bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractN‐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

Abstract3CLpro 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

AbstractDiabetic 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

AbstractBackgroundChromium 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.ObjectiveTo examine the content and release of chromium and cobalt from earrings randomly purchased in Denmark.MethodsThree 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).ResultsChromium 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.ConclusionEarrings 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

AbstractStates 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

AbstractBackgroundSeveral 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.MethodsThe 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.ResultsThe 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).ConclusionsThe 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

AbstractIn 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

AbstractA 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

AbstractMentoring 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

AbstractThis 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

AbstractFishers 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

AbstractIn 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

AimsBecause 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 resultsImmunohistochemical 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.ConclusionThe 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

AbstractAn 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

AbstractBackgroundIn 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.AimsTo 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.MethodsA 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.ResultsOf 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%).ConclusionApproximately 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

AbstractThe 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.