bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adverse Events With Sustained-Release Donepezil in Alzheimer Disease
Authors: Lee Chunsoo , Lee Kyungsang , Yu Hyewon , Ryu Seung-Ho , Moon Seok Woo , Han Changsu , Lee Jun-Young , Lee Young Min , Kim Shin-Gyeom , Kim Ki Woong , Lee Dong Woo , Kim Seong Yoon , Lee Sang-Yeol , Bae Jae Nam , Jung Young-Eun , Kim Jeong Lan , Kim Byung-Soo , Shin Il-Seon , Kim Young Hoon , Kim Bong Jo , Kang Hyo Shin , Myung Woojae , Carroll Bernard J. , Kim Doh Kwan 
Published: June 2017

AbstractPurpose/BackgroundSustained-release, high-dose (23 mg/d) donepezil has been approved for treatment of moderate to severe Alzheimer disease (AD). Based on a previous clinical trial, body weight of less than 55 kg is a risk factor for adverse events with donepezil 23 mg/d treatment in global population.Methods/ProceduresTo clarify whether this finding is consistent across ethnic groups that vary in absolute body mass, we recruited Korean patients aged 45 to 90 years with moderate to severe AD who had been receiving standard donepezil immediate release 10 mg/d for at least 3 months. After screening, we analyzed a final cohort of 166 patients who received donepezil 23 mg/d for 24 weeks to compare the occurrence of treatment-emergent adverse events (TEAEs) between patients with high versus low body mass index (BMI) based on the World Health Organization overweight criteria for Asian populations (23 kg/m2).Findings/ResultsTreatment-emergent adverse events were reported by 79.45% of patients in the lower BMI group and 58.06% of patients in the higher BMI group (odds ratio, 2.79; 95% confidence interval, 1.39–5.63; χ2= 7.58,P= 0.006). In a multivariable survival analysis, the group with lower BMI showed a higher occurrence of TEAEs (hazard ratio, 1.83; 95% confidence interval, 1.25–2.68;P= 0.002).Implications/ConclusionsIn Korean patients with moderate to severe AD receiving high-dose donepezil over 24 weeks, TEAEs were significantly more common in those with lower BMI (not clinically overweight), especially nausea. This finding may inform clinical practice for Asian patients.
Is There a Relationship Between Treatment With Direct Antiviral Agents for HCV Infection and the Development of Malignancies?
Authors: Saadi Tarek , Khoury Johad 
Published: June 2017

Background and Aims:
Direct antiviral agents (DAAs) have become the treatment of choice for patients with chronic hepatitis C virus (HCV) infection. As these drugs are new, it is important to learn the adverse events of these drugs in the short and long terms. We report on 7 patients who developed malignancies during treatment with DAAs or a short time after finishing treatment.

Methods:
We treated 133 patients with DAAs in our unit between January 2015 and June 2016, 100 (75%) of whom were treated with the combination of paritaprevir/ritonavir/ombitasvir with/without dasabuvir (PrOD). The distribution of HCV genotypes was as follow: G1b 114 (85.7%), G1a 3 (2.2%), G2 3 (2.2%), G3 10 (7.5%), G4 2 (1.5%). One hundred ten (82.7%) patients finished treatment. Adverse events were recorded during treatment and after finishing treatment. Efficacy was determined by assessment of serum HCV RNA.

Results:
We observed malignancies in 7 patients: 1 developed laryngeal carcinoma, 1 developed pancreatic adenocarcinoma, 1 developed oropharyngeal lymphoma, 1 developed recurrent aggressive transitional cell carcinoma of the urinary bladder, 1 developed recurrent aggressive hepatocellular carcinoma, and 2 patients developed de novo hepatocellular carcinoma. All of these patients had advanced liver disease.

Conclusions:
This report raises questions about DAAs and the possible development of malignancies. It will be important to look at large clinical trial data and real-world experience to determine if this relationship is real.
Zoonoses, One Health and complexity: wicked problems and constructive conflict
Authors: Waltner-Toews David 
Published: June 2017

Infectious zoonoses emerge from complex interactions among social and ecological systems. Understanding this complexity requires the accommodation of multiple, often conflicting, perspectives and narratives, rooted in different value systems and temporal–spatial scales. Therefore, to be adaptive, successful and sustainable, One Health approaches necessarily entail conflicts among observers, practitioners and scholars. Nevertheless, these integrative approaches have, both implicitly and explicitly, tended to marginalize some perspectives and prioritize others, resulting in a kind of technocratic tyranny. An important function of One Health approaches should be to facilitate and manage those conflicts, rather than to impose solutions.
This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’.
Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in theXenopusegg
Authors: Presler Marc , Van Itallie Elizabeth , Klein Allon M. , Kunz Ryan , Coughlin Margaret L. , Peshkin Leonid , Gygi Steven P. , Wühr Martin , Kirschner Marc W. 
Published: June 2017

AbstractFertilization triggers release from meiotic arrest and initiates events that prepare for the ensuing developmental program. Protein degradation and phosphorylation are known to regulate protein activity during this process. However, the full extent of protein loss and phospho-regulation is still unknown. We examined absolute protein and phospho-site dynamics after fertilization by mass spectrometry-based proteomics. To do this, we developed a new approach for calculating the stoichiometry of phospho-sites from multiplexed proteomics that is compatible with dynamic, stable and multi-site phosphorylation. Overall, the data suggest that degradation is limited to a few low abundance proteins. However, this degradation promotes extensive dephosphorylation that occurs over a wide range of abundances during meiotic exit. We also show that eggs release a large amount of protein into the medium just after fertilization, most likely related to the blocks to polyspermy. Concomitantly, there is a substantial increase in phosphorylation likely tied to calcium activated kinases. We identify putative degradation targets as well as new components of the block to polyspermy. The analytical approaches demonstrated here are broadly applicable to studies of dynamic biological systems.Significance StatementProtein phosphorylation and degradation drive critical events in early embryogenesis and the cell cycle; however, comprehensive and accurate analysis of these changes is currently difficult. Using a mass spectrometric approach, we present a quantitative view of the protein and posttranslational economy of the fertilization response in the frog egg. Protein degradation affects a small but very important class of proteins, while regulatory phosphorylation and protein release occur on a far larger scale. We have developed new, broadly applicable analytical methods for phosphorylation that provide absolute quantification with confidence intervals for improved interpretability of post-translational modification analysis.
Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release
Authors: Xuan Zhao , Manning Laura , Nelson Jessica , Richmond Janet E. , Colón-Ramos Daniel , Shen Kang , Kurshan Peri T. 
Published: June 2017

AbstractActive zone proteins cluster synaptic vesicles at presynaptic terminals and coordinate their release. In forward genetic screens we isolated a novelC. elegansactive zone gene,clarinet (cla-1). cla-1mutants exhibit defects in synaptic vesicle clustering, reduced spontaneous neurotransmitter release, increased synaptic depression and reduced synapse number. Ultrastructurally,cla-1mutants have fewer synaptic vesicles adjacent to the dense projection and an increased number of docked vesicles.Cla-1encodes 3 isoforms containing common C-terminal PDZ and C2 domains with homology to vertebrate active zone proteins Piccolo and RIM. The short isoform localizes exclusively to the active zone while a longer ~9000 amino acid isoform colocalizes with synaptic vesicles. Specific loss of CLA-1L results in synaptic vesicle clustering defects and increased synaptic depression, but not in reduced synapse number or mini frequency. Together our data indicate that specific isoformsof clarinetserve distinct functions, regulating synapse development, synaptic vesicle clustering and release.
The collective influence of 1, 25-dihydroxyvitamin D3with physiological fluid shear stress on osteoblasts
Authors: Li Yan , Yuan Jiafeng , Wang Qianwen , Sun Lijie , Sha Yunying , Li Yanxiang , Wang Lizhong , Wang Zhonghua 
Published: June 2017

Abstract1, 25-dihydroxyvitamin D3(1, 25 (OH)2D3) and mechanical stimuli in physiological environment play an important role in the pathogenesis of osteoporosis. The effects of 1, 25-dihydroxyvitamin D3alone and mechanical stimuli alone on osteoblasts have been widely investigated. This study reports the collective influences of 1, 25-dihydroxyvitamin D3and flow shear stress (FSS) on biological functions of osteoblasts. 1, 25 (OH)2D3were constructed in various kinds of concentration (0, 1, 10, 100 nmmol/L), while physiological fluid shear stress (12 dynes/cm2) were produced by using a parallel-plate fluid flow system. 1, 25 (OH)2D3affects the responses of ROBs to FSS, including the inhibition of NO releases and cell proliferation as well as the promotion of PGE2releases and cell differentiation. These findings provide a possible mechanism by which 1, 25(OH)2D3influences osteoblasts responses to FSS and may provide guidance for the selection of 1, 25(OH)2D3concentration and mechanical loading in order toin vitroproduce functional bone tissues.
MEA Viewer: a High-performance Interactive Application for Visualizing Electrophysiological Data
Authors: Bridges Daniel C. , Tovar Kenneth R. , Wu Bian , Hansma Paul K. , Kosik Kenneth S. 
Published: June 2017

AbstractMulti-electrode arrays (MEAs) have been used for many years to measure electrical activity in ensembles of many hundreds of neurons, and are used in research areas as diverse as neuronal connectivity and drug discovery. A high sampling frequency is required to adequately capture action potentials, also known as spikes, the primary electrical event associated with neuronal activity, and the resulting raw data files are large and difficult to visualize with traditional plotting tools. Many common approaches to deal with this issue, such as extracting spikes times and solely performing spike train analysis, significantly reduce data dimensionality. Unbiased data exploration benefits from the use of tools that minimize data transforms and such tools enable the development of heuristic perspective from data prior to any subsequent processing. Here we introduce MEA Viewer, a high-performance interactive application for the direct visualization of multi-channel electrophysiological data. MEA Viewer provides many high-performance visualizations of electrophysiological data, including an easily navigable overview of all recorded extracellular signals overlaid with spike timestamp data and an interactive raster plot. Beyond the fundamental data displays, MEA Viewer can signal average and spatially overlay the extent of action potential propagation within single neurons. This view extracts information below the spike detection threshold to directly visualize the propagation of action potentials across the plane of the MEA. This entirely new method of using MEAs opens up new and novel research applications for medium density arrays. MEA Viewer is licensed under the General Public License version 3, GPLv3, and is available athttp://github.com/dbridges/mea-tools.
Type 4 pili are dispensable for biofilm development in the cyanobacterium Synechococcus elongatus
Authors: Nagar Elad , Zilberman Shaul , Sendersky Eleonora , Simkovsky Ryan , Shimoni Eyal , Gershtein Diana , Herzberg Moshe , Golden Susan S. , Schwarz Rakefet 
Published: June 2017

SummaryThe hair‐like cell appendages denoted as type IV pili are crucial for biofilm formation in diverse eubacteria. The protein complex responsible for type IV pilus assembly is homologous with the type II protein secretion complex. In the cyanobacterium Synechococcus elongatus PCC 7942, the gene Synpcc7942_2071 encodes an ATPase homologue of type II/type IV systems. Here, we report that inactivation of Synpcc7942_2071 strongly affected the suite of proteins present in the extracellular milieu (exo‐proteome) and eliminated pili observable by electron microscopy. These results support a role for this gene product in protein secretion as well as in pili formation. As we previously reported, inactivation of Synpcc7942_2071 enables biofilm formation and suppresses the planktonic growth of S. elongatus. Thus, pili are dispensable for biofilm development in this cyanobacterium, in contrast to their biofilm‐promoting function in type IV pili‐producing heterotrophic bacteria. Nevertheless, pili removal is not required for biofilm formation as evident by a piliated mutant of S. elongatus that develops biofilms. We show that adhesion and timing of biofilm development differ between the piliated and non‐piliated strains. The study demonstrates key differences in the process of biofilm formation between cyanobacteria and well‐studied type IV pili‐producing heterotrophic bacteria.
Rethinking Organic Farming in the Post‐Socialist Context: Lessons from Bulgaria
Authors: Moschitz Heidrun , Stoeva Svetla , Slavova Petya , Pickard Dona , Georgieva Zdravka , Stolze Matthias 
Published: June 2017

SummaryOn the basis of an in‐depth qualitative study, this article discusses the case of Bulgaria as an example of a new EU Member State that implemented EU organic farming policies in a top‐down process during EU accession. We explore the difficulties in transposing a concept originating in Western Europe to post‐Socialist countries, and particularly ask what this transposing of an alien concept means for long‐term development of the organic sector. We found that the top‐down agenda‐setting for organic farming in Bulgaria resulted in inefficient policies that inhibited an orientation of producers towards the market's needs. Tacit assumptions underlying the concept of organic farming in Western Europe, such as the relevance of social capital could not be sustained in Bulgaria, which added to the challenges of policy implementation. To increase policy efficiency, we recommend a policy process that involves the expertise of all organic sector actors, including organic operators, but also policymakers, organic organisations, consumers and academic experts. Expertise and knowledge requirements are diverse, touching policy, market, collective action and practice‐oriented skills. Integrating these skills could maximise success in finding the best solution for implementing – and adjusting – a foreign concept meaningfully in a particular local context.
Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria
Authors: Rauber M. M. , Pickert J. , Holiangu L. , Möbs C. , Pfützner W. 
Published: June 2017

AbstractBackgroundChronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti‐IgE antibodies imply that IgE‐mediated mechanisms also play an important role in CU.MethodsReactivity of CU patients’ peripheral blood basophils (n=60) to specific anti‐FcεRI and IgE‐independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE‐mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria‐related symptoms were assessed by both UCT and CU‐Q2oL.ResultsStimulating CU patients’ basophils via FcεRI, we identified three distinct immunologic phenotypes. One subgroup of patients’ basophils reacted to FcεRI stimulation, whereas the others had anti‐FcεRI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum‐induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life.ConclusionsPatients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.
Laboratory parameter‐based machine learning model for excluding non‐alcoholic fatty liver disease (NAFLD) in the general population
Authors: Yip T. C.‐F. , Ma A. J. , Wong V. W.‐S. , Tse Y.‐K. , Chan H. L.‐Y. , Yuen P.‐C. , Wong G. L.‐H. 
Published: June 2017

SummaryBackgroundNon‐alcoholic fatty liver disease (NAFLD) affects 20%‐40% of the general population in developed countries and is an increasingly important cause of hepatocellular carcinoma. Electronic medical records facilitate large‐scale epidemiological studies, existing NAFLD scores often require clinical and anthropometric parameters that may not be captured in those databases.AimTo develop and validate a laboratory parameter‐based machine learning model to detect NAFLD for the general population.MethodsWe randomly divided 922 subjects from a population screening study into training and validation groups; NAFLD was diagnosed by proton‐magnetic resonance spectroscopy. On the basis of machine learning from 23 routine clinical and laboratory parameters after elastic net regulation, we evaluated the logistic regression, ridge regression, AdaBoost and decision tree models. The areas under receiver‐operating characteristic curve (AUROC) of models in validation group were compared.ResultsSix predictors including alanine aminotransferase, high‐density lipoprotein cholesterol, triglyceride, haemoglobin A1c, white blood cell count and the presence of hypertension were selected. The NAFLD ridge score achieved AUROC of 0.87 (95% CI 0.83‐0.90) and 0.88 (0.84‐0.91) in the training and validation groups respectively. Using dual cut‐offs of 0.24 and 0.44, NAFLD ridge score achieved 92% (86%‐96%) sensitivity and 90% (86%‐93%) specificity with corresponding negative and positive predictive values of 96% (91%‐98%) and 69% (59%‐78%), and 87% of overall accuracy among 70% of classifiable subjects in the validation group; 30% of subjects remained indeterminate.ConclusionsNAFLD ridge score is a simple and robust reference comparable to existing NAFLD scores to exclude NAFLD patients in epidemiological studies.
Astrocytes in a dish: Using pluripotent stem cells to model neurodegenerative and neurodevelopmental disorders
Authors: Crompton Lucy A. , Cordero‐Llana Oscar , Caldwell Maeve A. 
Published: June 2017

AbstractNeuroscience and Neurobiology have historically been neuron biased, yet up to 40% of the cells in the brain are astrocytes. These cells are heterogeneous and regionally diverse but universally essential for brain homeostasis. Astrocytes regulate synaptic transmission as part of the tripartite synapse, provide metabolic and neurotrophic support, recycle neurotransmitters, modulate blood flow and brain blood barrier permeability and are implicated in the mechanisms of neurodegeneration. Using pluripotent stem cells (PSC), it is now possible to study regionalised human astrocytes in a dish and to model their contribution to neurodevelopmental and neurodegenerative disorders. The evidence challenging the traditional neuron‐centric view of degeneration within the CNS is reviewed here, with focus on recent findings and disease phenotypes from human PSC‐derived astrocytes. In addition we compare current protocols for the generation of regionalised astrocytes and how these can be further refined by our growing knowledge of neurodevelopment. We conclude by proposing a functional and phenotypical characterisation of PSC‐derived astrocytic cultures that is critical for reproducible and robust disease modelling.
Partial‐mouth periodontal examination protocols for the determination of the prevalence and extent of gingival bleeding in adolescents
Authors: Machado Michely Ediani , Tomazoni Fernanda , Casarin Maísa , Ardenghi Thiago M. , Zanatta Fabricio Batistin 
Published: June 2017

AbstractObjectiveTo compare the performance of partial‐mouth periodontal examination (PMPE) protocols with different cut‐off points to the full‐mouth examination (FME) in the assessment of the prevalence and extent of gingival bleeding in adolescents.MethodsA cross‐sectional study was conducted involving 12‐year‐old adolescents. Following a systematic two‐stage cluster sampling process, 1134 individuals were evaluated. Different PMPE protocols were compared to the FME with six sites per tooth. Sensitivity, specificity, area under the ROC curve (AUC), intraclass correlation coefficient (ICC), relative and absolute biases and the inflation factor were assessed for each PMPE protocol with different cut‐off points for the severity of gingival bleeding.ResultsThe highest AUC values were found for the six‐site two‐diagonal quadrant (2‐4) (0.97), six‐site random half‐mouth (0.95) and Community Periodontal Index (0.95) protocols. The assessment of three sites [mesiobuccal (MB), buccal (B) and distolingual (DL)] in two diagonal quadrants and the random half‐mouth protocol had higher sensitivity and lower specificity than the same protocols with distobuccal (DB) sites. However, the use of DB sites led to better specificity and improved the balance between sensitivity and specificity, except for the two‐diagonal quadrant (1‐3) protocol. The ≥1 cut‐off point led to the most discrepant results from the FME.ConclusionSix‐site two‐diagonal quadrant (2‐4) and random half‐mouth assessments perform better in the evaluation of gingival bleeding in adolescents. However, when a faster protocol is needed, a two‐diagonal quadrant assessment using only MB, B and DL sites can be used with no important loss of information.