bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA)
Authors: Cenko Edina , Badimon Lina , Bugiardini Raffaele , Claeys Marc J , De Luca Giuseppe , de Wit Cor , Derumeaux Geneviève , Dorobantu Maria , Duncker Dirk J , Eringa Etto C , Gorog Diana A , Hassager Christian , Heinzel Frank R , Huber Kurt , Manfrini Olivia , Milicic Davor , Oikonomou Evangelos , Padro Teresa , Trifunovic-Zamaklar Danijela , Vasiljevic-Pokrajcic Zorana , Vavlukis Marija , Vilahur Gemma , Tousoulis Dimitris
Published: September 2021

The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as ‘post-acute COVID-19’ may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.
Third-party induced cyber incidents—much ado about nothing?
Authors: Benaroch Michel
Published: September 2021

Growing reliance on third-party services, such as cloud computing, is believed to increase client firms’ exposure to third-party induced cyber incidents. However, we lack empirical research on the prevalence and scale of third-party induced cyber incidents. Moreover, we do not know who pays more of the price for experiencing these incidents—the client firm and/or the third-party provider firm. We study these questions using a sample of 1397 cyber incidents in public firms between 2000 and 2020 of which 246 are third-party induced incidents. Our findings offer several novel insights. Third-party induced cyber incidents are not growing in prevalence any faster than other incidents, but they do compromise greater volumes of confidential data per incident. As to the price paid for third-party induced incidents, the picture is more nuanced. Client (first-party) firms suffer drops in equity returns that are comparable to those for homegrown incidents, while small third-party provider firms suffer significantly larger drops in equity returns and large third-party provider firms do not suffer a discernible drop in equity returns. We discuss implications of these findings for client firms and service providers.
COVIDium: a COVID-19 resource compendium
Authors: Satyam Rohit , Yousef Malik , Qazi Sahar , Bhat Adil Manzoor , Raza Khalid
Published: September 2021

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) disrupted the normal functioning throughout the world since early 2020 and it continues to do so. Nonetheless, the global pandemic was taken up as a challenge by researchers across the globe to discover an effective cure, either in the form of a drug or vaccine. This resulted in an unprecedented surge of experimental and computational data and publications, which often translated their findings in the form of databases (DBs) and tools. Over 160 such DBs and more than 80 software tools were developed, which are uncharacterized, unannotated, deployed at different universal resource locators and are challenging to reach out through a normal web search. Besides, most of the DBs/tools are present on preprints and are either underutilized or unrecognized because of their inability to make it to top Google search hits. Henceforth, there was a need to crawl and characterize these DBs and create a compendium for easy referencing. The current article is one such concerted effort in this direction to create a COVID-19 resource compendium (COVIDium) that would facilitate the researchers to find suitable DBs and tools for their research studies. COVIDium tries to classify the DBs and tools into 11 broad categories for quick navigation. It also provides end-users some generic hit terms to filter the DB entries for quick access to the resources. Additionally, the DB provides Tracker Dashboard, Neuro Resources, references to COVID-19 datasets and protein–protein interactions. This compendium will be periodically updated to accommodate new resources.

Database URL: The COVIDium is accessible through http://kraza.in/covidium/
Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials
Authors: Ortega-Paz Luis , Galli Mattia , Capodanno Davide , Franchi Francesco , Rollini Fabiana , Bikdeli Behnood , Mehran Roxana , Montalescot Gilles , Gibson C Michael , Lopes Renato D , Andreotti Felicita , Angiolillo Dominick J
Published: September 2021

Background

The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with coronavirus disease 2019 (COVID-19) remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic.

Methods and results

We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) vs. a standard-dose prophylactic anticoagulation regimen in critically and non-critically ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5154 patients followed on an average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death [17.8% vs. 18.6%; risk ratio (RR) 0.96, 95% confidence interval (CI) 0.78–1.18] but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15–2.60). Compared to prophylactic anticoagulation used at a standard dose, an escalated dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41–0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47–1.36), stroke (RR 0.94, 95%CI 0.43–2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29–4.95). There were no significant interactions in the subgroup analysis for critically and non-critically ill patients.

Conclusions

Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity.

Study registration

This study is registered in PROSPERO (CRD42021257203).
Is the Way Forward to Step Back? Documenting the Frequency With Which Study Goals Are Misaligned With Study Methods and Interpretations in the Epidemiologic Literature
Authors: Kezios Katrina L
Published: September 2021

In any research study, there is an underlying process that should begin with a clear articulation of the study’s goal. The study’s goal drives this process; it determines many study features, including the estimand of interest, the analytic approaches that can be used to estimate it, and which coefficients, if any, should be interpreted. Misalignment can occur in this process when analytic approaches and/or interpretations do not match the study’s goal; misalignment is potentially more likely to arise when study goals are ambiguously framed. In this study, misalignment in the observational epidemiologic literature was documented and how the framing of study goals contributes to misalignment was explored. The following 2 misalignments were examined: use of an inappropriate variable selection approach for the goal (a “goal–methods” misalignment) and interpretation of coefficients of variables for which causal considerations were not made (e.g., Table 2 Fallacy, a “goal–interpretation” misalignment). A random sample of 100 articles published 2014–2018 in the top 5 general epidemiology journals were reviewed. Most reviewed studies were causal, with either explicitly stated (n = 13; 13%) or associational-framed (n = 71; 69%) aims. Full alignment of goal–methods–interpretations was infrequent (n = 9; 9%), although clearly causal studies (n = 5 of 13; 38%) were more often fully aligned than were seemingly causal ones (n = 3 of 71; 4%). Goal–methods misalignments were common (n = 34 of 103; 33%), but most frequently, methods were insufficiently reported to draw conclusions (n = 47; 46%). Goal–interpretations misalignments occurred in 31% (n = 32) of the studies and occurred less often when the methods were aligned (n = 2; 2%) compared with when the methods were misaligned (n = 13; 13%).
Pacing therapy for atrioventricular dromotropathy: a combined computational–experimental–clinical study
Authors: Salden Floor C W M , Huntjens Peter R , Schreurs Rick , Willemen Erik , Kuiper Marion , Wouters Philippe , Maessen Jos G , Bordachar Pierre , Delhaas Tammo , Luermans Justin , Meine Mathias , Allaart Cornelis P , van Stipdonk Antonius M W , Prinzen Frits W , Lumens Joost , Vernooy Kevin
Published: September 2021

Aims

Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational–experimental–clinical study.

Methods and results

Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10–15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation.

Conclusion

Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval.
Screening Health-Promoting Compounds for Their Capacity to Induce the Activity of FOXO3
Authors: Jimenez Lucia , Silva Andreia , Calissi Giampaolo , Grenho Inês , Monteiro Rita , Mayoral-Varo Victor , Blanco-Aparicio Carmen , Pastor Joaquin , Bustos Victor , Bracher Franz , Megías Diego , Ferreira Bibiana I , Link Wolfgang
Published: September 2021

Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived β-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).
Does Adult Day Service Use Improve Well-Being of Black Caregivers of People Living With Dementia?
Authors: Parker Lauren J , Gitlin Laura N
Published: September 2021

Background and Objectives

Despite adult day services (ADS) being the most racially diverse home- and community-based service (HCBS), there is a paucity of research that has examined the impact of ADS on well-being measures among Black caregivers of people living with dementia. To address this gap, this study examined the association between the use of ADS and depressive symptoms among Black dementia caregivers.

Research Design and Methods

Using baseline data from 2 behavioral intervention trials, Advancing Caregiver Training (n = 72) and Care of Persons with Dementia in their Environments (n = 63), we conducted ordinary least squares regression to examine the association between ADS use in the past 6 months and depressive symptoms (n = 135). The dependent variable, depressive symptoms, was assessed by the 10-item Center for Epidemiologic Studies—Depression (CES-D) scale. The independent variable was assessed by self-report of ADS use in the past 6 months.

Results

Nearly 36% of the sample used ADS in the past 6 months. After controlling for caregiver characteristics associated with depression (burden, social support, self-rated health, caregiving relationship status, years caregiving, religious/spiritual coping, and demographic characteristics), caregivers who utilized ADS had a lowered CES-D score (B = −1.97, p = .03) compared to those who did not use ADS.

Discussion and Implications

Black dementia caregivers who utilized ADS had lower depressive symptoms compared to those who did not utilize ADS. ADS may be a critical HCBS that can provide relief to Black caregivers. Research is needed to examine additional benefits of ADS use among Black caregivers and the policy and programming needed to enhance access to ADS.
Desiderata for the development of next-generation electronic health record phenotype libraries
Authors: Chapman Martin , Mumtaz Shahzad , Rasmussen Luke V , Karwath Andreas , Gkoutos Georgios V , Gao Chuang , Thayer Dan , Pacheco Jennifer A , Parkinson Helen , Richesson Rachel L , Jefferson Emily , Denaxas Spiros , Curcin Vasa
Published: September 2021

Background

High-quality phenotype definitions are desirable to enable the extraction of patient cohorts from large electronic health record repositories and are characterized by properties such as portability, reproducibility, and validity. Phenotype libraries, where definitions are stored, have the potential to contribute significantly to the quality of the definitions they host. In this work, we present a set of desiderata for the design of a next-generation phenotype library that is able to ensure the quality of hosted definitions by combining the functionality currently offered by disparate tooling.

Methods

A group of researchers examined work to date on phenotype models, implementation, and validation, as well as contemporary phenotype libraries developed as a part of their own phenomics communities. Existing phenotype frameworks were also examined. This work was translated and refined by all the authors into a set of best practices.

Results

We present 14 library desiderata that promote high-quality phenotype definitions, in the areas of modelling, logging, validation, and sharing and warehousing.

Conclusions

There are a number of choices to be made when constructing phenotype libraries. Our considerations distil the best practices in the field and include pointers towards their further development to support portable, reproducible, and clinically valid phenotype design. The provision of high-quality phenotype definitions enables electronic health record data to be more effectively used in medical domains.
Rethinking the Virtuous Circle Hypothesis on Social Media: Subjective versus Objective Knowledge and Political Participation
Authors: Lee Sangwon , Diehl Trevor , Valenzuela Sebastián
Published: September 2021

Despite early promise, scholarship has shown little empirical evidence of learning from the news on social media. At the same time, scholars have documented the problem of information ‘snacking’ and information quality on these platforms. These parallel trends in the literature challenge long-held assumptions about the pro-social effects of news consumption and political participation. We argue that reliance on social media for news does not contribute to people’s real level of political knowledge (objective knowledge), but instead only influences people’s impression of being informed (subjective knowledge). Subjective knowledge is just as important for driving political participation, a potentially troubling trend given the nature of news consumption on social media. We test this expectation with panel survey data from the 2018 U.S. midterm elections. Two path model specifications (fixed effects and autoregressive) support our theoretical model. Implications for the study of the ‘dark side’ of social media and democracy are discussed.
Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia
Authors: Sleiman Sophie , Marshall Aren E , Dong Xiaomin , Mhanni Aziz , Alidou-D’Anjou Ismaël , Frosk Patrick , Marin Samantha E , Stark Zornitza , Del Bigio Marc R , McBride Arran , Sadedin Simon , Gallacher Lyndon ,   Care4Rare Canada Consortium, Christodoulou John , Boycott Kym M , Dragon François , Kernohan Kristin D
Published: September 2021

SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.
Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease
Authors: Bader-Meunier Brigitte , Martins Andreia Luís , Charbit-Henrion Fabienne , Meinzer Ulrich , Belot Alexandre , Cuisset Laurence , Faye Albert , Georgin-Lavialle Sophie , Quartier Pierre , Remy-Piccolo Vanessa , Ruemmele Frank , Uettwiller Florence , Viala Jérôme , Cerf Bensussan Nadine , Berrebi Dominique , Melki Isabelle
Published: September 2021

Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.
Intestinal Ultrasound to Evaluate Treatment Response During Pregnancy in Patients With Inflammatory Bowel Disease
Authors: De Voogd Floris , Joshi Harshad , Van Wassenaer Elsa , Bots Steven , D’Haens Geert , Gecse Krisztina
Published: September 2021

Introduction

Active disease in inflammatory bowel disease patients during pregnancy is associated with poor maternal and fetal outcomes. Objective evaluation of disease activity is a core strategy in IBD, and during pregnancy noninvasive modalities are preferred. We aimed to evaluate feasibility and accuracy of intestinal ultrasound (IUS) to objectify disease activity throughout pregnancy.

Methods

Pregnant patients with known IBD were included and followed throughout pregnancy for clinical disease activity, with fecal calprotectin (FCP) and with IUS every trimester. Feasibility of IUS was assessed for all colonic segments and terminal ileum (TI). Intestinal ultrasound outcomes to detect active disease and treatment response were compared with clinical scores combined with FCP.

Results

In total, 38 patients (22 CD, 16 UC) were included, with 27 patients having serial IUS. Feasibility of IUS decreases significantly in third trimester for TI (first vs third trimester: 91.3% vs 21.7%, P < .0001) and sigmoid (first vs third trimester: 95.6% vs 69.5%, P = .023). Intestinal ultrasound activity showed moderate to strong correlation with clinical activity (r = 0.60, P < .0001) and FCP (r = 0.73, P < .0001). Throughout pregnancy, IUS distinguished active from quiescent disease with 84% sensitivity and 98% specificity according to FCP combined with clinical activity. IUS showed disease activity in >1 segment in 52% of patients and detected treatment response with 80% sensitivity and 92% specificity.

Conclusions

IUS is feasible and accurate throughout pregnancy, although visualization of the sigmoid and TI decreases in the third trimester. IUS provides objective information on disease activity, extent, and treatment response, even during second and third trimester, and offers a noninvasive strategy to closely monitor patients during pregnancy.
Risk factors for prolonged air leak and need for intervention following lung resection
Authors: Dezube Aaron R , Dolan Daniel P , Mazzola Emanuele , Kucukak Suden , De Leon Luis E , Bueno Raphael , Marshall M Blair , Jaklitsch Michael T , Rochefort Matthew M
Published: September 2021

OBJECTIVES

Prolonged air leak (PAL; >5 days) following lung resection is associated with postoperative morbidity. We investigated factors associated with PAL and PAL requiring intervention.

METHODS

Retrospective review of all patients undergoing lobectomy, segmentectomy or wedge resection from 2016 to 2019 at our institution. Bronchoplastic reconstructions and lung-volume reduction surgeries were excluded. Incidence and risk factors for PAL and PAL requiring intervention were evaluated.

RESULTS

In total, 2384 patients were included. PAL incidence was 5.4% (129/2384); 22.5% (29/129) required intervention. PAL patients were more commonly male (56.6% vs 39.7%), older (mean age 69 vs 65 years) and underwent lobectomy or thoracotomy (all P < 0.001). Patients with PAL had longer length of stay (9 vs 3 days), more discharge needs and increased odds of complication (all P < 0.050).

Twenty-nine patients required intervention (9 chest tubes; 4 percutaneous drains; 16 operations). In 50% of operative interventions, an air leak source was identified; however, the median time from intervention to resolution was 13 days. Patients requiring intervention had increased steroid use, lower diffusion capacity for carbon monoxide and twice the length of stay versus PAL patients (all P < 0.050).

On univariable analysis, forced expiratory volume in 1 s (FEV1) <40%, diffusion capacity for carbon monoxide <50%, steroid use and albumin <3 had increased odds of intervention (P < 0.050).

CONCLUSIONS

Age, gender and operative technique were related to PAL development. Patients with worse forced expiratory volume in 1 s or diffusion capacity for carbon monoxide, steroid use or poor nutrition were less likely to heal on their own, indicating a population that could benefit from earlier intervention.
Clinical significance of part-solid lung cancer in the eighth edition TNM staging system
Authors: Okamoto Tatsuro , Miyawaki Michiyo , Toyokawa Gouji , Karashima Takashi , Abe Miyuki , Takumi Yohei , Hashimoto Takafumi , Osoegawa Atsuhi , Tagawa Tetsuzo , Takeuchi Hideya , Shimokawa Mototsugu , Sugio Kenji
Published: September 2021

OBJECTIVES

The ground-glass component of part-solid tumour (PST) was eliminated as a clinical T (cT) descriptor in the eighth edition of the tumour, node and metastasis (TNM) staging system. We aimed to validate the new cT descriptor and investigate the prognostic impact of PST in the new staging system.

METHODS

Non-small-cell lung cancer (NSCLC) patients (n = 1061) who underwent lung resection and were available for the assessment of thin-section computed tomography images were retrospectively reviewed. Tumours with a solid component (SC) size-to-whole tumour size (STR) ratio of 0, those with 0 < STR < 1 and those with an STR of 1 were defined as pure ground-glass tumours, PSTs and solid tumours (STs), respectively.

RESULTS

Tumours with an SC diameter of >30 mm were less frequently observed among PSTs than among STs (4.83% vs 32.6%, P < 0.001). The postoperative 5-year survival of NSCLC patients with ground-glass tumour, PST and ST was 97.6%, 89.0% and 76.3%, respectively. In the survival analysis of patients with an SC diameter ≤30 mm, significant differences were observed among PST and ST (5-year survival, 90.7% vs 74.6%, P < 0.001). The multivariable analysis showed that age <70 years old, female sex, procedures with a lobectomy or more, SC size, pN0 disease and PST were independent predictors of a better survival among all PST and ST patients.

CONCLUSIONS

Among patients with cT1 tumours, those with PST showed a significantly better survival than did those with ST. Small-sized PST tumours may not be suitable for the new cT descriptor.
The remodelled intersection between copyright and antitrust law to straighten the bargaining power asymmetries in the digital platform economy
Authors: Iaia Vincenzo
Published: September 2021

This article provides an assessment of the interplay between copyright, contract freedom and antitrust law in the current digital platform economy, as it was settled by the European legal strategy for a (fair) digital single market. It primarily focuses on the Digital Single Market (DSM) Directive and the Digital Markets Act (DMA) Proposal, evaluating if competition law instruments represent exceptional or structural remedies to correct the current failures of contract freedom and copyright enforcement within the delicate balance between authors, editors and online platforms.
The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A
Authors: Ona Genís , Sampedro Frederic , Romero Sergio , Valle Marta , Camacho Valle , Migliorelli Carolina , Mañanas Miguel Ángel , Antonijoan Rosa Maria , Puntes Montserrat , Coimbra Jimena , Ballester Maria Rosa , Garrido Maite , Riba Jordi
Published: September 2021

Background

The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist.

Methods

Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design.

Results

The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported.

Conclusion

The salvinorin-A–mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.
Reconstruction of Twisted Steinberg Algebras
Authors: Armstrong Becky , de Castro Gilles G , Clark Lisa Orloff , Courtney Kristin , Lin Ying-Fen , McCormick Kathryn , Ramagge Jacqui , Sims Aidan , Steinberg Benjamin
Published: September 2021

We show how to recover a discrete twist over an ample Hausdorff groupoid from a pair consisting of an algebra and what we call a quasi-Cartan subalgebra. We identify precisely which twists arise in this way (namely, those that satisfy the local bisection hypothesis), and we prove that the assignment of twisted Steinberg algebras to such twists and our construction of a twist from a quasi-Cartan pair are mutually inverse. We identify the algebraic pairs that correspond to effective groupoids and to principal groupoids. We also indicate the scope of our results by identifying large classes of twists for which the local bisection hypothesis holds automatically.
From ‘shelving sovereignty’ to ‘regularized patrol’?: prospect theory and Sino–Japanese islands dispute (2012–14)
Authors: Jie Dalei
Published: September 2021

The article draws on prospect theory to explain the variation of China’s risk propensity during the 2012–14 Diaoyu/Senkaku islands disputes with Japan. China’s initial reference point 1.0 regarding the disputed islands was the ‘shelving agreement’ ‘shelving the sovereignty dispute and a tacit acceptance of Japan’s de facto exclusive control. So after Japan’s ‘nationalization’ of the Diaoyu/Senkaku islands, China was clearly in a domain of losses. China was thus highly risk-acceptant by intensifying maritime and air patrolling, engaging in provocative behaviors, and suspending crisis management mechanisms. Meanwhile, China’s reference point evolved. Discourse analysis of Chinese official statements and media coverage indicated that regularized patrolling or joint control became China’s reference point 2.0. As it started to act from a domain of gains, Chinese behaviors turned risk-averse by scaling back patrolling and resuming negotiations over crisis management mechanisms.
Systemic Optimization and Validation of Normal and Reversed-Phase Eco-Friendly Chromatographic Methods for Simultaneous Determination of Paracetamol and Phenylephrine Hydrochloride in the Presence of Paracetamol Impurities
Authors: Farid Joliana F , Mostafa Nadia M , Fayez Yasmin M , Essam Hebatallah M
Published: September 2021

Background

Chromatographic behavior of different substances in normal and reversed phases is an interesting area in the scientific community.

Objective

The work aimed to optimize and validate chromatographic separation methods for simultaneous determination of paracetamol (PAR) and phenylephrine HCl (PHE) in the presence of PAR impurities, namely p-aminophenol, p-nitrophenol, acetanilide, and p-chloroacetanilide with further quantification of these toxic impurities.

Methods

TLC method based on normal phase separation was carried out on aluminum sheets of silica gel 60 F254 using ethanol:chloroform:ammonia as a developing system, followed by densitometric measurements. While HPLC is based on reversed phase separation using a C18 column against acetonitrile:phosphate buffer pH 5 as a mobile phase.

Results

PAR and PHE were determined by the TLC-densitometric method in concentration ranges of 3–25 and 0.1–3 µg/band, respectively, and determined by the HPLC method over concentration ranges of 5–400 and 2–80 µg/mL, respectively. Both methods were optimized and validated. Furthermore, they were successfully applied for pharmaceutical formulations with precision <2%. Moreover, results of a statistical comparison with the official methods confirm the methods’ validity claims.

Conclusion

Two eco-friendly chromatographic methods were developed to determine PAR and PHE in their binary mixtures, pharmaceutical formulations, and in the presence of PAR-related impurities with further quantification of these toxic impurities.

Highlights

These simple chromatographic methods are the first methods developed for simultaneous determination of PAR and PHE in the presence of PAR-related impurities.
Mathematical Modeling for HPLC Separation and Quantification of an Anti hypertensive Combination by Response Surface Methodology
Authors: Hemdan Ahmed M
Published: September 2021

Background

Determination of a multi-component mixture by HPLC requires many preliminary runs for method development which is both time-consuming and expensive due to the usage of large solvent volumes.

Objective

In the present study, the main objective was to reduce the preliminary runs that are required for optimizing the method conditions and also shorten the run time of analysis to be suitable for quality control laboratories where there are a large number of samples to be analyzed.

Methods

That was achieved using a two-factor, three-level response surface experiment which is a multivariate design that predicts the significant factors for optimizing the studied responses.

Results

The response surface design suggests that both acetonitrile ratio and flow rate are significant factors for full resolution of the studied mixture: atenolol, amiloride, and hydrochlorothiazide. The studied mixture was fully separated and determined in less than 5 min with perfect resolution.

Conclusion

Experimental design is a very beneficial tool for optimization of the method conditions in HPLC, especially if the studied mixture ingredients have overlapping peaks. For atenolol, amiloride, and hydrochlorothiazide, acetonitrile and flow rate were found to be the significant factors that affected the resolution of the studied mixture.

Highlights

Response surface design is a powerful tool that could be used for predicting the significant factors for separation in HPLC. Optimization of the method conditions was done using a limited number of preliminary runs. The studied ternary mixture was fully separated in less than 5 min with the aid of experimental design.
Attempted Murder of a Young Child Followed by an Attempted Suicide of the Mother by Injection of Insulin Aspart: Identification of Quantification of Insulin by LC–HRMS and UPLC–MS-MS in Blood of the Two Cases
Authors: Arbouche Nadia , Godard Estelle , Gheddar Laurie , Raul Jean-Sébastien , Kintz Pascal
Published: September 2021

The identification and quantification of insulin and its analogs have always been a challenge in the forensic field. Murder, suicide attempts and induced hypoglycemia in the context of factitious disorders have been described with the use of synthetic analogs of human insulin. There is very less information in the literature about aspart insulin concentrations in overdose cases. In this paper, we present a case of a nurse who tried to murder her 10-year-old daughter by injecting her aspart insulin and who, later, tried to commit suicide by injecting herself the same hormone. Two empty syringes and a FIASP® Flextouch pen were found in the woman’s apartment. A liquid chromatography coupled to high resolution mass spectrometry (LC–HRMS) method was developed in order to identify and discriminate aspart insulin from human insulin in blood samples as well as in syringes and pen, while an liquid chromatography coupled to tandem mass spectrometry (LC–MS-MS) method was developed for the quantification of insulin in blood samples. Aspart insulin tested positive at 5.7 and 2.4 ng/mL in the blood specimens of the mother and the child, respectively. The substance contained in the syringes and pen also corresponded to aspart insulin. Although the mother claims to have injected an overdose of aspart insulin, the concentrations found were in the therapeutic range for subjects under therapy. Due to the high instability of insulin and the long time elapsed between sampling and forensic analysis (8 months) due to administrative reasons, the concentration at the time of collection was probably much higher. In this case, it was possible to identify aspart insulin and discriminate it from human insulin in a context of attempted murder and subsequent attempted suicide using high-resolution mass spectrometry, which is of paramount importance in forensic medicine.
Quantifying Sexual Constitution: Abraham Myerson's Endocrine Study of Male Homosexuality, 1938-1942
Authors: McLaughlin Matthew J
Published: September 2021

Using the new medical science of endocrinology, scientific sex researchers in the 1920s and 1930s began studying sex hormone excretion as a means to search for the biological basis of human sexuality. One of these researchers was Abraham Myerson, a leading psychiatrist and researcher from Boston who conducted a series of innovative endocrine experiments between 1938 and 1942 in an effort to establish a relationship between sex hormone excretion patterns and homosexuality in men. While prevailing cultural models of heteronormativity identified male homosexuality as an abnormal case of biological femininity in men, Myerson’s framework and experimental research transcended this limiting duality of sexual biology. Adopting the theory of bisexuality, he argued that all men possessed a natural variability of masculine and feminine traits in their biological, social, and sexual characteristics, and that the disparity among these traits could be quantified and understood using sex hormones. In reconstructing Myerson’s research methods and data analysis, this paper uncovers how he established a distinctive diagnostic method and classification system for male homosexuality and illuminates how he conceptualized and categorized male sexuality as quantifiable and independent of personality.
Moderating Diversity, Collective Commitment, and Discrimination: The Role of Ethical Leaders in the Public Sector
Authors: Moon Kuk-Kyoung , Christensen Robert K
Published: September 2021

Despite public administration’s growing interest in personnel diversity and ethical leadership, little is known about the effectiveness of ethical leadership in managing diverse public workforces. Can ethical leadership moderate the relationships between demographic diversity and key organizational outcomes? To answer, we synthesize four theories about demographic diversity, ethical leadership, and inclusion: social categorization theory, social exchange theory, social learning theory, and optimal distinctiveness theory. These theories illuminate the interrelationships between diversity, ethical leadership, and two types of collective organizational outcomes: affective commitment climate and race-based employment discrimination. Using panel data from the US federal government, feasible generalized least squares models indicate that racial diversity is negatively related to affective commitment climate and positively related to race-based employment discrimination. The results also show that ethical leadership beneficially moderates the associations of racial diversity with the two organizational outcomes. These findings suggest that ethical leadership aids public managers and personnel in racially diverse public agencies.
Head Impact Modeling to Support a Rotational Combat Helmet Drop Test
Authors: Terpsma Ryan , Carlsen Rika Wright , Szalkowski Ron , Malave Sushant , Fawzi Alice Lux , Franck Christian , Hovey Chad
Published: September 2021

Introduction

The Advanced Combat Helmet (ACH) military specification (mil-spec) provides blunt impact acceleration criteria that must be met before use by the U.S. warfighter. The specification, which requires a helmeted magnesium Department of Transportation (DOT) headform to be dropped onto a steel hemispherical target, results in a translational headform impact response. Relative to translations, rotations of the head generate higher brain tissue strains. Excessive strain has been implicated as a mechanical stimulus leading to traumatic brain injury (TBI). We hypothesized that the linear constrained drop test method of the ACH specification underreports the potential for TBI.

Materials and Methods

To establish a baseline of translational acceleration time histories, we conducted linear constrained drop tests based on the ACH specification and then performed simulations of the same to verify agreement between experiment and simulation. We then produced a high-fidelity human head digital twin and verified that biological tissue responses matched experimental results. Next, we altered the ACH experimental configuration to use a helmeted Hybrid III headform, a freefall cradle, and an inclined anvil target. This new, modified configuration allowed both a translational and a rotational headform response. We applied this experimental rotation response to the skull of our human digital twin and compared brain deformation relative to the translational baseline.

Results

The modified configuration produced brain strains that were 4.3 times the brain strains from the linear constrained configuration.

Conclusions

We provide a scientific basis to motivate revision of the ACH mil-spec to include a rotational component, which would enhance the test’s relevance to TBI arising from severe head impacts.
New observations on the corallivorous nudibranchPhestilla melanobrachia: morphology, dietary spectrum and early development
Authors: Yiu Sam King Fung , Chung Sheena Suet-Wah , Qiu Jian-Wen
Published: September 2021

Phestilla melanobrachia is a coral-eating nudibranch widely distributed in the tropical Pacific. Previous studies have revealed only two colour morphs of P. melanobrachia, an orange form preying on various orange Dendrophyllia and Tubastraea spp. and a dark green form preying on the black Tubastraea micrantha and Tubastraea diaphana. Both colour morphs live in relatively deep waters (15–25 m) of exposed shores. We conducted morphological and molecular analysis, which revealed a beige colour morph of P. melanobrachia that feeds on the hermatypic scleractinian coral Turbinaria peltata in shallow waters (<10 m). The three genera of corals all belong to the family Dendrophylliidae, but Dendrophyllia and Tubastraea are azooxanthellates whereas Turbinaria is zooxanthellate. Consistent with their diet, the beige colour morph has a high abundance of dinoflagellate cells in the ceratal tips, whereas the other two colour morphs contain only few or no dinoflagellate cells in their cerata. Our finding of this new colour morph extends the knowledge about the diet, ecological niche and potential ecological impact of this species of corallivorous nudibranch.
TransLnc: a comprehensive resource for translatable lncRNAs extends immunopeptidome
Authors: Lv Dezhong , Chang Zhenghong , Cai Yangyang , Li Junyi , Wang Liping , Jiang Qiushuang , Xu Kang , Ding Na , Li Xia , Xu Juan , Li Yongsheng
Published: September 2021

LncRNAs are not only well-known as non-coding elements, but also serve as templates for peptide translation, playing important roles in fundamental cellular processes and diseases. Here, we describe a database, TransLnc (http://bio-bigdata.hrbmu.edu.cn/TransLnc/), which aims to provide comprehensive experimentally supported and predicted lncRNA peptides in multiple species. TransLnc currently documents approximate 583 840 peptides encoded by 33 094 lncRNAs. Six types of direct and indirect evidences supporting the coding potential of lncRNAs were integrated, and 65.28% peptides entries were with at least one type of evidence. Considering the strong tissue-specific expression of lncRNAs, TransLnc allows users to access lncRNA peptides in any of the 34 tissues involved in. In addition, both the unique characteristic and homology relationship were also predicted and provided. Importantly, TransLnc provides computationally predicted tumour neoantigens from peptides encoded by lncRNAs, which would provide novel insights into cancer immunotherapy. There were 220 791 and 237 915 candidate neoantigens binding by major histocompatibility complex (MHC) class I or II molecules, respectively. Several flexible tools were developed to aid retrieve and analyse, particularly lncRNAs tissue expression patterns, clinical relevance across cancer types. TransLnc will serve as a valuable resource for investigating the translation capacity of lncRNAs and greatly extends the cancer immunopeptidome.
Assessment of pre-donation glomerular filtration rate: going back to basics
Authors: Mariat Christophe , Mjøen Geir , Watschinger Bruno , Sever Mehmet Sukru , Crespo Marta , Peruzzi Licia , Oniscu Gabriel C , Abramowicz Daniel , Hilbrands Luuk , Maggiore Umberto
Published: September 2021

The 2017 version of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines is the most recent international framework for the evaluation and care of living kidneys donors. Along with the call for an integrative approach evaluating the long-term end-stage kidney disease risk for the future potential donor, several recommendations are formulated regarding the pre-donation glomerular filtration rate (GFR) adequacy with no or little consideration for the donor candidate’s age or for the importance of using reference methods of GFR measurements. Herein, we question the position of the KDIGO guidelines and discuss the rationale and modalities for a more basic, but no less demanding GFR evaluation enabling a more efficient selection of potential kidney donors.