bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Paradoxical Perception of Contemporary Democracy, and the Question of its Future
Authors: Coicaud Jean‐Marc 
Published: February 2019

AbstractThis article explores the perception of democracy today, at the national and international levels. This perception is rather paradoxical. On the one hand, democracy is celebrated. As such it functions as a benchmark of political legitimacy. On the other hand, it is criticized. The article provides explanations for this state of affairs. Among the explanations put forward in order to account for the criticisms of democracy the article stresses the deepening of economic inequalities and a sense of social alienation that has been growing in recent years among the people that globalization and its associated policies are affecting negatively. For the way forward the article offers suggestions in order to improve the reputation and reality of democracy. In this regard it argues that the possibility to improve democracy, both at the national and international levels, is to a large extent based on making it more inclusive (especially economically speaking) and reflective.
Longitudinal Findings from a Randomized Clinical Trial of Varenicline for Alcohol Use Disorder with Comorbid Cigarette Smoking
Authors: Bold Krysten W. , Zweben Allen , Fucito Lisa M. , Piepmeier Mary E. , Muvvala Srinivas , Wu Ran , Gueorguieva Ralitza , O'Malley Stephanie S. 
Published: February 2019

BackgroundThis study is the first to examine longitudinal posttreatment outcomes of a placebo‐controlled trial of varenicline for alcohol use disorder (AUD) with comorbid cigarette smoking.MethodsParticipants were 131 adults (n = 39 female) seeking alcohol treatment in a randomized, double‐blind, parallel group, placebo‐controlled, 16‐week multisite trial of varenicline combined with medical management (MM). Timeline follow‐back assessments of alcohol and smoking behavior were conducted at the end of treatment (4 months), with follow‐ups at 6, 9, and 12 months. Outcomes were percentage of heavy drinking days (PHDD), percent of participants with no heavy drinking days (NHDD), cotinine‐confirmed prolonged smoking abstinence (PA), and good clinical outcome on either NHDD or PA.ResultsTreatment improvements were maintained posttreatment. For the sample overall, PHDD or NHDD did not differ significantly by treatment condition (ps > 0.13), but varenicline produced higher rates of PA versus placebo at 4, 9, and 12 months (p < 0.05). Significant differences were observed by sex: Males had higher rates of NHDD with varenicline (28.9%) versus placebo (6.4%) at the end of treatment (p = 0.004), and these effects were maintained at 12 months (varenicline: 40.0% vs. placebo: 19.2%, p = 0.03). Higher rates of PA were seen for varenicline in both males (8.9%) and females (21.1%) versus placebo (males/females: 0%) at the end of treatment (p = 0.05), and this effect was maintained at 12 months for females (varenicline: 21.1% vs. placebo, 0.0%, p = 0.05).ConclusionsVarenicline treatment combined with MM appears to have enduring benefits for patients with co‐occurring AUD and cigarette smoking, and these effects may differ by sex.
Incorporating Writing into a Personalized Normative Feedback Intervention to Reduce Problem Drinking Among College Students
Authors: Young Chelsie M. , Neighbors Clayton 
Published: February 2019

BackgroundPersonalized normative feedback (PNF) interventions have repeatedly been found to reduce drinking among undergraduates. However, effects tend to be small, potentially due to inattention to and inadequate processing of the information. Adding a writing component to PNF interventions may allow for greater cognitive processing of the feedback, thereby boosting intervention efficacy. Additionally, expressive writing (EW) has been shown to reduce drinking intentions; however, studies have not examined whether it can reduce drinking behavior. The present experiment evaluated whether including a writing task would improve the efficacy of PNF and whether EW alone can be used to reduce drinking and alcohol‐related problems.MethodsHeavy drinking undergraduates (N = 250) were randomized to receive either: (i) PNF about their alcohol use; (ii) EW about a negative, heavy drinking occasion; (iii) PNFplus writing about the norms feedback; or (iv) attention control feedback about their technology use in an online brief intervention. Participants (N = 169) then completed a 1‐month follow‐up survey about their past month alcohol use and alcohol‐related problems online.ResultsPNFplus writing reduced alcohol‐related problems compared to all other conditions. No significant reductions were found for EW. Both PNF and PNFplus writing reduced perceived norms and perceived norms mediated intervention effects for both feedback conditions.ConclusionsThe current findings suggest that adding a writing component to traditional norms‐based feedback approaches might be an efficacious strategy, particularly for reducing alcohol‐related consequences.
Willing to Work But Not to Wait: Individuals with Greater Alcohol Use Disorder Show Increased Delay Discounting Across Commodities and Less Effort Discounting for Alcohol
Authors: Phung Quan H. , Snider Sarah E. , Tegge Allison N. , Bickel Warren K. 
Published: February 2019

BackgroundDelay discounting refers to the devaluation of a reward given increasing delays to delivery. Similarly, effort discounting refers to the devaluation of a reward given increasing effort required to obtain it. Individuals with substance use disorder show higher rates of delay discounting, exacerbating short‐term positive reinforcement at the expense of long‐term consequences. This study explores how effort discounting compares to delay discounting behavior among alcohol users as well as how these preferences change between monetary and alcohol rewards.MethodsA total of 100 participants completed an online survey through Amazon Mechanical Turk. Participant alcohol use was evaluated using DSM‐5 and the Alcohol Use Disorders Identification Test criteria. All participants completed 4 randomized discounting tasks involving delay or effort discounting, in which the reward was money or alcohol. A follow‐up experiment (n = 423) added the alcohol purchase task to assess alcohol valuation.ResultsIndividuals with greater alcohol use disorder (AUD) severity discounted future money and alcohol significantly more than those with less AUD. However, individuals meeting more DSM‐5 criteria were only willing to perform more effort for alcohol. The follow‐up experiment replicated these findings and demonstrated that individuals with greater AUD also showed an increased valuation of alcohol and alcohol value‐mediated effort discounting.ConclusionsThese results suggest that individuals with greater AUD were less willing to wait for money or alcohol. While all participants were willing to work for money regardless of AUD severity, individuals with greater AUD showed increased valuation of alcohol drinks and were willing to exert more effort to obtain alcohol. Together, these results paint a picture of individuals with increased AUD as both more impulsive and willing to work to obtain alcohol, contributing to our understanding of decision making among individuals who abuse substances.
Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity
Authors: El‐Boraie Ahmed , Taghavi Taraneh , Chenoweth Meghan J. , Fukunaga Koya , Mushiroda Taisei , Kubo Michiaki , Lerman Caryn , Nollen Nicole L. , Benowitz Neal L. , Tyndale Rachel F. 
Published: February 2019

AbstractThe nicotine metabolite ratio (NMR; 3‐hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome‐wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European‐ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine‐d2/(nicotine‐d2 + cotinine‐d2)). CYP2A6 genotypes and the NMR were assessed in European‐ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory‐based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR‐stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.
Molecular cloning of WIF1 and HMGA2 reveals ear‐preferential expression while uncovering a missense mutation associated with porcine ear size in WIF1
Authors: Liang J. , Zhang Y. , Wang L. , Liu X. , Yan H. , Wang L. , Zhang L. 
Published: February 2019

SummaryConsiderable diversity exists in porcine ear size, which is an important morphological feature of pig breeds. Previously, we localized four crucial candidate genes—high mobility group AT‐hook 2 (HMGA2), LEM domain‐containing 3 (LEMD3), methionine sulfoxide reductase B3 (MSRB3) and Wnt inhibitory factor 1 (WIF1)—on Sus Scrofa chromosome 5 affecting porcine ear size, then cloned LEMD3 and MSBR3. In this study, we performed rapid amplification of cDNA ends to obtain full‐length cDNA sequences of 2338‐bp WIF1 and 2998‐bp HMGA2. Using quantitative real‐time PCR, we revealed that WIF1 expression was highest in ear cartilage of 60‐day‐old pigs and that this is therefore a better candidate gene for ear size than HMGA2. We further screened coding sequence variants in both genes and identified only one missense mutation (WIF1:c.1167C>G) in a conserved epidermal growth factor‐like domain from the mammalian WIF1 protein. The protein‐altering mutation was significantly associated with ear size across the Large White × Minzhu hybrid and Beijing Black pig populations. When WIF1:c.1167C>G was included as fixed effect in the model to re‐run a genome‐wide association study in the Large White × Minzhu intercross population the P‐value of the peak SNP on SSC5 from re‐running the genome‐wide association study dropped from 2.45E‐12 to 7.33E‐05. Taken together, the WIF1:c.1167C>G could be an important mutation associated with ear size. Our findings provide helpful information for further studies of the molecular mechanisms controlling porcine ear size.
Primary lymphangioma circumscriptum of the vulva presenting as warty plaques
Authors: Gude Geethanjali , Gupta Parikshaa , Sharma Ramesh Kumar , Rajwanshi Arvind 
Published: February 2019

AbstractLymphangioma circumscriptum is a benign hamartomatous malformation involving the lymphatic system of skin and subcutaneous tissue. It can involve any part of the body with maximum predilection for proximal parts of limbs. Vulvar involvement is quite infrequent. Based on the aetiopathogenesis, it can be either primary or secondary, with the secondary form being relatively more common in vulva. We report an exceedingly rare case of primary lymphangioma circumscriptum in a post‐menopausal female presenting with multiple warty, papulo‐nodular lesions on both labia majora. The patient was diagnosed histopathologically and managed surgically by wide local excision with primary closure.
Development and validation of a multiple‐choice questionnaire‐based theoretical test in direct ophthalmoscopy
Authors: Jørgensen Morten , Savran Mona Meral , Christakopoulos Christos , Bek Toke , Grauslund Jakob , Toft Peter Bjerre , Ziemssen Focke , Konge Lars , Sørensen Torben Lykke , Subhi Yousif 
Published: February 2019

AbstractPurposeDirect ophthalmoscopy can reveal systemic, neurologic and ophthalmic conditions, but is poorly mastered among young physicians. A theoretical test is needed to measure effect of educational interventions. We developed and gathered validity evidence for a multiple‐choice questionnaire (MCQ)‐based theoretical test in direct ophthalmoscopy.MethodsThe MCQ was developed by interviewing experts. Then, validity evidence was evaluated using Messick's validity framework. Content was ensured by inviting the experts to contribute in a Delphi‐like process. Response process was ensured by piloting and by streamlining all instructions. Then, the test was taken by ophthalmologists and by medical students without experience in direct ophthalmoscopy. Results were used to evaluate internal structure (item quality analysis and internal consistency), relations to other variables (correlation of test scores to experience level) and consequences (establishment of pass–fail score and the consequences of its use).ResultsThe first phase of the study yielded 100 MCQs. In second phase, we identified that 60 items fulfilled predefined relevance and item quality requirements. These items demonstrated very high internal consistency (Cronbach's alpha = 0.95), significantly discriminated medical students from specialists (p < 0.001, independent samples t‐test) and the established pass–fail score of 50 (83%) correct answers resulted in no false positives (students passing) and no false negatives (specialists failing). A Decision study identified that sampling 15 items suffice for certification.ConclusionWe developed and validated an MCQ‐based theoretical test in direct ophthalmoscopy that enables an evidence‐based approach to measuring, evaluating and certifying the theoretical knowledge necessary for direct ophthalmoscopy.
Correlation between skeletal muscle fiber type and free amino acid levels in Japanese Black steers
Authors: Mashima Daisuke , Oka Yoshiaki , Gotoh Takafumi , Tomonaga Shozo , Sawano Shoko , Nakamura Mako , Tatsumi Ryuichi , Mizunoya Wataru 
Published: February 2019

AbstractFree amino acids are important components of tastants and flavor precursors in meat. To clarify the correlation between muscle fiber type and free amino acids, we determined the concentrations of various free amino acids and dipeptides in samples of different muscle tissues (n = 21), collected from 26‐month‐old Japanese Black steers (n = 3) at 2 days postmortem. The proportions of the myosin heavy chain (MyHC), slow (MyHC1) and fast (MyHC2) isoforms were determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). The contents of free amino acids and dipeptides were measured by high performance liquid chromatography (HPLC). The MyHC isoform composition varied among the tissue samples. The MyHC1 proportion ranged from 6.9% ± 3.9% to 83.3% ± 16.7%. We confirmed that there was a strong positive correlation between MyHC1 composition and total free amino acid concentrations, including those for two dipeptides. Among the 31 measured free amino acids and dipeptides, 11 showed significant positive correlations and five showed significant negative correlations with MyHC1 composition. These results suggest that a high MyHC1 content induces high free amino acid contents in bovine muscles possibly because of greater oxidative metabolism. This high level of free amino acids could contribute to the intense flavor of meat that is rich in slow‐twitch fibers.
Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues
Authors: Ittner Lars M. , Klugmann Matthias , Ke Yazi D. 
Published: February 2019

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno‐associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene‐therapy approaches, is emerging. Here, we reviewed literature that used AAVs to study and model AD and discuss potential gene therapy strategies.Linked ArticlesThis article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
Integrative molecular profiling identifies a novel cluster of estrogen receptor‐positive breast cancer in very young women
Authors: Park Charny , Yoon Kyong‐Ah , Kim Jihyun , Park In Hae , Park Soo Jin , Kim Min Kyeong , Jang Wooyeong , Cho Soo Young , Park Boyoung , Kong Sun‐Young , Lee Eun Sook 
Published: February 2019

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)‐positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.
Phase I study of tirabrutinib (ONO‐4059/GS‐4059) in patients with relapsed or refractory B‐cell malignancies in Japan
Authors: Munakata Wataru , Ando Kiyoshi , Hatake Kiyohiko , Fukuhara Noriko , Kinoshita Tomohiro , Fukuhara Suguru , Shirasugi Yukari , Yokoyama Masahiro , Ichikawa Satoshi , Ohmachi Ken , Gion Naokazu , Aoi Arata , Tobinai Kensei 
Published: February 2019

We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second‐generation, enhanced‐selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B‐cell non−Hodgkin lymphoma (B‐cell NHL) and chronic lymphocytic leukemia (CLL). This was an open‐label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose‐limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1‐4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B‐cell NHL/CLL.
Severe asthma—A population study perspective
Authors: Backman Helena , Jansson Sven‐Arne , Stridsman Caroline , Eriksson Berne , Hedman Linnea , Eklund Britt‐Marie , Sandström Thomas , Lindberg Anne , Lundbäck Bo , Rönmark Eva 
Published: February 2019

SummaryBackgroundSevere asthma is a considerable challenge for patients, health‐care professionals and society. Few studies have estimated the prevalence of severe asthma according to modern definitions of which none based on a population study.ObjectiveTo describe characteristics and estimate the prevalence of severe asthma in a large adult population‐based asthma cohort followed for 10‐28 years.MethodsN = 1006 subjects with asthma participated in a follow‐up during 2012‐14, when 830 (mean age 59 years, 56% women) still had current asthma. Severe asthma was defined according to three internationally well‐known criteria: the ATS workshop definition from 2000 used in the US Severe Asthma Research Programme (SARP), the 2014 ATS/ERS Task force definition and the GINA 2017. All subjects with severe asthma according to any of these criteria were undergoing respiratory specialist care and were also contacted by telephone to verify treatment adherence.ResultsThe prevalence of severe asthma according to the three definitions was 3.6% (US SARP), 4.8% (ERS/ATS Taskforce), and 6.1% (GINA) among subjects with current asthma. Although all were using high ICS doses and other maintenance treatment, >90% did not have controlled asthma according to the asthma control test. Severe asthma was related to age >50 years, nasal polyposis, impaired lung function, sensitization to aspergillus, and tended to be more common in women. Further, neutrophils in blood significantly discriminated severe asthma from other asthma.Conclusions and Clinical RelevanceSevere asthma differed significantly from other asthma in terms of demographic, clinical and inflammatory characteristics, results suggesting possibilities for improved treatment regimens of severe asthma. The prevalence of severe asthma in this asthma cohort was 4%‐6%, corresponding to approximately 0.5% of the general population.