bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonrandom missing data can bias Principal Component Analysis inference of population genetic structure
Authors: Yi Xueling , Latch Emily K. 
Published: August 2021

AbstractPopulation genetic studies in non‐model systems increasingly use next‐generation sequencing to obtain more loci, but such methods also generate more missing data that may affect downstream analyses. Here we focus on the principal component analysis (PCA) which has been widely used to explore and visualize population structure with mean‐imputed missing data. We simulated data of different population models with various total missingness (1%, 10%, 20%) introduced either randomly or biased among individuals or populations. We found that individuals biased with missing data would be dragged away from their real population clusters to the origin of PCA plots, making them indistinguishable from true admixed individuals and potentially leading to misinterpreted population structure. We also generated empirical data of the big brown bat (Eptesicus fuscus) using restriction site‐associated DNA sequencing (RADseq). We filtered three data sets with 19.12%, 9.87%, and 1.35% total missingness, all showing nonrandom missing data with biased individuals dragged towards the PCA origin, consistent with results from simulations. We highlight the importance of considering missing data effects on PCA in non‐model systems where nonrandom missing data are common due to varying sample quality. To help detect missing data effects, we suggest to (1) plot PCA with a colour gradient showing per sample missingness, (2) interpret samples close to the PCA origin with extra caution, (3) explore filtering parameters with and without the missingness‐biased samples, and (4) use complementary analyses (e.g., model‐based methods) to cross‐validate PCA results and help interpret population structure.
A Systematic Framework to Understand Transnational Governance for Cybersecurity Risks from Digital Trade
Authors: Huang Keman , Madnick Stuart , Choucri Nazli , Zhang Fang 
Published: August 2021

AbstractGoverning cybersecurity risks from digital trade is a growing responsibility for governments and corporations. This study develops a systematic framework to delineate and analyze the strategies that governments and corporations take to address cybersecurity risks from digital trade. It maps out the current landscape based on a collection of 75 cases where governments and corporations interact to govern transnational cybersecurity risks. This study reveals that: first, governing cybersecurity risks from digital trade is a global issue whereby most governments implement policies with concerning that the cybersecurity risks embedded within purchasing transnational digital products can influence their domestic political and societal systems. Second, governments dominates the governance interactions by implementing trade policies whereas corporations simply comply. Corporations do, however, have chances to take more active roles in constructing the governance system. Third, supply chain cybersecurity risks have more significant impacts on governance mode between governments and corporations whereas concerns on different national cybersecurity risks do not. Fourth, the interactions between governments and corporations reveal the exisitence of loops that can amplify or reduce cybersecurity risks. This provides policy implications on transnational cybersecurity governance for policy makers and business leaders to consider their potential options and understand the global digital trade environment when cybersecurity and digital trade overlap.
Cocaine cue‐induced mesocorticolimbic activation in cocaine users: Effects of personality traits, lifetime drug use, and acute stimulant ingestion
Authors: D'Amour‐Horvat Valérie , Cox Sylvia M. L. , Dagher Alain , Kolivakis Theodore , Jaworska Natalia , Leyton Marco 
Published: August 2021

AbstractStimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine‐related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once followingd‐amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue‐induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue‐induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS‐11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration ofd‐amphetamine did not augment the cue‐induced activations, but, in cocaine users, drug cue‐induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.
Immunotherapy for the treatment of penile intraepithelial neoplasia associated with human papilloma virus type 16 using topical imiquimod and human papilloma virus vaccination
Authors: Kim Tae Yeb , Das Moushumi , Poppito Natalie , Jarrett Paul 
Published: August 2021

AbstractPenile intraepithelial neoplasia (PeIN) is frequently associated with human papilloma virus (HPV). Three cases of PeIN associated with HPV‐type 16 were successfully treated with topical imiquimod and concurrent HPV vaccination. Human papilloma vaccine protects against oncogenic human papilloma viruses. In New Zealand, a decline in incidence of PeIN is anticipated with the recent funding of human papilloma vaccine for boys and young men aged 9–26 years. Therefore, HPV vaccination may have a role for treatment of PeIN and prophylaxis.
An empirical bioethical examination of Norwegian and British doctors' views of responsibility and (de)prioritization in healthcare
Authors: Everett Jim A. C. , Maslen Hannah , Nussberger Anne‐Marie , Bringedal Berit , Wilkinson Dominic , Savulescu Julian 
Published: August 2021

AbstractIn a world with limited resources, allocation of resources to certain individuals and conditions inevitably means fewer resources allocated to other individuals and conditions. Should a patient's personal responsibility be relevant to decisions regarding allocation? In this project we combine the normative and the descriptive, conducting an empirical bioethical examination of how both Norwegian and British doctors think about principles of responsibility in allocating scarce healthcare resources. A large proportion of doctors in both countries supported including responsibility for illness in prioritization decisions. This finding was more prominent in zero‐sum scenarios where allocation to one patient means that another patient is denied treatment. There was most support for incorporating prospective responsibility (through patient contracts), and low support for integrating responsibility into co‐payments (i.e. through requiring responsible patients to pay part of the costs of treatment). Finally, some behaviours were considered more appropriate grounds for deprioritization (smoking, alcohol, drug use)—potentially because of the certainty of impact and direct link to ill health. In zero‐sum situations, prognosis also influenced prioritization (but did not outweigh responsibility). Ethical implications are discussed. We argue that the role that responsibility constructs appear to play in doctors' decisions indicates a needs for more nuanced—and clear—policy. Such policy should account for the distinctions we draw between responsibility‐sensitive and prognostic justifications for deprioritization.
In male Hodgkin lymphoma patients, impaired fertility may be improved by non‐gonadotoxic therapy
Authors: Laddaga Filomena Emanuela , Masciopinto Pierluigi , Nardelli Claudia , Vacca Margherita Patrizia , Masciandaro Paola , Arcuti Elena , Cicinelli Ettore , Specchia Giorgina , Musto Pellegrino , Gaudio Francesco 
Published: August 2021

SummaryThe outcome of patients with Hodgkin lymphoma (HL) has improved significantly in recent years, and now attention is increasingly being focused on the well‐being of these young patients. This study aimed to analyse the influence of HL and its treatment on the spermatogenic status of 46 male HL patients with available spermiograms, treated between 2008 and 2016. Analysing prognostic factors at diagnosis, we found that the number of spermatozoa was reduced in stage III–IV; motility and vitality were reduced in stage III–IV and in the presence of B symptoms; and abnormal forms were increased in patients with elevated erythrocyte sedimentation rate (ESR) and low albumin. Furthermore, we found that haematopoietic stem cell transplantation (HSCT) was associated with a severe impairment of fertility in terms of sperm motility. In HL‐treated patients who did not undergo HSCT we found a statistically significantly improved fertility in terms of motility. In this study, we found that HSCT induced infertility in the majority of male patients with HL, but that first‐line treatment could improve the impaired fertility status caused by disease. Further studies are needed in larger case series to investigate risk factors for impaired fertility at HL diagnosis and after treatment.
Influence of avocado orchard landscapes on amphibians and reptiles in the trans‐Mexican volcanic belt
Authors: Vega‐Agavo María Ismaela , Suazo‐Ortuño Ireri , Lopez‐Toledo Leonel , Gómez‐Tagle Alberto , Sillero Neftalí , Pineda‐López Rubén , Alvarado‐Díaz Javier 
Published: August 2021

AbstractCommercial fruit orchards are embedded in a landscape of native forest and diverse kinds of agroecosystems. The landscape structure of these systems is a major driver of biodiversity response. Generally, it is assumed that high levels of biodiversity occur in perennial systems largely due to their high structural complexity. However, little is known about the influence of other landscape attributes on these levels of biodiversity. Avocado (Persea americana) constitutes about 25 percent of the global fresh fruit trade. In Mexico, avocado trees flourish about the same altitude as pine–oak forests (POFs). We studied the response of the local herpetofauna to conversion of POF to avocado orchards (AOs). We also explored the effects of forest cover on species that differ in their levels of habitat specialization. In the avocado belt in Michoacan, we sampled 12 sites representing a gradient of AO embedded in native POF to evaluate the variation in structure of local assemblages of amphibians and reptiles. Reduction of POF cover negatively affected specialist frog and snake species, but this relationship varied among buffers around sampling sites. Generalist species of amphibians and lizards showed increased abundances and richness in sites with low POF cover, whereas snake richness and abundance were higher in sites with high POF cover. Our study suggests that POF conversion to AO is a driver favoring the persistence and success of generalist but not specialist herpetofauna species. Therefore, to conserve the diversity of amphibians and reptiles in these agroecosystems, it is important to ensure high proportion of POF patches.Abstract in Spanish is available with online material.
Parent–Child Joint Behaviors in Novel Object Play Create High‐Quality Data for Word Learning
Authors: Chen Chi‐hsin , Houston Derek M. , Yu Chen 
Published: August 2021

This research takes a dyadic approach to study early word learning and focuses on toddlers’ (N = 20, age: 17–23 months)information seekingand parents’information providingbehaviors and the ways the two are coupled in real‐time parent–child interactions. Using head‐mounted eye tracking, this study provides the first detailed comparison of children’s and their parents’ behavioral and attentional patterns in two free‐play contexts: one with novel objects with to‐be‐learned names (Learning condition) and the other with familiar objects with known names (Play condition). Children and parents in the Learning condition modified their individual and joint behaviors when encountering novel objects with to‐be‐learned names, which created clearer signals that reduced referential ambiguity and potentially facilitated word learning.
Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands
Authors: Reumers Stacha F. I. , Erasmus Corrie E. , Bouman Karlijn , Pennings Maartje , Schouten Meyke , Kusters Benno , Duijkers Floor A. M. , van der Kooi Anneke , Jaeger Bregje , Verschuuren‐Bemelmans Corien C. , Faber Catharina G. , van Engelen Baziel G. , Kamsteeg Erik‐Jan , Jungbluth Heinz , Voermans Nicol C. 
Published: August 2021

AbstractCentronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype–genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0–80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.
Role of the CCL2‐CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting
Authors: Xu Maosen , Wang Yang , Xia Ruolan , Wei Yuquan , Wei Xiawei 
Published: August 2021

AbstractThe chemokine ligand CCL2 and its receptor CCR2 are implicated in the initiation and progression of various cancers. CCL2 can activate tumour cell growth and proliferation through a variety of mechanisms. By interacting with CCR2, CCL2 promotes cancer cell migration and recruits immunosuppressive cells to the tumour microenvironment, favouring cancer development. Over the last several decades, a series of studies have been conducted to explore the CCL2‐CCR2 signalling axis function in malignancies. Therapeutic strategies targeting the CCL2‐ CCR2 axis have also shown promising effects, enriching our approaches for fighting against cancer. In this review, we summarize the role of the CCL2‐CCR2 signalling axis in tumorigenesis and highlight recent studies on CCL2‐CCR2 targeted therapy, focusing on preclinical studies and clinical trials.
Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
Authors: Amore Benny M. , Cramer Clay T. , MacDougall Diane E. , Sasiela William J. , Emery Maurice G. 
Published: August 2021

AbstractBempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double‐blind, parallel‐design clinical study assessed the effects of steady‐state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half‐maximal inhibition (IC50) estimated at greater than 1000 μM (>1670‐fold the bempedoic acid 180 mg/day steady‐state unbound maximum concentration). In monkeys, individual rate‐corrected QT intervals showed no time‐ or dose‐dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia’s formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration‐QTcF analysis showed that maximum bempedoic acid concentration at steady‐state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was −0.5 (−5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady‐state bempedoic acid at a supratherapeutic dose of 240 mg was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.
Upadacitinib pharmacokinetics and exposure‐response analyses of efficacy and safety in psoriatic arthritis patients – Analyses of phase III clinical trials
Authors: Muensterman Elena , Engelhardt Benjamin , Gopalakrishnan Sathej , Anderson Jaclyn K. , Mohamed Mohamed‐Eslam F. 
Published: August 2021

AbstractUpadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure‐response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure‐response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.
Extinction risk is linked to lifestyle in freshwater gastropods
Authors: Neubauer Thomas A. , Georgopoulou Elisavet 
Published: August 2021

AbstractAimFreshwater ecosystems and their biota are severely endangered by global change today, and predicted extinction levels are skyrocketing for many taxa. Most studies have focused on entire clades, while approaches testing for selective extinction risk with respect to ecological traits are rare. As studies are typically based on modern faunas, the generality of the detected patterns in the context of the current biodiversity crisis remains uncertain. We use a dataset of fossil and modern freshwater gastropods to investigate extinction probability in dependence of lifestyle and geographic distribution.LocationEurope, Miocene to present‐day.MethodsWe performed generalized linear mixed modelling to test for a relationship between extinction probability and taxonomic group (Caenogastropoda vs. Hygrophila, reflecting different lifestyles) and range size, while using time as random effect. Extinction and survival of modern representatives was predicted based on IUCN conservation status. To identify the types of faunas with elevated extinction risk with respect to lifestyle, we tested for a relationship between the proportion of Caenogastropoda and lake surface area and geological duration using generalized linear models.ResultsWe found a clear relationship between extinction likelihood and lifestyle, which is linked to differences in range sizes and is independent of geological time. Caenogastropoda are more prone to go extinct. A strong positive relationship between the proportion of Caenogastropoda and geological duration was found, showing that Caenogastropoda are more dominant in long‐lived lakes.Main conclusionsThe elevated extinction risk of caenogastropods is linked to their smaller geographic ranges, which reflects their comparably poor colonization ability, and urges enhanced conservation efforts. Their high diversity and high degree of endemism in long‐lived lakes render, especially these archives of evolution important conservators of biodiversity. As most of these lakes are under severe anthropogenic pressure, concerted conservation measures are needed to ensure the survival of their unique biota.
Research priorities for children with neurological impairment and medical complexity in high‐income countries
Authors: Diskin Catherine , Malik Kristina , Gill Peter J , Rashid Nada , Chan Carol Y , Nelson Katherine E , Thomson Joanna , Berry Jay , Agrawal Rishi , Orkin Julia , Cohen Eyal 
Published: August 2021

AimTo identify the highest‐priority clinical research areas related to children with neurological impairment and medical complexity among clinicians and caregivers.MethodA modified, three‐stage Delphi study using online surveys and guided by a steering committee was completed. In round 1, clinicians and family caregivers suggested clinical topics and related questions that require research to support this subgroup of children. After refinement of the suggestions by the steering committee, participants contributed to 1 (family caregivers) or 2 (clinicians) subsequent rounds to develop a prioritized list.ResultsA diverse international expert panel consisting of 49 clinicians and 12 family caregivers provided 601 responses. Responses were distilled into 26 clinical topics comprising 126 related questions. The top clinical topics prioritized for research were irritability and pain, child mental health, disorders of tone, polypharmacy, sleep, aspiration, behavior, dysautonomia, and feeding intolerance. The clinician expert panel also prioritized 10 specific research questions.InterpretationStudy findings support a research agenda for children with neurological impairment and medical complexity focused on addressing clinical questions, prioritized by an international group of clinicians and caregivers.