bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryo-EM analyses of wild-type and oncogenic KIT mutants reveal structural oncogenic plasticity and a novel “Achilles heel” for therapeutic intervention
Authors: Krimmer Stefan G. , Bertoletti Nicole , Suzuki Yoshihisa , Katic Luka , Mohanty Jyotidarsini , Shu Sheng , Lee Sangwon , Lax Irit , Mi Wei , Schlessinger Joseph
Published: September 2022

The receptor tyrosine kinase KIT and its ligand SCF are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo-EM structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the symmetric arrangement of ligand-occupied KIT dimers is converted into asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an “Achilles heel” for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. SCF binding to this mutant fully restores the conformation of wild-type KIT dimers, revealing an unexpected structural plasticity of oncogenic mutants that may offer new therapeutic modality.
Camellia sinensis solvent extract confers trophocidal and cysticidal effects against Acanthamoeba castellanii
Authors: Fakae Lenu B. , Harun Mohammad S. R. , Ting Darren Shu Jeng , Dua Harminder S. , Cave Gareth W.V. , Zhu Xing-Quan , Stevenson Carl W. , Elsheikha Hany M.
Published: September 2022

Aim

We examined the anti-acanthamoebic efficacy of solvent extract of C. sinensis) and its chemical constituents against trophozoites and cysts of A. castellanii.

Materials and methods

The effects of C. sinensis solvent extract on A. castellanii was investigated by using anti-trophozoite, anti-encystation, and anti-excystation assays. The solvent extract was also fractionated using Gas Chromatography and the chemical constituents of C. sinensis were tested, individually or combined, against the trophozoites.

Results

Trophozoite replication was inhibited within 24-72 h with exposure to 625-5000 µg/mL of C. sinensis solvent extract. C. sinensis also exhibited a dose-dependent inhibition of encystation, with a marked cysticidal activity at 2500-5000 µg/mL concentrations. Two constituents of C. sinensis, namely epigallocatechin-3-gallate and caffeine, significantly inhibited trophozoite replication and encystation at 100 μM and 200 μM, respectively. Cytotoxicity analysis showed that 156.25-2500 µg/mL of solvent extract was not toxic to human corneal epithelial cells, while up to 625 µg/mL was not toxic to Madin-Darby Canine Kidney cells.

Conclusions

This study shows the anti-acanthamoebic potential of C. sinensis solvent extract against trophozoites and cysts. Further pre-clinical studies are required to elucidate the in vivo efficacy and safety of C. sinensis solvent extract.

Graphical abstract
Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders
Authors: Leung Calvin S. , Rosenzweig Shoshanna , Yoon Brian , Marinelli Nicholas A. , Hollingsworth Ethan W. , Maguire Abbie M. , Cowen Mara M. , Schmidt Michael , Imitola Jaime , Gamsiz Uzun Ece D. , Lizarraga Sofia B.
Published: September 2022

Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.
Genetic Risk Factors for ME/CFS Identified using Combinatorial Analysis
Authors: Das Sayoni , Taylor Krystyna , Kozubek James , Sardell Jason , Gardner Steve
Published: September 2022

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients.

Methods

We applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case-control design with 1,000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and results compared for overlap and reproducibility.

Results

Combinatorial analysis revealed 199 SNPs mapping to 14 genes, that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3-5 SNPs. p-values for these communities range from 2.3 × 10−10 to 1.6 × 10−72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS.

Conclusions

This study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients.
Awareness and practice of the principles of circular economy among built environment professionals
Authors: Amudjie Judith , Agyekum Kofi , Adinyira Emmanuel , Amos-Abanyie Samuel , Kumah Victoria Maame Afriyie
Published: September 2022

Purpose

This study examines the level of awareness and practice of the principles of circular economy (CE) among built environment (BE) professionals in Ghana.

Design/methodology/approach

A structured questionnaire survey was used to solicit the views of 162 BE professionals working in construction, consulting and developer firms on the issue under investigation. Data were analysed through descriptive and inferential analysis.

Findings

The findings revealed that the BE professionals possessed moderate awareness of the six CE principles (i.e. repair, recycle, reuse, renewable energy usage, reduce and redesign) examined. The findings further revealed that only two out of the six principles (i.e. repair and reuse) received some moderate level of practice among the professionals.

Practical implications

Practically, the findings would be relevant to government, policymakers, researchers and other construction professionals. For the government and policymakers, these findings would inform them on the laws and policies to enact to increase awareness and practice of CE principles. For researchers, these findings will assist in exploring gaps for further studies. For the construction professionals, the findings would inform them of the need to step up measures to practice the various principles of CE in their firms adequately.

Originality/value

This study provides insights into an under-investigated topic in the construction industry worldwide. It offers new and additional insights into the current state-of-the-art practice of CE principles among BE professionals.
Chinese multinationals post-merger integration evolutions in developed markets from autonomy to actual-form integration: a lens of ambidexterity
Authors: Yang Yanan
Published: September 2022

Purpose

This paper aims to examine how Chinese multinational enterprises’ (CMNEs) autonomy-style post-merger integration (PMI) modes of managing developed-market targets evolve into actual-form integration through the lens of ambidexterity.

Design/methodology/approach

This study adopts multi-case comparisons with content analysis. A data set was collected from 37 conversations by in-depth interviewing 29 respondents regarding four cases of Chinese acquisitions in the German market.

Findings

This study develops a three-stage framework that theorised CMNEs’ autonomy PMIs’ evolution to actual-form integration over time and the effect on acquisition value based on structural, temporal and contextual ambidexterity manifestations. The findings divide the evolutionary trajectory into two sub-trajectories, from great autonomy to autonomy-integration balanced or full integration, to illuminate the effect of different degrees of actual-form integration on value creation or value destruction.

Originality/value

The existing literature on CMNEs’ PMI discovered that CMNEs frequently grant ample autonomy when managing targets acquired from developed markets. However, long-term acquisition benefit is dependent on combining autonomy and actual-form integration; insights into how this can be accomplished are limited. The research is unique in that it reveals the evolutions of CMNEs’ PMIs on developed-market targets, from autonomy to actual-form integration through the lens of ambidexterity.
Industry 4.0 in industrial district SMEs: understanding collective knowledge transfer by research and transfer institutes
Authors: Hervas-Oliver Jose-Luis
Published: September 2022

Purpose

This paper aims to understand the contribution of research and transfer institutes (RTIs) to digitising in traditional Marshallian industrial districts (IDs). This study answers how to digitise small and medium-size enterprises (SMEs) in IDs capitalising on RTIs? As collective actors, RTIs introduce change in local/regional innovation systems where they are embedded.

Design/methodology/approach

This paper uses qualitative evidence based on interviews and secondary data analysis on digitising the Vinalopo Footwear district in Spain.

Findings

This paper provides empirical insights about how RTIs perform research and development (R&D) and non-R&D activities to digitise, facilitated by leading firms that frequently engage with RTIs. Subsequently, leading firms interact and diffuse Industry 4.0 within their networks of SMEs. RTIs activate digitising in districts avoiding the manifested reluctance of SMEs to engage with them, capitalising on leading firms’ networks orchestration.

Research limitations/implications

Because of the chosen research approach, the findings are limited to the chosen setting and method.

Practical implications

This paper includes implications for policymakers, responding to the paradox of how to activate knowledge transfer from RTIs to SMEs, when the latter are reluctant to use RTIs.

Originality/value

This paper fulfils an identified need to study how to digitise IDs and clusters.
Serial robotic plasma additive manufacturing on complex NURBS surface
Authors: Wang Zhaoqin , Shi Yu , Wang Xiaorong
Published: September 2022

Purpose

This paper aims to investigate the additive manufacturing (AM) approach of a spatial complex curve feature (SCCF, mapped from two-dimensional nonuniform rational B-splines [2D-NURBS] curve) on a complex surface based on a serial robot using plasma built-up welding, and lays a foundation for plasma AM SCCFs on complex surfaces by combining the NURBS theory with the serial robotic kinematics.

Design/methodology/approach

Combining serial robotic kinematics and NURBS theory, a SCCF mapped from a square-like 2D-NURBS curve is prepared on a predefined complex NURBS surface using serial robotic plasma AM. The interpolation points C (ui) on the square-like 2D-NURBS curve are obtained using the equi-chord length interpolation method, and mapped on a predefined NURBS surface to get mapped points S (ui, vj). The homogeneous transformation matrix T = [n o a S (ui, vj)] of the plasma torch is calculated using the mapped points S (ui, vj) and the designated posture [n o a]. Using the inverse kinematics of the serial robot, the joint vector θ of the serial robot can be computed. After that, the AM programs are generated and transferred into the serial robotic controller and carried out by the serial robot of Motoman-UP6. The 2D-NURBS curve (square-like) is considered as AM trajectory planning curve, while its corresponding SCCF mapped from the 2D-NURBS curve as AM trajectory.

Findings

Simulation and experiments show that the preparation of SCCF (mapped from 2D-NURBS curve) on complex NURBS surface using robotic plasma AM is feasible and effective.

Originality/value

A SCCF mapped from a 2D-NURBS curve is prepared on a complex NURBS surface using the serial robotic plasma AM for the first time. It provides a theoretical and technical basis for plasma AM to produce SCCFs on complex surfaces. With the increasing demand for surface remanufacturing of complex parts, the serial robotic plasma AM of SCCFs on complex NURBS surfaces has a broad application prospect in aero-engine components, high-speed rail power components, nuclear industry components and complex molds.
The organizational culture of scale-ups and performance
Authors: Strengers Julia , Mutsaers Leonie , van Rossum Lisa , Graamans Ernst
Published: September 2022

Purpose

Scale-ups have a crucial role in our society and economy, are known for their fast growth and high performance and undergo significant organizational change. Research on the organizational elements that ensure scale-ups sustaining high performance is limited. This empirical study aims to investigate the organizational culture in scale-ups using the Competing Values Framework, including the clan, adhocracy, the market, hierarchy cultures and its relation to performance.

Design/methodology/approach

Quantitative and qualitative data were collected in five scale-ups. Surveys provided data of 116 employees on organizational culture, assessed using the Organizational Culture Assessment Instrument (OCAI) and perceived performance. The aggregate outcomes and performance measures were analyzed using correlation analysis. Interviews were held with ten top managers and mirrored against the quantitative data.

Findings

The results show that top managers and employees have different perspectives on the culture scale-ups are supposed to have. Top managers perceive market culture as more and hierarchy culture as less present in their organizations than employees. The clan and adhocracy culture are positively correlated to performance and are preferred by employees. Market and hierarchy culture types are negatively correlated to performance and are least preferred by employees.

Research limitations/implications

It enables scale-up leaders to specifically intervene when cultural elements are experienced by employees that will not drive performance and fit the high performance and fast-growing scale-up environment.

Originality/value

This study is the first that showed that organizational-wide surveys, combined with in-depth interviews, are suitable for top managers of scale-ups to diagnose the organizational culture and the effect on the organization's performance.
Bringing a background variable into focus: a multimethod investigation of IT security climate’s influence on elicited IT security beliefs
Authors: Warner Janis , Wipawayangkool Kamphol
Published: September 2022

Purpose

IT security breaches plague organizations worldwide, yet there continues to be a paucity of comprehensive research models for protective technologies. This study aims to develop an IT security user behavior model focusing on the protective technology anti-spyware which includes organizational climate, a theory of planned behavior (TPB) background variable and elicited salient user beliefs.

Design/methodology/approach

A multimethod approach, including interviews and a survey, is used to elicit salient user beliefs and test hypotheses of the influences of perceived IT security climate on those user beliefs and ultimately user behavioral intentions. Primary data were collected through interviews following the prescribed TPB methodology and an offline survey method with 254 valid responses recorded. Partial least squares was used to investigate the hypotheses.

Findings

The authors found that attitudinal beliefs – protecting organizational interests for data/privacy, preventing disruptions to work and control beliefs – monetary resources and time constraints mediate significant relationships between IT security climate and attitude and perceived behavioral control, respectively. Implications are discussed.

Originality/value

This study is the first, to the best of the authors’ knowledge, that uses both interviews and a survey to examine the relationships among IT security climate, elicited user beliefs and behavioral intentions in a TPB-based model for a protective technology.
Positive affective tone as an underlying mechanism between leader's motivating language and career outcomes
Authors: Syed Fauzia , Naseer Saima , Bashir Fatima , Fatima Tasneem
Published: September 2022

Purpose

Recent evidence suggests that leaders' communication is central to an organization's success. The purpose of the current research is to examine how the leader's motivating language (direction giving, empathetic and meaning-making) translates into positive career outcomes through the mechanism of positive affective tone.

Design/methodology/approach

A three-wave time-lagged research design was applied to collect data (N = 320) from employees of the telecom sector of Pakistan.

Findings

Employing structural equation modeling (SEM) analysis, the study results indicate that high levels of leader's motivating language (direction giving and meaning-making) result in positive affective tone in employees, which further creates career motivation (career insight, career resilience and career identity) and career satisfaction. In contrast, positive affective tone does not mediate between empathetic language and career motivation (career insight, career resilience and career identity) and career satisfaction relationship.

Research limitations/implications

The present study's findings explicate the unique effects and mechanism through which leaders motivating language becomes influential in reaping its benefits for followers' career outcomes. More research is warranted to examine other attitudinal and behavioral outcomes of leaders motivating language. This study research prepares future researchers to investigate other mediators and moderators in the leaders motivating language–career outcomes relationship. The authors recommend further implications of the study's findings for research and practice in the domain of leadership, affect and careers.

Originality/value

The current study opens up a new perspective in leaders motivating language literature by examining the underlying mechanism of positive affective tone.
Exploring third-party’s brand rankings from consumers’ persuasion knowledge
Authors: Huang Li-Shia , Huang Wan-Ju , Lin Hsiao-Yun
Published: September 2022

Purpose

Given the importance of third-party endorsements as external cues during purchase evaluations, the manipulation of endorsements may raise consumers’ suspicion and thereby reduce the effectiveness of marketing messages. Consumers find it increasingly difficult to distinguish between authentic and biased brand reviews. This research conducts two experiments regarding brand rankings of third-parties in four industries. Study 1 aims to probes the interaction effect of persuasion knowledge and fairness of rating method (fair vs. unfair) on brand rankings’ credibility and brand image enhancement. Study 2 examines the interplay of dispositional persuasion knowledge and reputation of third parties (high vs. low).

Design/methodology/approach

This research builds on an analysis of data (Study 1, N = 122; Study 2, N = 123) from Taiwan, where brand rankings held by third-party organizations are regular. The hypotheses were tested using SPSS’s PROCESS macro.

Findings

Drawing on previous research of persuasion knowledge, the authors find that a fair rating method and a high reputation of third-party organization can mitigate the negative effect of persuasion knowledge.

Practical implications

The results of this research suggest that marketers need to manage third-party endorsements carefully. Consumer skepticism toward these endorsements (e.g. third-party’s brand rankings) can be weakened when persuasion attempt is considered appropriate.

Originality/value

This is one of the first efforts to empirically explore the influences of persuasion knowledge on third-party endorsements. The importance of this work is underscored by the fact that a growing number of third-party endorsements are sponsored or even manipulated by brand owners.
Configurational path of successful entrepreneurship based on open government data: a QCA analysis
Authors: Zhang Han , Kang Fei , Li Huiying
Published: September 2022

Purpose

In the era of big data, data have become an essential factor of production. In the context of open government data (OGD), encouraging the commercial development of OGD is significant for promoting mass innovation and entrepreneurship. This study aims to explore the configurational impact of data supply, external environment and entrepreneurial foundation on data-driven entrepreneurship.

Design/methodology/approach

This research used a fuzzy set qualitative comparative analysis (fsQCA). Fourteen start-ups using OGD were taken as a case sample.

Findings

This study produces two paths to achieving high entrepreneurial performance, one is a financing-enhanced entrepreneurial path and the other is a data-driven entrepreneurial path. Besides, four conditions are necessary for high performance of OGD-based entrepreneurship: good data quality, mature legal environment, favorable market environment and abundant big data entrepreneurial talents.

Practical implications

The findings have important practical implications for formulating policies related to promoting the application of government open data and innovation and entrepreneurship in terms of strengthening top-level design, improving the legal environment, developing the data market and cultivating entrepreneurial talents.

Originality/value

Although many studies have been conducted on OGD, studies on the paths to successful entrepreneurship based on OGD are limited. In this study, this issue is investigated from a configurational perspective by using the fsQCA technique.
A gain of function ryanodine receptor 2 mutation (R1760W‐RyR2) in catecholaminergic polymorphic ventricular tachycardia
Authors: Li Siyuan , Lv Tingting , Yang Jing , Li Kun , Yang Ying , Zhang Ping
Published: September 2022

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with Ca2+ leak predominantly caused by ryanodine receptor 2 (RyR2) mutations. We identified a R1760W‐RyR2 mutation located between the N‐terminal domain and the central domain of RyR2 in a CPVT patient by DNA sequencing. Recombinant mutant RyR2−2801mcherry plasmid generated by the overlap extension polymerase chain reaction and seamless cloning was transfected in HEK293 cells for the cell model. Single‐cell luminal and cytosolic Ca2+ imaging was measured by endoplasmic reticulum (ER) luminal Ca2+‐sensitive protein D1ER and Fura‐2 AM on a confocal laser scanning microscope, respectively. We found that in RyR2 mutant cells, the propensity for store‐overload‐induced Ca2+ release (SOICR) was enhanced representing increased Ca2+ oscillations, reduced activation and termination thresholds of spontaneous Ca2+ release; and the sensitivity to cytosolic Ca2+ activation was increased manifesting reduced steady state ER Ca2+ levels. Our results indicated that R1760W‐RyR2 mutation induced calcium leak, representing a gain of function. Further, antiarrhythmic drugs propafenone and flecainide significantly suppressed SOICR caused by the R1760W‐RyR2 mutation at a concentration of 20 μM, which was lower than the concentration at which carvedilol suppressed SOICR.
Rural primary care workforce views on trauma‐informed care for parents experiencing complex trauma: A descriptive study
Authors: Reid Carol , Bennetts Shannon K. , Nicholson Jan M. , Amir Lisa H. , Chamberlain Catherine
Published: September 2022

Background

An important service system for rural parents experiencing complex trauma is primary health care.

Aim

To investigate workforce knowledge, attitudes and practices, and barriers and enablers to trauma‐informed care in rural primary health care.

Material & Methods

This study used a descriptive, cross‐sectional design. It involved an on‐line survey conducted in 2021 in rural Victoria, Australia. Participants were the primary health care workforce. The main outcome measures were study‐developed and included, a 21‐item Knowledge, Attitudes and Practices tool, a 16‐item Barriers and Enablers to Trauma‐Informed Care Implementation tool, and three open‐ended questions.

Results

The 63 respondents were from community health (n = 40, 63%) and child and family services (n = 23, 37%). Many (n = 43, 78%) reported undertaking trauma‐informed care training at some point in their career; with 32% (n = 20) during higher education. Respondents self‐rated their knowledge, attitudes and practices positively. Perceived enablers were mainly positioned within the service (e.g. workforce motivation and organisational supports) and perceived barriers were largely external structural factors (e.g. availability of universal referral pathways, therapeutic‐specific services). Open‐ended comments were grouped into four themes: (1) Recognition and understanding; (2) Access factors; (3) Multidisciplinary and collaborative approaches; and (4) Strengths‐based and outcome‐focused approaches.

Discussion & Conclusion

Primary health care is an important driver of population health and well‐being and critical in rural contexts. Our findings suggest this sector needs a rural trauma‐informed care implementation strategy to address structural barriers. This also requires policy and system development. Long‐term investment in the rural workforce and primary care service settings is essential to integrate trauma‐informed care.
Impact of COVID‐19 on the management and outcomes of ureteric stones in the UK: a multicentre retrospective study
Authors: Byrne Matthew H.V. , Georgiades Fanourios , Light Alexander , Lovegrove Catherine E. , Dominic Catherine , Rahman Josephine , Kathiravelupillai Senthooran , Klatte Tobias , Saeb‐Parsy Kasra , Kumar Rajeev , Howles Sarah , Stewart Grant D. , Turney Ben , Wiseman Oliver ,   the COVID Stones Collaborative
Published: September 2022

Objectives

To determine if management of ureteric stones in the UK changed during the coronavirus disease 2019 (COVID‐19) pandemic and whether this affected patient outcomes.

Patients and methods

We conducted a multicentre retrospective study of adults with computed tomography‐confirmed ureteric stone disease at 39 UK hospitals during a pre‐pandemic period (23/3/2019–22/6/2019) and a period during the pandemic (the 3‐month period after the first severe acute respiratory syndrome coronavirus‐2 case at individual sites). The primary outcome was success of primary treatment modality, defined as no further treatment required for the index ureteric stone. Our study protocol was published prior to data collection.

Results

A total of 3735 patients were included (pre‐pandemic 1956 patients; pandemic 1779 patients). Stone size was similar between groups (P > 0.05). During the pandemic, patients had lower hospital admission rates (pre‐pandemic 54.0% vs pandemic 46.5%, P < 0.001), shorter mean length of stay (4.1 vs 3.3 days, P = 0.02), and higher rates of use of medical expulsive therapy (17.4% vs 25.4%, P < 0.001). In patients who received interventional management (pre‐pandemic 787 vs pandemic 685), rates of extracorporeal shockwave lithotripsy (22.7% vs 34.1%, P < 0.001) and nephrostomy were higher (7.1% vs 10.5%, P = 0.03); and rates of ureteroscopy (57.2% vs 47.5%, P < 0.001), stent insertion (68.4% vs 54.6%, P < 0.001), and general anaesthetic (92.2% vs 76.2%, P < 0.001) were lower. There was no difference in success of primary treatment modality between patient cohorts (pre‐pandemic 73.8% vs pandemic 76.1%, P = 0.11), nor when patients were stratified by treatment modality or stone size. Rates of operative complications, 30‐day mortality, and re‐admission and renal function at 6 months did not differ between the data collection periods.

Conclusions

During the COVID‐19 pandemic, there were lower admission rates and fewer invasive procedures performed. Despite this, there were no differences in treatment success or outcomes. Our findings indicate that clinicians can safely adopt management strategies developed during the pandemic to treat more patients conservatively and in the community.
Modulation of the mammalian GABAA receptor by type I and type II positive allosteric modulators of the α7 nicotinic acetylcholine receptor
Authors: Arias Hugo R. , Germann Allison L. , Pierce Spencer R. , Sakamoto Seiji , Ortells Marcelo O. , Hamachi Itaru , Akk Gustav
Published: September 2022

Background and Purpose

Positive allosteric modulators of the α7 nicotinic acetylcholine (nACh) receptor (α7‐PAMs) possess promnesic and procognitive properties and have potential in the treatment of cognitive and psychiatric disorders including Alzheimer's disease and schizophrenia. Behavioural studies in rodents have indicated that α7‐PAMs can also produce antinociceptive and anxiolytic effects that may be associated with positive modulation of the GABAA receptor. The overall goal of this study was to investigate the modulatory actions of selected α7‐PAMs on the GABAA receptor.

Experimental Approach

We employed a combination of cell fluorescence imaging, electrophysiology, functional competition and site‐directed mutagenesis to investigate the functional and structural mechanisms of modulation of the GABAA receptor by three representative α7‐PAMs.

Key Results

We show that the α7‐PAMs at micromolar concentrations enhance the apparent affinity of the GABAA receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi‐effective at binary αβ and ternary αβγ GABAA receptors. Functional competition and site‐directed mutagenesis indicate that the α7‐PAMs bind to the classic anaesthetic binding sites in the transmembrane region in the intersubunit interfaces, which results in stabilization of the active state of the receptor.

Conclusion and Implications

We conclude that the tested α7‐PAMs are micromolar‐affinity, intermediate‐ to low‐efficacy allosteric potentiators of the mammalian αβγ GABAA receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABAA receptors to α7‐PAMs, we propose that doses used to produce nACh receptor‐mediated behavioural effects in vivo are likely to modulate GABAA receptor function.
Real‐world usage of sulphonylureas in Asian patients with type 2 diabetes using the Joint Asia Diabetes Evaluation (JADE) register
Authors: Lim Lee‐Ling , Lau Eric S. H. , Cheung Johnny T. K. , Chan Siew Pheng , Ji Linong , Lim Soo , Sirinvaravong Sirinart , Unnikrishnan A. G. , Luk Andrea O. Y. , Cortese Viviana , Durocher Alexandra , Chan Juliana C. N.
Published: September 2022

Aims

To explore the patterns of use of oral glucose‐lowering drugs (OGLDs) in Asian patients with type 2 diabetes (T2D), focusing on sulphonylureas (SUs), and to describe patient profiles according to treatment regimen.

Methods

We conducted a cross‐sectional analysis of data from adults with T2D from 11 Asian countries/regions with structured assessment enrolled in the prospective Joint Asia Diabetes Evaluation (JADE) register between November 2007 and December 2019. Patients receiving insulin and/or injectable glucagon‐like peptide‐1 receptor agonists were excluded.

Results

Amongst 62 512 patients (mean ± standard deviation age: 57.3 ± 11.8 years; 53.6% men), 54 783 (87.6%) were treated with OGLDs at enrolment. Most received one (37.5%) or two (44.2%) OGLDs. In the entire cohort, 59.4% of treated patients received SU‐based therapy with variations amongst countries/regions. Overall, 79.5% of SU regimens were based on SUs plus metformin, and 22.1% on SUs plus dipeptidyl peptidase‐4 inhibitors. Among SU users, gliclazide was most commonly prescribed (46.7%), followed by glimepiride (40.0%) and glibenclamide (8.1%). More gliclazide users entered the cohort with glycated haemoglobin levels <53 mmol/mol (7%) than non‐gliclazide SU users (odds ratio [OR] 1.09, 95% CI 1.02‐1.17), with less frequent self‐reported hypoglycaemia in the 3 months before registration (OR 0.81, 95% CI 0.72‐0.92; adjusted for sociodemographic factors, cardiometabolic risk factors, complications, use of other OGLDs, country/region and year of registration).

Conclusion

In Asia, SUs are a popular OGLD class, often combined with metformin. Good glycaemic control and safety profiles associated with the use of SUs, including gliclazide, support their position as a key treatment option in patients with T2D.
Salmon of the Southeastern U.S.: Sucker migrations deliver resource subsidies to oligotrophic stream
Authors: White Mack , Wheeler Kit , Hudson Ryan R. , Murdock Justin N.
Published: September 2022

The ability for migratory fishes to move commonly limiting resources such as nitrogen (N) and phosphorus (P) between discrete environments can have pronounced effects on recipient ecosystems. To further understand the geographic and taxonomic scope of migratory fish resource subsidies, we quantified N and P subsidies delivered by adfluvial suckers (Smallmouth Buffalo,Ictiobus bubalus) via excretion, eggs and carcasses to a small oligotrophic stream during their annual spawning migration. We also compared nutrient inputs from migrant buffalo with watershed nutrient export to assess the likelihood that delivered nutrients were ecologically important. We estimated that approximately 67,000 buffalo delivered 730 kg of N and 80 kg of P to Citico Creek as a result of excretion and egg subsidies across three migration waves. We estimated that carcasses delivered negligible amounts of N and P due to extremely low retention. The ratio of migrant inputs (Mw) to system export (Ew;Mw/Ew) varied amongst three migration waves and compounds (i.e. dissolved inorganic nitrogen, ammonium and soluble reactive phosphorus), with values forMw/Ewranging from 0.25 to 5.10, reflecting the potential of nutrient subsidies to exceed nutrients exported from the system under certain conditions. Our findings suggest that suckers have the potential to deliver large resource subsidies to their spawning habitats and that these subsidies may be ecologically important, thus warranting additional consideration of the functional relevance of nongame fishes and their migrations.
Analysis of cutaneous bacterial microbiota of Thai patients with seborrheic dermatitis
Authors: Dityen Kanthaporn , Soonthornchai Wipasiri , Kueanjinda Patipark , Kullapanich Chitrasak , Tunsakul Naruemon , Somboonna Naraporn , Wongpiyabovorn Jongkonnee
Published: September 2022

Seborrheic dermatitis (SD) is a chronic inflammatory skin condition that occurs in body areas that contain profuse sebaceous glands. Skin microbiota are diverse across ethnic groups and its dysbiosis has been implicated in the pathogenesis of SD. Here, we reported the contribution of cutaneous bacterial microbiota to SD in the Thai population. Healthy individuals and patients with scalp SD were recruited into the study. Normal skin, scalp skin lesion (SL) and non‐lesion sites (SNL) samples were collected using a tape stripping method and next‐generation sequencing of 16S rRNA for microbiome analysis. Although bacterial diversity in all sample groups was not statistically different, a population of bacteria commonly found on skin of scalp showed signs of dysbiosis. Apart from the reduction of Corynebacterium spp., SD‐specific microbiota was dominated by Firmicutes at taxa level and Pseudomonas spp., Staphylococcus spp. and Micrococcus spp. at genus level. The dysbiosis of the skin microbiota in SD was specifically described as an alteration of bacteria populations commonly found on scalp skin, implying that managing and controlling the cutaneous bacterial microbiome can alleviate and prevent SD and pave the way for the development of new SD treatments.
A, B, C, 1, 2, 3: How an amendment to the New York State education law will give private school students an equitable education to public school students
Authors: Guariglia Elizabeth M.
Published: September 2022

In 2018, in his lawsuit against Governor Andrew Como, Naftuli Moster alerted the world to the inequality between public and private education in New York State. This Note proposes amending the Felder Amendment to ensure that private school students in New York State are given a “substantially equivalent” education to those students in public schools. By making the Felder Amendment more specific in the guidelines it uses to assess the quality of the private schools, New York State can ensure that all children are being given an equitable education.
Is it time for popcorn? Daily box office earnings and aggregate stock returns
Authors: Oz Seda , Fortin Steve
Published: September 2022

We quantitatively measure the interactions between daily consumption and the stock market. We find that daily consumption, proxied by the cyclical component of theatrical box office earnings, can significantly and positively predict stock returns for up to 5 days. We also demonstrate a trading strategy using our consumption measures that yield nontrivial excess returns with little risk. These findings suggest that the box office effect is an economically important factor for equities. The framework implies that daily consumption carries value‐relevant public information, which leads to price reaction at a daily frequency.
Physiological and metabolic responses of chemolithoautotrophic NO3− reducers to high hydrostatic pressure
Authors: Pérez‐Rodríguez Ileana , Sievert Stefan M. , Fogel Marilyn L. , Foustoukos Dionysis I.
Published: September 2022

We investigated the impact of pressure on thermophilic, chemolithoautotrophic reducing bacteria of the phyla Campylobacterota and Aquificota isolated from deep‐sea hydrothermal vents. Batch incubations at 5 and 20 MPa resulted in decreased consumption, lower cell concentrations, and overall slower growth in Caminibacter mediatlanticus (Campylobacterota) and Thermovibrio ammonificans (Aquificota), relative to batch incubations near standard pressure (0.2 MPa) conditions. Nitrogen isotope fractionation effects from chemolithoautotrophic reduction by both microorganisms were, on the contrary, maintained under all pressure conditions. Comparable chemolithoautotrophic reducing activities between previously reported natural hydrothermal vent fluid microbial communities dominated by Campylobacterota at 25 MPa and Campylobacterota laboratory isolates at 0.2 MPa, suggest robust similarities in cell‐specific reduction rates and doubling times between microbial populations and communities growing maximally under similar temperature conditions. Physiological and metabolic comparisons of our results with other studies of pressure effects on anaerobic chemolithoautotrophic processes (i.e., microbial S0‐oxidation coupled to Fe(III) reduction and hydrogenotrophic methanogenesis) suggest that anaerobic chemolithoautotrophs relying on oxidation–reduction (redox) reactions that yield higher Gibbs energies experience larger shifts in cell‐specific respiration rates and doubling times at increased pressures. Overall, our results advance understanding of the role of pressure, its relationship with temperature and redox conditions, and their effects on seafloor chemolithoautotrophic reduction and other anaerobic chemolithoautotrophic processes.
Iron status among HIV‐infected adults during the first year of antiretroviral therapy in Tanzania
Authors: Abioye Ajibola Ibraheem , Sudfeld Christopher R. , Hughes Michael D. , Aboud Said , Muhihi Alfa , Ulenga Nzovu , Nagu Tumaini J. , Wang Molin , Mugusi Ferdinand , Fawzi Wafaie W.
Published: September 2022

Background

The influence of inflammation on iron status among people living with HIV (PLWHIV) has not been well explored. We evaluated the trajectory of iron status among PLWHIV during the first year of highly active antiretroviral therapy (HAART), compared alternative approaches for inflammation correction, and assessed the associations of iron status with HIV‐1 viral load and anthropometric outcomes.

Methods

We conducted a secondary analysis of data from a randomized trial among 400 adults initiating HAART in Tanzania. Ferritin and C‐reactive protein (CRP) were measured at baseline, 1, 6 or 12 months. Ferritin was considered in four ways: unadjusted, and adjusted for inflammation using higher cut‐off (HC), Thurnham‐corrected (TC) and regression‐corrected (RC) approaches. For unadjusted, TC and RC ferritin, iron deficiency (ID) was defined using ferritin < 15 μg/L and elevated iron status was defined using ferritin > 150 μg/L among females and > 200 μg/L among males. For HC ferritin, elevated iron status was defined based on serum ferritin > 500 μg/L, while ID was defined using ferritin < 70 μg/L in the presence of inflammation and < 15 μg/L in the absence of inflammation. Regression models evaluated the trajectory of ferritin concentration across categories of baseline characteristics, and assessed the association of iron status with viral and anthropometric outcomes.

Results

The prevalence of iron deficiency at HAART initiation was 9% for unadjusted, 17% for HC, 12% for TC and 22% for RC ferritin. The prevalence of elevated iron status was 42% for unadjusted, 18% for HC, 31% for TC, and 15% for RC ferritin. The prevalence of iron deficiency for all three methods increased during the first year of HAART, while the prevalence of elevated iron status decreased. Baseline elevated iron status defined using HC ferritin was associated with a greater risk of HIV‐1 viral load > 1000 copies/mL [relative risk (RR) = 4.29, 95% CI: 1.38–13.3] and incidence of being underweight [body mass index (BMI) < 18.5 kg/m2, hazard ratio (HR) = 3.65, 95% confidence interval (CI): 1.38–9.67]. Neither baseline‐elevated iron status defined using TC or RC ferritin nor baseline iron deficiency defined using any of the three methods was associated with HIV‐1 viral load or anthropometric outcomes.

Conclusions

Whether and how inflammation correction is done influences findings of studies of iron status among PLWHIV.
Perspectives of topical formulations for melasma
Authors: de Freitas Andréa Carolina Pinheiro , Rigon Roberta Balansin , Bagatin Ediléia , Leonardi Gislaine Ricci
Published: September 2022

Melasma is acquired hyperpigmentation that mainly affects the face, can cause negative changes in self‐esteem, and mostly affects women. Treatment is difficult, and different drugs can be used in mono or combination therapy. In this article, we present a brief overview of melasma, how to evaluate it, and a synthesis of the most commonly used topical therapies and their indications, including sunscreens, pharmacological agents, and plant extracts. Hydroquinone (4%) in monotherapy or combined with corticosteroids (dexamethasone and fluocinolone acetonide) and retinoids (tretinoin); arbutin (1%); methimazole (5%); kojic (2%), azelaic (20%), and tranexamic (5%) acids are the pharmacological agents that stand out. Correct application of these substances determines a variable improvement in melasma but often causes adverse reactions such as erythema, itching, and burning at the application site. Vitamin C can contribute to the reduction of melasma and have little or no adverse effects while sunscreens are normally used as coadjuvant therapies. In conclusion, we have compiled specific topical therapies for treating melasma and discussed those that are the most used currently. We consider it important that prescribers and researchers evaluate the best cost–benefit ratio of topical therapeutic options and develop new formulations, enabling efficacy in the treatment with safety and comfort during application, through the reduction of adverse effects.
‘It stopped you thinking about food’ – The experiences of mealtimes and attending a post‐meal support group for young people with anorexia nervosa
Authors: Monaghan Margaret , Doyle Louise
Published: September 2022

Anorexia nervosa presents as an international public health concern as it is the mental health problem with the greatest risk of mortality, and the average age of onset is decreasing. For those experiencing anorexia nervosa, mealtimes have long been recognized as a difficult and distressing time when young people need additional support. However, the post mealtime period can be associated with even greater distress, yet there is little research on interventions to support young people in this vulnerable time, and even less on how young people experience these interventions. This study, therefore, explores young peoples' perceptions of mealtimes and a post mealtime support group. Using a qualitative descriptive design, telephone interviews were conducted with a purposive sample of six young people who participated in a post‐meal support group while an inpatient in a Child and Adolescent Mental Health Unit. Using a semi‐structured interview guide, participants were asked about their experiences of this support group and their perceptions of how to improve this intervention. Content analysis resulted in the development of three themes: ‘The Challenges of Mealtimes and Post Mealtimes’, ‘The Benefits of Post‐meal Support Groups’, and ‘Improving Unhelpful Aspects of Post‐meal Support Groups’. Findings are reported in accordance with COREQ guidelines and suggest that for young people experiencing anorexia nervosa, post mealtimes are often more distressing than the meal itself and that participants found post‐meal support groups to be a helpful intervention in reducing post‐mealtime distress. Post‐meal support groups can be improved by ensuring a consistent approach from staff and providing staff with the training and knowledge required to support those affected by eating disorders.