bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical-genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy
Authors: Koh Eun-Ik , Oluoch Peter O. , Ruecker Nadine , Proulx Megan K. , Soni Vijay , Murphy Kenan C. , Papavinasasundaram Kadamba G. , Reames Charlotte J. , Trujillo Carolina , Zaveri Anisha , Zimmerman Matthew D. , Aslebagh Roshanak , Baker Richard E. , Shaffer Scott A. , Guinn Kristine M. , Fitzgerald Michael , Dartois Véronique A. , Ehrt Sabine , Hung Deborah T. , Ioerger Thomas R. , Rubin Eric , Rhee Kyu Y. , Schnappinger Dirk , Sassetti Christopher M.
Published: April 2021

Current chemotherapy againstMycobacterium tuberculosis(Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug-drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based onin vitroassays alone. In this study, we utilize conditionalMtbknockdown mutants of essential genes as an experimentally-tractable surrogate for drug treatment, and probe the relationship betweenMtbcarbon metabolism and chemical-genetic interactions (CGI). We examined the anti-tubercular drugs isoniazid, rifampicin and moxifloxacin, and found that CGI are differentially responsive to the metabolic state, defining both environment-independent and –dependent interactions. Specifically, growth on thein vivo-relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependentin vitroCGI could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of novel chemical-genetic-environmental interactions that can be used to optimize drug-drug interactions as well as provide a framework for understandingin vitrocorrelates ofin vivoefficacy.

Significance

Efforts to improve tuberculosis therapy include optimizing multi-drug regimens to take advantage of drug-drug synergies. However, the complex host environment has a profound effect on bacterial metabolic state and drug activity, making predictions of optimal drug combinations difficult. In this study, we leverage a newly developed library of conditional knockdownMycobacterium tuberculosismutants in which genetic depletion of essential genes mimics the effect of drug therapy. This tractable system allowed us to assess the effect of growth condition on predicted drug-drug interactions. We found that these interactions can be differentially sensitive to the metabolic state and selectin vitro-defined interactions can be leveraged to accelerate bacterial killing during infection. These findings suggest new strategies for optimizing tuberculosis therapy.
Honeybee Queen mandibular pheromone induces starvation in Drosophila
melanogaster, implying a role for nutrition signalling in the evolution
of eusociality
Authors: Lovegrove Mackenzie R. , Duncan Elizabeth J. , Dearden Peter K.
Published: April 2021

Eusocial insect societies are defined by the reproductive division of
labour, a social structure that is generally enforced by the reproductive
dominant or ‘queen’. Reproductive dominance is maintained through behavioural
dominance in some species as well as production of queen pheromones in others,
or a mixture of both. Queen mandibular pheromone (QMP) is produced by honeybee
(Apis mellifera) queens and has been
characterised chemically. How QMP acts to repress worker reproduction, and how
it has evolved this activity, remains less well understood. Surprisingly, QMP is
capable of repressing reproduction in non-target arthropods which have not
co-evolved with QMP, are never exposed to QMP in nature, and are up to 530
million years diverged from the honeybee.

Here we show that, in Drosophila melanogaster,
QMP treatment mimics nutrient limiting conditions, leading to disrupted
reproduction. Exposure to QMP induces an increase in food consumption,
consistent with that observed in D. melanogaster in
response to starvation conditions. This response induces the activation of two
checkpoints within the ovary that inhibit oogenesis. The first is the 2a/b
ovarian checkpoint in the germarium, which reduces the flow of presumptive
oocytes. A stage 9 ovarian checkpoint is also activated, causing degradation of
oocytes. The magnitude of activation of both checkpoints is indistinguishable
between QMP treated and starved individuals.

As QMP seems to trigger a starvation response in an insect highly diverged
from honeybees, we propose that QMP originally evolved by co-opting nutrition
signalling pathways to regulate reproduction, a key step in the evolution of
eusociality.
No observable guide-RNA-independent off-target mutation induced by prime editor
Authors: Gao Runze , Fu Zhi-Can , Li Xiangyang , Wang Ying , Wei Jia , Li Guangye , Wang Lijie , Wu Jing , Xue Wei , Huang Xingxu , Yang Li , Chen Jia
Published: April 2021

Prime editor (PE) has been recently developed to induce efficient and precise ontarget editing, whereas its guide RNA (gRNA)-independent off-target effects remain unknown. Here, we used whole-genome and whole-transcriptome sequencing to determine gRNA-independent off-target mutations in cells expanded from single colonies, in which PE generated precise editing at on-target sites. We found that PE triggered no observable gRNA-independent off-target mutation genome-wide or transcriptome-wide in transfected human cells, highlighting its high specificity.
Crystal structure and Hirshfeld surface analysis of 6-amino-8-(2,6-dichlorophenyl)-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile
Authors: Naghiyev Farid N. , Tereshina Tatiana A. , Khrustalev Victor N. , Akkurt Mehmet , Rzayev Rovnag M. , Akobirshoeva Anzurat A. , Mamedov İbrahim G.
Published: April 2021

In the molecular structure of the title compound, C16H13Cl2N5, the 1,4-dihydropyridine ring of the 1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrimidine ring system adopts a screw-boat conformation, while the 1,3-diazinane ring is puckered. In the crystal, intermolecular N—H...N and C—H...N hydrogen bonds form molecular sheets parallel to the (110) and (\overline{1}10) planes, crossing each other. Adjacent molecules are further linked by C—H...π interactions, which form zigzag chains propagating parallel to [100]. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from N...H/H...N (28.4%), H...H (24.5%), C...H/H...C (21.4%) and Cl...H/H...Cl (16.1%) contacts.
Crystal structure and Hirshfeld surface analysis of 6-amino-8-phenyl-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrimidine-7,9-dicarbonitrile
Authors: Naghiyev Farid N. , Tereshina Tatiana A. , Khrustalev Victor N. , Akkurt Mehmet , Khalilov Ali N. , Akobirshoeva Anzurat A. , Mamedov İbrahim G.
Published: April 2021

In the title compound, C16H15N5, the 1,4-dihydropyridine ring has a shallow boat conformation, while the 1,3-diazinane ring adopts an envelope conformation. In the crystal, pairwise N—H...N hydrogen bonds generate centrosymmetric dimers featuring R
2
2(12) motifs and C—H...N contacts connect these dimers to form double layers lying parallel to (001). Weak C—H...π and N—H...π interactions help to consolidate the double layers and van der Waals interactions occur between layers. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from H...H (38.5%), N...H/H...N (33.3%) and C...H/H...C (27.3%) contacts.
5-[(1,3-Dimethyl-5-oxo-2-sulfanylideneimidazolidin-4-ylidene)amino]-2-methylisoindoline-1,3-dione
Authors: Kotha Sambasivarao , Gupta Naveen Kumar , Ansari Saima
Published: April 2021

The title N,N-dimethylthiohydantoin containing an N-methylated pthalimide group, C14H12N4O3S, arose from an unexpected reaction in a deep eutectic dimethylthiourea–tartaric acid solvent system. The mean planes of the ring systems are twisted at an angle of 73.84 (17)°. In the crystal, weak C—H...O hydrogen bonds connect the molecules.
An investigation on the existence of warped product irrotational screen-real lightlike submanifolds of metallic semi-Riemannian manifolds
Authors: Shanker Gauree , Yadav Ankit
Published: April 2021

Purpose

The purpose of this paper is to study the geometry of screen real lightlike submanifolds of metallic semi-Riemannian manifolds. Also, the authors investigate whether these submanifolds are warped product lightlike submanifolds or not.

Design/methodology/approach

The paper is design as follows: In Section 3, the authors introduce screen-real lightlike submanifold of metallic semi Riemannian manifold. In Section 4, the sufficient conditions for the radical and screen distribution of screen-real lightlike submanifolds, to be integrable and to be have totally geodesic foliation, have been established. Furthermore, the authors investigate whether these submanifolds can be written in the form of warped product lightlike submanifolds or not.

Findings

The geometry of the screen-real lightlike submanifolds has been studied. Also various results have been established. It has been proved that there does not exist any class of irrotational screen-real r-lightlike submanifold such that it can be written in the form of warped product lightlike submanifolds.

Originality/value

All results are novel and contribute to further study on lightlike submanifolds of metallic semi-Riemannian manifolds.
Social media and the spread of COVID-19 infodemic
Authors: Adekoya Clement Ola , Fasae Joseph Kehinde
Published: April 2021

Purpose

The purpose of this paper is to investigate the social media application and the spread of COVID-19 infodemic in Nigeria.

Design/methodology/approach

A descriptive survey research design was used for this study. A total of 1,200 social media users, regardless of their professions, were randomly selected for the study betweenmid-June and July 2020. Stratified and purposive sampling techniques were used for this study. The questionnaire was designed using Google form and administered using WhatsApp and Telegram to social media users above 18 years old in Nigeria. The data generated was analyzed using descriptive (frequency count) and inferential (mean) statistics, and was presented in tables.

Findings

It was found that people make use of social media during COVID-19 pandemic for diverse reasons such as listening to announcement to be informed, knowing the necessary measures to take by those infected and spreading up-to-date information on the pandemic. Social media tools were highly used during the COVID-19 pandemic, especially WhatsApp and Zoom. Findings reflected that misinformation was spread on social media. This study also showed that the infodemic associated with COVID-19 is managed by confirming the source of the information before sharing it and trusting information from reliable sources.

Research limitations/implications

The result of this research will contribute to the body of knowledge on social media application, fake news and the spread of COVID-19 infodemic in Nigeria and beyond.

Practical implications

Infodemic is a disaster in the health sector. The spread of infodemic is capable of misleading people, losing trust in government, health providers and health regulatory authorities. This study will help social media users to know how to properly manage social media infodemic during a pandemic or any health-related situations.

Originality/value

This study is novel as it approaches fake news from a COVID-19 perspective. Very few articles emanate from the developing countries in this area. This was because most of the narrative around fake news previously centered around the Western occurrences such as the Iraqi invasion by the USA, the US presidential elections and BREXIT. COVID-19 has demonstrated that the developing world is not immune from fake news as well. This study, therefore, assessed the management of infodemic associated with COVID-19 in Nigeria.
Outpatient regulation system in health management: economic benefits of technological innovations
Authors: Camargo Jr Alceu Salles
Published: April 2021

Purpose

The purpose of this paper is to evaluate the economic benefits of managing an outpatient appointments system with technological innovations.

Design/methodology/approach

This study uses a quantitative methodological procedures aiming to evaluate the cost-benefit relation and also the payback of the management and operation of an outpatient appointments system with technological innovations.

Findings

This study found a great benefit-cost relation of 30.6 showing the great economic value and social impact of managing an outpatient appointments regulation system with technological innovations.

Research limitations/implications

This study presents contribution to the literature discussion about the economic evaluation of the benefits of managing and operating more effective outpatient appointments systems because of important technological innovations.

Practical implications

This paper presents and discusses the most important and commonly used strategies and technological innovations to deal with and to manage an outpatient appointment regulation system aiming to reduce the patient no-show rates.

Social implications

The findings of this study show a great benefit-cost relation of about 30.6 which is being reverted to the society.

Originality/value

There not exist many similar studies in the pertinent literature, mostly with the Brazilian contexts.
Assessing inter-organizational performance through customer value: a literature review
Authors: Coletta Lucrezia , Vainieri Milena , Noto Guido , Murante Anna Maria
Published: April 2021

Purpose

This study aims to systematically review the literature on the use of customer value for the evaluation of inter-organizational performance, with a wide perspective embracing different contexts and settings.

Design/methodology/approach

Searching within the Scopus and ISI Web of Science databases, a systematic literature review has been conducted analyzing 41 papers published between 1991 and 2020.

Findings

Categorization of customer value and inter-organizational performance measures were developed and the main differences among different settings were discussed.

Practical implications

The results presented in this study may be helpful for practitioners and managers who, in the completion of their activities, have to maintain strong and frequent relationships with other organizations. In fact, practitioners and managers interested in enhancing customer value and measuring inter-organizational performance may find an innovative perspective linking the two dimensions. They could find the categorizations presented in this study as a starting point for developing a performance evaluation framework suitable for evaluating their present business relationships. In fact, the categorizations provide a panorama of how scholars have measured until now inter-organizational performance through customer value, and therefore, they could choose the measures more appropriate for their situation.

Originality/value

No systematic literature review of the use of customer value for assessing inter-organizational performance has previously been undertaken, especially considering different settings.
Effect of gender and personality characteristics on the speed tendency based on advanced driving assistance system (ADAS) evaluation
Authors: Pan Cunshu , Xu Jin , Fu Jinghou
Published: April 2021

Purpose

This study aims to explore the relationship between speed behavior of participants and driving styles on interchange ramps. A spiral interchange in Chongqing was selected as an experimental road to carry out field driving experiment.

Design/methodology/approach

The continuous operating speed during experiment was selected by Mobile Eye, and the driving style was selected via two inventories.

Findings

Different driving behaviors showed great differences in age, driving mileage and driving experience. During driving process, male pursued driving stimulation more, whereas female pursued driving steadiness more. Therefore, driving characteristics of male were more disadvantageous to driving safety than that of female. Except for the large speed difference at the entrance and exit of the ramps, the differences at other positions were small. And the operating speed of male was slightly higher than that of female. The difference between different genders at the ascending end position achieved 4–5 kph, and the difference at other feature points were mostly 1–2 kph. During driving process, risky participants were more likely to pursue driving stimulation, and the poor speed control behavior was reflected in wide range of desired operating speed. Based on the results of analyzing at feature points, melancholy and sanguine participants more tended to take a high operating speed, and the poor speed control behavior was reflected in the most widely desired speed range. The speed control behavior of mixed participants was more cautious.

Originality/value

Advanced driving assistance system combined with two inventories was used to explore difference of speed behavior.
US Securities and Exchange Commission (SEC) expands accredited investor definition
Authors: Adler Sara , Greenberg Joel I. , LeBas William G. , Fleishhacker Ellen
Published: April 2021

Purpose

To explain amendments to the definition of “accredited investor” approved by the SEC in August 2020 and to describe the impact of the changes.

Design/methodology/approach

Explains how the amendments expand the pool of qualified investors in various subsections of the definition, explains related amendments, and then discusses the implications of the changes.

Findings

The amendments, among other things: (i) permit natural persons to qualify as accredited investors based on certain professional credentials or, for investments in private funds, based on “knowledgeable employee” status”; (ii) add LLCs and other specified entity types to the list of potentially-qualifying entities, and add a “catch-all” category for unspecified entities (although with different quantitative standards); (iii) add the term “spousal equivalent” to the definition; and (iv) codify certain related staff interpretive positions. In addition, the amendments revise the definition of “qualified institutional buyer” to include additional entity types to avoid inconsistencies with the new accredited investor definition.

Originality/value

Expert analysis and guidance from experienced securities attorneys who counsel clients on all manner of SEC regulatory policy matters.
Multi-stakeholder perspective on the role of universities in place branding
Authors: Bisani Shalini , Daye Marcella , Mortimer Kathleen
Published: April 2021

Purpose

The purpose of this paper is to create a conceptual framework to demonstrate the role of universities as knowledge partners in place branding networks.

Design/methodology/approach

This research adopts a case study strategy to explore the perceptions of institutional and community stakeholders in Northamptonshire. The objective is to examine the regional activities and engagement of a single-player university in a peripheral region and explore its potential for widening stakeholder participation. Qualitative data was collected through interviews and focus groups and thematically analysed.

Findings

The university played a complementary “partnership” role to other institutional stakeholders, particularly the public sector. As a knowledge partner, the university filled gaps in information (know-what), skills (know-how) and networks (know-who). The last two aspects are potentially unique to the university’s role in place branding networks and require further development.

Research limitations/implications

The conceptual framework demonstrates the potential of a single-player university in a peripheral region to enhance the capabilities and skills of stakeholders in place branding networks and widen stakeholder participation. Future researchers can use the framework to develop recommendations for universities’ role in place branding based on their unique situation.

Originality/value

There has been limited research on how universities participate and influence participation in place branding. The exploration of this topic in the context of a rural, marginalised region is also novel.
The impact of financial defence mechanisms and phantasy on risky investment intention
Authors: Aren Selim , Nayman Hamamcı Hatice
Published: April 2021

Purpose

The purpose of this paper is to investigate the relationship between defence mechanisms, one of the unconscious processes, and phantasy. In addition, the scale of financial defence mechanisms, which is a version of the defence mechanisms adapted to financial issues, has been developed and tested.

Design/methodology/approach

For this purpose, first, a pilot study was conducted for the financial defence mechanism scale. The data was collected 179 subjects in Turkey through online surveys with convenience sampling method between the dates of 6 March and 21 March 2020, and then additional data was collected in Turkey between the dates of 28 April and 14 June 2020. The total number of subjects is 644. The authors exploited IBM SPSS Statistics and AMOS for analysis. Exploratory factor analysis, ANOVA, Independent t-test and Correlation analysis were performed. In addition, confirmatory factor analysis was performed after additional data collection process with structural equation modelling.

Findings

As a result of the analyses, only two of the defence mechanisms (mature and neurotic) and three of the financial defence mechanisms (mature, neurotic and immature) were found to be positively correlated with phantasy, which is considered a determinant of financial bubbles. In addition, a positive relationship was found between risky investment intention and two of the defence mechanisms (immature and neurotic) and three of the financial defence mechanisms (mature, immature and neurotic).

Originality/value

The study is unique due to its findings and developed scale. The findings are valuable in that the theoretically alleged relations were also obtained empirically.
The content of the nurses in the lead programme for empowering community nurse leadership in implementing evidence
Authors: Vogel Ruth , Bours Gerrie , Erkens Petra , Metzelthin Silke , Zwakhalen Sandra , van Rossum Erik
Published: April 2021

Purpose

This study aims to provide a detailed description of the nurses in the lead (NitL) programme for empowering community nurse leadership in implementing evidence.

Design/methodology/approach

The NitL programme is described using the template for intervention description and replication-checklist.

Findings

The NitL programme consists of two components. The first component is a systematic approach with implementation steps and tools to empower community nurses in implementing evidence targeted at encouraging functional activities of older adults offered via a Web-based eLearning programme. The second component is training to empower community nurses in enabling team members to change their practice, which focussed on motivational interviewing, influencing behaviour, dealing with resistance to change and coaching delivered as a combination of group training in practice and background theory via a web-based eLearning programme.

Research limitations/implications

Further research is needed to evaluate the feasibility and effects of the NitL programme.

Practical implications

The NitL programme has been developed in cooperation with community nurses to meet their needs in practice and has the potential to develop leadership for the core tasks of community nurses.

Originality/value

The NitL programme has been developed to empower the leadership of community nurses in implementing evidence targeted at encouraging functional activities of older adults. The leadership role of community nurses is key for delivering high-quality care and implementing evidence within the community care setting for encouraging functional activities of older adults to preserve their independence.
Infections – we might run but we cannot hide
Authors: Thorp John M
Published: April 2021

Deputy Editor‐in‐Chief, Dr John M Thorp, discusses his top articles from this issue in an audio podcast available at: https://soundcloud.com/bjog/may‐editors‐choice‐2021.
Age‐associated expression of p21and p53 during human wound healing
Authors: Chia Chee W. , Sherman‐Baust Cheryl A. , Larson Sara A. , Pandey Ritu , Withers Roxanne , Karikkineth Ajoy C. , Zukley Linda M. , Campisi Judith , Egan Josephine M. , Sen Ranjan , Ferrucci Luigi
Published: April 2021

In mice, cellular senescence and senescence‐associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof‐of‐concept study, we investigated the expressions of p16, p21, and other senescence‐associated biomarkers during human wound healing in 24 healthy subjects using a double‐biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex‐matched younger (30.2 ± 1.3 years) and 12 sex‐matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase‐4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence‐associated β‐galactosidase (SA‐β‐gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.
Efficacy and safety of current treatment options for peripheral retinal haemangioblastomas: a systematic review
Authors: Hajjaj Anass , van Overdam Koen A. , Gishti Olta , Ramdas Wishal D. , Kiliç Emine
Published: April 2021

Importance

Approximately twenty per cent of Von Hippel–Lindau patients with retinal haemangioblastomas (RH) suffer from visual impairment. Various treatment options are available for peripheral RH. However, management of peripheral RH is complex due to multifocality and bilaterality.

Objective

To summarize published evidence on efficacy and safety of different interventions for peripheral RH and to provide treatment recommendations for specialists.

Evidence review

Comprehensive searches were performed using Medline, Embase, Web of Science and Google Scholar database on 4 March 2020. English publications that described outcomes related to efficacy or complications in at least two patients with peripheral RH were included. Efficacy and safety were estimated by complete tumour eradication rate, pretherapeutic and treatment‐related complication rate. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to calculate the risk estimate of complications between treatment options.

Findings

Twenty‐seven articles were included in this review describing nine different treatment options for peripheral RH: laser photocoagulation (n = 230), cryotherapy (n = 50), plaque radiotherapy (n = 27), vitreoretinal surgery (n = 88), photodynamic therapy (PDT; n = 14), transpupillary thermotherapy (TTT; n = 10), external beam radiotherapy (n = 3), systemic treatment (n = 7) and intravitreal anti‐VEGF (n = 2). Complete tumour eradication was achieved in 86.7% (95% CI: 83.5–89.9%) of all eyes. For the different treatments, this was after laser photocoagulation 89.9% (86.1–93.7%), cryotherapy 70.2% (57.0–83.4%), plaque radiotherapy 96.3% (89.1–100.0%), vitreoretinal surgery (100.0%), PDT 64.3% (38.3–90.3%) and TTT 80.0% (53.8–100.0%). No complete tumour eradication was achieved after systemic therapy, external beam radiotherapy or intravitreal anti‐VEGF. Photodynamic therapy and vitreoretinal surgery showed the highest complication rate after treatment compared to the other treatments (OR 10.5 [95% CI: 2.9–38.4]) and (OR 5.9 [95% CI: 3.4–9.9]), respectively. Cases that had pretherapeutic complications showed a higher treatment‐related complication rate (OR 14.8 [95% CI: 7.3–30.0]) than cases without complications before treatment.

Conclusions and Relevance

These findings suggest that laser photocoagulation is the safest and most effective treatment method for peripheral RH up to 1.5 mm in diameter. Vitreoretinal surgery has the highest success rate for complete tumour eradication and may be the most suitable treatment option in the presence of pretherapeutic complications and for larger tumours.
Protective mechanism of Astragalus Polysaccharides against Cantharidin‐induced liver injury determined in vivo by liquid chromatography/mass spectrometry metabolomics
Authors: Huang Xiaoduo , Tang Wenchao , Lin Chang , Sa Zongge , Xu Mengdan , Liu Jieying , Wang Lina , Li Wen , Chen Yunzhi , Yang Changfu
Published: April 2021

Cantharidin (CTD) is a promising anticancer drug; however, its dosage is limited by hepatotoxicity. We previously showed that Astragalus polysaccharides (APS) effectively improved chemical liver injury. In this study, we established a CTD‐induced subacute liver injury mouse model and examined the effects of APS on weight, liver indexes, histopathology, serum biochemical indexes and liver metabolism. Compared with the control group, mice in the CTD model group had obvious liver damage, which was partially prevented by APS. Metabolomics demonstrated that CTD caused liver damage mainly by regulating glycerophospholipid metabolism, ABC transporter pathways and choline metabolism in cancer in vivo. APS regulated primary bile acid biosynthesis and glycerophospholipid metabolism, thus decreasing the liver damage caused by CTD. This study revealed the protective mechanism of APS against CTD‐induced liver injury from the perspective of metabolomics. The results provide an important basis for analysing the mechanism of CTD‐induced liver toxicity and for assessing clinical treatment options to reduce CTD liver toxicity.
An overview of microglia ontogeny and maturation in the homeostatic and pathological brain
Authors: Mendes Monique S. , Majewska Ania K.
Published: April 2021

Microglia are the resident immune cells of the central nervous system (CNS) and are increasingly recognized as critical players in development, brain homeostasis, and disease pathogenesis. The lifespan, maintenance, proliferation, and turnover of microglia are important factors that regulate microglial behavior and affect their roles in the CNS. However, emerging evidence suggests that microglia are morphologically and phenotypically distinct in different brain areas, at different ages, and during disease. Ongoing research focuses on understanding how microglia acquire specific phenotypes in response to extrinsic cues in the environment and how phenotypes are specified by intrinsic properties of different populations of microglia. With the development of pharmacological and genetic tools that allow the investigation of microglia in vivo, there have been considerable advances in understanding molecular signatures of both homeostatic microglia and those reacting to injury and disease. Here, we review the master gene regulators that define microglia as well as discuss the evidence that microglia are heterogeneous and fall into distinct clusters that display specific intrinsic properties and perform unique tasks in different settings. Taken together, the information presented supports the idea that microglia morphology and transcriptional heterogeneity should be considered when studying the complex nature of microglia and their roles in brain health and disease.
Performance of a HER2 testing algorithm specific for p53‐abnormal endometrial cancer
Authors: Vermij Lisa , Singh Naveena , Leon‐Castillo Alicia , Horeweg Nanda , Oosting Jan , Carlson Joseph , Smit Vincent , Gilks Blake , Bosse Tjalling
Published: April 2021

Aims

Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53‐abnormal (p53abn) molecular subtype and independent of histological subtype. HER2 testing should therefore be molecular subtype‐directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC‐specific HER2 immunohistochemistry (IHC) scoring method and evaluated its reproducibility and performance to establish an optimal diagnostic HER2 testing algorithm for p53abn EC.

Methods and results

HER2 IHC slides of 78 p53abn EC were scored by six gynaecopathologists according to predefined EC‐specific IHC scoring criteria. Interobserver agreement was calculated using Fleiss’ kappa and the first‐order agreement coefficient (AC1). The consensus IHC score was compared with HER2 dual in‐situ hybridisation (DISH) results. Sensitivity and specificity were calculated. A substantial interobserver agreement was found using three‐ or two‐tiered scoring [κ = 0.675, 95% confidence interval (CI) = 0.633–0.717; AC1 = 0.723, 95% CI = 0.643–0.804 and κ = 0.771, 95% CI = 0.714–0.828; AC1 = 0.774, 95% CI = 0.684–0.865, respectively]. Sensitivity and specificity for the identification of HER2‐positive EC was 100 and 97%, respectively, using a HER2 testing algorithm that recommends DISH in all cases with moderate membranous staining in >10% of the tumour (IHC+). Performing DISH on all IHC‐2+ and ‐3+ cases yields a sensitivity and specificity of 100%.

Conclusions

Our EC‐specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC‐2+/‐3+ cases has perfect test accuracy for identifying HER2‐positive EC.
Cell signaling in cutaneous T‐cell lymphoma microenvironment: promising targets for molecular‐specific treatment
Authors: Rendón‐Serna Natalia , Correa‐Londoño Luis A. , Velásquez‐Lopera Margarita M. , Bermudez‐Muñoz Maria
Published: April 2021

Cutaneous T‐cell lymphomas (CTCL) result from the infiltration and proliferation of a population of T cells in the skin, inducing changes in the activity of both T cells and surrounding skin cells. In the CTCL microenvironment, cell interactions mediated by cell signaling pathways are altered. Defining changes in cell signaling enables to understand T‐cell deregulations in the CTCL microenvironment and thus the progression of the disease. Moreover, characterizing signaling networks activated in CTCL stages can lead to consider new molecular biomarkers and therapeutic targets. Focusing on mycosis fungoides (MF), the most frequent variant of CTCL, and Sézary syndrome (SS), its leukemic variant, this review highlights recent molecular and genetic findings revealing modifications of key signaling pathways involved in (1) cell proliferation, cell growth, and cell survival such as MAP kinases and PI3K/Akt; (2) immune responses derived from TCR, TLR, JAK/STAT, and NF‐kB; and (3) changes in tissue conditions such as extracellular matrix remodeling, hypoxia, and angiogenesis. Alterations in these signaling networks promote malignant T‐cell proliferation and survival, T‐cell migration, inflammation, and suppression of immune regulation of malignant T cells, making a skin microenvironment that allows disease progression. Targeting key proteins of these signaling pathways, using molecules already available and used in research, in clinical trials, and with other disease indications, can open the way to different therapeutic options in CTCL treatment.
Acute pulmonary embolism in patients presenting pulmonary deterioration after hospitalisation for non‐critical COVID‐19
Authors: Polo Friz Hernan , Gelfi Elia , Orenti Annalisa , Motto Elena , Primitz Laura , Donzelli Tino , Intotero Marcello , Scarpazza Paolo , Vighi Giuseppe , Cimminiello Claudio , Boracchi Patrizia
Published: April 2021

Background

Emerging evidence suggests an association between COVID‐19 and acute pulmonary embolism (APE).

Aims

To assess the prevalence of APE in patients hospitalised for non‐critical COVID‐19 who presented clinical deterioration, and to investigate the association of clinical and biochemical variables with a confirmed diagnosis of APE in these subjects.

Methods

All consecutive patients admitted to the internal medicine department of a general hospital with a diagnosis of non‐critical COVID‐19, who performed a computer tomography pulmonary angiography (CTPA) for respiratory deterioration in April 2020, were included in this retrospective cohort study.

Results

Study populations: 41 subjects, median (interquartile range) age: 71.7 (63–76) years, CPTA confirmed APE = 8 (19.51%, 95% confidence interval (CI): 8.82–34.87%). Among patients with and without APE, no significant differences were found with regards symptoms, comorbidities, treatment, Wells score and outcomes. The optimal cut‐off value of d‐dimer for predicting APE was 2454 ng/mL, sensitivity (95% CI): 63 (24–91), specificity: 73 (54–87), positive predictive value: 36 (13–65), negative predictive value: 89 (71–98) and AUC: 0.62 (0.38–0.85). The standard and age‐adjusted d‐dimer cut‐offs, and the Wells score ≥2 did not associate with confirmed APE, albeit a cut‐off value of d‐dimer = 2454 ng/mL showed an relative risk: 3.21; 95% CI: 0.92–13.97; P = 0.073. Heparin at anticoagulant doses was used in 70.73% of patients before performing CTPA.

Conclusion

Among patients presenting pulmonary deterioration after hospitalisation for non‐critical COVID‐19, the prevalence of APE is high. Traditional diagnostic tools to identify high APE pre‐test probability patients do not seem to be clinically useful. These results support the use of a high index of suspicion for performing CTPA to exclude or confirm APE as the most appropriate diagnostic approach in this clinical setting.
Quasi long‐pulsed 1064nm Nd:YAG (micro pulsed) technology for the treatment of active acne: A case series
Authors: Artzi Ofir , Koren Amir , Shehadeh Wasim , Friedman Or
Published: April 2021

Background

Acne vulgaris is common dermatologic condition with an estimated prevalence of 80%. Acne has been shown to have a significant impact on patient quality of life and mental health, especially as inflammatory lesions typically occur on cosmetically sensitive areas with the potential for permanent scarring. There have been numerous advances in the treatment of inflammatory acne with light‐based and laser devices. This technology permits effective treatment of active acne and scarring, with a short recovery and a decreased side effect profile as compared to medicinal standard‐of‐care and photodynamic therapies.

Objective

The case series study was aimed at evaluating the safety and efficacy of a 1064 nm Nd: YAG Quasi‐longed pulse laser treatment for acne vulgaris.

Methods

This was a prospective study of 19 subjects with moderate to severe. All subjects received 1064 nm Nd: YAG Quasi‐longed pulse laser treatments, at 8 J/cm2 fluence and accumulated 1000–4000 kJ according to treatment area at two weeks intervals. Primary end point was reaching a minimal AGSS score of between 1 and 2. Acne severity was assessed by two independent dermatologists according to AGSS scale before each treatment session and at the follow‐up visit (8 weeks following last treatment). Subjects’ self‐assessment of Patient Global Impression of Change (PGIC) and overall satisfaction were also recorded. Safety was assessed by recording pain, adverse events, and downtime throughout the trial.

Results

Investigator's US FDA AGSS scoring of acne appearance improvement shows an average of 6.6 treatments were required to reach the minimal AGSS score endpoint. Significant reduction in AGSS scores was recorded after 2 treatments (4.21 ± 0.65 vs 3.05 ± 0.83 p = 1.63E−05), and maintained a statistically significant reduction rate throughout the trial. Minimal AGSS scores were still detected after 8 weeks following final treatment. Subjects scored high satisfaction rates and PGIC scores (2.9 and 5.3, respectively). Some patients reported transient erythema as only adverse events recorded in the study.

Conclusion

The 1064 nm Nd: YAG Quasi‐longed pulse laser was found to be safe and highly effective for the treatment of facial acne. The treatments were well tolerated, and the subjects experienced no pain and no downtime. Light‐based treatments do and will probably continue to play an important and enlarging role in acne management.
A Full Digital Workflow for the Duplication of an Existing Implant Retained Overdenture Prosthesis: A Novel Approach
Authors: Tasopoulos Theodoros , Kouveliotis George , Karoussis Ioannis , Rfa Silva Nelson , Zoidis Panagiotis
Published: April 2021

The purpose of this clinical case report is to describe a fully digital workflow for the duplication of an existing implant retained overdenture, highlighting the benefits of digitally fabricated dentures. The patient presented with an existing mandibular implant retained overdenture on Locator attachments that needed to be replaced. The existing overdenture was duplicated/scanned with the use of an intraoral scanner and was 3D printed using acrylic resin. This resin duplicate was sectioned in the midline and served as a unilateral record base to digitally record maxillo‐mandibular relationship. The occlusal relationship was scanned unilaterally with the record base (sectioned duplicate) in place, and the procedure was repeated for the opposite side. All scans (edentulous, bite registrations and preliminary scan) were superimposed and the software managed to position and stich everything together. A try‐in copy denture (ProArtCAD Try in, Ivoclar Vivadent AG, Schaan, Liechtenstein) was milled in order to imitate the conventional wax teeth try‐in. A definitive milled overdenture was fabricated and delivered. A reinforcing polyetheretherketone mesh was fabricated, utilizing computer assisted design/computer assisted manufacturing technology and was incorporated into the pre‐designed customized space into the polymethylmethacrylate base, using indirect light‐polymerized nano‐filled composite resin (crea.lign; bredent GmbH & Co. KG). Occlusion was verified and the patient was instructed oral hygiene, home maintenance and was informed for the required recall visits.
Noble gases in cluster chondrite clasts and their host breccias
Authors: Müsing Kim , Busemann Henner , Huber Liliane , Maden Colin , Riebe My E. I. , Wieler Rainer , Metzler Knut
Published: April 2021

We measured noble gases in “cluster chondrite clasts” from nine unequilibrated ordinary chondrites (UOCs). For five meteorites, we also present data for so‐called “clastic matrix,” the impact‐brecciated material in which the angular to subrounded cluster chondrite clasts are often embedded. Cluster chondrite clasts are characterized by close‐fit texture of deformed and indented chondrules with lower amounts of fine‐grained interchondrule matrix than in other UOCs (Metzler 2012). They are ubiquitous in UOCs and may indicate accretion and compaction of hot and deformable chondrules within hours or days after formation. Clastic matrix of four of the five meteorites contains He and Ne implanted by the solar wind (SW), indicating that they are regolith breccias. In contrast, cluster chondrite clasts are essentially devoid of SW, confirming that they are fragments of “primary accretionary rocks” (Metzler 2012). Trapped Kr and Xe in all samples are essentially primordial (type “Q”). Trapped Xe concentrations in cluster chondrite clasts are similar to values in other UOCs of similar metamorphic grade despite their low fractions of primordial gas‐bearing fine‐grained materials. This possibly indicates that the interchondrule matrix in cluster chondrite clasts is more pristine than matrix of regular UOCs. Later loss of primordial gases during parent body metamorphism is mirrored in the decreasing concentrations of primordial noble gases with increasing petrologic type. Relative to cluster chondrite lithologies, clastic matrix often contains excesses of cosmogenic noble gases, most likely due to precompaction exposure in the parent body regolith.
High frequency of upper aerodigestive tract manifestations in mucous membrane pemphigoid
Authors: Endo Hiroyasu , Rees Terry D. , Niwa Hideo , Kuyama Kayo , Oshima Maya , Serizawa Tae , Tanaka Shigeo , Iijima Morio , Komiya Masamichi
Published: April 2021

Objective

The objective of this study was to evaluate the frequency of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid associated with desquamative gingivitis.

Subjects and Methods.

Data from 25 patients were collected by retrospective chart review. Their upper aerodigestive had been evaluated using a conventional flexible fiberscope. Oral disease activity was quantified on the basis of the Mucous Membrane Pemphigoid Disease Area Index activity score.

Results

Lesions of the upper aerodigestive tract were confirmed in nine symptomatic patients (9/25, 36%), of which five (5/25, 20%) had laryngeal involvement. No lesions were seen in the asymptomatic patients on fiberscope examination. There was a statistically significant difference in the symptoms, high oral disease activity score, and linear IgA deposition on direct immunofluorescence between patients with and without upper aerodigestive tract lesions (p = .001, .001, .002, respectively).

Conclusion

The high frequency of considerable complications highlights the importance of confirming the presence of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid having desquamative gingivitis. Signs including the presence of symptoms, high oral disease activity score, or linear IgA deposition on direct immunofluorescence might indicate a higher risk of upper aerodigestive tract involvement.
Canine ocular onchocerciasis in New Mexico: Risk factors for disease
Authors: Taylor Melise E. , Auten Candace R. , Foster Tania , Ebbs Erika , Hofkin Bruce V.
Published: April 2021

Objective

To determine whether dogs are at variable risk of developing canine ocular onchocerciasis based on coat color or size, factors that may influence feeding behavior of the putative vectors of Onchocerca lupi¸ the filarial nematode parasite causing this disease.

Animals studied

One hundred twenty‐five client‐owned dogs diagnosed with confirmed or suspected onchocerciasis. 1255 dogs without signs of this disease were utilized for comparison.

Procedures

Dogs lacking signs of canine onchocerciasis were assessed for coat color and weight. Proportions of dogs with these characteristics were used to predict signalment in a group of dogs with this disease, if the investigated characteristics were unrelated to disease risk. Predicted values were compared statistically with observed values in the diseased dog population. Black fly color preference was assessed utilizing black, brown, and white traps and statistically assessing any differences in trapping based on trap color.

Results

Results suggest that large, black dogs are more likely to develop canine ocular onchocerciasis than was predicted by chance alone (p = 0.012). Results for smaller dogs with other coat colors were not significant. An increased risk for black dogs was supported by trapping data, as black flies were trapped significantly more often in black traps (p < 0.001).

Conclusion

While factors other than size and color probably also influence the likelihood of O. lupi infection and disease development, our results may assist clinicians in their diagnosis of canine ocular onchocerciasis and provide them with a tool to help educate their clients as to their dogs’ risk of developing this disease.