bluuebunny/crossref_metadata_2025 huggingface dataset:
The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts
Authors: Szoka Lukasz , Karna Ewa , Andrulewicz‐Botulinska Edyta , Hlebowicz‐Sarat Kornelia , Palka Jerzy A.
Published: May 2019

The mechanism for differential effects of human immune deficiency virus protease inhibitors (HIVPIs), nelfinavir (NEL) and indinavir (IND) on collagen metabolism disturbances was studied in human skin fibroblasts. It has been considered that HIVPIs‐dependent deregulation of collagen biosynthesis involves prolidase (an enzyme providing proline for collagen biosynthesis), glutamine (Gln) (a substrate for proline biosynthesis), nuclear factor‐κB (NF‐κB) (a transcription factor that inhibit expression of type I collagen genes), β1 integrin receptor and Akt signalling. It was found that NEL impaired collagen biosynthesis and the process was more pronounced in the presence of Gln, while IND stimulated collagen biosynthesis. NEL‐dependent inhibition of collagen biosynthesis was accompanied by massive intracellular accumulation of type I collagen, while IND slightly induced this process. This effect of NEL was reversed by ascorbic acid but not N‐acetylcysteine. The mechanism for the NEL‐dependent defect in collagen metabolism was found at the level of prolidase activity, β1 integrin signalling and NF‐κB. NEL inhibited expression of β1 integrin receptor, Akt and ERK1/2 and increased expression of p65 NF‐κB. However, inhibitors of p65 NF‐κB did not prevent NEL‐dependent inhibition of collagen biosynthesis suggesting that this transcription factor is not involved in studied mechanism. Using PI3K inhibitor wortmannin that prevent phosphorylation of Akt revealed that NEL‐dependent inhibition of Akt results in inhibition of collagen biosynthesis. The data suggest that differential effect of NEL and IND on collagen metabolism involves NEL‐dependent down‐regulation of Akt signalling and proline availability for collagen biosynthesis.
Vestibular Neuroscience for the Headache Specialist
Authors: Balaban Carey D. , Black Robert D. , Silberstein Stephen D.
Published: May 2019

Background

The vestibular system is a multifaceted, integrative sensory system that is often referred to as the “multi‐sensory” sense. There is an extensive literature about the vestibular sensory organs and afferent nerve pathways; however, this rich resource is often unknown to the headache specialist.

Aims

In this review, we highlight the significance of vestibular sensory processing beyond its role in the maintenance of balance. The role of the vestibular system in migraine pathophysiology is emphasized, not just in how it impacts dizziness or nausea, but also in its higher order effects on mood and cognition. How the vestibular system responds to current and new migraine therapies, such as anti‐CGRP (calcitonin gene‐related peptide) antibodies, is also discussed.

Conclusions

The vestibular system is not just about balance; this should be taken into account by clinicians as they assess their patients' associated non‐headache symptoms. There is a co‐occurrence of migraine and vestibular‐based problems and a confluence of disciplines relevant to vestibular migraine.
Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis
Authors: Joshita Satoru , Umemura Takeji , Yamashita Yuki , Sugiura Ayumi , Yamazaki Tomoo , Fujimori Naoyuki , Matsumoto Akihiro , Tanaka Eiji
Published: May 2019

Aim

Fibrate addition to ursodeoxycholic acid (UDCA) therapy has been shown to improve both liver biochemistry and long‐term prognosis in primary biliary cholangitis (PBC) patients showing an incomplete biochemical response to UDCA alone. We herein describe the clinical outcome of seven cases of PBC that received the new selective peroxisome proliferator‐activated receptor α modulator, pemafibrate, in combination with UDCA therapy to investigate the biochemical and plasma lipid responses to the drug.

Methods

Of 124 initially enrolled PBC patients, 12 treated with UDCA alone and seven receiving UDCA plus bezafibrate showed alkaline phosphatase (ALP) levels above the upper limit of normal (330 U/L). Ultimately, seven patients with PBC and dyslipidemia who had agreed to biweekly visits at our hospital for UDCA plus pemafibrate combination therapy were retrospectively analyzed.

Results

In the four cases that switched from bezafibrate to pemafibrate, ALP became significantly decreased (0.031) and γ‐glutamyltransferase tended to decrease (0.063) over the 3 months following pemafibrate addition. Two patients showed a greater than 50% reduction in ALP. No remarkable differences were observed for plasma lipid levels, alanine aminotransferase, aspartate aminotransferase, or the liver fibrosis marker Mac‐2 binding protein glycosylation isomer between these time points. No adverse drug reactions were recorded.

Conclusions

Pemafibrate might be another option for PBC patients with an incomplete response to UDCA therapy.
Real‐world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group
Authors: Mashiba Toshie , Joko Kouji , Kurosaki Masayuki , Ochi Hironori , Hasebe Chitomi , Akahane Takehiro , Sohda Tetsuro , Tsuji Keiji , Mitsuda Akeri , Kimura Hiroyuki , Narita Ryoichi , Ogawa Chikara , Furuta Koichiro , Shigeno Masaya , Okushin Hiroaki , Ito Hiroshi , Kusakabe Atsunori , Satou Takashi , Kawanami Chiharu , Nakata Ryo , Kobashi Haruhiko , Tamada Takashi , Ide Yasushi , Yagisawa Hitoshi , Morita Atsuhiro , Matsushita Tomomichi , Okada Kazuhiko , Izumi Namiki
Published: May 2019

Aim

The present study aimed to determine the real‐world efficacy and safety of the non‐structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection.

Methods

This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post‐treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study.

Results

Treatment outcomes for EBR/GZR were good in direct‐acting antiviral (DAA)‐naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A‐L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A‐L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A‐Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91–16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy.

Conclusions

The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first‐line treatment for DAA‐naïve patients with HCV.
Self‐regulated learning and training effectiveness
Authors: Lourenco Daniel , Ferreira Aristides I.
Published: May 2019

In recent years, training has shifted towards a more learner‐centred perspective. At the same time, rapidly changing workplaces emphasize the importance of self‐regulatory processes in the workplace. In the light of these trends, this research investigates the role of self‐regulated learning in training effectiveness. A theoretical model in which self‐regulated learning plays a central role in training evaluation was developed and validated using the structural equation method with a sample of 137 individuals. The results indicate that self‐regulated learning mediates the relationship between training climate and both transfer motivation and training evaluation. These findings indicate that the concept of self‐regulated learning plays a key role in the relationship between training context variables and organizational outcomes and offer new insights into the way organizations can improve training effectiveness.
Effects of insularity on insect leaf herbivory and chemical defences in a Mediterranean oak species
Authors: Moreira Xoaquín , Castagneyrol Bastien , de la Mata Raúl , Fyllas Nikolaos M. , Galmán Andrea , García‐Verdugo Carlos , Larrinaga Asier R. , Abdala‐Roberts Luis
Published: May 2019

Aim

Research on plant–herbivore interactions has shown that islands typically have low abundances and diversity of herbivores because of barriers to dispersal, isolation and reduced land area. Islands commonly have lower levels of herbivory relative to mainland regions, and, as a consequence, insular plants should exhibit lower levels of defences than their mainland counterparts. Despite these predictions, there are significant gaps in our understanding of insularity effects on plant–herbivore interactions. For instance, most work addressing the effects of insularity on plant–herbivore interactions have compared one or a few islands with a single mainland site. In addition, studies have measured herbivory or plant defences but not both, and the influence of abiotic factors has been neglected.

Location

Mediterranean Basin (from Spain to Greece).

Taxon

Quercus ilex L.

Methods

We conducted a large‐scale study to investigate whether insect leaf herbivory and plant chemical defences in holm oak (Quercus ilex L.) differ between insular versus mainland populations. We further investigated mechanisms by which insularity effects on herbivory may take place by assessing the influence of defences and climatic variables on herbivory.

Results

We found that insular populations exhibited lower herbivory and higher defences (condensed tannins) than their mainland counterparts. Our analyses, however, suggest that these concomitant patterns of insect herbivory and plant defences were seemingly unrelated as island versus mainland differences in defences did not account for the observed pattern in herbivory. Furthermore, climatic factors did not explain insularity effects on either herbivory or plant defences.

Main conclusions

Overall, this study provides one of the most robust assessments to date on insularity effects on herbivory and builds towards a better understanding of the ecology and evolution of plant–insect interactions in insular ecosystems.
Association of left atrium voltage amplitude and distribution with the risk of atrial fibrillation recurrence and evolution after pulmonary vein isolation: An ultrahigh‐density mapping study
Authors: Ballesteros Gabriel , Ravassa Susana , Bragard Jean , Ramos Pablo , López Begoña , Vives Enrique , Neglia Renzo , Wise Bernardo , González Arantxa , Moreno María U. , Díez Javier , García‐Bolao Ignacio
Published: May 2019

Introduction

Ultrahigh‐density‐voltage mapping (uHDVM) is a new tool that can add new insights into the pathophysiology of atrial fibrillation (AF). The aim of this study was to evaluate the performance of uHDVM in predicting postablation AF recurrence (AFR).

Methods and Results

We included 98 consecutive patients undergoing pulmonary vein isolation for AF (40.8% persistent) using an uHDVM system and followed for 1 year. The left atrium (LA) mean voltage (Vm) and the Vslope (slope of the voltage histogram calculated by linear interpolation, with the relative frequency on the vertical axis and the bipolar potential on the horizontal axis) were calculated from 12 567 ± 5486 points per map.

Patients with AFR (N = 29) had lower Vm and higher Vslope as compared with patients without AFR (N = 69). Receiver operating characteristic curves identified Vm as the strongest predictor of AFR, with a higher incidence of AFR in patients with Vm 0.758 mV (57.6%) or lower than patients with Vm higher than 0.758 mV (15.4%; P < .0001). Among patients with Vm higher than 0.758 mV, patients with Vslope 0.637 or higher exhibited higher (P = .043) AFR incidence (31.3%) than patients with Vslope lower than 0.637 (10.2%). This classification showed incremental predictive value over relevant covariables. Vm values were lower and Vslope values were higher in patients that progressed from paroxysmal to persistent AF. Patients with Vslope 0.637 or higher had a 14.2% incidence of postablation atypical atrial flutter, whereas patients with Vslope lower than 0.637 did not present this outcome.

Conclusions

The risk of AFR, atrial flutter, and progression from paroxysmal to persistent AF can be detected by quantitative analysis of LA uHDVM identifying diverse patterns of atrial substrate alterations.
Supranormal heart rate during peak exercise stress test triggering type‐1 Brugada ECG pattern
Authors: Tijskens Maxime , Heidbuchel Hein , Sarkozy Andrea
Published: May 2019

We present a remarkable maximal capacity exercise test of a 52‐year‐old patient diagnosed with Brugada syndrome (BrS). As the patient reaches a supranormal sinus heart rate, the type‐1 electrocardiogram pattern of BrS appeared and then disappeared immediately after cessation of exercise.
Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR‐219a‐5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1
Authors: Yan Jing , Bu Xiaomin , Li Zhuoling , Wu Jia , Wang Cheng , Li Dandan , Song Jiaxi , Wang Junjun
Published: May 2019

Circulating microRNAs (miRNAs) have emerged as diagnostic and prognostic biomarkers for traumatic brain injury (TBI). However, a comprehensive characterization of the serum miRNA profile in patients with TBI and the roles of these potential markers in neuronal regulation have rarely been reported. In this study, the levels of 754 serum miRNAs were initially determined in two pooled samples of 15 severe traumatic brain injury (sTBI) patients and 15 healthy controls using a TaqMan Low Density Array. The markedly upregulated miRNAs in sTBI patients were subsequently validated individually by quantitative reverse‐transcription PCR (RT‐qPCR) in another larger cohort consisting of 81 sTBI patients, 81 mild traumatic brain injury (mTBI) patients and 82 age/sex‐matched healthy controls. Seven miRNAs, including miR‐103a‐3p, miR‐219a‐5p, miR‐302d‐3p, miR‐422a, miR‐518f‐3p, miR‐520d‐3p and miR‐627, were significantly upregulated in both sTBI and mTBI patients compared with their expression in controls. Among these miRNAs, miR‐219a‐5p not only discriminated sTBI and mTBI patients from controls but also discriminated between sTBI and mTBI patients. We further show here that in the neuronal cell injury model, upregulated miR‐219a‐5p inhibits the expression of CCNA2 and CACUL1 and further regulates akt/Foxo3a and p53/Bcl‐2 signaling pathways, causing a notable change in the expression of cleaved caspase‐3, thereby inducing neuronal apoptosis. These results indicate that these seven selected miRNAs could serve as novel biomarkers for TBI. In particular, miR‐219a‐5p is a potentially valuable indicator of the diagnosis, prognosis of TBI and appears to regulate neuronal apoptosis and death.

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Weight status and diets of children aged 1–12 years attending a tertiary public paediatric outpatient clinic
Authors: Mathew Suja M , Bell Lucinda K , Mauch Chelsea , Magarey Anthea M
Published: May 2019

Aim

To assess the weight status and diets of a sample of paediatric outpatients, explore the relationship between the two and compare child weight status with parental perception of child weight and parents' self‐reported weight.

Methods

Parents/carers of 1–12‐year‐olds attending paediatric outpatients at Flinders Medical Centre, South Australia, between October 2015 and May 2016 completed a demographic and validated age‐based dietary questionnaire (toddlers (1–3 years), pre‐schoolers (>3 to <5 years) or children (5–12 years)). Dietary risk scores (low/moderate/high/very high) were calculated for toddlers and pre‐schoolers and diet quality and food behaviours scores for children. Body mass index (BMI)z‐score and weight status were determined from measured height and weight.

Results

Of 114 toddlers, 115 pre‐schoolers and 250 children, 65% were of a healthy weight, 10% underweight and 25% overweight or obese. Most (~80%) toddlers and pre‐schoolers had diets classified as ‘moderate’ risk, and the diets (35–90%) and behaviours (90%) of most 5–12‐year‐olds fell short of the guidelines. There was no significant relationship between overall diet risk or quality and BMIz‐score. Healthier food behaviours scores were inversely correlated with BMIz‐scores (ß −0.061, 95% confidence interval (CI) −0.089, −0.033,P< 0.005). Parents' perception of child weight status was inaccurate. Parent's self‐reported weight status was significantly associated with the BMIz‐scores of toddlers (ß 0.301, 95% CI 0.189–1.174,P= 0.007) and pre‐schoolers (ß 0.220, 95% CI 0.032–0.859,P= 0.035).

Conclusions

Poor diets and high rates of overweight/obesity highlight the need for screening within the paediatric outpatient setting. Parents' own weight status, and their inaccurate perception of their child's, should be considered future intervention targets for improving child and parent health.
Predictive factors for not undergoing RNA testing in patients found to have hepatitis C serology and impact of an automatic alert
Authors: Morales‐Arraez Dalia , Alonso‐Larruga Ana , Diaz‐Flores Felicitas , García Dopico Jose A. , de Vera Antonia , Quintero Enrique , Hernández‐Guerra Manuel
Published: May 2019

The process of diagnosis and linkage to care in cases of hepatitis C virus (HCV) infection remains an obstacle to disease control. The aims of this study were to evaluate predictive factors for not undergoing RNA testing among patients with positive HCV serology and impact of incorporating an automated electronic alert with recommendations in clinical practice. We collected HCV antibody tests requested from October 2011 to September 2014 to evaluate the rate of RNA testing and predictive factors for not undergoing RNA testing. Since October 2014, an automated alert notification has been implemented to remind physicians for testing RNA after a positive HCV test and referral to specialist care. 41 403 HCV antibody tests were requested from 34 073 patients. 870 (2.55%) patients tested positive. After a median of follow‐up of 57.0 months (range 45.6‐82.1), 37.6% did not have RNA testing. The independent predictors for not undergoing RNA testing were primary care serology requests (P < 0.001), no history of drug use (P = 0.005) and a lack of social support (P = 0.015). The intervention impact was evaluated in a pre‐alert cohort (October 2011‐September 2014) and a post‐alert cohort (October 2014‐September 2015). After the incorporation of the alert, the rate of RNA testing increased from 62.4% to 77.7% (P < 0.001). Incomplete assessment of HCV infection is a challenge in primary care. The implementation of an automated alert for recommending RNA testing after a positive HCV antibody test is feasible in clinical practice and increases the rate of patients with RNA testing.
Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease
Authors: Vazquez‐Villaseñor I. , Garwood C. J. , Heath P. R. , Simpson J. E. , Ince P. G. , Wharton S. B.
Published: May 2019

Aims

Cellular senescence plays a role in organismal ageing and has been linked to persistent DNA damage in age‐related diseases. Brain senescence has been described in astrocytes and microglia, but it is less well understood in neurones. Evidence suggests that neurones activate a senescence‐like mechanism that could contribute to neurodegeneration. We aimed to determine whether a persistent DNA damage response (DDR) and senescence activation are features of motor neurone disease (amyotrophic lateral sclerosis, ALS/MND).

Methods

We examined expression of senescence (p16 and p21) and DNA damage markers (8‐OHdG and γH2AX) in motor cortex (MCx), frontal association cortex (FACx) and occipital cortex (OCx) in post‐mortem tissue donated by patients with ALS/MND and controls.

Results

Nuclear expression of p16 and p21 was detected in glial cells; double immunofluorescence for p16/p21 and glial fibrillary acidic protein (GFAP) suggested that some of these cells were GFAP+ astrocytes. p21 nuclear expression was also found in neurones. Higher levels of p16+ (glia, P = 0.028) and p21+ (glia, P = 0.003; neurones, P = 0.008) cells were found in the FACx of ALS/MND donors but not in the MCx or OCx. Expression of p16 and p21 did not correlate with 8‐OHdG or γH2AX.

Conclusions

Expression of p16 and p21 in glia, mainly in astrocytes, suggests senescence induction in these cells; however, neuronal p21 expression might reflect a more general mechanism of age‐related cell cycle dysregulation. The significantly higher proportion of cells expressing either p16 or p21 in the FACx of ALS/MND donors could indicate senescence activation and cell cycle dysregulation in early stages of the disease.
Sexual lability during an individual's life: the case of the sedge Carex secalina
Authors: Bogdanowicz Agnieszka M. , Lembicz Marlena , Żukowski Waldemar
Published: May 2019

Various environmental and physiological factors that affect sex expression in plants have been identified. We made the presumption that in perennials, age may be a key factor that significantly diversifies sex expression over consecutive years of an individual's life. To test this hypothesis, we chose the sedge Carex secalina, a plant that reproduces only sexually and exhibits different sex expression patterns. These patterns had been previously observed in natural populations. In a four‐year experiment, the sex of spikes formed on reproductive tillers of 100 individuals originating from three populations was monitored. A significant association between individuals’ age and number of female/male spikes was found for each population. In addition, significant differences between the populations in the ratio of shoots with bisexual spikes to shoots with unisexual spikes were revealed. We also showed that the proportion of shoots with bisexual spikes in the individual populations changed significantly with the age of an individual and that in the successive years of the individual's life, the production level of female and male structures changed. Moreover, an age‐dependent decrease in both the number and length of female and male spikes was observed.
Phylogenomic analysis reveals multiple evolutionary origins of selfing from outcrossing in a lineage of heterostylous plants
Authors: Zhong Li , Barrett Spencer C. H. , Wang Xin‐Jia , Wu Zhi‐Kun , Sun Hua‐Ying , Li De‐Zhu , Wang Hong , Zhou Wei
Published: May 2019

Evolutionary transitions from outcrossing to selfing often occur in heterostylous plants. Selfing homostyles originate within distylous populations and frequently evolve to become reproductively isolated species. We investigated this process in 10 species of Primula section Obconicolisteri using phylogenomic approaches and inferred how often homostyly originated from distyly and its consequences for population genetic diversity and floral trait evolution.

We estimated phylogenetic relationships and reconstructed character evolution using the whole plastome comprised of 76 protein‐coding genes. To investigate mating patterns and genetic diversity we screened 15 microsatellite loci in 40 populations. We compared floral traits among distylous and homostylous populations to determine how phenotypically differentiated homostyles were from their distylous ancestors.

Section Obconicolisteri was monophyletic and we estimated multiple independent transitions from distyly to homostyly. High selfing rates characterised homostylous populations and this was associated with reduced genetic diversity. Flower size and pollen production were reduced in homostylous populations, but pollen size was significantly larger in some homostyles than in distylous morphs.

Repeated transitions to selfing in section Obconicolisteri are likely to have been fostered by the complex montane environments that species occupy. Unsatisfactory pollinator service is likely to have promoted reproductive assurance in homostyles leading to subsequent population divergence through isolation.
Surgical management of a large radicular cyst using modified guided tissue regeneration techniques: a case report with 4 years follow‐up
Authors: Camargo J.M.P. , Braga T. , Camargo R. , Love R.M. , Reher P.
Published: May 2019

This case report discusses the management of a large radicular cyst using current periapical surgery techniques associated with the use of modified guided tissue regeneration (GTR) techniques. The cyst involved several anterior teeth and measured 40 mm in its widest dimension, involving both cortical plates, and extending into the floor of the nose. The surgical endodontics techniques used here included the use of enhanced magnification, minimal root resection, ultrasonic root‐end preparation and retrograde obturation with a bioceramic root repair material. The large bone defect was reconstructed with the use of a mixture of autogenous bone harvested from the mandibular ramus, Bio‐oss® and platelet‐rich fibrin (PRF), covered with a thin PRF membrane acting as a modified GTR. The combination of these techniques ensured successful clinical, radiographic and tomographic outcomes after 4 years of follow‐up.
Can noninvasive testing identify benign patterns of suggested pre‐excitation on electrocardiogram?
Authors: Robinson Jeffrey A. , Anderson Jeffrey B. , Knilans Timothy K. , Spar David S. , Czosek Richard J.
Published: May 2019

Background

The presence of anterograde conduction through an accessory pathway (AP) has been linked to sudden cardiac death. Unfortunately, pre‐excitation associated with classic pathways can be difficult to differentiate from benign APs such as nodofascicular fibers.

Objective

Identifying characteristics on electrocardiogram (ECG) and exercise that differentiate classic and benign AP connections in suggested pre‐excitation patterns.

Methods

Retrospective review of patients presenting between 1995 and 2017 with ventricular pre‐excitation on ECG, determined to have either typical left‐lateral AP during electrophysiology study (EPS), or benign, or no AP determined by either transesophageal electrophysiology study (TEP), or EPS.

Results

A total of 96 patients were included, 14.2 years (4‐24), 45% female, 90% Caucasian. Of these, 60 (63%) had a classic APs identified on EPS and 58 (97%) underwent successful ablation. Conversely, 36 (37%) had benign pathways identified. ECG findings differed between the groups: PR‐interval 102 versus 120 ms (P < .0001), QRS‐duration 110 versus 102 ms (P < .0001), QRS‐axis 74 versus 59 degrees (P = .0005), and QRS onset to peak R/S in limb leads 64 versus 42 ms (P < .0001), and precordial leads 66 versus 46 ms (P < .0001). Change in QRS duration during exercise differed between the groups: 25 versus 2 ms (P < .0001) and ECG characteristics identified the presence of an AP with 97% sensitivity and 94% negative predictive value.

Conclusion

Classic and benign APs exhibit different ECG characteristics, though clinical overlap does not allow for absolute differentiation. These data may help with risk stratification decision making though does not obviate the need for additional invasive testing.
Genetic dissection of drought and heat‐responsive agronomic traits in wheat
Authors: Li Long , Mao Xinguo , Wang Jingyi , Chang Xiaoping , Reynolds Matthew , Jing Ruilian
Published: May 2019

High yield and wide adaptation are principal targets of wheat breeding but are hindered by limited knowledge on genetic basis of agronomic traits and abiotic stress tolerances. In this study, 277 wheat accessions were phenotyped across 30 environments with non‐stress, drought‐stressed, heat‐stressed, and drought‐heat‐stressed treatments and were subjected to genome‐wide association study using 395 681 single nucleotide polymorphisms. We detected 295 associated loci including consistent loci for agronomic traits across different treatments and eurytopic loci for multiple abiotic stress tolerances. A total of 22 loci overlapped with quantitative trait loci identified by biparental quantitative trait loci mapping. Six loci were simultaneously associated with agronomic traits and abiotic stress tolerance, four of which fell within selective sweep regions. Selection in Chinese wheat has increased the frequency of superior marker alleles controlling yield‐related traits in the four loci during past decades, which conversely diminished favourable genetic variation controlling abiotic stress tolerance in the same loci; two promising candidate paralogous genes colocalized with such loci, thereby providing potential targets for studying the molecular mechanism of stress tolerance–productivity trade‐off. These results uncovering promising alleles controlling agronomic traits and/or multiple abiotic stress tolerances, providing insights into heritable covariation between yield and abiotic stress tolerance, will accelerate future efforts for wheat improvement.
The TYRP1‐mediated protection of human tyrosinase activity does not involve stable interactions of tyrosinase domains
Authors: Dolinska Monika B. , Wingfield Paul T. , Young Kenneth L. , Sergeev Yuri V.
Published: May 2019

Tyrosinases are melanocyte‐specific enzymes involved in melanin biosynthesis. Mutations in their genes cause oculocutaneous albinism associated with reduced or altered pigmentation of skin, hair, and eyes. Here, the recombinant human intra‐melanosomal domains of tyrosinase, TYRtr (19–469), and tyrosinase‐related protein 1, TYRP1tr (25–472), were studied in vitro to define their functional relationship. Proteins were expressed or coexpressed in whole Trichoplusia ni larvae and purified. Their associations were studied using gel filtration and sedimentation equilibrium methods. Protection of TYRtr was studied by measuring the kinetics of tyrosinase diphenol oxidase activity in the presence (1:1 and 1:20 molar ratios) or the absence of TYRP1tr for 10 hr under conditions mimicking melanosomal and ER pH values. Our data indicate that TYRtr incubation with excess TYRP1tr protects TYR, increasing its stability over time. However, this mechanism does not appear to involve the formation of stable hetero‐oligomeric complexes to maintain the protective function.
Trends and factors in antipsychotic use of outpatients with anxiety disorders in Taiwan, 2005–2013: A population‐based study
Authors: Huang Chih‐Wan , Chiu Yu‐Wen , Chen Pei‐Jung , Yu Nan‐Wen , Tsai Hui‐Ju , Chang Chia‐Ming
Published: May 2019

Aim

Antipsychotics off‐label use is common in clinical practice but information is limited in regards to the trends of antipsychotic use in specific mental disorders in Taiwan. This study aimed to examine the trends and associated factors of antipsychotic use among outpatients with anxiety disorders in Taiwan during 2005–2013.

Methods

We assessed the annual prescriptions of antipsychotic use in nine consecutive years (2005–2013) using the National Health Insurance Research Database among adults (aged ≥18 years) with anxiety disorders in outpatient visits in Taiwan. We applied logistic regression to examine the trends and associated factors of antipsychotic use.

Results

The proportion of antipsychotic medication use for anxiety disorder increased from 8.4% in 2005 to 9.1% in 2013. First‐generation antipsychotics (FGA) use was more than that of second‐generation antipsychotics (SGA) use in patients with anxiety disorder through the 9‐year period. Sulpiride and flupentixol were the two most common FGA in the treatment of anxiety disorder. Patients with specific anxiety disorder (post‐traumatic stress disorder, panic disorder/agoraphobia, generalized anxiety disorder, and obsessive–compulsive disorder), female sex, younger age (age < 65 years), comorbidity with major depression or minor depression, antidepressants concurrent use, and visits to psychiatrists, medical centers and primary care were significantly more likely to take prescribed antipsychotics.

Conclusion

Antipsychotic off‐label use significantly increased among patients with anxiety disorder in this national representative cohort. Such increased use of antipsychotics could be driven by augmentation of their prescription for major depression. As their efficacy and safety remain uncertain, further study is warranted.
Cellular characterization of actin gene concerned with contact‐dependent mechanisms in Naegleria fowleri
Authors: Sohn Hae‐Jin , Song Kyoung‐Ju , Kang Heekyoung , Ham A‐Jeong , Lee Jae‐Ho , Chwae Yong‐Joon , Kim Kyongmin , Park Sun , Kim Jong‐Hyun , Shin Ho‐Joon
Published: May 2019

Free‐living amoeba, Naegleria fowleri, destroys target cells through contact‐dependent mechanisms, such as phagocytosis and/or trogocytosis. A previous experiment showed that the nf‐actin gene consisted of 1.2 kbp, produced a 50.1 kDa recombinant protein (Nf‐actin), and was localized on the cytoskeleton, pseudopodia and amoebastome. In this study, cellular characterization of the nf‐actin gene concerned with contact‐dependent mechanisms in N fowleri was performed. The nf‐actin gene was amplified from a gene‐cloned vector, pEXQP5‐T7/NT TOPO. The nf‐actin gene was introduced into the Ubi‐pEGFP‐C2 vector, and Ubi‐pEGFP‐C2/nf‐actin was transfected into N fowleri trophozoites. Strong GFP fluorescence was detected in N fowleri trophozoites transfected with Ubi‐pEGFP‐C2/nf‐actin. Expression of EGFP‐Nf‐actin protein was detected by Western blot analysis. The nf‐actin‐overexpressing N fowleri showed significantly increased adhesion activity against extracellular matrix components, fibronectin, collagen I and fibrinogen, compared with wild‐type N fowleri. Moreover, nf‐actin‐overexpressing N fowleri showed increased phagocytic activity and cytotoxicity in comparison with wild‐type N fowleri. In summary, the overexpressed nf‐actin gene has an important function in ability to increase cell adhesion, cytotoxicity and phagocytosis by N fowleri.
Combined microRNAome and transcriptome analysis of follicular phase and luteal phase in porcine ovaries
Authors: Zhang Xiaodong , Zhang Liang , Shang Jinnan , Tao Qiangqiang , Tian Mi , Ma Yingchun , Xu Yiliang , Ding Yueyun , Zhou Rong , Li Kui , Yin Zongjun
Published: May 2019

The aim of this study was to explore the expression difference of miRNAs and mRNAs between the follicular phase (FP) and luteal phase (LP) in porcine ovaries and provide a theoretical basis for the research on mammalian reproductive regulation. RNA‐Seq and miRNA‐Seq were used to identify differentially expressed genes (DEGs) and miRNAs (DEMs) between the FP and LP in ovaries of six sows (3‐year‐old Yorkshire pigs with similar weights and same parities). Bioinformatic analysis was used to screen potential genes and miRNAs related to porcine ovarian function. Real‐time qualitative PCR was used to validate the sequencing results. RNA‐Seq results showed that 3,078 genes were up‐regulated, and 1,444 genes were down‐regulated in the LP compared with the FP, and DEGs were significantly enriched in 242 Gene Ontology (GO) terms and 33 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. miRNA‐Seq identified 112 DEMs, of which 25 were up‐regulated and 87 were down‐regulated in the LP compared with the FP. We obtained 186 intersection genes (IGs) between the 4,522 DEGs and 2,444 target genes predicted from the 112 DEMs. After constructing a miRNA‐gene‐pathway network, we identified key miRNAs and genes including miR‐17‐3p, miR‐214, miR‐221‐5p, miR‐125b, FGF1, YWHAG, YWHAZ, FDFT1 and DHCR24, which are enriched in Hippo and PI3K‐Akt signalling pathways, and various metabolic pathways. These results indicate that these key genes and miRNAs may play important roles in the developmental transition from FP to LP in porcine ovaries and represent candidate targets for further study.
Effects of cooling rates on the quality of Prochilodus lineatus (Valenciennes, 1836) sperm
Authors: de Jesus Paula Daniella Aparecida , Murgas Luis David Solis , Castro Tássia Flávia Dias , de Lima Assis Isadora , Neto Rafael Vilhena Reis , Marcussi Silvana
Published: May 2019

This study aims to investigate the effect of different cooling rates on the semen cryopreservation of curimba (Prochilodus lineatus). Nineteen ejaculates were obtained from adults males and cryopreserved at 15°C/min (CR15), 30°C/min (CR30) (controlled temperature inside and outside straw, speed was stable during freezing) and direct freezing in liquid nitrogen vapour (~35.6°C/min) (CRNV). The straws were thawed and seminal parameters evaluated. DNA fragmentation through the comet assay was assessed. A fresh sperm sample was not frozen and used for analyses. Data were submitted to an analysis of variance (ANOVA), and means were compared by Scott–Knott test (p < 0.05) using the R Software. Mean motility percentage was 100%, and motility duration was 39.5 ± 5.7 s for the fresh sperm (subjective analysis); 58.9 ± 8.0% and 24.5 ± 5.7 s for CR15; 64.8 ± 4.8% and 26.5 ± 7.1 s for CR30; and 50.1 ± 16% and 25.7 ± 4.7 s for CRNV, respectively. Motility percentages were higher and equal between CR15 and CR30 compared to CRNV (p < 0.05). Some sperm motion kinetics, namely average path velocity (VAP) and straight line velocity (VAS), were higher for CR30 (p < 0.05), while curvilinear velocity (VCL) and velocity progression (PRO) were lower for CRNV (p < 0.05). Straightness (STR) and wobble (WOB) were the same among treatments (p > 0.05). Sperm morphology results indicated higher means for total morphological sperm alterations in CRNV. All cooling rates caused sperm DNA fragmentation, although CR30 provided a less harmful effect. This is the first report for cryopreserved P. lineatus sperm preserved under different controlled cooling rates. The cooling rate of 30°C/min is indicated for the cryopreservation of this fish sperm as it led to the lowest detrimental spermatozoa effects.
Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception
Authors: Loeza‐Alcocer Emanuel , McPherson Thomas P. , Gold Michael S.
Published: May 2019

Key points

While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body.

Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability.

GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception.

Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors.

Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.

It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension‐induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.
Numerical Simulations for Chemotaxis Models
Authors: Dallakyan Gurgen
Published: May 2019

In the paper, we study the usage of numerical methods in solution of mathematical models of biological problems. More specifically, Keller-Segel type chemotaxis models are discussed, their numerical solutions by sweep and Lax-Friedrichs methods are obtained and interpreted biologically.
High School Football and the Athletic-Market Economy: Recruiting, Producing, and Manufacturing Talent
Authors: Macaulay Charles , Cooper Joseph , Dougherty Shaun
Published: May 2019

There are two cultural narratives often purported within the American sports cultures of basketball and football. First, those participating within these sports are African American athletes from poor communities lacking educational and economic opportunities. Second, the meritocratic myth perpetuating American society feeds the notion no matter where an individual is from their talent will elevate them to the next level. There have already been a few studies who have challenged these myths. This study seeks to continue the conversation by collecting community data on 7,670 high school football recruits for the years 2000 to 2016. This study seeks to provide a broad overview of the interscholastic football landscape as well as determine production levels of schools. This study finds that while players are recruited from a diverse range of communities and school types, as a school becomes more productive they tend to be located within wealthier urban communities, have a diverse student body, and have a higher likelihood of being a private school.
Abdominal ultrasound should become part of standard care for early diagnosis and management of necrotising enterocolitis: a narrative review
Authors: van Druten Jacqueline , Khashu Minesh , Chan Sherwin S , Sharif Saeed , Abdalla Hassan
Published: May 2019

Necrotising enterocolitis (NEC) is a leading cause of death and disability in preterm newborns. Early diagnosis through non-invasive investigations is a crucial strategy that can significantly improve outcomes. Hence, this review gives particular attention to the emerging role of abdominal ultrasound (AUS) in the early diagnosis of NEC, its performance against abdominal radiograph and the benefits of AUS use in daily practice. AUS has been used in the diagnosis and management of NEC for a couple of decades. However, its first-line use has been minimal, despite growing evidence demonstrating AUS can be a critical tool in the early diagnosis and management of NEC. In 2018, the NEC group of the International Neonatal Consortium recommended using AUS to detect pneumatosis and/or portal air in preterm NEC as part of the ‘Two out of three’ model. To facilitate widespread adoption, and future improvement in practice and outcomes, collaboration between neonatologists, surgeons and radiologists is needed to generate standard operating procedures and indications for use for AUS. The pace and scale of the benefit generated by use of AUS can be amplified through use of computer-aided detection and artificial intelligence.
Impact of hospitalisation of children on parental dietary habits: a qualitative study
Authors: Church Kirstyn , Campbell David , Halliday Vanessa
Published: May 2019

Objective

To explore how prolonged hospitalisation of a child with a neurological condition influences the dietary habits of parents, taking account of their attitudes and perceptions of this experience.

Design

Qualitative study using semi-structured interviews and inductive thematic analysis.

Subjects

Fifteen parents of children (aged 2–16 years) with a neurological condition resulting in prolonged periods of hospitalisation were recruited.

Results

Mothers (n=13) and fathers (n=2) who were interviewed experienced frequent hospital visits brought about by their child’s condition, or associated medical complications. Dietary habits of parents were affected throughout their time in hospital. Three key themes were identified relating to how hospitalisation influenced this: (1) access to food, (2) emotional and physical well-being and (3) impact on eating patterns and food choice.

Conclusions

Findings from this study suggest that parents in these circumstances need to be better supported within the hospital setting as a number of barriers exist when it comes to accessing food in hospital and making healthy food choices. Additionally, having a child in hospital has a considerable effect on a parent’s emotional well-being, which further impacts on their dietary habits. The long-term physical and mental health implications of this may influence their ability to care for the sick child.
Adherence to metformin is reduced during school holidays and weekends in children with type 1 diabetes participating in a randomised controlled trial
Authors: Leggett Catherine , Giles Lynne , Anderson Jemma Jay Angela , Doogue Matthew , Couper Jennifer , Pena Alexia Sophie
Published: May 2019

Background

Non-adherence to treatment in childhood chronic illness has serious consequences for health and healthcare costs. Accurate detailed objective data on adherence are minimal in this age group.

Objective

To evaluate medication adherence using electronic monitoring systems in children with type 1 diabetes (T1D).

Design

A cohort study of 90 T1D children (aged 13.6±2.5 years, 41 males) from two paediatric diabetes clinics, participated in a 12-month double-blind, randomised, placebo-controlled trial (1:1 allocation). This cohort provided 28 336 days of study observations; 7138 school holiday and 8875 weekend/public holiday days.

Method

Adherence to intervention (metformin (n=45) or placebo (n=45)) was measured objectively by Medication Event Monitoring Systems (MEMS) including proportion of medication doses taken and daily adherence patterns and by tablet count at 3, 6 and 12 months. The trial was completed in June 2015.

Results

There was an average (SD) of 363.3 (42) days of MEMS observations available for each study participant (94.1 (12.6) school holiday days and 117.1 (13.4) weekend/public holiday days). Adherence reduced during school holidays (adjusted OR (aOR) 0.81; 95% CI 0.72 to 0.91; p<0.001) and during weekends/public holidays (aOR 0.74; 95% CI 0.69 to 0.80; p<0.001). Adverse effects to the intervention did not affect overall adherence (aOR 0.77; 95% CI 0.3 to 2.01; p=0.6). Age, gender, body mass index, diabetes duration, insulin dose, HbA1c (Haemoglobin A1c) or socioeconomic status did not predict adherence.

Conclusion

Medication adherence was reduced during school holidays and on weekends in children with T1D. Clinical characteristics including socioeconomic status and the presence of adverse effects did not predict adherence.

Trial registration number

ACTRN12611000148976.