among young adult smokers in England, lower‐status occupational groups were more likely to use e‐cigarettes on a non‐daily basis than to have never used compared with higher status occupational groups. Compared with people in full‐time employment, those without employment were less likely to use e‐cigarettes daily than to have never used.
A Wolf in Sheep’s clothing: A case report series of oral manifestations of multiple myeloma
Authors: Beaumont Sophie , Koo Ray Mun , Harrison Simon J.
Published: November 2020

Multiple myeloma is the most common haematological malignancy accounting for 10 % of all haematological cancers. Treatment of myeloma has evolved in recent years leading to improved survival. Lesions related to myeloma are frequently observed within the oral cavity and jawbone. In addition, many of the therapeutic agents have side effects with implications for provision of dental treatment. This case series aims to highlight some of these presentations to remind dental practitioners to be vigilant. Observation of suspicious lesions within the oral cavity or jawbone might warrant further investigation.
An in vitro endodontic model to quantify the accessory canal filling potential of the vertical and lateral condensation techniques
Authors: Wolf Thomas Gerhard , Willems Louisa , Briseño‐Marroquín Benjamín
Published: November 2020

The purpose of this study was to determine the accessory canal filling potential of vertical and lateral condensation techniques in simulated root canals. A total of 130 prepared transparent, straight‐simulated root canals with nine accessory canals (0.02 mm), prepared at different levels from the apical, were obturated with vertical (n = 100) and 30 lateral condensation (n = 30) techniques. 50.33% of the accessory canals obturated with vertical condensation were completely filled with gutta‐percha; 37.78% completely filled with gutta‐percha and sealer. 61.11% of the accessory canals were completely filled with sealer only using the lateral condensation technique. The vertical condensation technique filled the accessory canals more frequently than the lateral condensation techniques. The lateral condensation technique was not capable of delivering gutta‐percha to any of the accessory canals. The apical third showed the lowest accessory canal filling frequency with both techniques.
Comparison of infection risks and clinical outcomes in patients with and without SARS‐CoV‐2 lung infection under renin–angiotensin–aldosterone system blockade: Systematic review and meta‐analysis
Authors: Chu Chang , Zeng Shufei , Hasan Ahmed A. , Hocher Carl‐Friedrich , Krämer Bernhard K. , Hocher Berthold
Published: November 2020

Aims

Angiotensin‐converting enzyme‐2 (ACE2) is the receptor for SARS‐CoV‐2. Animal studies suggest that renin–angiotensin–aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS‐CoV‐2 infection.

Methods and Results

The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non‐COVID‐19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia‐related death cases in ACEI‐treated non‐COVID‐19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non‐COVID‐19 patients) did not alter pneumonia risk in patients. Pneumonia‐related death cases in ARB‐treated non‐COVID‐19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS‐CoV‐2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID‐19 patients showed that RAAS blockade reduces all‐cause mortality by 24% (OR = 0.76, P = .04).

Conclusion

ACEIs reduce the risk of getting infected with the SARS‐CoV‐2 virus. Blocking the RAAS may decrease all‐cause mortality in COVID‐19 patients. ACEIs also reduce the risk of non‐COVID pneumonia. All‐cause mortality due to non‐COVID pneumonia is reduced by ACEI and potentially by ARBs.
Pembrolizumab‐induced vitiligo in a patient with lung adenocarcinoma: A case report
Authors: Bulat Vedrana , Likic Robert , Bradic Lada , Speeckaert Reinhart , Azdajic Marija Delas
Published: November 2020

Pembrolizumab is an immune checkpoint inhibitor designed to block the interaction between programmed cell death‐1 and programmed cell death‐ligands 1 and 2. It shows efficacy in the treatment of patients with advanced nonsmall‐cell lung cancer, among others. Side effects may involve immune‐related adverse events, including vitiligo.

We hereby present a 63‐year‐old Caucasian female with metastatic nonsmall‐cell lung cancer. Immunohistochemical analysis showed programmed death‐ligand 1 expression on 100% of tumour cells. The patient was eligible for immunotherapy and received pembrolizumab every 3 weeks as the first‐line treatment. Three months after initiation of immunotherapy with pembrolizumab, depigmentation appeared on her upper right thoracic area of the skin overlying the affected lung lobe. Immunotherapy was generally well tolerated. Excellent response in our subject with complete remission during 16 months of follow‐up potentially indicates that cutaneous immune‐related adverse events, such as vitiligo, might be associated with increased efficacy of pembrolizumab in metastatic lung adenocarcinoma.
Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine
Authors: Yip Vincent L.M. , Pertinez Henry , Meng Xiaoli , Maggs James L. , Carr Daniel F. , Park B. Kevin , Marson Anthony G. , Pirmohamed Munir
Published: November 2020

Aims

Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates.

Methods

A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11‐epoxide. Nonlinear mixed effects modelling was used to build a population‐PK model.

Results

In total, 248 observations were collected from 80 subjects. A 1‐compartment PK model with first‐order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h−1. Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1‐416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11‐epoxide.

Conclusion

Our data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11‐epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.
Effects of CD20 antibodies and kinase inhibitors on B‐cell receptor signalling and survival of chronic lymphocytic leukaemia cells
Authors: Cavallini Chiara , Galasso Marilisa , Pozza Elisa Dalla , Chignola Roberto , Lovato Ornella , Dando Ilaria , Romanelli Maria G. , Krampera Mauro , Pizzolo Giovanni , Donadelli Massimo , Scupoli Maria T.
Published: November 2020

Recently, clinical trial results have established inhibitors of B‐cell receptor (BCR)‐associated kinase (BAKi), with or without CD20 moniclonal antibodies (mAbs), as the preferred first‐line treatment for most chronic lymphocytic leukaemia (CLL) patients. Using phosphospecific flow cytometry, we showed that in leukaemic cells from CLL patients the CD20 therapeutic antibodies — rituximab, ofatumumab, and obinutuzumab — inhibited BCR signalling pathways targeting preferentially pBTKY551 — but not BTKY223 — and pAKT. On the contrary, ibrutinib and idelalisib reduced pBTKY223 to a higher extent than pBTKY551. The strong reduction of pAKT induced by idelalisib was enhanced by its combination with rituximab or ofatumumab. Moreover, CD20 mAbs and BAKi induced the death of leukaemia cells that was significantly potentiated by their combination. Analysis of the enhancement of cell death in these combinations revealed an approximately additive enhancement induced by rituximab or obinutuzumab combined with ibrutinib or idelalisib. Taken together, our data identified negative regulatory effects of CD20 mAbs and their combinations with BAKi on BCR signalling and cell survival in CLL. In conclusion, this study advances our understanding of mechanisms of action of CD20 mAbs as single agents or in combination with BAKi and could inform on the potential of combined therapies in ongoing and future clinical trials in patients with CLL.
Induction of therapeutic levels of HbF in genome‐edited primary β039‐thalassaemia haematopoietic stem and progenitor cells
Authors: Mingoia Maura , Caria Cristian A. , Ye Lin , Asunis Isadora , Marongiu M. Franca , Manunza Laura , Sollaino M. Carla , Wang Jiaming , Cabriolu Annalisa , Kurita Ryo , Nakamura Yukio , Cucca Francesco , Kan Yuet W. , Marini M. Giuseppina , Moi Paolo
Published: November 2020

Hereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β‐thalassaemia. The homozygous mutation c.‐196 C>T in the Aγ‐globin (HBG1) promoter, which causes Sardinian δβ0‐thalassaemia, is able to completely rescue the β‐major thalassaemia phenotype caused by the β039‐thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood. Here, we describe a CRISPR/Cas9 genome‐editing approach, combined with the non‐homologous end joining (NHEJ) pathway repair, aimed at reproducing the effects of this naturally occurring HPFH mutation in both HBG promoters. After selecting the most efficient guide RNA in K562 cells, we edited the HBG promoters in human umbilical cord blood‐derived erythroid progenitor 2 cells (HUDEP‐2) and in haematopoietic stem and progenitor cells (HSPCs) from β0‐thalassaemia patients to assess the therapeutic potential of HbF induction. Our results indicate that small deletions targeting the −196‐promoter region restore high levels of fetal haemoglobin (HbF) synthesis in all cell types tested. In pools of HSPCs derived from homozygous β039‐thalassaemia patients, a 20% editing determined a parallel 20% increase of HbF compared to unedited pools. These results suggest that editing the region of HBG promoters around the −196 position has the potential to induce therapeutic levels of HbF in patients with most types of β‐thalassaemia irrespective of the β‐globin gene (HBB) mutations.
Chimeric antigen receptor (CAR) natural killer (NK)‐cell therapy: leveraging the power of innate immunity
Authors: Rafei Hind , Daher May , Rezvani Katayoun
Published: November 2020

Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered.
Intravenous iron: do we adequately understand the short‐ and long‐term risks in clinical practice?
Authors: Rund Deborah
Published: November 2020

Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron‐restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.
A complication risk score to evaluate clinical severity of thalassaemia syndromes
Authors: Vitrano Angela , Meloni Antonella , Addario Pollina Walter , Karimi Mehran , El‐Beshlawy Amal , Hajipour Mahmoud , Di Marco Vito , Hussain Ansari Saqib , Filosa Aldo , Ricchi Paolo , Ceci Adriana , Daar Shahina , Titi Singer Sylvia , Naserullah Zaki A. , Pepe Alessia , Scondotto Salvatore , Dardanoni Gabriella , Bonifazi Fedele , Vichinsky Elliott , Maggio Aurelio
Published: November 2020

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion‐dependent thalassaemia (TDT)], Group B [transfused non‐TDT (NTDT)] and Group C (non‐transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left‐ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients’ treatment.
Management of relapse in acute promyelocytic leukaemia treated with up‐front arsenic trioxide‐based regimens
Authors: Fouzia N. A. , Sharma Vibhor , Ganesan Saravanan , Palani Hamenth K. , Balasundaram Nithya , David Sachin , Kulkarni Uday P. , Korula Anu , Devasia Anup J. , Nair Sukesh C. , Janet Nancy Beryl , Abraham Aby , Mani Thenmozhi , Lakshmanan Jeyaseelan , Balasubramanian Poonkuzhali , George Biju , Mathews Vikram
Published: November 2020

The standard of care for patients with acute promyelocytic leukaemia (APL) relapsing after front‐line treatment with arsenic trioxide (ATO)‐based regimens remains to be defined. A total of 67 patients who relapsed after receiving ATO‐based up‐front therapy and were also salvaged using an ATO‐based regimen were evaluated. The median (range) age of patients was 28 (4–54) years. While 63/67 (94%) achieved a second molecular remission (MR) after salvage therapy, three (4·5%) died during salvage therapy. An autologous stem cell transplant (auto‐SCT) was offered to all patients who achieved MR, 35/63 (55·6%) opted for auto‐SCT the rest were administered an ATO + all‐trans retinoic acid maintenance regimen. The mean (SD) 5‐year Kaplan–Meier estimate of overall survival and event‐free survival of those who received auto‐SCT versus those who did not was 90·3 (5·3)% versus 58·6 (10·4)% (P = 0·004), and 87·1 (6·0)% versus 47·7 (10·3)% (P = 0·001) respectively. On multivariate analysis, failure to consolidate MR with an auto‐SCT was associated with a significantly increased risk of relapse [hazard ratio (HR) 4·91, 95% confidence interval (CI) 1·56–15·41; P = 0·006]. MR induction with ATO‐based regimens followed by an auto‐SCT in children and young adults with relapsed APL who were treated with front‐line ATO‐based regimens was associated with excellent long‐term survival.
A prognostic index for extranodal marginal‐zone lymphoma based on the mucosa‐associated lymphoid tissue International Prognostic Index and serum β2‐microglobulin levels
Authors: Kim Hyung‐Don , Cho Hyungwoo , Jeong Hyehyun , Bang Kyunghye , Kim Shin , Lee Kyoungmin , Kang Eun Hee , Park Jung Sun , Park Chan‐Sik , Huh Jooryung , Ryu Jin‐Sook , Lee Sang‐Wook , Yoon Dok Hyun , Oh Sung Yong , Suh Cheolwon
Published: November 2020

The mucosa‐associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum β2‐microglobulin level in the context of MALT‐IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to β2‐microglobulin level, MALT‐IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high β2‐microglobulin levels had significantly worse progression‐free survival (PFS) and overall survival (OS) outcomes. A high β2‐microglobulin level was independently associated with poor PFS and OS. β2‐microglobulin levels further stratified patients in the MALT‐IPI intermediate‐risk group in terms of PFS and OS. A new prognostic index based on the MALT‐IPI and the β2‐microglobulin level, MALT‐IPI‐B, was proposed. The MALT‐IPI‐B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT‐IPI‐B enabled the identification of patients with poor survival outcomes who were classified into the intermediate‐risk group by the MALT‐IPI. In conclusion, this new β2‐microglobulin‐based prognostic index may have the specific advantage of identifying high‐risk patients who may require systemic treatment.
Focus on monoclonal antibodies targeting B‐cell maturation antigen (BCMA) in multiple myeloma: update 2021
Authors: Demel Ivo , Bago Julio Rodriguez , Hajek Roman , Jelinek Tomas
Published: November 2020

Remarkable advances have been achieved in the treatment of multiple myeloma (MM) in the last decade, which saw targeted immunotherapy, represented by anti‐CD38 monoclonal antibodies, successfully incorporated across indications. However, myeloma is still considered curable in only a small subset of patients, and the majority of them eventually relapse. B‐cell maturation antigen (BCMA) is expressed exclusively in mature B lymphocytes and plasma cells, and represents an ideal new target for immunotherapy, presented by bispecific antibody (bsAb) constructs, antibody‐drug conjugates (ADCs) and chimeric antigen receptor T (CAR‐T) cells. Each of them has proved its efficacy with the potential for deep and long‐lasting responses as a single agent therapy in heavily pretreated patients. As a result, belantamab mafodotin was approved by the United States Food and Drug Administration for the treatment of relapsed/refractory MM, as the first anti‐BCMA agent. In the present review, we focus on monoclonal antibodies targeting BCMA – bsAbs and ADCs. The data from preclinical studies as well as first‐in‐human clinical trials will be reviewed, together with the coverage of their constructs and mechanisms of action. The present results have laid the groundwork for the ongoing or upcoming clinical trials with combinatory regimens, which have always been a cornerstone in the treatment of MM.
Iron accumulation in the choroid plexus, ependymal cells and CNS parenchyma in a rat strain with low‐grade haemolysis of fragile macrocytic red blood cells
Authors: Wimmer Isabella , Scharler Cornelia , Kadowaki Taro , Hillebrand Sophie , Scheiber‐Mojdehkar Barbara , Ueda Shuichi , Bradl Monika , Berger Thomas , Lassmann Hans , Hametner Simon
Published: November 2020

Iron accumulation in the CNS is associated with many neurological diseases via amplification of inflammation and neurodegeneration. However, experimental studies on iron overload are challenging, since rodents hardly accumulate brain iron in contrast to humans. Here, we studied LEWzizi rats, which present with elevated CNS iron loads, aiming to characterise choroid plexus, ependymal, CSF and CNS parenchymal iron loads in conjunction with altered blood iron parameters and, thus, signifying non‐classical entry sites for iron into the CNS. Non‐haem iron in formalin‐fixed paraffin‐embedded tissue was detected via DAB‐enhanced Turnbull Blue stainings. CSF iron levels were determined via atomic absorption spectroscopy. Ferroportin and aquaporin‐1 expression was visualised using immunohistochemistry. The analysis of red blood cell indices and serum/plasma parameters was based on automated measurements; the fragility of red blood cells was manually determined by the osmotic challenge. Compared with wild‐type animals, LEWzizi rats showed strongly increased iron accumulation in choroid plexus epithelial cells as well as in ependymal cells of the ventricle lining. Concurrently, red blood cell macrocytosis, low‐grade haemolysis and significant haemoglobin liberation from red blood cells were apparent in the peripheral blood of LEWzizi rats. Interestingly, elevated iron accumulation was also evident in kidney proximal tubules, which share similarities with the blood–CSF barrier. Our data underscore the importance of iron gateways into the CNS other than the classical route across microvessels in the CNS parenchyma. Our findings of pronounced choroid plexus iron overload in conjunction with peripheral iron overload and increased RBC fragility in LEWzizi rats may be seminal for future studies of human diseases, in which similar constellations are found.
Hybrids of aurantiamide acetate and isopropylated genipin as potential anti‐inflammatory agents: The design, synthesis, and biological evaluation
Authors: Wang Hongwei , Gao Sufan , Li Jiaming , Ma Xiaodong , Liu Wandong , Qian Shihu
Published: November 2020

A novel series of hybrids designed on the basis of aurantiamide acetate and isopropylated genipin were synthesized and biologically evaluated as anti‐inflammatory agents. Among them, compound 7o exhibited the best inhibitory activity against TNF‐α secretion (IC50 = 16.90 μM) and was selected for further in vitro and in vivo functional study. The results demonstrated that 7o was capable of suppressing the expression of LPS‐induced iNOS and COX‐2, as well as reducing the production of NO at the concentration of 5 μM, which may be resulted from its regulation of NF‐κB signaling and MAPK signaling. Moreover, compound 7o exhibited favorable in vivo anti‐inflammatory activity with an inhibition rate of 53.32% against xylene‐induced ear swelling in mice at the dose of 5 mg/kg.