bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?
Authors: Routier Laura , Verny Florine , Barcia Giulia , Chemaly Nicole , Desguerre Isabelle , Colleaux Laurence , Nabbout Rima 
Published: June 2019

AbstractMyoclonic‐atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array‐CGH and whole‐exome sequencing in 27 patients. We considered non‐synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease‐causing variants in 11 patients (41%). Single variants were found in some known epilepsy‐associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.
Inter‐lab concordance of variant classifications establishes clinical validity of expanded carrier screening
Authors: Kaseniit Kristjan E. , Collins Elizabeth , Lo Christine , Moyer Krista , Mar‐Heyming Rebecca , Kang Hyunseok P. , Muzzey Dale 
Published: June 2019

AbstractExpanded carrier screening (ECS) panels that use next‐generation sequencing aim to identify pathogenic variants in coding and clinically relevant non‐coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170‐condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline‐based criteria to their corresponding per‐variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency‐weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene‐level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel‐wide false‐positive rate. Finally, because ECS is intended to serve all reproductive‐age couples, we show that classification of novel variants is feasible and scales predictably for a large population.
A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH
Authors: Zhu Hao , Chen Xiaomei , Ahmed Mariam , Wang Yaning , Liu Qi , Uppoor Ramana S. , Kuemmel Colleen , Mehta Mehul 
Published: June 2019

In this paper, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and, thus, differ in absorption at elevated gastric pH. However, routine bioequivalence trials using subjects with normal gastric pH (i.e., ~ 1) may fail to identify these differences because dissolution/absorption profiles of the two formulations at normal gastric pH are similar. In the case of palbociclib, it is confirmedthat the free base and salt formulations showed different absorption in patients with different gastric pH. Significant reduction in drug absorption was observed only in patients with elevated gastric pH using free base formulation. The discovery that the free base had significantly reduced absorption hinged on the inclusion of enough patients with elevated gastric pH to detect a difference in a bioequivalence trial. This raises a concern, as demonstrated through simulation, that dissolution/absorption differences in other formulations could be missed in routine bioequivalence trials. Aside from differences in active pharmaceutical ingredients (APIs), other factors, such as changes in excipients or manufacturing methods, may also lead to exposure differences between formulations at elevated gastric pH. For formulations containing different forms of the same active moiety or the same API and showing different dissolution profiles at elevated pH (i.e., pH ~ 4–6.8), evaluation of bioequivalence with gastric pH modulators (e.g., a H2 blocker) in addition to routine bioequivalence assessments may help to ensure therapeutic equivalence in patients with elevated gastric pH.
Descriptions of diabetes burnout from individuals with Type 1 diabetes: an analysis of YouTube videos
Authors: Abdoli S. , Hessler D. , Vora A. , Smither B. , Stuckey H. 
Published: June 2019

AbstractAimThe purpose of the study was to analyse self‐descriptions of diabetes burnout in individuals with Type 1 diabetes via YouTube videos.MethodsIn this qualitative descriptive study, a systematic approach was used to search YouTube videos with a title, description or content specifically about diabetes burnout dated between 2007 and 2017. Irrelevant or duplicated videos were excluded using eligibility criteria. All videos meeting inclusion criteria (n = 32) from individuals with Type 1 diabetes were transcribed verbatim and analysed using a qualitative content analysis approach. Descriptive statistics were used to analyse video characteristics.ResultsThe four major themes associated with diabetes burnout were: (i) feeling mentally drained and physically tired of dealing with self‐care; (ii) experiencing a detachment from self, diabetes care and support system; (iii) being powerless and paralysed to ‘climb out’ of diabetes burnout; and (iv) contributing potential factors to diabetes burnout.ConclusionsSelf‐descriptions of diabetes burnout suggest that it is a combination of emotions and behaviours on a spectrum from exhaustion to detachment accompanied by an overwhelming sense of powerlessness. More studies are needed to further clarify diabetes burnout and its distinction from, or overlap with, other related psychosocial concepts in diabetes care.
Yaks and sheep trigger different changes in the grasshopper assemblages of the Qilian Mountains via differentially altering plant assemblages
Authors: Hu Jing , Hassan Wail M. , Chen Guorong , Li Yanlin , Fan Wenqiao , Wang Wei 
Published: June 2019

1. The Qilian Mountains represent one of the key livestock‐raising grasslands in China. The two main herbivore species raised in this area – yaks and sheep – are of critical economical value. Grasshoppers compete with these animals for available nutrients, creating multifaceted relationships between livestock, grasshoppers and plants. A clear understanding of such relationships is lacking and is urgently needed to guide conservation efforts.2. This study aims to document the effects of yak and sheep grazing on grasshopper assemblages and to elucidate the underlying mechanisms of such effects.3. It is shown here that yaks and sheep impact grasshopper assemblages differently. Grasshopper assemblages exhibited lower density, biodiversity, richness, and evenness of distribution in yak‐grazed pastures than in grazing‐free grasslands. Sheep‐grazed pastures exhibited a dramatically divergent picture, with elevated density, biodiversity and richness, and a slightly decreased evenness of distribution. Grasshoppers were generally larger in grazed pastures than in grazing‐free grasslands, especially in yak‐grazed plots.4. The present study suggests that differences between yak and sheep pastures in plant assemblage structure and plant traits are probably the underlying forces driving the differences in grasshopper assemblage structure and grasshopper traits, respectively.5. The study shows that the grasshopper habitat indicator species differ between yak and sheep pastures, raising the possibility that such indicators can be used to monitor grassland usage and degradation in the Qilian Mountains.6. These results provide novel insights into the dynamic interactions of common domesticated herbivore species, grasshoppers and plants in Qilian Mountains, which augment current knowledge and may ultimately lead to better conservation practices.
Rapid discontinuation of sodium channel–blocking antiseizure drugs evokes focal edema in the splenium corporis callosi: A matched case‐control study
Authors: Zöllner Johann Philipp , Rosenow Felix , Wagner Marlies , Hattingen Elke , Müller‐Eschner Monika , Strzelczyk Adam 
Published: June 2019

AbstractObjectiveFocal edema of the splenium of the corpus callosum (FESCC) is infrequently seen in patients with epilepsy who are undergoing video–electroencephalography (EEG) monitoring. It is diagnosed by qualitative visual inspection of the magnetic resonance imaging (MRI) and is usually assumed to be a dichotomous phenomenon. Rapid reduction of anticonvulsants has been proposed as a cause. In this study we investigate the relationship between dose reduction of anticonvulsants and the occurrence of FESCC, based on absolute drug doses.MethodsWe examined in detail the anticonvulsive therapy of all patients during video‐EEG monitoring between 2014 and 2018. We compared patients with a radiologically diagnosed FESCC to controls in a 1:2 case‐control analysis matched by age, epilepsy syndrome, and adjacent time of admission. In a separate correlation analysis, we examined quantitative effects of reduction of antiseizure drugs on diffusion restriction in the corpus callosum.ResultsOf 326 patients who had an MRI following video‐EEG monitoring, 12 (3.7%) had FESCC. Antiseizure drugs were reduced to a significantly greater extent in FESCC patients than in the 24 controls (P < 0.001). Sodium channel–blocking antiseizure drugs were reduced (P < 0.001) and reintroduced (P < 0.001) significantly faster in FESCC patients, and the duration of anticonvulsant discontinuation was longer in FESCC patients (P < 0.001). The separate correlation analysis in 325 patients shows a weak correlation between diffusion restriction in the splenium and the reduction rate of sodium channel–blocking anticonvulsants (r = −0.15, P = 0.03) as well as the duration of their discontinuation (r = −0.16, P = 0.01). No such effects were found for anticonvulsants with other modes of action.SignificanceOur findings substantiate that FESCC is associated with high rates of dose reduction of anticonvulsants, specifically those acting on sodium channels. Our results cautiously suggest that reducing sodium‐channel blockers has a small effect on diffusivity in the splenium below the visual threshold.
The spatial scale of dispersal revealed by admixture tracts
Authors: Duranton Maud , Bonhomme François , Gagnaire Pierre‐Alexandre 
Published: June 2019

AbstractEvaluating species dispersal across the landscape is essential to design appropriate management and conservation actions. However, technical difficulties often preclude direct measures of individual movement, while indirect genetic approaches rely on assumptions that sometimes limit their application. Here, we show that the temporal decay of admixture tracts lengths can be used to assess genetic connectivity within a population introgressed by foreign haplotypes. We present a proof‐of‐concept approach based on local ancestry inference in a high gene flow marine fish species, the European sea bass (Dicentrarchus labrax). Genetic admixture in the contact zone between Atlantic and Mediterranean sea bass lineages allows the introgression of Atlantic haplotype tracts within the Mediterranean Sea. Once introgressed, blocks of foreign ancestry are progressively eroded by recombination as they diffuse from the western to the eastern Mediterranean basin, providing a means to estimate dispersal. By comparing the length distributions of Atlantic tracts between two Mediterranean populations located at different distances from the contact zone, we estimated the average per‐generation dispersal distance within the Mediterranean lineage to less than 50 km. Using simulations, we showed that this approach is robust to a range of demographic histories and sample sizes. Our results thus support that the length of admixture tracts can be used together with a recombination clock to estimate genetic connectivity in species for which the neutral migration‐drift balance is not informative or simply does not exist.
A topical heparinoid‐containing product improves epidermal permeability barrier homeostasis in mice
Authors: Yao Ye , Guo Pan , Feng Xiaoyue , Shen Chunping , Huang Junkai , Zhang Jiechen , Elias Peter M. , Hu Lizhi , Man Mao‐Qiang 
Published: June 2019

AbstractBecause of the importance of epidermal functions, including stratum corneum hydration and maintenance of permeability barrier homeostasis, in the pathogenesis of a variety of cutaneous and systemic disorders, a wide range of products has been developed to improve epidermal functions. However, the underlying mechanisms whereby certain products, including heparinoid‐containing product, are far little understood. In the present study, we assessed the impact of a heparinoid‐containing product, Hirudoid® cream, on epidermal permeability barrier function and expression levels of a panel of epidermal mRNA related to the formation/maintenance of the permeability barrier in mouse skin. Our results showed that while the baseline levels of transepidermal water rates remained unchanged, treatment with Hirudoid® cream twice daily for 7 days significantly accelerated permeability barrier recovery and increased stratum corneum hydration. In parallel, expression levels of epidermal mRNA for certain differentiation marker‐related proteins, lipid synthetic enzymes, keratinocyte proliferation and antimicrobial peptides also increased significantly. Together, these results provide the underlying mechanisms by which topical Hirudoid® cream improves epidermal permeability barrier and antimicrobial function. Because of its benefits for epidermal functions, heparinoid‐containing product could be more useful in the management of skin conditions, characterized by abnormal permeability barrier and antimicrobial function.
Trait‐based range expansion aided in the global radiation of Crocodylidae
Authors: Nicolaï Michaël P. J. , Matzke Nicholas J. 
Published: June 2019

AbstractAimAlmost half of the extant species of Crocodylia (nine genera, sensu Benton & Clark) belong to the genus Crocodylus, which originated in the Miocene. Today, this genus has a circumtropical distribution, with representatives found in Asia, Oceania, Africa and the Neotropics. However, its geographical origin and the historical events behind its rapid diversification and global radiation are still debated. Here, we inferred the evolution of a set of life traits that aid in dispersal and how they influenced the biogeography of Crocodylus.LocationGlobal.Time periodCretaceous to the present.Major taxa studiedCrocodylidae.MethodsWe estimated biogeographical history on a published phylogeny using probabilistic biogeography models. Next, we identified four life traits likely to promote range expansion and used a trait‐based dispersal model jointly to infer evolution of these traits and their influence on the dispersal of crocodilians. Finally, we used diversification analyses to identify shifts in diversification rates.ResultsAn Asian origin was reconstructed for Crocodylus. Despite the small size of the phylogeny, statistical model comparison reports substantially improved the model fit of trait‐dependent over trait‐independent dispersal models. In individual tests, the four life traits considered (salt tolerance, large size, large clutches and habitat generalism) appear to be correlated statistically with higher dispersal probabilities. However, the traits are likely to be correlated with each other, and we hypothesize that they all reflect the gradual evolution of a range‐expansion phenotype in early Crocodylus that resulted in increased diversification of the clade.Main conclusionsIncreased dispersal in the genus Crocodylus was associated with the gradual evolution of a range‐expansion phenotype. Interestingly, the evolution of the range‐expansion phenotype was also associated with the diversification of the genus in a period of global crocodilian extinction, indicating that range expansion might have served as a potential driver of speciation. This suggests that the concept of “spatial sorting”, normally applied at the population genetic level at the leading edge of an expanding population, might also act on a macroevolutionary scale.
Digital Work Practices: Affordances in Design Education
Authors: Crosby Alexandra , Pham Kane , Peterson J. Fiona , Lee Thomas 
Published: June 2019

AbstractThis article draws from a multi‐disciplinary, multi‐institutional research project on digital work practices and graduate work readiness. Utilising the concept of technology affordances, we focus on the potential for domain‐specific learning experiences within design education. For the purpose of this project, we have articulated digital capabilities in design by adapting affordance categories in terms of three levels of complexity for scaffolded learning: functional, perceptual and adaptive. In order to further develop the relationship between technology affordances and design education, we analyse data from an industry roundtable in relation to our developed digital capability descriptor. The findings suggest that employers need designers with highly adaptive capabilities to work in increasingly complex interdisciplinary work environments. We also found that the role of designers has changed significantly in recent years that require higher educational institutions to involve industry when developing curricula.
Trauma‐informed care: A qualitative study exploring the views and experiences of professionals in specialist health services for adults with intellectual disabilities
Authors: Truesdale Maria , Brown Michael , Taggart Laurence , Bradley Aoife , Paterson Douglas , Sirisena Chammy , Walley Robert , Karatzias Thanos 
Published: June 2019

AbstractBackgroundTrauma and its sequelae is recognised as a major morbidity factor in people with intellectual disabilities, however, a lack of inquiry into how health care professionals address trauma in this adult population exists.AimsTo explore specialist intellectual disability practitioners perspectives on current health provision and developments to address trauma.MethodsTwenty‐five qualitative interviews were conducted with practitioners across 6 health service areas in the UK. Data were analysed using thematic content analysis.FindingsSeven central themes emerged: (a) unmasked trauma; (b) trauma informed care; (c) person‐centred care and support; (d) multi‐disciplinary working; (e) reasonable adjustments; (f) barriers to treatment and (g) awareness, training and education.ConclusionTrauma‐informed care and multi‐disciplinary working are essential components for future service development. Advances in the evidence‐base for effective psychological interventions for PTSD and training and education of health care staff are needed in order to improve service provision amongst this population.
Model averaging fails to improve the extrapolation capability of the island species–area relationship
Authors: Matthews Thomas J. , Aspin Thomas W. H. 
Published: June 2019

AbstractAimOne of the main applications of the island species–area relationship (SAR) is to predict species richness in areas of habitat too large to be sampled, but there are few clear guidelines for choosing an appropriate model for this purpose. We therefore aimed to test whether a multi‐model averaging approach could improve the accuracy of predictions made by extrapolating the ISAR. Specifically, we compared the performance of multi‐model averaging with that of the default ISAR model of choice, the power model, in predicting species richness in large habitat islands.LocationGlobalTaxaVertebrates, invertebrates and plantsMethodsWe removed the largest islands from 120 habitat island datasets, and fitted both the power model and a multi‐model average curve (averaging the predictions of up to 20 ISAR models) to this filtered dataset. We then assessed the accuracy of both approaches in predicting the species richness of the largest island in the original dataset using the log error of extrapolation (LEE) metric. A generalized additive regression modelling framework was used to determine whether any dataset characteristics could explain variation in the LEE values for the power model (LEE‐POW).ResultsThe power model gave the more accurate richness predictions for 58% of the analysed datasets and the multi‐model averaged curve gave the more accurate predictions for the remaining 42%. Both the power models (61% of LEE‐POW values were positive) and the multi‐model averaged curve (60% were positive) had a slightly greater tendency to over predict the observed richness. The confidence intervals were also on average narrower for the power model predictions (median 95% confidence interval width = 18 species) than for the multi‐model averaged curve predictions (median 95% confidence interval width = 78). The range in island areas and richness values explained a small amount of the variation in LEE‐POW.Main conclusionsContrary to expectation, multi‐model averaging was less accurate than the power model in the majority of cases, and thus does not appear to be a panacea for uncertainty in model choice when extrapolating the ISAR. However, further research is urgently needed to evaluate the performance of a multi‐model averaging approach at larger spatial scales.