bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK‐906), a dopamine D2/D3 receptor antagonist, in patients with gastroparesis
Authors: Kuo Braden , Scimia Cecilia , Dukes George , Zhang Wenwen , Gupta Saurabh , Chen Chunlin , Chuang Emil , Camilleri Michael
Published: June 2021

Background

Gastroparesis is a chronic gastric motility disorder. Dopamine D2/D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK‐906), a dopamine D2/D3 receptor antagonist, is under development for chronic treatment of moderate‐to‐severe gastroparesis. Nonclinical data suggest trazpiroben will have D2/D3 receptor antagonism comparable with metoclopramide or domperidone.

Aims

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice‐daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis.

Methods

This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary, respectively.

Results

Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4‐5 hours), and D2/D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume‐to‐fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs −26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182).

Conclusions

Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.
A survey of gastroenterologists in the United States on the use of central neuromodulators for treating irritable bowel syndrome
Authors: Nulsen Benjamin , LeBrett Wendi , Drossman Douglas A. , Chang Lin
Published: June 2021

Background

Central neuromodulators are an effective treatment for irritable bowel syndrome (IBS) but may be used less frequently than other therapies.

Aims

To survey gastroenterologists in the United States (US) about their use of neuromodulators in patients with IBS.

Methods

A 23‐question survey was distributed to gastroenterologists in the United States. Comparisons in prescribing practices were conducted between (a) gastroenterologists who were “high prescribers” versus “low prescribers” of neuromodulators in patients with IBS and (b) gastroenterologists and “gastroenterology experts” in the use of neuromodulators using descriptive statistics and multivariable logistic regression analyses.

Results

The 525 gastroenterologists who were surveyed used neuromodulators for a median range of 21%‐30% of their patients with IBS. Neuromodulators were described as extremely/very important in managing IBS by 55% of clinicians. Significant predictors of high‐prescribing behaviour were academic versus clinical practice setting (odds ratio [OR] 2.60 [95% CI 1.61‐4.20]), disorders of brain‐gut interaction focused practice (OR 4.80 [2.60‐8.84]), and greater perceived effectiveness of neuromodulators (OR 2.75 [1.30‐5.84]). Compared to gastroenterologists, experts prescribed neuromodulators to a higher percentage of their patients with IBS (41%‐50% vs 21%‐30%; P = 0.019) and more frequently found neuromodulators effective (70% vs 27%; P = 0.003). However, concern about side effects was the most common barrier to neuromodulator use (59%).

Conclusions

The majority of US gastroenterologists believe central neuromodulators are important in treating IBS, and 27% believe they are effective in most patients. High prescribers are in academic practice, focus in IBS and perceive central neuromodulators as effective. Education is needed to improve gastroenterologists' prescribing behaviour.
Enhancing the Interface between Standard‐setters and Academic Research
Authors: Pinnuck Matt , Stevenson Kevin
Published: June 2021

This article points to gaps between academic research and the needs of accounting standard‐setters. In part it attributes those gaps to the academic literature seeming to be inaccessible and oriented to ideas apparently unrelated to the policy‐making issues facing standard‐setters. As a means of partially reducing that perceived inaccessibility, the paper provides a way for standard‐setters to identify and classify the various forms of academic accounting research so that they can evaluate their usefulness. Two prominent strands of research (agency theory/costly contracting and value relevance) are, as illustrations, analysed so that standard‐setters can see how they might approach those strands. The paper suggests a users’ needs/demand driven approach to improving understanding, rather than a supply (by academics) driven approach. Finally, the paper explains how the performance metrics faced by academics can be inconsistent with the readiness expressed by standard‐setters to have academics assist them. The paper provides a suggestion as to how there could be some alignment of academic performance metrics and standard‐setters’ needs.
Learning a new geometric concept: The role of working memory and of domain‐specific abilities
Authors: Rivella Carlotta , Cornoldi Cesare , Caviola Sara , Giofrè David
Published: June 2021

It has been suggested that not only domain‐specific factors but also working memory (WM) may play a crucial role in mathematical learning included Geometry, but the issue has not been deeply explored. In the present study, we examined the role of domain‐specific factors and of verbal versus visuospatial WM on geometric learning of a new geometrical figure (trapezoid), never presented previously by the teachers participating to the study, after a lecture also involving manipulatives. Results on 105 children in their Year 4 indicated that not only some domain‐specific components (geometric declarative knowledge and calculation) but also visuospatial working memory had a significant specific impact on the ability of solving geometric problems requiring to calculate the perimeter and the area of the new figure. On the contrary, verbal WM and geometrical mental imagery did not offer a specific contribution. These findings could have important educational implications, stressing the importance of taking into account the main different aspects supporting the acquisition of geometry.
Identification of 3D motifs based on sequences and structures for binding to CFI‐400945, and deep screening‐based design of new lead molecules for PLK‐4
Authors: Abdullah Maaged , Guruprasad Lalitha
Published: June 2021

PLK‐4 kinase plays an essential role in the cell cycle from regulating centriole duplication till cytokinesis and is therefore an attractive drug target in cancers such as breast, lung, and central nervous system tumors. CFI‐400945 is an efficient PLK‐4 inhibitor and inhibits other non‐PLK family proteins at nanomolar concentrations. We have compared PLK‐4 with other kinases to understand its similarity based on multiple sequence alignments from protein sequences of primary structures, outer and buried residues, and compact active site conservation based on three‐dimensional motifs. These in‐depth studies provide information on known interface targets and design of more selective inhibitors to PLK‐4. Further, pharmacophore features based on CFI‐400945 bound to PLK‐4 were used for searching library of compounds that were screened using deep learning methods to bind PLK‐4. The shortlisted molecules were docked into PLK‐4 active site and were validated using molecular docking and molecular dynamics simulations studies. MM‐PBSA calculations revealed the stability of hit molecules and PLK‐4 complexes in comparison with CFI‐400945 and the contribution to binding from key active site residues.
Frontiers in G‐Quadruplex therapeutics in cancer: Selection of small molecules, peptides and aptamers
Authors: Banerjee Nilanjan , Panda Suman , Chatterjee Subhrangsu
Published: June 2021

G‐Quadruplex, a unique secondary structure in nucleic acids found throughout human genome, elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, RNAs and telomere, G‐Quadruplex structure regulates transcription, translation, splicing, etc. Changes in its structure and stability leads to differential expression of oncogenes causing cancer. Thus, targeting G‐Quadruplex structures with small molecules/other biologics has shown elevated research interest. Covering previous reports, in this review, we try to enlighten the facts on the structural diversity in G‐Quadruplex ligands aiming to provide newer insights to design first‐in‐class drugs for the next‐generation cancer treatment.
Intrinsic drug potential of oxazolo[5,4‐d]pyrimidines and oxazolo[4,5‐d]pyrimidines
Authors: Zhirnov Victor V. , Velihina Yevheniia S. , Mitiukhin Oleg P. , Brovarets Volodymyr S.
Published: June 2021

The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine‐based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their importance for development and discovery of newer potential therapeutic agents (Curr Top Med Chem, 16, 2016, 3133; Int J Pharm Pharm Sci, 8, 2016, 8; BMC Chem, 13, 2019, 44). For a long time, relatively little attention has been paid to their fused rings that are oxazolopyrimidines, whose chemical structure is similar to that of natural purines because probably none of these compounds were found in natural products or their biological activities turned out to be unexpressed (Bull Chem Soc Jpn, 43, 1970, 187). Recently, however, a significant number of studies have been published on the biological properties of oxazolo[5,4‐d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the regulation of the cell life cycle, whereas oxazolo[4,5‐d]pyrimidines, on the contrary, represent a poorly studied class of compounds. Limited access to this scaffold has resulted in a corresponding lack of biological research (Eur J Organ Chem, 18, 2018, 2148). Actually, oxazolo[5,4‐d]pyrimidine is a versatile scaffold used for the design of bioactive ligands against enzymes and receptors. This review focuses on biological targets and associated pathogenetic mechanisms, as well as pathological disorders that can be modified by well‐known oxazolopyrimidines that have been proven to date. Many molecular details of these processes are omitted here, which the interested reader will find in the cited literature. This work also does not cover the methods for the synthesis of the oxazolopyrimidines, which are exhaustively described by De Coen et al. (Eur J Organ Chem, 18, 2018, 2148). The review as well does not discuss the structure–activity relationship, which is described in detail in the original works and deliberately, whenever possible, cites not primary sources, but mostly relevant review articles, so that the reader who wants to delve into a particular problem will immediately receive more complete information. It is expected that the information presented in this review will help readers better understand the purpose of the development of oxazolopyrimidines and the possibility of their development as drugs for the treatment of a wide range of diseases.
Fragment‐based screening and hit‐based substructure search: Rapid discovery of 8‐hydroxyquinoline‐7‐carboxylic acid as a low‐cytotoxic, nanomolar metallo β‐lactamase inhibitor
Authors: Shin Woo Shik , Nguyen Megin E. , Bergstrom Alexander , Jennings Isabella R. , Crowder Michael W. , Muthyala Ramaiah , Sham Yuk Yin
Published: June 2021

Metallo‐β–lactamases (MBLs) are zinc‐containing carbapenemases that inactivate a broad range of β–lactam antibiotics. There is a lack of β–lactamase inhibitors for restoring existing β–lactam antibiotics arsenals against common bacterial infections. Fragment‐based screening of a non‐specific metal chelator library demonstrates 8‐hydroxyquinoline as a broad‐spectrum nanomolar inhibitor against VIM‐2 and NDM‐1. A hit‐based substructure search provided an early structure–activity relationship of 8‐hydroxyquinolines and identified 8‐hydroxyquinoline‐7‐carboxylic acid as a low‐cytotoxic β–lactamase inhibitor that can restore β–lactam activity against VIM‐2‐expressing E. coli. Molecular modeling further shed structural insight into its potential mode of binding within the dinuclear zinc active site. 8‐Hydroxyquinoline‐7‐carboxylic acid is highly stable in human plasma and human liver microsomal study, making it an ideal lead candidate for further development.
Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N‐formyl peptide receptors agonists
Authors: Vergelli Claudia , Khlebnikov Andrei I. , Crocetti Letizia , Guerrini Gabriella , Cantini Niccolò , Kirpotina Liliya N. , Schepetkin Igor A. , Cilibrizzi Agostino , Quinn Mark T. , Rossi Patrizia , Paoli Paola , Giovannoni Maria Paola
Published: June 2021

N‐formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4‐(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6‐membered compounds, all exhibiting the same 4‐bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five‐membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.
Fragment‐based in silico design of SARS‐CoV‐2 main protease inhibitors
Authors: Ahmad Sarfraz , Usman Mirza Muhammad , Yean Kee Lee , Nazir Mamoona , Abdul Rahman Noorsaadah , Trant John F. , Abdullah Iskandar
Published: June 2021

3CLpro is essential for SARS‐CoV‐2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography‐guided fragment‐based drug discovery approach was employed to design new inhibitors for SARS‐CoV‐2 3CLpro. All small molecules co‐crystallized with SARS‐CoV‐2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS‐CoV‐2 3CLpro inhibitors with improved binding, and structures are provided.
Ginkgetin alleviates high glucose‐evoked mesangial cell oxidative stress injury, inflammation, and extracellular matrix (ECM) deposition in an AMPK/mTOR‐mediated autophagy axis
Authors: Wei Lin , Jian Pan , Erjiong Huang , Qihan Zhu
Published: June 2021

Diabetic nephropathy constitutes the leading cause for end‐stage kidney disease. Ginkgetin is a common natural non‐toxic biflavone and fulfills pleiotropic pharmacological characterizations, such as anti‐inflammation and kidney injury. Nevertheless, its efficacy in diabetic nephropathy remains elusive. Here, ginkgetin exhibited little cytotoxicity in glomerular mesangial cells. Of note, ginkgetin restrained high glucose (HG)‐induced mesangial cell proliferation and oxidative stress by inhibiting ROS and malonaldehyde levels, but enhancing antioxidant SOD activity. Additionally, ginkgetin suppressed HG‐evoked transcript and release of inflammatory cytokine TNF‐α, IL‐1β, and IL‐6. Concomitantly, the increased extracellular matrix (ECM) deposition in HG‐treated glomerular mesangial cells was attenuated by ginkgetin via decreasing expression of collagen IV, fibronectin, and laminin. Intriguingly, ginkgetin‐restored HG‐impaired autophagy; whereas blocking autophagy by its inhibitor 3‐MA overturned ginkgetin function against HG‐evoked mesangial cell dysfunction. Mechanistically, ginkgetin‐mediated AMPK/mTOR axis accounted for HG‐impaired autophagy. Importantly, blockage of AMPK signaling reversed ginkgetin‐restored autophagy and its protective efficacy against HG‐induced dysfunction in mesangial cells. Thus, these findings highlight that ginkgetin may attenuate HG‐evoked mesangial cell hyperplasia, oxidative stress, inflammation, and ECM accumulation by activating AMPk/mTOR‐mediated autophagy pathway. Therefore, ginkgetin may alleviate the progression of diabetic nephropathy by regulating glomerular mesangial cell dysfunction, supporting a promising therapeutic agent against diabetic nephropathy.
Chromium and cobalt release from metallic earrings from the Danish market
Authors: Wennervaldt Michael , Ahlström Malin G. , Menné Torkil , Haulrig Morten B. , Alinaghi Farzad , Thyssen Jacob P. , Johansen Jeanne D.
Published: June 2021

Background

Chromium and cobalt are important skin sensitizers. It has, however, been difficult to identify causative exposures. Studies on nickel allergy have demonstrated piercing as critical for both sensitization and elicitation. It may be speculated that the same applies for chromium and cobalt.

Objective

To examine the content and release of chromium and cobalt from earrings randomly purchased in Denmark.

Methods

Three hundred four earrings were examined with x‐ray fluorescence (XRF) spectrometry. Earrings with measured content of chromium or cobalt were spot tested with diphenylcarbazide spot test (n = 166) or Nitroso‐R spot‐test (n = 99), respectively. Chromium and cobalt release were quantified in a selected subsample (n = 100) with the artificial sweat test (EN 1811).

Results

Chromium was present in 54.6% (166/304) of earrings and cobalt was present in 72.0% (219/304),− measured by XRF. All chromium spot tests for chromium VI were negative. The cobalt spot test was positive for one component. Chromium release was found from 59/100 (median concentration = −0.06 μg/cm2/week) and cobalt release from 29/100 (median concentration = −0.06 μg/cm2/week) of earrings in tested subsample.

Conclusion

Earrings for piercing release chromium and cobalt and may on a case basis be a source of chromium and cobalt allergy.
Are prescription drug monitoring laws effective for all? Evidence from administrative data
Authors: Gupta Sumedha , Al Achkar Morhaf , Ray Bradley
Published: June 2021

States have responded to the opioid epidemic by implementing statewide prescription drug monitoring programs (PDMPs). By helping identify patients at “high risk” for suspected misuse, diversion, and doctor shopping, mandatory PDMPs aim to reduce prescription‐opioid misuse and related overdose mortality. So far, however, there is little research on whether prescribing declines following mandatory PDMP laws were targeted toward patient‐age groups with a higher incidence of prescription‐opioid misuse. To examine the heterogeneous impacts of state laws on different patient‐age groups, this study exploits the implementation of PDMP reforms in Kentucky starting July 20, 2012. The analysis uses novel data from PDMPs, including the universe of opioid prescriptions dispensed between January 2012 and November 2013. Individual prescriber‐level difference‐in‐differences, with Indiana as the control state, show that practitioners responded to Kentucky's new laws as expected, by prescribing opioids to fewer patients and authorizing fewer prescriptions and days of supply per prescription. Opioid prescribing declined most sharply to patient sub‐populations with the highest past incidence of prescription‐opioid‐involved overdose mortality—ages 25–54 years. Considering the implication for overdose mortality, we find that Kentucky's PDMP reform was associated with significant declines in prescription‐opioid overdose deaths, particularly among adolescents and younger adults (ages 15–34 years). However, the decline in prescription‐opioid‐involved mortality was offset by an increase in illicit‐drug mortality, resulting in no net change in total drug‐overdose mortality in Kentucky following its mandatory PDMP.
Predictive model for atrial fibrillation in hypertensive diabetic patients
Authors: Abellana Rosa , Gonzalez‐Loyola Felipe , Verdu‐Rotellar Jose‐Maria , Bustamante Alejandro , Palà Elena , Clua‐Espuny Josep Lluis , Montaner Joan , Pedrote Alonso , del Val‐Garcia Jose Luis , Ribas Segui Domingo , Muñoz Miguel Angel
Published: June 2021

Background

Several scores to identify patients at high risk of suffering atrial fibrillation have been developed. Their applicability in hypertensive diabetic patients, however, remains uncertain. Our aim is to develop and validate a diagnostic predictive model to calculate the risk of developing atrial fibrillation at five years in a hypertensive diabetic population.

Methods

The derivation cohort consisted of patients with both hypertension and diabetes attended in any of the 52 primary healthcare centres of Barcelona; the validation cohort came from the 11 primary healthcare centres of Terres de l’Ebre (Catalonia South) from January 2013 to December 2017. Multivariable Cox regression identified clinical risk factors associated with the development of atrial fibrillation. The overall performance, discrimination and calibration of the model were carried out.

Results

The derivation data set comprised 54 575 patients. The atrial fibrillation rate incidence was 15.3 per 1000 person/year. A 5‐year predictive model included age, male gender, overweight, heart failure, valvular heart disease, peripheral vascular disease, chronic kidney disease, number of antihypertensive drugs, systolic and diastolic blood pressure, heart rate, thromboembolism, stroke and previous history of myocardial infarction. The discrimination of the model was good (c‐index = 0.692; 95% confidence interval, 0.684‐0.700), and calibration was adequate. In the validation cohort, the discrimination was lower (c‐index = 0.670).

Conclusions

The model accurately predicts future atrial fibrillation in a population with both diabetes and hypertension. Early detection allows the prevention of possible complications arising from this disease.
Subcontracting and the incidence of change orders in procurement contracts
Authors: Jung Hojin , Kosmopoulou Georgia , Press Robert , Sicotte Richard
Published: June 2021

In public procurement, most contracts are renegotiated ex post and involve subcontractors. We examine whether there is a causal link between subcontractor use and the incidence of change orders to amend the original scope of a project. Since subcontracting is likely related to unobserved project complexity, we use a novel IV, the predicted level of subcontracting from a method modeled after Christakis et al. (2010), to estimate the likelihood of renegotiation. The results establish that subcontractors are associated with an increased likelihood of change orders as well as a higher dollar amount renegotiated.
Online dental trauma course for medical education
Authors: Yeng Thai , O’Sullivan Anthony J. , Shulruf Boaz
Published: June 2021

A literature review identified a knowledge deficit among medical doctors about dental trauma management. To overcome this knowledge gap, a proposal to integrate dental traumatology teaching into the medical curriculum was made to raise medical students' awareness of, and familiarity with managing dental injuries. Despite the challenges of teaching dental trauma, online courses are viewed as a practical learning approach for students to access course material during their busy university schedules. In focusing on the constructivist model, this article details the design and development of the online dental trauma course. It is an example of a learner‐led, fully online course. The six steps involved in the course development were as follows: (1) structured order from preclinical to clinical topics; (2) content covering all essential information on TDI diagnosis and management; (3) illustrative materials to support engagement and motivation to complete the course; (4) feedback processes to evaluate the learning process; (5) interactions between peers, educators, and learning materials to help facilitate learning; and (6) content that encompasses mainly visual learning styles. The online dental trauma course has the potential to make important contributions to medical education.
Benefits, positive factors and difficulties perceived by mentors participating in a mentoring programme aimed at youth in residential care
Authors: Garcia‐Molsosa Marta , Collet‐Sabé Jordi , Montserrat Carme
Published: June 2021

Mentoring programmes targeting young people in residential care need to promote long‐term mentorships. Youth in residential care are a sensitive population that can be particularly affected by the ending of a mentorship relationship, due to their troubled bonding history. However, little is known about the difficulties mentors may encounter in such programmes, how to help mentors overcome problems, have a good mentoring experience and, ultimately, how to retain mentors. Within the framework of a pilot mentoring program aimed at youth in residential care carried out in five European countries, a two‐phase study was designed to (1) explore positive factors and difficulties faced by mentors and (2) analyse the perceived benefits of participating in such a program. This article reports on findings from sixteen interviews with mentors in Spain and a survey of 62 mentors in Austria, Croatia, France, Germany and Spain. Factors that contribute to promoting a better mentoring experience and longer‐term mentorships include taking care of the relationship between mentor and youth in residential care, encouraging youth in residential care to participate in decision‐making and promoting collaboration between stakeholders. Minimising the impact of negative external factors from different contexts is also important. Finally, a key role is played by reinforcing mentor well‐being, personal growth, socialisation and social awareness. [Correction added on 09 August 2021, after first online publication: The fifth sentence has been updated with more details of the mentors.]
Making Sense of War Memories: An Analysis of Dutch Veteran Return Trips to Former Yugoslavia
Authors: Driessen Siri
Published: June 2021

This article analyzes the war memories and processes of meaning‐making of Dutch veterans who returned to places related to their deployment in former Yugoslavia in the 1990s. It argues that the incentive to return can be found in the difficulties that veterans have in assigning positive meaning to their deployment because existing collective and cultural memories about the war and the genocide in Srebrenica do not align with many of the veterans’ experiences during and after the war. In the analysis of interviews conducted with seventeen Dutch veterans, attention is paid to their wartime memories, motivation to return, and experiences during the return trips. Returning to former places of deployment provides a way to reconcile memories, especially traumatic ones. The building of these memories passes through several phases: introspection; opening up to family, friends, and relatives; and helping others.
Fishing behaviours and fisher effect in decision‐making processes when facing depredation by marine predators
Authors: Janc Anaïs , Guinet Christophe , Pinaud David , Richard Gaëtan , Monestiez Pascal , Tixier Paul
Published: June 2021

Fishers aim to optimise cost–benefit ratios of their behaviour when exploiting resources. Avoidance of interactions with marine predators (i.e. their feeding on catches in fishing gear, known as depredation) has recently become an important component of their decisions. How fishers minimise these interactions whilst maximising fishing success is poorly understood. This issue is addressed in a sub‐Antarctic, long‐line fishery confronted with extensive depredation by sperm whales Physeter macrocephalus and killer whales Orcinus orca by examining a 15‐year data set. Whereas a broad range of behaviours was identified from spatio‐temporal and operational descriptors, none combined high fishing success with low frequency of interactions. With experience, fishers favoured exploitation of productive patches with high frequencies of interactions over avoidance behaviours. Such decisions, although potentially optimal in the short term, are likely to intensify pressures on fish stocks and impact depredating whales. Therefore, the present study provides additional evidence to inform management decisions pertaining to the coexistence between fisheries and marine predators.
“Nobody likes a whistleblower.” Witnessing silenced racism and homophobia at work
Authors: Lescoat Pierre
Published: June 2021

In France, racist acts and riots appear consistently in the media. At the same time, racism in the French language is a debated concept often reduced to a matter of geography or class. In this short essay, I tell the story of 4 friends who experienced racism in an international, upper‐class community, stressing the diversity of their reactions. In the workplace, someone who speaks up runs the risk of losing his/her reputation, which maintains racism in organizations. I extend the analysis of silence with how the word “race” is silenced in the French language, limiting the ability to know and face racism. I end up with a reflexive account of film and its ability to reveal my own unconscious racism. This is a call to create a diversity of discourses so that new forms of subjectivizations emerge to collectively fight racism and all forms of discriminations.
NTRK fusions are extremely rare in bone tumours
Authors: Lam Suk Wai , Briaire‐de Bruijn Inge H , van Wezel Tom , Cleven Arjen H G , Hogendoorn Pancras C W , Cleton‐Jansen Anne‐Marie , Bovée Judith V M G
Published: June 2021

Aims

Because of the efficacy of tropomyosin receptor kinase (Trk) inhibitor therapy in tumours with rearrangements of the neurotrophic tyrosine kinase receptor genes (NRTK genes), there has been a surge in demand for NTRK fusion screening. To date, most studies involving mesenchymal tumours have focused on soft tissue tumours, and data on bone tumours are sparse. Hence, we aimed to explore the frequency of NTRK fusions in a large series of primary bone tumours.

Methods and results

Immunohistochemical expression of pan‐Trk was successfully assessed in 354 primary bone tumours by the use of tissue microarrays. In a selection of positive cases, additional molecular analysis for NTRK fusions was performed with anchored multiplex polymerase chain reaction‐based targeted next‐generation sequencing. Positivity was found in 19 cases (5%), which comprised Ewing sarcoma (n = 6, 33%), osteosarcoma (n = 11, 13%), and giant‐cell tumour of bone (n = 2, 3%). In all except one case, cytoplasmic staining was observed. Weak staining was most often observed (n = 13), although five cases showed moderate staining and one case showed focal strong staining. Molecular analysis was successful in six cases, all of which were negative for NTRK fusions.

Conclusion

The likelihood of finding an NTRK fusion in bone tumours in clinical practice is extremely low. This may imply that, if more comprehensive large‐scale molecular studies confirm this, routine predictive NTRK testing in bone tumour patients with advanced disease may be reconsidered.
Essential jobs, remote work and digital surveillance: Addressing the COVID‐19 pandemic panopticon
Authors: ALOISI Antonio , DE STEFANO Valerio
Published: June 2021

An unprecedented COVID‐19‐induced explosion in digital surveillance has reconfigured power relationships in professional settings. This article critically concentrates on the interplay between technology‐enabled intrusive monitoring and the augmentation of managerial prerogatives in physical and digital workplaces. It identifies excessive supervision as the common denominator of “essential” and “remotable” activities, besides discussing the various drawbacks faced by the two categories of workers during (and after) the pandemic. It also assesses the adequacy of the current European Union legal framework in addressing the expansion of data‐driven management. Social dialogue, workers' empowerment and digital literacy are identified as effective ways to promote organizational flexibility, well‐being and competitiveness.
Support for and willingness to be involved in voluntary assisted dying: a multisite, cross‐sectional survey study of clinicians in Victoria, Australia
Authors: Sellars Marcus , Tacey Mark , McDougall Rosalind , Hayes Barbara , Pratt Bridget , Hempton Courtney , Detering Karen , Aldrich Rosemary , Benson Melanie , Kirwan Jeffrey , Gold Michelle , O'Driscoll Lisa , Ko Danielle
Published: June 2021

Background

In the Australian state of Victoria, specialist doctors are central to the operation of voluntary assisted dying (VAD). However, a broad range of clinicians may be involved in the care of patients requesting or using VAD.

Aims

To describe levels of support for and willingness to be involved in VAD and consider factors associated with clinician support for the VAD legislation and physicians' willingness to provide VAD in practice.

Methods

A multisite, cross‐sectional survey of clinicians in seven Victorian hospitals. All clinicians were invited to complete an online survey measuring demographic characteristics, awareness of and support for the VAD legislation, willingness to participate in VAD related activities and reasons for willingness or unwillingness to participate in VAD.

Results

Of 5690 who opened the survey, 5159 (90.1%) were included in the final sample and 73% (n = 3768) supported the VAD legislation. The strongest predictor of support for the VAD legislation was clinical role. Forty percent (n = 238) of medical specialists indicated they would be willing to participate in either the VAD consulting or coordinating role. Doctors did not differ in willingness between high impact (44%) and low impact specialty (41%); however, doctors specialising in palliative care or geriatric medicine were significantly less willing to participate (27%).

Conclusion

Approximately 73% of surveyed staff supported Victoria's VAD legislation. However, only a minority of medical specialists reported willingness to participate in VAD, suggesting potential access issues for patients requesting VAD in accordance with the legal requirements in Victoria.
The ‘new normal’ in post–COVID‐19 pediatric dental practice
Authors: Maru Viral
Published: June 2021

The COVID‐19 pandemic has posed an extraordinary challenge to the world. Dental healthcare personnel are considered to be at high risk as they work in close proximity to the oral cavity of patients. New procedures of approach and management should be incorporated in different aspects of routine dental practice. In addition, pediatric dentists are posed with unique and extraordinary challenges of parental anxiety and behavioral guidance of pediatric patients and parents/guardians. The aim of this study was to highlight the changing perceptions of pediatric dental practice as the ‘new normal’ in the post‐COVID era.
Correlates of extinction risk in Australian squamate reptiles
Authors: Senior Anna F. , Böhm Monika , Johnstone Christopher P. , McGee Matthew D. , Meiri Shai , Chapple David G. , Tingley Reid
Published: June 2021

Aim

Identification of particular traits that predispose species to elevated extinction risk is an important component of proactive conservation. We capitalise on a recent strategic extinction risk assessment of all Australian squamate reptiles to identify intrinsic life history traits and extrinsic threats that correlate with extinction risk. We further assess whether extinction risk correlates differ between species impacted by different threatening processes (habitat loss vs. invasive species).

Location

Australia.

Taxon

Squamate reptiles.

Methods

We used the IUCN Red List data for Australian squamates, and publicly available datasets for 14 intrinsic and extrinsic traits. We used phylogenetically controlled Bayesian inference to test hypotheses regarding relationships between extinction risk and species traits, environment, and threat measures.

Results

We found that intrinsic characteristics (habitat specialisation, small range size and large body size), as well as extrinsic factors (high human footprint, accessibility from human population centres, cold temperatures and high rainfall), predispose a species to extinction. Similar predictors were important in threat‐specific analyses, although relationships were generally more uncertain.

Conclusions

Our results largely accord with those of global and regional studies of extinction risk in reptiles and of terrestrial vertebrates more broadly. Our findings illustrate that there is no single pathway to extinction among Australian squamates.
Tissue remodelling and increased DNA damage in patients with incompetent valves in chronic venous insufficiency
Authors: Ortega Miguel A. , Fraile‐Martínez Oscar , García‐Montero Cielo , Pekarek Leonel , Alvarez‐Mon Miguel A. , Guijarro Luis G. , del Carmen Boyano Maria , Sainz Felipe , Álvarez‐Mon Melchor , Buján Julia , García‐Honduvilla Natalio , Asúnsolo Ángel
Published: June 2021

Chronic venous insufficiency (CVI), in which blood return to the heart is impaired, is a prevalent condition worldwide. Valve incompetence is a complication of CVI that results in blood reflux, thereby aggravating venous hypertension. While CVI has a complex course and is known to produce alterations in the vein wall, the underlying pathological mechanisms remain unclear. This study examined the presence of DNA damage, pro‐inflammatory cytokines and extracellular matrix remodelling in CVI‐related valve incompetence. One hundred and ten patients with CVI were reviewed and divided into four groups according to age (<50 and ≥50 years) and a clinical diagnosis of venous reflux indicating venous system valve incompetence (R) (n = 81) or no reflux (NR) (n = 29). In vein specimens (greater saphenous vein) from each group, PARP, IL‐17, COL‐I, COL‐III, MMP‐2 and TIMP‐2 expression levels were determined by RT‐qPCR and immunohistochemistry. The younger patients with valve incompetence showed significantly higher PARP, IL‐17, COL‐I, COL‐III, MMP‐2 and reduced TIMP‐2 expression levels and a higher COL‐I/III ratio. Young CVI patients with venous reflux suffer chronic DNA damage, with consequences at both the local tissue and systemic levels, possibly associated with ageing.
Retrospective study of phaeohyphomycosis in aquarium‐housed fish, with first descriptions of Exophiala lecanii‐corni and Neodevriesia cladophorae in fish
Authors: Armwood Abigail R. , Cañete‐Gibas Connie F. , Dill‐Okubo Jennifer A. , Wiederhold Nathan P. , Camus Alvin C.
Published: June 2021

A broadening fish host range is affected by novel and known pigmented fungal pathogens. A review of 2,250 piscine submissions received by the Aquatic Pathology Service, University of Georgia, revealed 47 phaeohyphomycosis cases (2.1%), representing 34 bony and cartilaginous fish species. The majority involved bony fish (45/47, 95.7%) and were predominantly marine (41/47, 87.2%), with only a few freshwater species (4/47, 8.5%). Cartilaginous fish cases included two zebra sharks (Stegostoma fasciatum) (2/47, 4.3%). Northern seahorses (Hippocampus erectus) had the highest incidence overall (7/47, 14.9%). Culture and sequencing of the internal‐transcribed spacer region of the rDNA (ITS), large ribosomal subunit gene D1/D2 domains (LSU) and the DNA polymerase II gene (RPB2) were performed for fungal identification when fresh tissue was obtainable. Exophiala, Ochroconis and Neodevriesia spp. were identified, with Exophiala as the most common fungal genus (8/11, 72.7%). Exophiala lecanii‐corni and Neodevriesia cladophorae were described for the first time from fish. Microscopically, lesions were characterized by necrosis, granulomatous inflammation and angioinvasion most frequently affecting the skin/fin, skeletal muscle and kidneys. In this study of diverse aquarium‐housed fish species, phaeohyphomycosis cases occurred sporadically and in rare outbreaks with variable pathologic presentations, tissue distributions and severities.
Effect of septal deviation on nasomaxillary shape: A geometric morphometric study
Authors: Abou Sleiman Roni , Saadé Antoine
Published: June 2021

Nasal cavities in their primitive stage communicate with the oral cavity until the 8th week of intrauterine life where the posterior palate initiates its development. Hence, starting from the initial growth phases, a significant connection lays between the nasal structures and the maxillary bone and witnessing key functional roles, among which the respiration. Proper nasal breathing has been proven to be a crucial factor for the maturity of the craniofacial complex, and obstruction of the respiratory airway due to nasal septum deviation can generate clinically significant reduction of the nasal airflow. This situation will imply irreversible repercussions that hinders the harmonious development of the craniofacial complex. In order to understand such potential impacts of septal deviation, our first objective was to materialize the relation between septum deviation, and both nasal cavity and maxillary structures. For the second objective, we used Procrustes analysis to assess the shape variation of these two anatomical regions, the bivariate plots of Principal Components to evaluate their shape space, and a two‐block Partial Least Square (PLS) to explore their covariation. We analysed, in this cross‐sectional study, 62 posteroanterior cephalometric radiographs of adult subjects from both sexes (23 males, 39 females; mean age 25.3 years) collected from the database of the Department of Orthodontics at Lebanese University. Landmarks were plotted and variables were calculated and divided into nasal septum, nasal cavity and maxillary ones. The sample was further divided into two groups based on septal deviation severity (a septal deviation is considered minor if <6). The results suggested that nasal septum deviation was correlated to reduced nasal cavity area and a reduced maxillary area. Moreover, the comparison of the two groups concluded that the difference between all variables was statistically significant with higher scores in the minor septal deviation group. These findings were corroborated with the shape analysis where the mean centroid size of nasal cavity and that of the maxilla in the group of reduced septal deviation were significantly greater than those of the group with increased angle of deviation. Results of PLS analysis concluded to a strong covariation between nasal septum and nasomaxillary complex. These conclusions support the early septoplasty in growing patients as a solution to redirect the normal course of growth and re‐establish a good function of the nasomaxillary complex.
“There are traitors among us”: On the Emotional Vicissitudes of Populist Politics
Authors: Fierman Julia
Published: June 2021

This article examines fellowship and accusations of betrayal among members of a populist movement in contemporary Argentina. Drawing on ethnographic fieldwork conducted among self‐described “militants” of the Kirchnerist movement, a contemporary iteration of Peronism, this work makes a uniquely anthropological intervention into existing literature on populist politics, which tends to focus on populism’s demonization of the enemy of “the people.” In contrast, this article argues that a focus on the demonization of an external enemy misses essential dimensions of the social world of Peronist politics, which is primarily characterized by loving bonds of fellowship between Peronist militants. I show how, in moments of uncertainty, this emphasis on fellowship morphs into a preoccupation with treachery, such that concern with the potential insubordination of one’s fellow Peronists eclipses animus towards external enemies. This article argues for greater attention to the lived experiences of adherents to populist movements to encourage a more holistic and nuanced understanding of the social world of populist politics.
Excreta quality and digestive function of singly versus couple caged Sardinian partridges (Alectoris barbara barbara Bonnaterre, 1790) as non‐invasive indicators of birds’ coping ability to forced pairing
Authors: Ahmed Fahad , Pudda Flavia , Muzzeddu Marco , Schiavone Achille , Varcasia Antonio , Nery Joana , Serra Giuseppe , Seidavi Alireza , Cappai Maria Grazia
Published: June 2021

The Sardinian partridge is a monogamous wild bird species of least concern according to IUCN list at present, though formerly accounted among threatened species for decades. The creation of couples is crucial in captivity, because forced pairing in cages can lead to poor welfare of birds, specially of females. This study investigated the impact of single versus couple caging of Sardinian partridges during non‐laying period based on the collection and interpretation of indirect and non‐invasive parameters (feed intake; space availability; excreta quality; and nutrient utilization). A total of 24 couples of breeding partridges were enrolled for two consequent phases of a same investigation (lasting 15 days each). During phase 1, all couples were fed ad libitum with a pelleted complete diet (DM, 905 g kg−1 of diet; CP, 160 g kg−1; and EE, 25 g kg−1). In phase 2, each male from 12 out of 24 couples was moved to an identical cage close to that where the female remained alone, to keep visual contact. The rest of couples continued to be kept like in phase 1. During phases 1 and 2, feed intake and excreta outputs were recorded daily. Pooled excreta of the last 3 days from couples and single birds were assessed for pH and DM, CP and ash content. Nutrient digestibility was calculated. No significant differences were noted between single versus couple caging regarding body weight (438 vs. 422 g respectively) or nutrient digestibility. However, singly housed males reduced daily feed intakes and females increased daily feed intake per g−1 BW (0.041 vs. 0.052 g, respectively, p < 0.001). Our results suggest that singly caged partridges from permanent couples can improve the access to feed and reduce competition during the non‐mating season.