bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple regulatory mechanisms control the production of CmrRST, an atypical signal transduction system in Clostridioides difficile
Authors: Garrett Elizabeth M. , Mehra Anchal , Sekulovic Ognjen , Tamayo Rita
Published: October 2021

Clostridioides difficile, an intestinal pathogen and leading cause of nosocomial infection, exhibits extensive phenotypic heterogeneity through phase variation by site-specific recombination. The signal transduction system CmrRST, which encodes two response regulators (CmrR and CmrT) and a sensor kinase (CmrS), impacts C. difficile cell and colony morphology, surface and swimming motility, biofilm formation, and virulence in an animal model. CmrRST is subject to phase variation through site-specific recombination and reversible inversion of the ‘cmr switch’, and expression of cmrRST is also regulated by c-di-GMP through a riboswitch. The goal of this study was to determine how the cmr switch and c-di-GMP work together to regulate cmrRST expression. We generated “phase locked” strains by mutating key residues in the right inverted repeat flanking the cmr switch. Phenotypic characterization of these phase locked cmr-ON and -OFF strains demonstrates that they cannot switch between rough and smooth colony morphologies, respectively, or other CmrRST-associated phenotypes. Manipulation of c-di-GMP levels in these mutants showed that c-di-GMP promotes cmrRST expression and associated phenotypes independent of cmr switch orientation. We identified multiple promoters controlling cmrRST transcription, including one within the ON orientation of cmr switch and another that is positively autoregulated by CmrR. Overall, this work reveals a complex regulatory network that governs cmrRST expression and a unique intersection of phase variation and c-di-GMP signaling. These findings suggest that multiple environmental signals impact the production of this signaling transduction system.

IMPORTANCE

Clostridioides difficile is a leading cause of hospital-acquired intestinal infections in the U.S. The CmrRST signal transduction system controls numerous physiological traits and processes in C. difficile, including cell and colony morphology, motility, biofilm formation, and virulence. Here we define the complex, multi-level regulation of cmrRST expression, including stochastic control through phase variation, modulation by the second messenger c-di-GMP, and positive autoregulation by CmrR. The results of this study suggest that multiple, distinct environmental stimuli and selective pressures must be integrated to appropriately control cmrRST expression.
Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction
Authors: Scheithauer Torsten P.M. , Herrema Hilde , Yu Hongbing , Bakker Guido J. , Winkelmeijer Maaike , Soukhatcheva Galina , Dai Derek , Ma Caixia , Havik Stefan R. , Balvers Manon , Davids Mark , Meijnikman Abraham S. , Aydin Ömrüm , van den Born Bert-Jan H. , Besselink Marc G. , Busch Olivier R. , de Brauw Maurits , van de Laar Arnold , Belzer Clara , Stahl Martin , de Vos Willem M. , Vallance Bruce A. , Nieuwdorp Max , Verchere C. Bruce , van Raalte Daniël H.
Published: October 2021

Objective

Hyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied but causal links remain enigmatic.

Design

Obese individuals with or without T2D were included from two independent Dutch cohorts. Human data was translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice.

Results

Flagellin is part of the bacterial locomotor appendage flagellum, present on gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice.

Conclusion

We postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta cell failure in time and represents a novel therapeutic target.

Graphical abstract
Crystal structure and Hirshfeld surface analysis of (3aSR,6RS,6aSR,7RS,11bSR,11cRS)-2,2-dibenzyl-2,3,6a,11c-tetrahydro-1H,6H,7H-3a,6:7,11b-diepoxydibenzo[de,h]isoquinolin-2-ium trifluoromethanesulfonate
Authors: Atioğlu Zeliha , Akkurt Mehmet , Mammadova Gunay Z. , Mlowe Sixberth
Published: October 2021

In the cation of the title salt, C30H28NO2
+·CF3O3S−, the four tetrahydrofuran rings adopt envelope conformations. In the crystal, pairs of cations are linked by dimeric C—H...O hydrogen bonds, forming two R
2
2(6) ring motifs parallel to the (001) plane. The cations and anions are connected by further C—H...O hydrogen bonds, forming a three-dimensional network structure. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (47.6%), C...H/H...C (20.6%), O...H/H...O (18.0%) and F...H/H...F (9.9%) interactions.
The incorporation of Mainland Chinese tourists' experiences into the Taiwan hotel branding process
Authors: Liu Kuo-Ning , Hu Clark
Published: October 2021

Purpose

The purpose is to understand the importance of brand experience in the Taiwan hotel branding process; also, this study is to investigate the moderating effect of brand experience on the relationship between brand positioning and non-financial brand performance in Taiwan upscale hotels, focusing on mainland Chinese tourists.

Design/methodology/approach

The structural equation modeling (SEM) analysis was used to conduct questionnaire analysis. This study examined data collected from Chinese tourists who stayed at Taiwan upscale hotels.

Findings

The brand experience of an upscale hotel brand can affect its brand image, product attributes, brand loyalty and customer satisfaction. By investigating the moderating effect of brand experience, the study revealed the brand image perceptions of hotel guests with a positive brand experience to significantly influence non-financial brand performance. The product attribute perceptions of hotel guests with a more positive brand experience were also found to have a more significant effect on nonfinancial brand performance.

Originality/value

In the highly competitive hotel industry, the application of brand experience to marketing practice has drawn much industry attention. There is a strong possibility that upscale hotel companies will eventually find value in adopting the measurement instruments and suggestions presented here to assess and guide their marketing practices.
Benefits and barriers associated with take-home-naloxone in the view of Italian service providers
Authors: Rolando Sara , Beccaria Franca , Ronconi Susanna
Published: October 2021

Purpose

Spanning almost 30 years, Italy’s experience with take-home-naloxone (THN) provides an interesting case study on the international scene because of its specific history, regulation and trends in overdose (OD) rates. Accordingly, this study aims to contribute to the evidence base for THN and its delivery in a different setting.

Design/methodology/approach

The study focuses on service providers’ perceptions of the benefits, risks and barriers associated with THN provision. Data was collected using a mixed-methods approach as follows: an online structured questionnaire (no. of respondents = 63) and two focus groups (no. of total participants = 18).

Findings

Findings show that service providers believe the benefits of THN far outweigh the risks and accrue to services, as well as users. The study also suggests that the barriers in Italy are mostly ideological and political, and illustrates how resistance to administering THN can re-emerge when ODs are no longer a social emergency. Furthermore, the study found that health and social workers have different attitudes which are also reflected at the level of public and private services, thereby shaping slightly different models of THN supply.

Originality/value

The study suggests that barriers associated to THN are more ideological and political rather than concrete, which explains why, even where it seems long established, can easily re-emerge once ODs are no longer a social emergency.
Makin Dirasa Makin Terasa: the case of Mamart Food
Authors: Mohd Alwi Norhayati , Zainal Abidin Nor Hafizah , Mokhtar Norsyahida
Published: October 2021

Learning outcome

At the end of this case study, students should be able to identify issues relating to the external and internal environment of a business; explain how traditional marketing differ to social media marketing strategy and how digital marketing could be applied for frozen food company, identify alternatives to address the production capacity issue and challenges of contract manufacturing; identify and discuss measures that a company could adopt to effectively manage the working capital; apply various business management tools, concepts and theories in different decision-making settings – tools or concepts such as Porter’s five forces, SWOT analysis, PESTEL; and use analytical and logical skills through problem solving.

Case overview/synopsis

This case presents Khir, CEO of Mamart Food, facing several challenges in the post Covid-19 pandemic. Mamart Food is a SME manufacturing company located in Peninsular Malaysia. It competes in a frozen food industry. The case highlights the turbulence which Khir had to face due to the production capacity issue. He had the dilemma of balancing between the opportunity to boost sales and the capacity to meet demand. The dilemma emerged during the Movement Control Order in place and was expected to continue in the post MCO period. Quite a number of frustrated stockists over the unmet demand have started to aggressively voice out their dissatisfaction. Seeing the growing number of complaints, Khir had to act fast. Being the CEO, Khir must resolve the tension between Suliana, the production manager and Hisham, the sales and marketing manager. Failing which, it could be detrimental to the survival of Mamart Food. The most effective strategy for Mamart Food therefore needs to be formulated immediately.

Complexity academic level

This case is designed mainly for final year students in Accounting or Business undergraduate programmes.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Change tolerance, group focus and students' entrepreneurial intentions: does gender matter?
Authors: Haddad Gloria , Haddad Ghada , Nagpal Gautam
Published: October 2021

Purpose

This study examines the impact of cultural dimensions on entrepreneurial intentions (EIs) and the mediating role of planned behavior (TPB) determinants between change tolerance (CT), group focus (GF), and EIs for both men and women in the context of international business schools.

Design/methodology/approach

Using a quantitative research design, data were collected in France through anonymous questionnaires. The data consisted of responses from 480 business students. Structural equation modeling (SEM) and the bootstrap method with PROCESS macro were used to determine the significance of the mediation effects.

Findings

Results reveal the strong impact of CT on the EIs of both men and women through TPB antecedents. They also indicate that GF has an indirect effect on EIs through TPB antecedents for men and an indirect multiple mediation effect on EIs through CT and TPB antecedents for both men and women.

Originality/value

The extended TPB model is original in that it supports both the determinants of planned behavior and cultural dimensions and provides a valuable perspective through its findings on cultural and gender diversity in entrepreneurship.
Developing faithful stewardship for environment through green HRM
Authors: Ahmed Umair , Umrani Waheed Ali , Yousaf Amna , Siddiqui Muhammad Athar , Pahi Munwar Hussain
Published: October 2021

Purpose

This paper aims to assess the nexus between green human resource management (GHRM) practices, green culture, environmental responsibility and environmental performance (EP).

Design/methodology/approach

Using a supervisor-subordinated nested design and multi-time data collection approach through convenience sampling, the authors obtained 330 responses from 15 hotels operating in the metropolitan cities of Pakistan.

Findings

The study results indicate the prominence of GHRM practices toward enhancing hotels’ EP. The authors also found green culture and environmental responsibility as potential mediators in the direct association between GHRM and EP. In addition, the findings suggest that the GHRM and environmental association can be deeper when individuals exhibit green values and showcase green responsibility about their environment. Taken together, the findings of the present study found support for all direct and indirect hypothesized relationships hence, forwarding notable implications for theory and practice.

Research limitations/implications

This paper forwards both theoretical and practical implications. Drawing upon ability-motivation-opportunity (AMO) theory, this paper asserts that GHRM practices shall be used to improve EP through green values and environmental responsibility. The authors specifically suggest that pro-environment personnel practices can nourish green culture and a pro-environment sense of responsibility that facilitates in robust pro-environment results.

Originality/value

The study advances and addresses gaps found in prior studies to help support organizational scholars, practitioners and pro-environment enthusiasts to understand the interplay of GHRM, culture, responsibility and EP.
Crowd intelligence evolution based on complex network
Authors: Liu Jianran , Ji Wen
Published: October 2021

Purpose

In recent years, with the increase in computing power, artificial intelligence can gradually be regarded as intelligent agents and interact with humans, this interactive network has become increasingly complex. Therefore, it is necessary to model and analyze this complex interactive network. This paper aims to model and demonstrate the evolution of crowd intelligence using visual complex networks.

Design/methodology/approach

This paper uses the complex network to model and observe the collaborative evolution behavior and self-organizing system of crowd intelligence.

Findings

The authors use the complex network to construct the cooperative behavior and self-organizing system in crowd intelligence. Determine the evolution mode of the node by constructing the interactive relationship between nodes and observe the global evolution state through the force layout.

Practical implications

The simulation results show that the state evolution map can effectively simulate the distribution, interaction and evolution of crowd intelligence through force layout and the intelligent agents’ link mode the authors proposed.

Originality/value

Based on the complex network, this paper constructs the interactive behavior and organization system in crowd intelligence and visualizes the evolution process.
Internet of things challenges of sustainable supply chain management in the manufacturing sector using an integrated q-Rung Orthopair Fuzzy-CRITIC-VIKOR method
Authors: Yang Kaijun , Duan Tingting , Feng Jiaojiao , Mishra Arunodaya Raj
Published: October 2021

Purpose

The “Internet of Things (IoT)” is a platform for involving smart devices via the Internet at a worldwide scale. It supports the “supply chain (SC)” and “information and communication technology (ICT)” infrastructure to be well integrated into an organization and externally with customers and suppliers. The “sustainable supply chain (SSC)” is currently unavoidable if a company seeks to satisfy the aggressive change in its customers' requirements. Numerous studies have confirmed that manufacturing firms have to accelerate the shift of their focus toward sustainability and the implementation of novel technologies, such as IoT, to accomplish their organizational goals most effectively. Although the literature consists of many theoretical approaches to IoT and numerous studies that have extremely concentrated upon the IoT technology and its potential applications, it lacks research with a focus on the challenges that arise when applying IoT to the “sustainable supply chain management (SSCM)”.

Design/methodology/approach

The present study proposes an integrated framework using the “Criteria Importance Through Intercriteria Correlation (CRITIC)” and “VlseKriterijumska optimizcija I kaompromisno resenje in Serbian (VIKOR)” models and employs to evaluate the IoT challenges to implement the SSCM. For estimating the criteria weights, the CRITIC tool is utilized. The organization's prioritization is obtained by the VIKOR procedure, which delivers simple mathematical procedures with precise and consistent outcomes.

Findings

To exhibit the practicality of the introduced model, a case study is taken to evaluate the IoT challenges to implement the SSCM within the “q-Rung Orthopair Fuzzy Sets (q-ROFSs)” environment. Moreover, the authors exhibit a sensitivity investigation over given parameter values, examining the stability of developed approach. Finally, the authors draw attention to a comparison between developed q-ROF-CRITIC-VIKOR decision-making approach with an existing q-ROF-TOPSIS method to show its superiority and potency.

Originality/value

The outcome of the study lies in observing the top benefits of individual businesses, and their entire SSCs can be found by implementing IoT. This paper investigates the most important challenges that individual firms and entire SSCs might while applying IoT. It provides a deep insight regarding the effects of IoT upon SSCM and the issues every firm need to contemplate when it is to apply IoT solutions.
Elevation of circulating neutrophil extracellular traps, interleukin (IL)‐8, IL‐22, and vascular endothelial growth factor in patients with venomous snake mamushi (Gloydius blomhoffii) bites
Authors: Ogura Yasuaki , Fukuchi Kensuke , Morimoto Hiroki , Yuki Tsurumi , Otsuka Masaki , Shimauchi Takatoshi , Honda Tetsuya , Tokura Yoshiki
Published: October 2021

Mamushi bites cause swelling and pain that extend from the bitten site. The coagulopathic, anti‐coagulopathic, and vasculopathic actions of mamushi venom result in various laboratory abnormalities, occasionally with muscular, renal, and other organ damage. We investigated the serum biomarkers that were associated with the pathogenesis of mamushi bites, focusing on markers related to tissue‐damage and neutrophil activation. Twenty patients (one case of grade 2, 13 cases of grade 3, and six cases of grade 4 of severity) seen by us in one summer season were enrolled. Peripheral blood samples were taken from the patients on day 0, day 2, and day 7 after mamushi bites. In addition to routine blood examination, serum samples were subjected to enzyme‐linked immunosorbent assay for citrullinated histone H3 (CitH3), interleukin (IL)‐8, IL‐17A, IL‐22, vascular endothelial growth factor (VEGF), high mobility group box protein 1 (HMGB1), tumor necrosis factor (TNF)‐α, and IL‐33. Creatinine kinase (CK) values significantly correlated with prothrombin time (PT) levels, suggesting that muscular damage is associated with exaggerated coagulation and fibrinolysis. In the vast majority of patients, HMGB1, TNF‐α, and IL‐33 were under detection levels. Neutrophil counts did not correlate with PT or CK, indicating that the coagulation disorder and muscular damage were virtually independent of the neutrophil activation. The neutrophil number significantly correlated with CitH3, a representative marker of neutrophil extracellular traps. Moreover, there were significant correlations between neutrophil number, CitH3, IL‐8, IL‐22, and VEGF. Our study suggests that there are two major cascades in mamushi bites. One is an already characterized venom effect on coagulation, vessels, and muscles. In the other novel cascade, we propose that neutrophil activation with IL‐8 leads to the production of IL‐22 and VEGF. This sequential event may contribute to both vascular damage and repair.
Variation in plant carbon, nitrogen and phosphorus contents across the drylands of China
Authors: Xiong Junlan , Dong Longwei , Lu Jingli , Hu Weigang , Gong Haiyang , Xie Shubin , Zhao Dongmin , Zhang Yahui , Wang Xiaoting , Deng Yan , Ran Jinzhi , Niklas Karl J. , Degen Allan , Deng Jianming
Published: October 2021

Determining large‐scale patterns of plant elemental concentrations and stoichiometry along environmental gradients is critical for understanding plant adaptive strategies and predicting ecosystem biogeochemistry processes. However, it remains unclear as to how plant carbon (C), nitrogen (N) and phosphorus (P) concentrations and their stoichiometry in different organs (leaves, stems and roots) respond to large‐scale environmental gradients in drylands.

We determined C, N and P concentrations and their ratios in leaves, stems and roots of plants growing in the dryland ecosystems of China. Using threshold indicator taxa analyses, we identified indicator species of plant C, N and P responses to aridity and soil properties.

The arithmetic averaged concentrations of C, N and P in drylands were 414, 18.7 and 1.38 mg/g for leaves respectively; 445, 12.1 and 1.08 mg/g for stems respectively; and 418, 10.5 and 0.89 mg/g for roots respectively. The C:N, C:P and N:P ratios were 25.2, 386 and 16.3 for leaves respectively; 42.8, 592 and 14.8 for stems respectively; and 46.8, 658 and 15.6 for roots respectively. Aridity and soil pH generally exerted positive effects on plant N and negative effects on C and P concentrations and, thus, were related negatively to C:N ratios and positively to C:P and N:P ratios. The C, N and P concentrations in organs generally increased with increasing corresponding soil C, N and P concentrations. Shrubs were mainly positive indicators of plant C, N and P concentrations in response to aridity and soil pH, and negative indicators of soil nutrients. In contrast, herbaceous species were mainly positive indicators of soil nutrients and negative indicators of aridity and soil pH.

These findings indicate that plants tend to accumulate N rather than C and P with increasing aridity and soil pH. The identification of indicator species for plant elements in response to aridity and soil traits informs our understanding of species‐specific biogeographic patterns of organ elements and potential adaptive strategies of plants in drylands.

A free Plain Language Summary can be found within the Supporting Information of this article.
An ontology of water and land in North Bihar, India★
Authors: Cortesi Luisa
Published: October 2021

The floodplain of the Himalayas is a land formed and destroyed incessantly by the water of its rivers. Measures intended for flood control, aimed at separating productive land from river water through earth levees, have instead worsened the inundations, disrupting the beneficial flow of soil through floodwaters, obstructing water drainage, and resulting in enormous waterlogged areas. This article proposes that the failure of flood control in Bihar, India, is due to misunderstanding the river as a matter of water only, hence attempting the conceptual naturalization of an otherwise relative ontological distinction between water and land. Local knowledge of water reveals that neither water nor land can even be named, let alone understood, without the other. Informed by ethnographic fieldwork and multidisciplinary research in North Bihar, this article presents land and water as being in intimate correspondence with each other. By virtue of comparison, the ethnographic encounter is held to defy other ontologies of water that see the two substances as being in opposition. As a result, this article posits ontologies of natural substances as ‘watertight’, sclerotic, mutually exclusive, unable to adapt, and prone to be caught in a semiotic conflict.
The ‘Market’ in Criminal Law Theory
Authors: Farmer Lindsay
Published: October 2021

The market is central to the political liberalism at the heart of contemporary criminal law theory. But while it is assumed that we live in a market society, there is little reflection on what this means for criminal law, most criminal law theory barely acknowledging either market crimes or the market as an institution. This paper makes the case for criminal law theory to engage with the market and to reflect on the ways in which it shapes the role played by criminal law in a market society. By understanding the market as a form of social ordering it is possible to think more systematically about its relationship with the criminal law. The paper identifies how the criminal law has been central to the constitution and regulation of markets, before setting out four areas in which criminal law theory can critically engage with the place of markets in contemporary society.
Cart Challenges, Empirical Methods, and Effectiveness of Judicial Review
Authors: Barczentewicz Mikołaj
Published: October 2021

This paper considers methodological standards in public law scholarship, showing the perils of current issues with access to relevant data and the promise of what can be achieved using better data and computational methods. It focusses on the effectiveness of Cart challenges – the largest group of claims for judicial review in the High Court – and discusses how the empirical question of the effectiveness of judicial review is linked with the normative question of what counts as ‘success’. The article demonstrates the perils of inattention to data limitations in the analyses of Cart claims by the Independent Review of Administrative Law and by the government and shows the promise of better data and computational methods through an unprecedented empirical study of Upper Tribunal decisions that followed Cart judicial reviews. It concludes that the government's claim that Cart challenges are a disproportionate burden on resources lacks adequate empirical basis.
Cabinet ministers and inequality
Authors: ALEXIADOU DESPINA
Published: October 2021

Scholars and commentators increasingly wonder whether governments’ failure to address socio‐economic inequalities is the result of unequal representation. Recent literature on policy responsiveness in the United States and Europe finds evidence that party and parliamentary policy proposals and actual policy outcomes are closer to the preferences of the rich than of the poor. However, the extent and character of such unequal representation remains thinly understood. Among the most thinly understoodmechanismsare the political conditions that link socio‐economic inequalities to unequal representation. This paper thickens our understanding of (unequal) representation by investigating the class composition of parliamentary cabinets and its effect on social welfare policy. With the aid of a new dataset on cabinet ministers’ social class, the paper shows that responsiveness to the social welfare preferences of poorer voters varies by cabinet ministers’ professional backgrounds, above and beyond the partisan orientation of the government.
Acylated anthocyanins: A review on their bioavailability and effects on postprandial carbohydrate metabolism and inflammation
Authors: Jokioja Johanna , Yang Baoru , Linderborg Kaisa M.
Published: October 2021

Anthocyanins, the natural red and purple colorants of berries, fruits, vegetables, and tubers, improve carbohydrate metabolism and decrease the risk factors of metabolic disorders, but their industrial use is limited by their chemical instability. Acylation of the glycosyl moieties of anthocyanins, however, changes the chemical properties of anthocyanins and provides enhanced stability. Thus, acylated anthocyanins are more usable as natural colorants and bioactive components of innovative functional foods. Acylated anthocyanins are common in pigmented vegetables and tubers, the consumption of which has the potential to increase the intake of health‐promoting anthocyanins as part of the daily diet. For the first time, this review presents the current findings on bioavailability, absorption, metabolism, and health effects of acylated anthocyanins with comparison to more extensively investigated nonacylated anthocyanins. The structural differences between nonacylated and acylated anthocyanins lead to enhanced color stability, altered absorption, bioavailability, in vivo stability, and colonic degradation. The impact of phenolic metabolites and their potential health effects regardless of the low bioavailability of the parent anthocyanins as such is discussed. Here, purple‐fleshed potatoes are presented as a globally available, eco‐friendly model food rich in acylated anthocyanins, which further highlights the industrial possibilities and nutritional relevance of acylated anthocyanins. This work supports the academic community and industry in food research and development by reviewing the current literature and highlighting gaps of knowledge.
Extremophile enzymes for food additives and fertilizers
Authors: Ramos Juan L.
Published: October 2021

The use of extremophile enzymes for industrial purposes has become very significant since the beginning of this century and it is envisaged an ample use of enzymes for environmental applications (fertilisers, food and feed additives, biodegradation, pharma) as well as in the biosynthesis of compounds through design of novel biosynthetic pathways.
Prognostic impact of chronological age on efficacy of immune checkpoint inhibitors in non‐small‐cell lung cancer: Real‐world data from 86 173 patients
Authors: Takamori Shinkichi , Shimokawa Mototsugu , Komiya Takefumi
Published: October 2021

Immune checkpoint inhibitors (ICIs) have become standard pharmacological therapies in patients with non‐small‐cell lung cancer (NSCLC). Because elderly patients with NSCLC are often excluded from clinical trials as a result of lower functional capacity or comorbidities, the prognostic impact of chronological age on the efficacy of ICIs is unclear. The National Cancer Database was queried for stage IV NSCLC patients between 2014 and 2015. Associations between ICI therapy and clinical characteristics were assessed using chi‐squared tests. Kaplan–Meier curves were compared using the log‐rank test. A Cox proportional hazards model was used to identify clinical characteristics predictive of overall survival (OS). This study included 24 136 patients with stage IV NSCLC aged ≥75 years and 62 037 patients with stage IV NSCLC aged <75 years. Patients aged ≥75 years treated with ICIs had significantly longer OS than those not treated with ICIs (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.58–0.64, p < 0.0001). The corresponding HR in patients aged <75 years was 0.67 (95% CI 0.65–0.68, p < 0.0001). Cox modeling confirmed the survival benefit of ICI therapy in patients aged ≥75 years (HR for patients not receiving ICIs 1.63 [95% CI: 1.55–1.71], p < 0.0001). The corresponding HR in patients aged <75 years was 1.47 (95% CI 1.43–1.51, p < 0.0001). Chronological age does not appear to negatively impact the survival benefit of ICI therapy in patients with stage IV NSCLC according to this large real‐world database analysis.
Genetic liability for substance use associated with medical comorbidities in electronic health records of African‐ and European‐ancestry individuals
Authors: Hartwell Emily E. , Merikangas Alison K. , Verma Shefali S. , Ritchie Marylyn D. ,   Regeneron Genetics Center, Kranzler Henry R. , Kember Rachel L.
Published: October 2021

Polygenic risk scores (PRS) represent an individual's summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record‐based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N = 18,612). Finally, we conducted phenome‐wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross‐trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes; however, they are not yet predictive enough to be useful diagnostically. The cross‐trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse.
A retrospective case series on transvaginal repair of rectovaginal fistula performed by a urogynaecology operative team in Australia
Authors: Thayalan Krishanthy , Krause Hannah , Goh Judith
Published: October 2021

Background

Rectovaginal fistula (RVF) is an abnormal epithelialised connection between the rectum and vagina. It is a common condition in limited resource settings and is caused almost exclusively by obstetric injury. In contrast, RVF is uncommonly seen in high resource settings.

Aims

This study aims to review the aetiology and effectiveness of RVF management in the high resource setting, identifying predictors for repair success and long‐term outcomes.

Materials and Methods

A retrospective case series study of patients who underwent transvaginal RVF repairs at two secondary healthcare facilities over a 14‐year period by one operative group.

Results

A total of 41 patients underwent 46 surgical repairs. All patients presented with flatal and/or faecal incontinence and aetiology was identifiable in 78.0% (n = 32). Obstetric cause was implicated in 26.8% (n = 11) and other causes include 26.8% (n = 11) from vaginal and abdominal surgery, 14.6% (n = 6) from perianal abscess, 7.32% (n = 3) as complications of Crohn’s disease and 2.44% (n = 1) as a complication of a cube pessary. Fistula was cured in 38 of 41 cases (92.7%) with a primary repair closure rate of 80.5% (n = 33). Post‐operative symptoms were limited to flatal incontinence in 4.88% (n = 2), faecal incontinence in 2.44% (n = 1), and persistent perineal pain in 7.32% (n = 3). The success of the surgical repair was not significantly impacted by fistula size, aetiology, presence of a stoma for diversion, history of prior repair, duration since RVF formation or repair technique.

Conclusions

This review identifies aetiology for RVF in the high resource setting and highlights the role of earlier surgical repair to minimise patient morbidity with good success in closure and reduction of post‐operative symptoms.
Providing children with COVID‐19 vaccinations is challenging due to lack of data and wide‐ranging parental acceptance
Authors: She Jiatong , Liu lanqin , Liu Wenjun
Published: October 2021

Aim

Vaccines are vital to ending the COVID‐19 pandemic and we reviewed the data on vaccinating children, and including them in clinical trials, as most of the activity has focused on adults.

Methods

English and Chinese databases, including PubMed, Elsevier Scopus, Web of Science, CNKI and CQVIP were searched, along with websites such as the World Health Organization and the University of Oxford.

Results

We identified 44 papers and 16 news items about vaccinating children against the virus, published from 10 February 2020 to 14 July 2021. Child vaccination has been slow and only a few countries have included children in Phase II or III clinical trials. The data on children were much more limited than on adults, but most children were asymptomatic or had mild symptoms and some deaths had been recorded. More clinical trials are needed to assess the safety and efficacy of vaccinating children, as higher vaccination levels can help to build up herd immunity. The percentage of parents willing to vaccinate their children against the virus ranged from 48.2% to 72.6%, with much lower rates for letting them participate in clinical trials.

Conclusion

Vaccines should be offered to children as soon as their safety and efficacy are established.
Drivers of depositor discipline in credit unions
Authors: Gómez‐Biscarri Javier , López‐Espinosa Germán , Mesa‐Toro Andrés
Published: October 2021

In this paper, we analyze whether credit unions are subject to market discipline by their (member) depositors and examine the drivers of such discipline. We first provide descriptive evidence of depositor discipline in credit unions: shares and deposits as well as savings interest rates react to variables that reflect the financial health of the credit union and its asset risk. We show that this discipline is long‐lasting and that it is mediated by the existence of a deposit guarantee scheme and by the strength of the relationship of members with the credit union. We then use proxies of the capability of members to process financial information to show that discipline is heavily influenced by member financial sophistication. Our results suggest that a type of market‐based discipline acts as a complement for regulation in controlling credit union risk taking, thus contributing to overall financial stability.
Management of chronic primary pelvic pain syndromes
Authors: Parsons Brian A. , Baranowski Andrew P. , Berghmans Bary , Borovicka Jan , Cottrell Angela M. , Dinis‐Oliveira Paulo , Elneil Sohier , Hughes John , Messelink Bert E. J. , de C Williams Amanda C. , Abreu‐Mendes Pedro , Zumstein Valentin , Engeler Daniel S.
Published: October 2021

Management of chronic pelvic pain (CPP) remains a huge challenge for care providers and a major burden for healthcare systems. Treating chronic pain that has no obvious cause warrants an understanding of the difficulties in managing these conditions. Chronic pain has recently been accepted as a disease in its own right by the World Health Organization, with chronic pain without obvious cause being classified as chronic primary pain. Despite innumerable treatments that have been proposed and tried to date for CPP, unimodal therapeutic options are mostly unsuccessful, especially in unselected individuals. In contrast, individualised multimodal management of CPP seems the most promising approach and may lead to an acceptable situation for a large proportion of patients. In the present review, the interdisciplinary and interprofessional European Association of Urology Chronic Pelvic Pain Guideline Group gives a contemporary overview of the most important concepts to successfully diagnose and treat this challenging disease.
Temporal stability in species richness but reordering in species abundances within avian assemblages of a tropical Andes conservation hot spot
Authors: Tinoco Boris A. , Latta Steven C. , Astudillo Pedro X. , Nieto Andrea , Graham Catherine H.
Published: October 2021

As the pace of environmental change increases, there is an urgent need for quantitative data revealing the temporal dynamics of local communities in tropical areas. Here, we quantify the stability of avian assemblages in the highly threatened, but poorly studied, Andean biodiversity hot spot. We evaluated the temporal variation in species richness and community composition of local bird assemblages in three habitat types (native forest, introduced forest, native shrub) using a unique, relatively long‐term data series from Cajas National Park and Mazán Reserve in the southern Andes of Ecuador. We sampled birds with mist nets using a standardized protocol over 11 years, from 2006 to 2016. Species richness remained stable over time across habitats, but community composition changed in the native forest. In particular, we observed taxonomic reordering in the native forest, in which the evenness in the distribution of abundances of taxa decreased over time. This finding is consistent with other studies where species richness remained constant over time while community composition changed. Our study highlights the value of long‐term studies in the tropical Andes as we show that species composition of birds in a montane forest is changing, consistent with global trends in biodiversity change.

Abstract in Spanish is available with online material.
Long‐term health outcomes in young women with polycystic ovary syndrome: A narrative review
Authors: Allen Lowri A. , Shrikrishnapalasuriyar Natasha , Rees Dafydd Aled
Published: October 2021

Polycystic ovary syndrome (PCOS) has long been recognized as a common disorder in young women leading to reproductive and cutaneous sequelae. However, the associated health risks are now known to extend beyond these familiar manifestations to a range of longer‐term comorbidities. Here we review the evidence for an association of PCOS with adverse long‐term health outcomes, discussing the pathophysiological mechanisms involved in addition to opportunities for therapeutic intervention. Cross‐sectional and longitudinal studies point to an increased risk of type 2 diabetes, hypertension and dyslipidaemia, with recent data confirming that these translate to an increased risk of cardiovascular events independently of obesity. Obstructive sleep apnoea, nonalcoholic fatty liver disease and endometrial cancer are also more prevalent, while mental health disorders, notably anxiety and depression, are common but under‐appreciated associations. Uncertainties remain as to whether these risks are apparent in all patients with PCOS or are confined to particular subtypes, whether risks persist post‐menopausally and how risk may be affected by ethnicity. Further work is also needed in establishing if systematic screening and targeted intervention can lead to improved outcomes. Until such data are available, clinicians managing women with PCOS should counsel patients on long‐term health risks and invest in strategies that limit progression to metabolic and non‐metabolic morbidities.
Runx3 regulates iron metabolism via modulation of BMP signalling
Authors: Kim Hyun‐Yi , Lee Jong‐Min , Lee You‐Soub , Li Shujin , Lee Seung‐Jun , Bae Suk‐Chul , Jung Han‐Sung
Published: October 2021

Objectives

Runx3, a member of the Runx family of transcription factors, has been studied as a tumour suppressor and key player of organ development. In a previous study, we reported differentiation failure and excessive angiogenesis in the liver of Runx3 knock‐out (KO) mice. Here, we examined a function of the Runx3 in liver, especially in iron metabolism.

Methods

We performed histological and immunohistological analyses of the Runx3 KO mouse liver. RNA‐sequencing analyses were performed on primary hepatocytes isolated from Runx3 conditional KO (cKO) mice. The effect of Runx3 knock‐down (KD) was also investigated using siRNA‐mediated KD in functional human hepatocytes and human hepatocellular carcinoma cells.

Result

We observed an iron‐overloaded liver with decreased expression of hepcidin in Runx3 KO mice. Expression of BMP6, a regulator of hepcidin transcription, and activity of the BMP pathway were decreased in the liver tissue of Runx3 KO mice. Transcriptome analysis on primary hepatocytes isolated from Runx3 cKO mice also revealed that iron‐induced increase in BMP6 was mediated by Runx3. Similar results were observed in Runx3 knock‐down experiments using HepaRG cells and HepG2 cells. Finally, we showed that Runx3 enhanced the activity of the BMP6 promoter by responding to iron stimuli in the hepatocytes.

Conclusion

In conclusion, we suggest that Runx3 plays important roles in iron metabolism of the liver through regulation of BMP signalling.
Histopathologic features of inverse psoriasis
Authors: Knabel Michael , Mudaliar Kumaran
Published: October 2021

Background

Inverse psoriasis represents a less commonly described form of psoriasis in intertriginous areas. The pathologic findings of inverse psoriasis are typically grouped in with those of plaque psoriasis, as the histopathologic features specific to inverse psoriasis have not received significant investigation.

Methods

A single institution, retrospective cohort study was performed to review biopsy slides for psoriasis occurring in typical intertriginous areas. Patient's charts were reviewed and only those where the clinical diagnosis of inverse psoriasis was also favored were included.

Results

Twelve patients met inclusion criteria: 58% male and 42% female, 18 to 86 years of age. Classic features of psoriasis such as hypogranulosis, confluent parakeratosis, and thinning of the suprapapillary plate were seen in 100%. Regular psoriasiform acanthosis and dilated tortuous dermal vessels were seen in 92%. Neutrophils were present in the scale in 83% and in the dermis in 100%. Features considered atypical for psoriasis included spongiosis in 83%, eosinophils in 67%, and focal serum in the scale in 42%.

Conclusions

While inverse psoriasis commonly exhibits features considered to be classic for psoriasis, it is not unusual for inverse psoriasis to show features considered atypical for plaque psoriasis such as dermal eosinophils, epidermal spongiosis, and focal serum in the scale.
Next‐generation sequencing confirms T‐cell clonality in a subset of pediatric pityriasis lichenoides
Authors: Raghavan Shyam S. , Wang Jennifer Y. , Gru Alejandro A. , Marqueling Ann L. , Teng Joyce M.C. , Brown Ryanne A. , Novoa Roberto A. , Kim Youn , Zehnder James , Zhang Bing Melody , Rieger Kerri E.
Published: October 2021

Background

Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T‐cell populations via PCR‐based assays. In this study, we sought to implement next‐generation sequencing (NGS) as a more sensitive and specific test to examine for T‐cell clonality within the pediatric population.

Methods

We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with NGS of T‐cell receptor beta (TRB) and gamma (TRG) genes.

Results

Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow‐up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T‐cell clonality. Two patients showed matching TRB clones from different anatomic sites.

Conclusions

T‐cell clonality is a common finding in PL, probably representing a “reactive clonality” rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma.