bluuebunny/crossref_metadata_2025 huggingface dataset:
Telomere length and oxidative stress variations in a murine model of Alzheimer’s disease progression
Authors: Martínez‐González Katia , Islas‐Hernández Azul , Martínez‐Ezquerro José Darío , Bermúdez‐Rattoni Federico , Garcia‐delaTorre Paola
Published: June 2020

Alzheimer's disease (AD) is the most common cause of dementia, and ageing is its major risk factor. Changes in telomere length have been associated with ageing and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg‐AD; B6; 129‐Psen1  Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9 and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild‐type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains, but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg‐AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.
Interplay between perivascular and perineuronal extracellular matrix remodelling in neurological and psychiatric diseases
Authors: Ulbrich Philipp , Khoshneviszadeh Mahsima , Jandke Solveig , Schreiber Stefanie , Dityatev Alexander
Published: June 2020

Vascular damage, central nervous system (CNS) injury, seizure or even psychological stress may trigger activation of microglia and infiltration of other immune cells, accompanied by high levels of expression and activity of extracellular proteases, such as matrix metalloproteinases (MMPs), and degradation/remodelling of the perivascular and perineuronal extracellular matrix (ECM). This acute response is followed by the recovery/chronic phase, during which the activation of astrocytes leads to the upregulated synthesis of ECM molecules, which, in combination with elevated expression of tissue inhibitor of metalloproteinases (TIMP) proteins, increases the aggregation of ECM molecules. This biphasic dysregulation of local balance between extracellular proteases and the ECM activates multiple temporally overlapping signalling cascades, involving receptor‐type protein tyrosine phosphatases, integrins, Toll‐like receptors, cell adhesion molecules, and ion channels, resulting in impaired synaptic plasticity and cognition. An additional level of complexity is related to the leakage of blood plasma proteins, such as fibrinogen, and the diffusion of perivascularly overproduced MMPs, TIMPs and ECM molecules into the CNS parenchyma, leading to diverse effects on neurons and incorporation of these molecules into the interstitial neural ECM. This review aims to outline these complex common mechanisms in stroke, CNS injury, depression, epilepsy, multiple sclerosis and cerebral small vessel disease and to discuss translational strategies to advance the development of new therapies for these neurological and psychiatric diseases.
Assessment of the quality of patient information sheets and informed consent forms for clinical trials at a hospital neurology service
Authors: Jaramillo Vélez A. G. , Aguas Compaired M. , Granados Plaza M. , Mariño E. L. , Modamio P.
Published: June 2020

Background and purpose

Clinical trials (CTs) aimed at vulnerable groups, such as patients with mental disorders, create ethical complexity. The patient information sheet (PIS) should provide all of the information about the CT that is relevant to the subject's decision to participate. After being informed, the subject will decide freely whether to take part in the CT and will read and sign the informed consent form (ICF). The objective was to assess the quality of PISs/ICFs from a hospital neurology service. The assessment was made using validated and reliable checklists of the information included in the PISs/ICFs of CTs with medicinal products.

Methods

The study comprised analyses of compliance with the checklists of 21 PISs and ICFs reviewed/approved during 2016–2017 by a medicinal research ethics committee.

Results

All PISs/ICFs were from multicenter CTs sponsored by pharmaceutical companies in different therapeutic areas, mainly Parkinson’s (52.4%) and Alzheimer’s (38.1%) diseases. The PISs from the neurology service demonstrated good compliance (≥80%) with the checklist, whereas ICFs should be improved. Sponsors omitted some relevant information, such as the study title or that the participant be informed of any information arising from the research that may be relevant to the subject’s health, although this information may be in the PIS.

Conclusions

The PISs/ICFs of CTs of medicinal products that are currently used need improvement. PISs and ICFs should be separate documents for each CT. In particular, the PISs/ICFs should consider the criteria related to the decision of participants, protect their rights and ensure that the information received is complete.
Using genetic relatedness to understand heterogeneous distributions of urban rat‐associated pathogens
Authors: Byers Kaylee A. , Booker Tom R. , Combs Matthew , Himsworth Chelsea G. , Munshi‐South Jason , Patrick David M. , Whitlock Michael C.
Published: June 2020

Urban Norway rats (Rattus norvegicus) carry several pathogens transmissible to people. However, pathogen prevalence can vary across fine spatial scales (i.e., by city block). Using a population genomics approach, we sought to describe rat movement patterns across an urban landscape and to evaluate whether these patterns align with pathogen distributions. We genotyped 605 rats from a single neighborhood in Vancouver, Canada, and used 1,495 genome‐wide single nucleotide polymorphisms to identify parent–offspring and sibling relationships using pedigree analysis. We resolved 1,246 pairs of relatives, of which only 1% of pairs were captured in different city blocks. Relatives were primarily caught within 33 meters of each other leading to a highly leptokurtic distribution of dispersal distances. Using binomial generalized linear mixed models, we evaluated whether family relationships influenced rat pathogen status with the bacterial pathogens Leptospira interrogans, Bartonella tribocorum, and Clostridium difficile, and found that an individual's pathogen status was not predicted any better by including disease status of related rats. The spatial clustering of related rats and their pathogens lends support to the hypothesis that spatially restricted movement promotes the heterogeneous patterns of pathogen prevalence evidenced in this population. Our findings also highlight the utility of evolutionary tools to understand movement and rat‐associated health risks in urban landscapes.
Forest responses to simulated elevated CO2 under alternate hypotheses of size‐ and age‐dependent mortality
Authors: Needham Jessica F. , Chambers Jeffrey , Fisher Rosie , Knox Ryan , Koven Charles D.
Published: June 2020

Elevated atmospheric carbon dioxide (eCO2) is predicted to increase growth rates of forest trees. The extent to which increased growth translates to changes in biomass is dependent on the turnover time of the carbon, and thus tree mortality rates. Size‐ or age‐dependent mortality combined with increased growth rates could result in either decreased carbon turnover from a speeding up of tree life cycles, or increased biomass from trees reaching larger sizes, respectively. However, most vegetation models currently lack any representation of size‐ or age‐dependent mortality and the effect of eCO2 on changes in biomass and carbon turnover times is thus a major source of uncertainty in predictions of future vegetation dynamics. Using a reduced‐complexity form of the vegetation demographic model the Functionally Assembled Terrestrial Ecosystem Simulator to simulate an idealised tropical forest, we find increases in biomass despite reductions in carbon turnover time in both size‐ and age‐dependent mortality scenarios in response to a hypothetical eCO2‐driven 25% increase in woody net primary productivity (wNPP). Carbon turnover times decreased by 9.6% in size‐dependent mortality scenarios due to a speeding up of tree life cycles, but also by 2.0% when mortality was age‐dependent, as larger crowns led to increased light competition. Increases in aboveground biomass (AGB) were much larger when mortality was age‐dependent (24.3%) compared with size‐dependent (13.4%) as trees reached larger sizes before death. In simulations with a constant background mortality rate, carbon turnover time decreased by 2.1% and AGB increased by 24.0%, however, absolute values of AGB and carbon turnover were higher than in either size‐ or age‐dependent mortality scenario. The extent to which AGB increases and carbon turnover decreases will thus depend on the mechanisms of large tree mortality: if increased size itself results in elevated mortality rates, then this could reduce by about half the increase in AGB relative to the increase in wNPP.
Divergence of Drosophila species: Longevity and reproduction under different nutrient balances
Authors: Watada Masayoshi , Hayashi Yusaku , Watanabe Kaori , Mizutani Shoko , Mure Ayumi , Hattori Yukako , Uemura Tadashi
Published: June 2020

How nutrition impacts growth, reproduction and longevity is complex because relationships between these life events are difficult to disentangle. As a first step in sorting out these processes, we carried out a comparative analysis of related species of Drosophila with distinct feeding habits. In particular, we examined life spans and egg laying of two generalists and three specialists on diets with distinct protein‐to‐carbohydrate ratios. In contrast to the generalist D. melanogaster, adult males of two specialists, D. sechellia and D. elegans, lived longer on a protein‐rich diet. These results and our previous studies collectively show that the diet to which larvae of each specialist species have adapted ensures a longer life span of adult males of that same species. We also found a species‐specific sexual dimorphism of life span in the above two specialists regardless of the diets, which was in sharp contrast to D. melanogaster. In D. melanogaster, males lived longer than females, whereas females of D. sechellia and D. elegans were longer‐lived than males, and those specialist females were exceedingly low in egg production, relative to the other species. We discuss our findings from perspectives of mechanisms, including a possible contribution of egg production to life span.
Non‐surgical periodontal therapy effectively improves patient‐reported outcomes: A systematic review
Authors: Khan Shahrukh , Khalid Taimur , Bettiol Silvana , Crocombe Leonard A.
Published: June 2020

Aim

Modern lifespan oral health research focuses on understanding the impact of periodontitis (or therapy) on clinical and patient‐based outcome measures to provide effective care, improve patient safety according to the quality standards. For better targeted intervention and effective disease management, this systematically review aimed to investigate the relationship between non‐surgical periodontal therapy and patient‐based outcomes using OHIP‐14.

Methods

Seven Databases were searched for studies on patient‐based outcomes responses to periodontal treatment. The time‐period defined from search was from January 1977 to January 2019. Two independent reviewers carried out data search, selection of studies, data extraction and quality assessment using Mixed Method Appraisal Tool. Prospective cohort studies, intervention studies and observational studies written in English demonstrating non‐surgical periodontal therapy response on the patient‐reported outcomes (using Oral Health Impact Profile 14) were included in the review.

Results

Thirteen studies were included in the review, which comprised of three randomised control trials, nine case series, and one was a quasi‐experimental study. Eleven out of the 13 studies reported significant improvement in OHIP‐14 scores amongst participants who had undergone non‐surgical periodontal therapy. Physical disability, psychological discomfort and functional limitation were domains that improved significantly after non‐surgical periodontal therapy in these studies. Physical pain was a common finding in short‐term follow‐up but improved significantly in long‐term follow‐up studies.

Conclusion

Based on clinical and patient‐based outcomes measurement, it is recommended that non‐surgical periodontal therapy is a “gold standard” approach towards improving patient‐based outcomes, reducing co‐morbidities and enhancing patient safely immediately and in long term.
Early Childhood Oral Health Impact Scale (ECOHIS): Literature review and Italian validation
Authors: Contaldo Maria , della Vella Fedora , Raimondo Eugenio , Minervini Giuseppe , Buljubasic Merima , Ogodescu Alexandru , Sinescu Cosmin , Serpico Rosario
Published: June 2020

Objective

The Early Childhood Oral Health Impact Scale (ECOHIS) is a questionnaire to elucidate the relationship between parental perception of the quality of life of their preschool children and their oral health status. Aim of the present work was to validate an Italian ECOHIS version and review the literature.

Methods

After adapting the original ECOHIS questionnaire from English to Italian (I‐ECOHIS), I‐ECOHIS was administered to parents of children afferent to the Dental Clinic of the University of Campania “Luigi Vanvitelli,” regardless of age. Children under 6 years of age underwent anamnestic survey and physical examination, to correlate the dmft index with the ECOHIS score.

Results

366 children have come to our observation. I‐ECOHIS was administered to all parents to establish its comprehensibility. 87 children (44 females and 43 males) under 6 years (5.2 ± 1.4 years) underwent dmft evaluation to determine I‐ECOHIS/oral health status correlation. Among the 87 children examined, the higher total score reached was 25/50. ANOVA analysis confirmed statistically significant correlations between ECOHIS score and dmft = 0 vs dmft equal/higher than 4.

Conclusion

The present pilot study validated the I‐ECOHIS questionnaire and revealed to be a good tool to distinguish children without caries experience from those with a high dmft. However, it was not correlated with the intermediate dmft level, thus confirming the importance of screening for caries.
Is there burnout related to work among Dutch dental hygienists?: Combining studies by using the UBOS and the UWES
Authors: Buunk‐Werkhoven Yvonne A. B. , Folgerts Oddy A. , Oudeman Stephanie E. M. , Hollaar Vanessa R. Y. , Schaufeli Wilmar B.
Published: June 2020

Objectives

To investigate the prevalence of burnout among Dutch young and more experienced dental hygienists and the work experience of young professional dental hygienists.

Material and methods

Two studies were carried out using the Dutch version of the Maslach Burnout Inventory; the Utrecht Burnout Scale (UBOS) and the Utrecht Work Engagement Scale (UWES). In Study I, 400 participants completed an online questionnaire, including the UBOS‐general version. In Study II, a questionnaire was distributed via social media to young professionals, including the UBOS‐health care version and the UWES‐9.

Results

2.5% of 157 dental hygienists (Study I) satisfied the norm of burnout. Dental hygienists' average work experience was 16.6 years, and one‐thirds worked 25‐32 hours per week. In Study II, 73 young professionals (M = 26.5 years) reported 32.9 weekly working hours. Three‐quarters were employed and worked in a dental clinical team practice. UWES‐mean scores indicated a moderate to high level of work engagement. Mostly, all aspects of burnout were low compared with the test Manual norms.

Conclusions

Exploratory findings show that generally burnout appears no threat for Dutch dental hygienists, and moderate to high level of work engagement coincides with a low level of burnout‐related symptoms.
Effect of water vapor and thermal history on nuclear waste feed conversion to glass
Authors: Marcial José , Pokorný Richard , Kloužek Jaroslav , Vernerová Miroslava , Lee SeungMin , Hrma Pavel , Kruger Albert
Published: June 2020

Water affects the glass melting process by interacting with the foam layer at the glass melt surface and by influencing the batch conversion reactions. Nuclear waste aqueous slurry feed maintains a high water vapor pressure in the melter atmosphere. To investigate to what extent water vapor affects the foaming during vitrification of nuclear waste in joule‐heated cold‐top melters, a series of feed expansion experiments were performed under humid and dry atmospheres using samples of low‐activity waste (LAW) melter feed simulants. Melting of feed pellets in the presence of water vapor slightly decreased the temperature of primary foam onset for an extensively foaming feed, but did not significantly affect the feed volume expansion by foaming or the foam‐collapse temperature. Sets of feed expansion experiments and evolved gas analyses were also performed to check the effect of thermal history on conversion behavior of LAW feed samples. The thermal history was varied by testing feed samples prepared as direct slurry, loose powder, and slow‐ and fast‐dried pellets. The sample preparation methods and the sample shape were not found to influence foaming parameters, except for the direct slurry where the low‐temperature swelling prevented the foam onset and collapse temperatures to be determined.
Modulation of immune responses using adjuvants to facilitate therapeutic vaccination
Authors: Schijns Virgil , Fernández‐Tejada Alberto , Barjaktarović Žarko , Bouzalas Ilias , Brimnes Jens , Chernysh Sergey , Gizurarson Sveinbjorn , Gursel Ihsan , Jakopin Žiga , Lawrenz Maria , Nativi Cristina , Paul Stephane , Pedersen Gabriel Kristian , Rosano Camillo , Ruiz‐de‐Angulo Ane , Slütter Bram , Thakur Aneesh , Christensen Dennis , Lavelle Ed C.
Published: June 2020

Therapeutic vaccination offers great promise as an intervention for a diversity of infectious and non‐infectious conditions. Given that most chronic health conditions are thought to have an immune component, vaccination can at least in principle be proposed as a therapeutic strategy. Understanding the nature of protective immunity is of vital importance, and the progress made in recent years in defining the nature of pathological and protective immunity for a range of diseases has provided an impetus to devise strategies to promote such responses in a targeted manner. However, in many cases, limited progress has been made in clinical adoption of such approaches. This in part results from a lack of safe and effective vaccine adjuvants that can be used to promote protective immunity and/or reduce deleterious immune responses. Although somewhat simplistic, it is possible to divide therapeutic vaccine approaches into those targeting conditions where antibody responses can mediate protection and those where the principal focus is the promotion of effector and memory cellular immunity or the reduction of damaging cellular immune responses as in the case of autoimmune diseases. Clearly, in all cases of antigen‐specific immunotherapy, the identification of protective antigens is a vital first step. There are many challenges to developing therapeutic vaccines beyond those associated with prophylactic diseases including the ongoing immune responses in patients, patient heterogeneity, and diversity in the type and stage of disease. If reproducible biomarkers can be defined, these could allow earlier diagnosis and intervention and likely increase therapeutic vaccine efficacy. Current immunomodulatory approaches related to adoptive cell transfers or passive antibody therapy are showing great promise, but these are outside the scope of this review which will focus on the potential for adjuvanted therapeutic active vaccination strategies.
Differential responses to expansion and crisis? The role of urban‐rural divides in long‐term demographic dynamics
Authors: Salvati Luca
Published: June 2020

Economic downturns in advanced countries may influence demographic dynamics, increasing regional differences in population trends and consolidating social divides in accessible and marginal regions. The present study proposes a quantitative framework analysing the latent impact of economic expansions and recessions on regional population dynamics in Greece. Selected indicators (population density, contribution of natural balance and migration balance to total population growth, gross fertility rate and crude birth rate, crude marriage rate, births per marriage, and crude mortality rate) were used to distinguish long‐term transitional processes (1956‐2017) from short‐term dynamics characterising the most recent economic expansion (2000‐2008) and recession (2009‐2017) in Greece. Indicators were calculated separately for Attica, a metropolitan region centred on Athens, where more than 30 per cent of country population was (and still is) settled, and the rest of Greece, allowing a detailed analysis of socio‐demographic dynamics in urban and rural areas. Results of this study indicate that regional population trends in Greece were influenced by a combination of factors reflecting long‐term transitional forces, urbanisation/suburbanisation processes, and short‐term impact of economic downturns.
Preventive measures to limit the spread of Trioza erytreae (Del Guercio) (Hemiptera: Triozidae) in mainland Europe
Authors: Urbaneja‐Bernat Pablo , Hernández‐Suárez Estrella , Tena Alejandro , Urbaneja Alberto
Published: June 2020

Trioza erytreae (Del Guercio) (Hemiptera: Triozidae) vectors the most important citrus disease, namely huanglongbing (HLB) or citrus greening. This vector has been recently found on the European mainland in the north‐western region of the Iberian Peninsula (Spain and Portugal), although HLB has not yet been detected in Europe. Thus, preventing the spread of the vector is currently an urgent priority. Here, we show two prevention methods to avoid the spread of this psyllid from areas where it is present to psyllid‐free areas. Our results showed that two types of anti‐insect mesh with a pore size of 0.4 × 0.77 mm2 and 0.27 × 0.77 mm2 were effective in excluding T. erytreae in two field experiments. These results have direct implications in the nursery plant production system, which should adopt meshes with pore sizes small enough to guarantee the exclusion of T. erytreae. Additionally, we evaluated the longevity of T. erytreae on fruit to understand the risk of dispersion of the psyllid with unprocessed fruit movement between infested and non‐infested areas. The longevity of T. erytreae on mandarin and lemon fruit under winter conditions (13.8°C and 85.4% of relative humidity) was 11 days for both fruits. We anticipate that our results could help enhance the preventive measures in citrus fruit areas without a presence of T. erytreae.
Regulation of Pv‐specific interneurons in the medial prefrontal cortex and reward‐seeking behaviors
Authors: Nahar Lailun , Grant Caleb A. , Hewett Cameron , Cortes Diego , Reker Ashlie N. , Kang Seungwoo , Choi Doo‐Sup , Nam Hyung W.
Published: June 2020

The corticostriatal circuitry and its glutamate‐γ‐aminobuturic acid (GABA) interactions play an essential role in regulating neuronal excitability during reward‐seeking behavior. However, the contribution of GABAergic interneurons in the corticostriatal circuitry remains unclear. To investigate the role of GABAergic interneurons, we focused on parvalbumin‐expressing fast‐spiking interneurons (Pv‐FSI) in the corticostriatal circuitry using the designer receptors exclusively activated by designer drugs approach in a Pv‐Cre mouse model. We hypothesize that Pv‐FSI activation elicits changes in cortical glutamate levels and reward‐seeking behaviors. To determine molecular and behavioral effects of Pv‐FSI, we performed microdialysis and operant conditioning tasks for sucrose and alcohol rewards. In addition, we also examined how alcohol reward itself affects Pv‐FSI functioning. Interestingly, our microdialysis results demonstrate that alcohol exposure inhibits Pv‐FSI functioning in the medial prefrontal cortex (mPFC) and this consequently can regulate glutamate levels downstream in the nucleus accumbens. For sucrose reward‐seeking behaviors, Pv‐FSI activation in the mPFC increases sucrose self‐administration whereas it does not promote alcohol seeking. For alcohol rewards, however, Pv‐FSI activation in the mPFC results in increased compulsive head entry in operant chambers during devaluation procedures. Overall, our results suggest that not only do Pv‐FSI contribute to changes in the cortical microcircuit and reward‐seeking behaviors but also that alcohol affects Pv‐FSI neurotransmission. Therefore, Pv‐FSI has prompted interest in their role in maintaining a balance in neuronal excitation/inhibition and in regulating reward‐seeking processes such as compulsivity, all of which are important factors for excessive alcohol seeking.

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Lysine in the lariat loop of arrestins does not serve as phosphate sensor
Authors: Vishnivetskiy Sergey A. , Zheng Chen , May Mira B. , Karnam Preethi C. , Gurevich Eugenia V. , Gurevich Vsevolod V.
Published: June 2020

Arrestins demonstrate strong preference for phosphorylated over unphosphorylated receptors, but how arrestins “sense” receptor phosphorylation is unclear. A conserved lysine in the lariat loop of arrestins directly binds the phosphate in crystal structures of activated arrestin‐1, ‐2, and ‐3. The lariat loop supplies two negative charges to the central polar core, which must be disrupted for arrestin activation and high‐affinity receptor binding. Therefore, we hypothesized that receptor‐attached phosphates pull the lariat loop via this lysine, thus removing the negative charges and destabilizing the polar core. We tested the role of this lysine by introducing charge elimination (Lys‐>Ala) and reversal (Lys‐>Glu) mutations in arrestin‐1, ‐2, and ‐3. These mutations in arrestin‐1 only moderately reduced phospho‐rhodopsin binding and had no detectable effect on arrestin‐2 and ‐3 binding to cognate non‐visual receptors in cells. The mutations of Lys300 in bovine and homologous Lys301 in mouse arrestin‐1 on the background of pre‐activated mutants had variable effects on the binding to light‐activated phosphorylated rhodopsin, while affecting the binding to unphosphorylated rhodopsin to a greater extent. Thus, conserved lysine in the lariat loop participates in receptor binding, but does not play a critical role in phosphate‐induced arrestin activation.

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Covid‐19 health crisis and lockdown associated with high level of sleep complaints and hypnotic uptake at the population level
Authors: Beck Francois , Léger Damien , Fressard Lisa , Peretti‐Watel Patrick , Verger Pierre ,   The Coconel Group
Published: June 2020

The Covid‐19 pandemic has disrupted the habits of billions of people around the world. Lockdown at home is mandatory, forcing many families, each member with their own sleep–wake habits, to spend 24 hr a day together, continuously. Sleep is crucial for maintaining immune systems and contributes deeply to physical and psychological health. To assess sleep problems and use of sleeping pills, we conducted a cross‐sectional study of a representative sample of the general population in France. The self‐reported sleep complaint items, which covered the previous 8 days, have been used in the 2017 French Health Barometer Survey, a cross‐sectional survey on various public health issues. After 2 weeks of confinement, 74% of the participants (1,005 subjects) reported trouble sleeping compared with a prevalence rate of 49% in the last general population survey. Women reported more sleeping problems than men, with greater frequency or severity: 31% vs. 16%. Unusually, young people (aged 18–34 years) reported sleep problems slightly more frequently than elderly people (79% vs. 72% among those aged 35 or older), with 60% of the younger group reporting that these problems increased with confinement (vs. 51% of their elders). Finally, 16% of participants reported they had taken sleeping pills during the last 12 months, and 41% of them reported using these drugs since the lockdown started. These results suggest that the COVID crisis is associated with severe sleep disorders among the French population, especially young people.
Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials
Authors: Nangia Gayatri , Vierling John M. , Kwo Paul , Brown Deborah D. , Klopfer Stephanie O. , Robertson Michael N. , Haber Barbara A. , Reddy K. Rajender
Published: June 2020

Direct‐acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16‐18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug‐related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.
Educator, judge, public defender: Conflicting roles for remediators of practising physicians
Authors: Bourgeois‐Law Gisèle , Regehr Glenn , Teunissen Pim W. , Varpio Lara
Published: June 2020

Context

Practising physicians who remediate their peers face unique challenges. Recent research suggests that leaders of regulatory and educational institutions (ie, those who might be seen as responsible for overseeing remediation programmes for practising physicians) view remediation as a duality: education and regulation. Research has yet to study the perspectives of remediators; therefore, to address that gap we asked: What is the nature of remediation as experienced by remediators?

Methods

We used a theory‐informing inductive data analysis study design with positioning theory as a sensitising concept. We interviewed nine remediators from five Canadian provinces, asking them to narrate particularly memorable remediation experiences, then exploring the stories in more depth by asking probing questions around topics related to the research question. We used a hermeneutic analytic approach to explore the meanings that participants gave to their remediation work by iteratively reading their stories, examining the sense making that participants achieved through these narratives, and identifying the positions and responsibilities they described.

Results

In their remediation narratives, participants variably position themselves in three different ways: (a) educator; (b) judge, and (c) public defender. For each position, remediators in turn framed the remediatee in a particular way. Participants shifted between educator, judge and public defender in response to evolving experiences with the remediatee, but they expressed preference for the educator position. However, they sometimes encountered serious obstacles to enacting that educator position. Those obstacles were imposed both by regulators and by remediatees.

Conclusions

This study suggests that the duality of remediation as both education and regulation may be contributing to the challenges faced by those working one to one with remediatees. Understanding the dual nature of remediation and equipping remediators with the tools to manage this duality might contribute to improving the experience for both remediators and remediatees, and ultimately to a greater number of successful remediation outcomes.
Mobilization of pdif modules in Acinetobacter: A novel mechanism for antibiotic resistance gene shuffling?
Authors: Balalovski Phillip , Grainge Ian
Published: June 2020

XerCD‐dif site‐specific recombination is a well characterized system, found in most bacteria and archaea. Its role is resolution of chromosomal dimers that arise from homologous recombination. Xer‐mediated recombination is also used by several plasmids for multimer resolution to enhance stability and by some phage for integration into the chromosome. In the past decade, it has been hypothesized that an alternate and novel function exists for this system in the dissemination of genetic elements, notably antibiotic resistance genes, in Acinetobacter species. Currently the mechanism underlying this apparent genetic mobility is unknown. Multidrug resistant Acinetobacter baumannii is an increasingly problematic pathogen that can cause recurring infections. Sequencing of numerous plasmids from clinical isolates of A. baumannii revealed the presence of possible mobile modules: genes were found flanked by pairs of Xer recombination sites, called plasmid‐dif (pdif) sites. These modules have been identified in multiple otherwise unrelated plasmids and in different genetic contexts suggesting they are mobile elements. In most cases, the pairs of sites flanking a gene (or genes) are in inverted repeat, but there can be multiple modules per plasmid providing pairs of recombination sites that can be used for inversion or fusion/deletion reactions; as many as 16 pdif sites have been seen in a single plasmid. Similar modules including genes for surviving environmental toxins have also been found in strains of Acinetobacter Iwoffi isolated from permafrost cores; this suggests that these mobile modules are an ancient adaptation and not a novel response to antibiotic pressure. These modules bear all the hallmarks of mobile genetic elements, yet, their movement has never been directly observed to date. This review gives an overview of the current state of this novel research field.
Basal ganglia calcification in a patient with static encephalopathy of childhood with neurodegeneration in adulthood/β‐propeller protein‐associated neurodegeneration
Authors: Umehara Fujio , Iwama Kazuhiro , Mizuguchi Takeshi , Matsumoto Naomichi
Published: June 2020

A 46‐year‐old Japanese woman presented with slowly progressing parkinsonism/dystonia in adulthood. She had a history of epilepsy and intellectual disability in childhood. Additionally, brain CT revealed bilateral calcification of the globus pallidus. Further investigation using T2‐weighted brain magnetic resonance imaging showed low signal intensity in the globus pallidus and the substantia nigra; T1‐weighted imaging revealed a parallel line of hyperintensity in the midbrain. We identified a de novo c.233C > A, p. Ser78* mutation on the WDR45 gene. Static encephalopathy of childhood with neurodegeneration in adulthood/β‐propeller protein‐associated neurodegeneration should be enlisted among the causes for parkinsonism/dystonia with basal ganglia calcification.
A study of male fertility control in Medicago truncatula uncovers an evolutionarily conserved recruitment of two tapetal bHLH subfamilies in plant sexual reproduction
Authors: Zheng Xiaoling , He Liangliang , Liu Ye , Mao Yawen , Wang Chaoqun , Zhao Baolin , Li Youhan , He Hua , Guo Shiqi , Zhang Liangsheng , Schneider Harald , Tadege Million , Chang Fang , Chen Jianghua
Published: June 2020

Male sterility is an important tool for plant breeding and hybrid seed production. Male‐sterile mutants are largely due to an abnormal development of either the sporophytic or gametophytic anther tissues. Tapetum, a key sporophytic tissue, provides nutrients for pollen development, and its delayed degeneration induces pollen abortion. Numerous bHLH proteins have been documented to participate in the degeneration of the tapetum in angiosperms, but relatively little attention has been given to the evolution of the involved developmental pathways across the phylogeny of land plants.

A combination of cellular, molecular, biochemical and evolutionary analyses was used to investigate the male fertility control in Medicago truncatula.

We characterized the male‐sterile mutant empty anther1 (ean1) and identified EAN1 as a tapetum‐specific bHLH transcription factor necessary for tapetum degeneration. Our study uncovered an evolutionarily conserved recruitment of bHLH subfamily II and III(a + c)1 in the regulation of tapetum degeneration. EAN1 belongs to the subfamily II and specifically forms heterodimers with the subfamily III(a + c)1 members, which suggests a heterodimerization mechanism conserved in angiosperms.

Our work suggested that the pathway of two tapetal‐bHLH subfamilies is conserved in all land plants, and likely was established before the divergence of the spore‐producing land plants.
Expression of cannabinoid CB1R–GPR55 heteromers in neuronal subtypes of the Macaca fascicularis striatum
Authors: Martínez‐Pinilla Eva , Rico Alberto J. , Rivas‐Santisteban Rafael , Lillo Jaume , Roda Elvira , Navarro Gemma , Franco Rafael , Lanciego José Luis
Published: June 2020

The cannabinoid CB1 receptor (CB1R) is the most abundant G protein–coupled receptor in the central nervous system, consistent with the important role of endocannabinoids as neuromodulators. Cannabinoids also modulate the function of G protein–coupled receptor 55 (GPR55), which forms heteroreceptor complexes with the CB1R in the striatum. The aim was to characterize cannabinoid CB1R–GPR55 heteromers (CB1R/GPR55Hets) in the basal ganglia input nuclei of nonhuman primates, Macaca fascicularis, both in projection neurons and interneurons, by the in situ proximity ligation assay. Striatal projecting neurons were identified by the retrograde neuroanatomical tracer, biotinylated dextran amine (BDA), injected into external or internal subdivisions of the globus pallidus. Triple immunofluorescent stains were carried out to visualize (1) BDA‐labeled neurons, (2) CB1R/GPR55Hets, and (3) striatal interneurons positive for choline acetyltransferase, parvalbumin, calretinin, or nitric oxide synthase. CB1R/GPR55Hets were identified within both types of projection neurons as well as all interneurons except those that are cholinergic. Moreover, CB1R/GPR55Hets were found specifically in the neuronal cell surface, and also in intracellular membranes. Further research efforts will be needed to confirm the intracellular occurrence of heteromers and their potential as therapeutic targets in diseases related to motor control imbalances, particularly within a parkinsonian context (with or without levodopa‐induced dyskinesia).
Question order bias revisited: A split‐ballot experiment on satisfaction with public services among experienced and professional users
Authors: Thau Mads , Mikkelsen Maria Falk , Hjortskov Morten , Pedersen Mogens Jin
Published: June 2020

Public decision‐makers increasingly rely on satisfaction surveys to inform budget and policy decisions. Yet, our knowledge of whether, and under what conditions, this input from public service users provides valid performance information remains incomplete. Using a preregistered split‐ballot experiment among government grant recipients in Denmark, this article shows that the ordering of survey questions can bias satisfaction measures even for highly experienced and professional respondents. We find that asking about overall satisfaction before any specific service ratings lowers overall user satisfaction, compared to the reverse order, while the correlations between specific ratings and overall satisfaction are relatively stable. Also, the question order effect outweighs that of a large‐scale embezzlement scandal, which unexpectedly hit the investigated government agency during the data collection. Our results support rising concerns that subjective performance indicators are susceptible to bias. We discuss how practitioners should approach satisfaction surveys to account for the risk of question order bias.
Improving the performance of public organizations: Financial resources and the conditioning effect of clientele context
Authors: Flink Carla , Molina Angel Luis
Published: June 2020

The link between expenditures and organizational performance is central to our understanding of public sector governance. Despite various empirical and theoretical accounts of how organizations buffer or exploit financial situations to stabilize outcomes, the literature remains split on how money influences organizational performance. This study sheds new light on this puzzle by developing an analysis of clientele contexts, and how such contexts intervene in the relationship between expenditure and performance. We analyse competing hypotheses for the heterogeneous effects of clientele contexts on funding and performance—one in which these contexts strengthen the relationship, and one in which they weaken the relationship. Through district‐level empirical analyses of public education data over a 17‐year period, we find that instructional spending changes influence student performance, and that the impact is conditioned by the socioeconomic mix of students. Organizations that serve low‐income communities see the greatest performance gains from increased monetary resources.
Use of a simulation‐based mastery learning curriculum to improve ultrasound‐guided vascular access skills of pediatric anesthesiologists
Authors: Ballard Heather A. , Tsao Michelle , Robles Alison , Phillips Mitch , Hajduk John , Feinglass Joseph , Barsuk Jeffrey H.
Published: June 2020

Background

Pediatric vascular access is inherently challenging due to the small caliber of children's vessels. Ultrasound‐guided intravenous catheter insertion has been shown to increase success rates and decrease time to cannulation in patients with difficult intravenous access. Although proficiency in ultrasound‐guided intravenous catheter insertion is a critical skill in pediatric anesthesia, there are no published competency‐based training curricula.

Aims

The objective of this study was to evaluate the performance of pediatric anesthesiologists who participated in a novel ultrasound‐guided intravenous catheter insertion simulation‐based mastery learning curriculum.

Methods

Pediatric anesthesia attendings, fellows, and rotating residents participated in the ultrasound‐guided intravenous catheter insertion simulation‐based mastery learning curriculum from August 2019 to February 2020. The 2‐hour curriculum consisted of participants first undergoing a simulated skills pretest followed by watching a video on ultrasound‐guided intravenous catheter insertion and deliberate practice on a simulator. Subsequently, all participants took a post‐test and were required to meet or exceed a minimum passing standard. Those who were unable to meet the minimum passing standard participated in further practice until they could be retested and met this standard. We compared pre to post‐test ultrasound‐guided intravenous catheter insertion skills and self‐confidence before and after participation in the curriculum.

Results

Twenty‐six pediatric anesthesia attendings, 12 fellows, and 38 residents participated in the curriculum. At pretest, 16/76 (21%) participants were able to meet or exceed the minimum passing standard. The median score on the pretest was 21/25 skills checklist items correct and improved to 24/25 at post‐test (95% CI 3.0‐4.0, P < .01). Self‐confidence significantly improved after the course from an average of 3.2 before the course to a postcourse score of 3.9 (95% CI 0.5‐0.9, P < .01; 1 = Not all confident, 5 = Very confident).

Conclusions

Simulation‐based mastery learning significantly improved anesthesiologists’ ultrasound‐guided intravenous catheter insertion performance in a simulated setting.
Resistance and susceptibility QTL identified in a rice MAGIC population by screening with a minor‐effect virulence factor fromXanthomonas oryzaepv.oryzae
Authors: Huerta Alejandra I. , Delorean Emily E. , Bossa‐Castro Ana M. , Tonnessen Bradley W. , Raghavan Chitra , Corral Rene , Pérez‐Quintero Álvaro L. , Leung Hei , Verdier Valérie , Leach Jan E.
Published: June 2020

Effective and durable disease resistance for bacterial blight (BB) of rice is a continuous challenge due to the evolution and adaptation of the pathogen,Xanthomonas oryzaepv.oryzae(Xoo), on cultivated rice varieties. Fundamental to this pathogens’ virulence is transcription activator‐like (TAL) effectors that activate transcription of host genes and contribute differently to pathogen virulence, fitness or both. Host plant resistance is predicted to be more durable if directed at strategic virulence factors that impact both pathogen virulence and fitness. We characterized Tal7b, a minor‐effect virulence factor that contributes incrementally to pathogen virulence in rice, is a fitness factor to the pathogen and is widely present in geographically diverse strains ofXoo. To identify sources of resistance to this conserved effector, we used a highly virulent strain carrying a plasmid borne copy of Tal7b to screen an indica multi‐parent advanced generation inter‐cross (MAGIC) population. Of 18 QTL revealed by genome‐wide association studies and interval mapping analysis, six were specific to Tal7b (qBB‐tal7b). Overall, 150 predicted Tal7b gene targets overlapped with qBB‐tal7bQTL. Of these, 21 showed polymorphisms in the predicted effector binding element (EBE) site and 23 lost the EBE sequence altogether. Inoculation and bioinformatics studies suggest that the Tal7b target in one of the Tal7b‐specific QTL, qBB‐tal7b‐8, is a disease susceptibility gene and that the resistance mechanism for this locus may be through loss of susceptibility. Our work demonstrates that minor‐effect virulence factors significantly contribute to disease and provide a potential new approach to identify effective disease resistance.