bluuebunny/crossref_metadata_2025 huggingface dataset:
Wx: a neural network-based feature selection algorithm for next-generation sequencing data
Authors: Park Sungsoo , Shin Bonggun , Choi Yoonjung , Kang Kilsoo , Kang Keunsoo
Published: November 2017

Motivation

Next-generation sequencing (NGS), which allows the simultaneous sequencing of billions of DNA fragments simultaneously, has revolutionized how we study genomics and molecular biology by generating genome-wide molecular maps of molecules of interest. For example, an NGS-based transcriptomic assay called RNA-seq can be used to estimate the abundance of approximately 190,000 transcripts together. As the cost of next-generation sequencing sharply declines, researchers in many fields have been conducting research using NGS. The amount of information produced by NGS has made it difficult for researchers to choose the optimal set of target genes (or genomic loci).

Results

We have sought to resolve this issue by developing a neural network-based feature (gene) selection algorithm called Wx. The Wx algorithm ranks genes based on the discriminative index (DI) score that represents the classification power for distinguishing given groups. With a gene list ranked by DI score, researchers can institutively select the optimal set of genes from the highest-ranking ones. We applied the Wx algorithm to a TCGA pan-cancer gene-expression cohort to identify an optimal set of gene-expression biomarker (universal gene-expression biomarkers) candidates that can distinguish cancer samples from normal samples for 12 different types of cancer. The 14 gene-expression biomarker candidates identified by Wx were comparable to or outperformed previously reported universal gene expression biomarkers, highlighting the usefulness of the Wx algorithm for next-generation sequencing data. Thus, we anticipate that the Wx algorithm can complement current state-of-the-art analytical applications for the identification of biomarker candidates as an alternative method.

Availability

https://github.com/deargen/DearWX

Contact

kangk1204@dankook.ac.kr

Supplementary information

Supplementary data are available at online.
Denaturants Alter the Flux through Multiple Pathways in the Folding of PDZ Domain
Authors: Liu Zhenxing , Thirumalai D.
Published: November 2017

Although we understand many aspects of how small proteins (number of residues less than about hundred) fold, it is a major challenge to understand how large proteins self-assemble. To partially overcome this challenge, we performed simulations using the Self-Organized Polymer model with Side Chains (SOP-SC) in guanidinium chloride (GdmCl), using the Molecular Transfer Model (MTM), to describe the folding of the 110-residue PDZ3 domain. The simulations reproduce the folding thermodynamics accurately including the melting temperature (Tm), the stability of the folded state with respect to the unfolded state. We show that the calculated dependence of lnkobs(kobsis the relaxation rate) has the characteristic Chevron shape. The slopes of the Chevron plots are in good agreement with experiments. We show that PDZ3 folds by four major pathways populating two metastable intermediates, in accord with the kinetic partitioning mechanism. The structure of one of the intermediates, populated after polypeptide chain collapse, is structurally similar to an equilibrium intermediate. Surprisingly, the connectivities between the intermediates and hence, the fluxes through the pathways depend on the concentration of GdmCl. The results are used to predict possible outcomes for unfolding of PDZ domain subject to mechanical forces. Our study demonstrates that, irrespective of the size or topology, simulations based on MTM and SOP-SC offer a framework for describing the folding of proteins, mimicking precisely the conditions used in experiments.
Patient‐level Factors and the Quality of Care Delivered in Pediatric Emergency Departments
Authors: Marcin James P. , Romano Patrick S. , Dayal Parul , Dharmar Madan , Chamberlain James M. , Dudley Nanette , Macias Charles G. , Nigrovic Lise E. , Powell Elizabeth C. , Rogers Alexander J. , Sonnett Meridith , Tzimenatos Leah , Alpern Elizabeth R. , Andrews‐Dickert Rebecca , Borgialli Dominic A. , Sidney Erika , Charles Casper T. , Michael Dean J. , Kuppermann Nathan ,   for the Pediatric Emergency Care Applied Research Network
Published: November 2017

Objective

Quality of care delivered to adult patients in the emergency department (ED) is often associated with demographic and clinical factors such as a patient's race/ethnicity and insurance status. We sought to determine whether the quality of care delivered to children in the ED was associated with a variety of patient‐level factors.

Methods

This was a retrospective, observational cohort study. Pediatric patients (<18 years) who received care between January 2011 and December 2011 at one of 12 EDs participating in the Pediatric Emergency Care Applied Research Network (PECARN) were included. We analyzed demographic factors (including age, sex, and payment source) and clinical factors (including triage, chief complaint, and severity of illness). We measured quality of care using a previously validated implicit review instrument using chart review with a summary score that ranged from 5 to 35. We examined associations between demographic and clinical factors and quality of care using a hierarchical multivariable linear regression model with hospital site as a random effect.

Results

In the multivariable model, among the 620 ED encounters reviewed, we did not find any association between patient age, sex, race/ethnicity, and payment source and the quality of care delivered. However, we did find that some chief complaint categories were significantly associated with lower than average quality of care, including fever (–0.65 points in quality, 95% confidence interval [CI] = –1.24 to –0.06) and upper respiratory symptoms (–0.68 points in quality, 95% CI = –1.30 to –0.07).

Conclusion

We found that quality of ED care delivered to children among a cohort of 12 EDs participating in the PECARN was high and did not differ by patient age, sex, race/ethnicity, and payment source, but did vary by the presenting chief complaint.
Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: An analysis from the EAACI AIT Guidelines Project
Authors: Bonertz A. , Roberts G. , Slater J. E. , Bridgewater J. , Rabin R. L. , Hoefnagel M. , Timon M. , Pini C. , Pfaar O. , Sheikh A. , Ryan D. , Akdis C. , Goldstein J. , Poulsen L. K. , van Ree R. , Rhyner C. , Barber D. , Palomares O. , Pawankar R. , Hamerlijnk D. , Klimek L. , Agache I. , Angier E. , Casale T. , Fernandez‐Rivas M. , Halken S. , Jutel M. , Lau S. , Pajno G. , Sturm G. , Varga E. M. , Gerth van Wijk R. , Bonini S. , Muraro A. , Vieths S.
Published: November 2017

Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region‐specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch‐to‐batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines.
A randomized, double‐blind, placebo‐controlled, dose‐finding trial with Lolium perenne peptide immunotherapy
Authors: Mösges R. , Kasche E. M. , Raskopf E. , Singh J. , Sohlich L. , Astvatsatourov A. , Shah‐Hosseini K. , Pirotton S. , Haazen L. , Durham S. R. , Legon T. , Zadoyan G. , Shamji M. H.
Published: November 2017

Background

A novel subcutaneous allergen immunotherapy formulation (gpASIT+™) containing Lolium perenne peptides (LPP) and having a short up‐dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety.

Methods

This prospective, double‐blind, placebo‐controlled, phase IIb, parallel, four‐arm, dose‐finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment.

Results

Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per‐protocol set). Also, 39% of patients in the 170‐μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen‐binding assays revealed a highly significant (P < .001) dose‐dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG4 levels increased to 1.6‐fold (70 μg), 3.1‐fold (170 μg) and 3.9‐fold (370 μg) (mPP).

Conclusion

Three‐week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.
Rhinitis and its impact on quality of life in swimmers
Authors: Surda P. , Putala M. , Siarnik P. , Walker A. , Bernic A. , Fokkens W.
Published: November 2017

Introduction

Limited data suggest that swimmers might be affected by rhinitis significantly more often than the general population. This can have impact on quality of life but also on performance. The aim of this study was to determine the prevalence and impact of QOL of rhinitis in swimming compared to nonswimming athletes and controls.

Materials and methods

This was an observational case‐control, questionnaire‐based study involving elite (n = 101) and nonelite swimming athletes (n = 107), nonswimming athletes (n = 38) and sex‐ and age‐matched controls (n = 50). The survey instrument consisted of a general and the miniRQLQ. Main question used to assess the prevalence of rhinitis was from the ISAAC study.

Results

Rhinitis was reported significantly more often by the elite swimmers (45%) than nonelite swimmers (31%), nonswimming athletes (32%) and controls (24%). Allergic rhinitis prevalence was similar in all groups (12%‐18%). The prevalence of nonallergic rhinitis (NAR) was significantly higher in elite swimmers (33%) and nonelite swimmers (22%) compared to nonswimming athletes and controls. Overall mean miniRQLQ score and all subdomains except the “eye” domain showed significantly reduced QOL in elite and nonelite swimmers compared to nonswimming athletes and controls. Regular nasal medication was used significantly less by elite swimmers (18%) compared to controls (67%) and nonswimming athletes (42%).

Conclusion

This study revealed a high prevalence of NAR in swimmers and related impact on QoL. These findings highlight the importance to increase the awareness towards upper airway disorders in the swimming athletes and to ensure adequate management.
Poor agreement in questionnaire‐based diagnostic criteria for adult atopic dermatitis is a challenge when examining cardiovascular comorbidity
Authors: Andersen Y. M. F. , Egeberg A. , Hamann C. R. , Skov L. , Gislason G. H. , Skaaby T. , Linneberg A. , Thyssen J. P.
Published: November 2017

Background

The association between atopic dermatitis (AD) and cardio‐metabolic risk factors is not yet established. Furthermore, no validated questionnaire‐based method of identifying adults with AD is currently available.

Objectives

To assess the cardio‐metabolic risk in adults with a history of AD using 3 different questionnaire‐based diagnostic criteria.

Methods

We utilized data from a general population study including questionnaire data and objective measurements of 9656 Danish adults. To identify adults with a history of AD, we used a question regarding physician‐diagnosed AD and 2 versions of the UK Working Party Diagnostic Criteria. Associations between AD status and cardio‐metabolic endpoints were estimated using survey weighted logistic and linear regression analysis.

Results

We identified 462 (4.8%) adults with self‐reported physician‐diagnosed AD, whereas 903 (9.4%) and 226 (2.3%) had AD according to the UK Working Party Criteria when at least 2 and 3of 4 minor criteria were fulfilled. The populations were not comparable in terms of occurrence of cardio‐metabolic risk factors. For example, the prevalence of obesity was lower in participants with physician‐diagnosed AD but overall higher in UK 2/4 and UK 3/4.

Conclusion

Due to the heterogeneity in the captured study populations in terms of the studied outcomes and absence of a gold standard, no conclusions regarding the cardio‐metabolic risk in adults with AD in a general population could be made. This study serves as an example of the challenges that are often encountered in questionnaire‐based epidemiologic studies and highlights the need of better definitions for this patient group.
The effect of 6% hydroxyethyl starch (130/0.4) on acute kidney injury in paediatric cardiac surgery: a prospective, randomised trial
Authors: Oh H.‐W. , Lee J.‐H. , Kim H.‐C. , Kim E.‐H. , Song I.‐K. , Kim H.‐S. , Kim J.‐T.
Published: November 2017

We have evaluated the effect of a colloid solution on acute kidney injury in paediatric cardiac surgery. A total of 195 patients were ramdomly divided into an hydroxyethyl starch group and a control group. In the starch group, 6% hydroxyethyl starch 130/0.4 (Volulyte®) was used as the primary fluid for volume resuscitation but was limited to 30 ml.kg−1. In the control group, only crystalloid fluid was used during the peri‐operative period. The incidence of acute kidney injury, peri‐operative transfusion, clinical outcomes and laboratory data were compared. The incidence of acute kidney injury determined by Paediatric Risk, Injury, Failure, Loss, End‐stage renal disease (pRIFLE) and Acute Kidney Injury Network (AKIN) criteria were no different between the two groups (starch group 40.8% vs. control group 30.0%; p = 0.150 using pRIFLE; 19.6% vs. 21.1% respectively, p = 0.602 using AKIN). There were no differences in clinical outcomes such as mortality, major adverse events, intensive care unit stay or duration of mechanical ventilation. Clotting time as measured using rotational thromboelastometry (ROTEM) was prolonged, and clot firmness after 10 min and maximal clot firmness were shorter in the starch group compared with the control group after sternal closure. There was no difference in transfusion between the two groups. Patients with acute kidney injury had worse clinical courses than those without acute kidney injury. We conclude that intra‐operative use of 6% hydroxyethyl starch 130/0.4 up to 30 ml.kg−1 was not associated with postoperative acute kidney injury in paediatric cardiac patients.
Systematic review of disparities in surgical care for Māori in New Zealand
Authors: Rahiri Jamie‐Lee , Alexander Zanazir , Harwood Matire , Koea Jonathan , Hill Andrew G.
Published: November 2017

Background

Health equity for Indigenous peoples in the context of surgery has recently become topical amongst surgeons in Australasia. Health inequities are amongst the most consistent and compelling disparities between Māori and New Zealand Europeans (NZE) in New Zealand (NZ). We aimed to investigate where ethnic disparities in surgical care may occur and highlight some of the potential contributing factors, over all surgical specialties, between Māori and NZE adults in NZ.

Methods

A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. A series of electronic searches were performed in Medline, Embase, PubMed and CINAHL.

Results

Ten studies met the inclusion criteria. All studies employed a range of indicators for surgical care including receipt of surgery following diagnosis, delays to treatment and post‐operative morbidity and mortality. Disparities in the receipt of surgical treatment for several cancers were observed for Māori and remained after adjustment for socioeconomic variables and extent of disease. Māori were more likely to experience delays in treatment and referral to other medical specialties involved in their care.

Conclusion

Despite the significant variation in the types of diseases, procedures and indicators of surgical care of the included studies, consistent findings are that disparities in different aspects of surgical care exist between Māori and NZE in NZ. This review highlights the need to better quantify the important issue of health equity for Māori in surgery given the lack of studies over the majority of surgical specialties.
Randomised crossover trial showed that using breast milk or sucrose provided the same analgesic effect in preterm infants of at least 28 weeks
Authors: Collados‐Gómez L , Ferrera‐Camacho P , Fernandez‐Serrano E , Camacho‐Vicente V , Flores‐Herrero C , García‐Pozo AM , Jiménez‐García R
Published: November 2017

Aim

Repeated, ongoing exposure to pain influences the growth, cognitive and motor functions, behaviour, personality and neurodevelopment of preterm infants. We compared the analgesic effects of expressed breast milk (EBM) and 24% oral sucrose on preterm neonates during venipuncture.

Methods

This multicentre randomised, noninferiority, crossover trial focused on five neonatal university units in Madrid, Spain, from October 2013 to October 2014. It comprised 66 preterm infants born at less than 37 weeks and randomly split into two groups. They received either EBM or sucrose two minutes before venepuncture, together with nonnutritive sucking and swaddling, then the opposite procedure at a later point. Pain was measured with the premature infant pain profile (PIPP) and crying was also measured.

Results

There were no statistically significant differences between the groups. The PIPP scores were seven (4–9) with breast milk and six (4–8.25) with sucrose (p = 0.28). The 11 infants born at under 28 weeks of age showed higher median scores of nine (9–14) for breast milk and four (4–7) for sucrose (p = 0.009).

Conclusion

EBM and 24% sucrose had the same analgesic effect during venipuncture in most of the preterm neonates, but sucrose worked better in extremely preterm infants.
Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood
Authors: Forsberg L , Adler M , Römer Ek I , Ljungdahl M , Navér L , Gustafsson LL , Berglund G , Chotigasatien A , Hammar U , Böhm B , Wide K
Published: November 2017

Aim

This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010.

Methods

Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated.

Results

Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest.

Conclusion

This small, clinical cohort showed no significant association between mothers’ prenatal exposure to lithium or mood disorders and their offspring's IQ.
Seed addition and biomass removal key to restoring native forbs in degraded temperate grassland
Authors: Johnson David P. , Catford Jane A. , Driscoll Don A. , Gibbons Philip
Published: November 2017

Questions

Long‐term restoration of native forb diversity can only be achieved if native forb species can recruit (colonize and establish) and reproduce. We asked whether native forbs in a temperate grassland were seed‐limited, and how the recruitment of native and exotic forbs is affected by grassland structure and resource availability.

Location

Australian Capital Territory, south‐eastern Australia.

Methods

We conducted a field experiment in a temperate grassland dominated by a native tussock grass to assess effects of: (1) addition of native forb seed, (2) thinning of native grass tussocks, (3) leaf litter removal, and (4) exotic plant removal on the recruitment of native and exotic forbs. These four actions can alter grassland structure and the availability of soil nutrients, soil moisture and light. We used GLMM to determine the importance of seed addition, grassland structure and resource availability on the richness and abundance of sown native forbs, and the abundance of exotic forb seedlings and unsown native forbs.

Results

Adding seed increased the species richness and abundance of native forbs. Tussock thinning and litter removal increased species richness and abundance of sown native forbs, and the abundance of exotic forb seedlings. Exotic plant removal also increased the abundance of sown native forbs. Abundance of unsown native forb species was unaffected by the experimental treatments. Species richness and abundance of native forbs and abundance of exotic forbs declined with increasing tussock grass cover. Leaf litter restricted the abundance of native forb species more than exotic forb species.

Conclusion

Native forb recruitment predominantly relied upon seed addition, suggesting that seed limitation is a major barrier to the recovery of degraded grasslands. Reducing the cover of living grass tussocks facilitated recruitment of native and exotic forbs, and removing litter disproportionally increased recruitment of native forbs compared with exotics. Combining seed addition with the reduction of both living and dead grass biomass should help restore native grassland forbs.
After Treatment with Methylene Blue is Effective against Delayed Encephalopathy after Acute Carbon Monoxide Poisoning
Authors: Zhao Ningjun , Liang Pengchong , Zhuo Xiaoying , Su Chenglei , Zong Xuemei , Guo Bingnan , Han Dong , Yan Xianliang , Hu Shuqun , Zhang Quanguang , Tie Xu
Published: November 2017

Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is the most severe and clinically intractable complication that occurs following acute CO poisoning. Unfortunately, the mechanism of DEACMP is still vague. Growing evidence indicates that delayed cerebral damage after CO poisoning is related to oxidative stress, abnormal neuro‐inflammation, apoptosis and immune‐mediated injury. Our recent report indicated that methylene blue (MB) may be a promising therapeutic agent in the prevention of neuronal cell death and cognitive deficits after transient global cerebral ischaemia (GCI). In this study, we aimed to investigate the potential of MB therapy to ameliorate the signs and symptoms of DEACMP. Rats were exposed to 1000 ppm CO for 40 min. in the first step; CO was then increased to 3000 ppm, which was maintained for another 20 min. The rats were implanted with 7‐day release Alzet osmotic mini‐pumps subcutaneously under the back skin, which provided MB at a dose of 0.5 mg/kg/day 1 hr after CO exposure. The results showed that MB significantly suppressed oxidative damage and expression of pro‐inflammatory factors, including tumour necrosis factor‐α and interleukin (IL)‐1β. MB treatment also suitably modulated mitochondrial fission and fusion, which is helpful in the preservation of mitochondrial function. Furthermore, MB dramatically attenuated apoptosis and neuronal death. Lastly, behavioural studies revealed that MB treatment preserved spatial learning and memory in the Barnes maze test. Our findings indicated that MB may have protective effects against DEACMP.
Longitudinal pathways between mental health difficulties and academic performance during middle childhood and early adolescence
Authors: Deighton Jessica , Humphrey Neil , Belsky Jay , Boehnke Jan , Vostanis Panos , Patalay Praveetha
Published: November 2017

There is a growing appreciation that child functioning in different domains, levels, or systems are interrelated over time. Here, we investigate links between internalizing symptoms, externalizing problems, and academic attainment during middle childhood and early adolescence, drawing on two large data sets (child: mean age 8.7 at enrolment, n = 5,878; adolescent: mean age 11.7, n = 6,388). Using a 2‐year cross‐lag design, we test three hypotheses – adjustment erosion, academic incompetence, and shared risk – while also examining the moderating influence of gender. Multilevel structural equation models provided consistent evidence of the deleterious effect of externalizing problems on later academic achievement in both cohorts, supporting the adjustment‐erosion hypothesis. Evidence supporting the academic‐incompetence hypothesis was restricted to the middle childhood cohort, revealing links between early academic failure and later internalizing symptoms. In both cohorts, inclusion of shared‐risk variables improved model fit and rendered some previously established cross‐lag pathways non‐significant. Implications of these findings are discussed, and study strengths and limitations noted.

Statement of contribution

What is already known on this subject?

Longitudinal research and in particular developmental cascades literature make the case for weaker associations between internalizing symptoms and academic performance than between externalizing problems and academic performance.

Findings vary in terms of the magnitude and inferred direction of effects. Inconsistencies may be explained by different age ranges, prevalence of small‐to‐modest sample sizes, and large time lags between measurement points.

Gender differences remain underexamined.

What does this study add?

The present study used cross‐lagged models to examine longitudinal associations in age groups (middle child and adolescence) in a large‐scale British sample.

The large sample size not only allows for improvements on previous measurement models (e.g., allowing the analysis to account for nesting, and estimation of latent variables) but also allows for examination of gender differences.

The findings clarify the role of shared‐risk factors in accounting for associations between internalizing, externalizing, and academic performance, by demonstrating that shared‐risk factors do not fully account for relationships between internalizing, externalizing, and academic achievement. Specifically, some pathways between mental health and academic attainment consistently remain, even after shared‐risk variables have been accounted for.

Findings also present consistent support for the potential impact of behavioural problems on children's academic attainment.

The negative relationship between low academic attainment and subsequent internalizing symptoms for younger children is also noteworthy.
GI‐530159, a novel, selective, mechanosensitive two‐pore‐domain potassium (K2P) channel opener, reduces rat dorsal root ganglion neuron excitability
Authors: Loucif Alexandre J C , Saintot Pierre‐Philippe , Liu Jia , Antonio Brett M , Zellmer Shannon G , Yoger Katrina , Veale Emma L , Wilbrey Anna , Omoto Kiyoyuki , Cao Lishuang , Gutteridge Alex , Castle Neil A , Stevens Edward B , Mathie Alistair
Published: November 2017

Background and Purpose

TREK two‐pore‐domain potassium (K2P) channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study, we describe a new, selective opener of TREK channels, GI‐530159.

Experimental Approach

The effect of GI‐530159 on TREK channels was demonstrated using 86Rb efflux assays, whole‐cell and single‐channel patch‐clamp recordings from recombinant TREK channels. The expression of K2P2.1 (TREK1), K2P10.1 (TREK2) and K2P4.1 (TRAAK) channels was determined using transcriptome analysis from single dorsal root ganglion (DRG) cells. Current‐clamp recordings from cultured rat DRG neurons were used to measure the effect of GI‐530159 on neuronal excitability.

Key Results

For recombinant human TREK1 channels, GI‐530159 had similar low EC50 values in Rb efflux experiments and electrophysiological recordings. It activated TREK2 channels, but it had no detectable action on TRAAK channels nor any significant effect on other K channels tested. Current‐clamp recordings from cultured rat DRG neurones showed that application of GI‐530159 at 1 μM resulted in a significant reduction in firing frequency and a small hyperpolarization of resting membrane potential.

Conclusions and Implications

This study provides pharmacological evidence for the presence of mechanosensitive TREK K2P channels in sensory neurones and suggests that development of selective K2P channel openers like GI‐530159 could aid in the development of novel analgesic agents.

Linked Articles

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
Empirical models of firms and industries
Authors: Aguirregabiria Victor , Slade Margaret
Published: November 2017

We review important developments in empirical industrial organization (IO) over the last three decades. The paper is organized around six topics: collusion, demand, productivity, industry dynamics, interfirm contracts and auctions. We present models that are workhorses in empirical IO and describe applications. For each topic, we discuss at least one empirical application using Canadian data.
Downregulation of dual‐specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas
Authors: Ichimanda Michihiro , Hijiya Naoki , Tsukamoto Yoshiyuki , Uchida Tomohisa , Nakada Chisato , Akagi Tomonori , Etoh Tsuyoshi , Iha Hidekatsu , Inomata Masafumi , Takekawa Mutsuhiro , Moriyama Masatsugu
Published: November 2017

It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual‐specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas. In this study, we found that downregulation of DUSP4 was related to constitutive activation of ERKs in CRC cells. Restoration of DUSP4 resulted in inactivation of ERKs, leading to suppression of both proliferation and invasiveness, as shown by treatment with an MEK inhibitor. Furthermore, immunohistochemistry revealed that DUSP4 expression was upregulated in the superficial region of CRC tissue, whereas it was significantly downregulated in the deep region. In contrast, ERKs in the deep region were markedly hyperactivated compared to those in the superficial region. These results suggest that activation of the MAPK signaling pathway caused by downregulation of DUSP4 is responsible for progression of CRCs and would be a promising therapeutic target.
Clinical significance of disease‐specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma
Authors: Hattori Keiichiro , Sakata‐Yanagimoto Mamiko , Suehara Yasuhito , Yokoyama Yasuhisa , Kato Takayasu , Kurita Naoki , Nishikii Hidekazu , Obara Naoshi , Takano Shingo , Ishikawa Eiichi , Matsumura Akira , Hasegawa Yuichi , Chiba Shigeru
Published: November 2017

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.
Non‐operative treatment as a strategy for patients with parastomal hernia: a multicentre, retrospective cohort study
Authors: Kroese L. F. , Lambrichts D. P. V. , Jeekel J. , Kleinrensink G. J. , Menon A. G. , de Graaf E. J. R. , Bemelman W. A. , Lange J. F.
Published: November 2017

Aim

Parastomal hernia is the most common complication following stoma construction. Surgical treatment is usually chosen over non‐operative treatment, but a clear rationale for the choice of management is often lacking. This study aims to investigate the reasons for non‐operative treatment, cross‐over rates and postoperative complications.

Method

A multicentre, retrospective cohort study was conducted. Patients diagnosed with a parastomal hernia between January 2007 and December 2012 were included. Data on baseline characteristics, primary surgery and hernias were collected. For non‐operative treatment, reasons for this treatment and cross‐over rates were evaluated. For all patients undergoing surgery (surgical treatment and cross‐overs), complication and recurrence rates were analysed.

Results

Of the 80 patients included, 42 (53%) were in the surgical treatment group and 38 (48%) in the non‐operative treatment group. Median follow‐up was 46 months (interquartile range 24–72). The reasons for non‐operative treatment were absence of symptoms in 12 patients (32%), comorbidities in nine (24%) and patient preference in three (7.9%). In 14 patients (37%) reasons were not documented. Eight patients (21%) crossed over from non‐operative treatment to surgical treatment, of whom one needed emergency surgery. In 23 patients (55%), parastomal hernia recurred after the original surgical treatment, of whom 21 (91%) underwent additional repair.

Conclusion

Parastomal hernia repair is associated with high recurrence and additional repair rates. Non‐operative treatment has a relatively low cross‐over and emergency surgery rate. Given these data, non‐operative treatment might be a better choice for patients without complaints or with comorbidities.
Renal protection strategies after heart transplantation
Authors: Reichart Daniel , Reichenspurner Hermann , Barten Markus Johannes
Published: November 2017

Renal dysfunction caused by calcineurin inhibitor (CNI) nephrotoxicity occurs often and contributes significantly to late mortality after heart transplantation (HTx). Over the last decades, this has prompted many clinical studies in an effort to develop kidney‐protecting immunosuppressive strategies including delayed CNI start, minimization, withdrawal, or even de novo CNI avoidance. In the past, these strategies often failed due to the lack of efficacy. Since 2009, novel CNI‐reducing strategies have been under investigation. These strategies minimize renal damage using induction agents such as antithymocyte globulin and alternative immunosuppressive agents such as the mechanistic target of rapamycin inhibitors (sirolimus or everolimus) or mycophenolate. This review outlines the recent results of using these renal protection strategies including their drawbacks. We also discuss alternative approaches to optimize individual immunosuppressive therapies after HTx.
Family behaviours that have an impact on the self‐management activities of adults living with Type 2 diabetes: a systematic review and meta‐synthesis
Authors: Vongmany J. , Luckett T. , Lam L. , Phillips J. L.
Published: November 2017

Aims

To identify family behaviours that adults with Type 2 diabetes’ perceive as having an impact on their diabetes self‐management.

Background

Research suggests that adults with Type 2 diabetes perceive that family members have an important impact on their self‐management; however, it is unclear which family behaviours are perceived to influence self‐management practices.

Methods

This meta‐synthesis identified and synthesized qualitative studies from the databases EMBASE, Medline and CINAHL published between the year 2000 and October 2016. Studies were eligible if they provided direct quotations from adults with Type 2 diabetes, describing the influence of families on their self‐management. This meta‐synthesis adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) statement.

Results

Of the 2606 studies screened, 40 were included. This meta‐synthesis identified that adults with Type 2 diabetes perceive family behaviours to be either: 1) facilitators of diabetes self‐management; 2) barriers to diabetes self‐management; or 3) equivocal behaviours with the potential to both support and/or impede diabetes self‐management. Seven sub‐themes were identified within these themes, including: four facilitator sub‐themes (‘positive care partnerships’; ‘family watchfulness’; ‘families as extrinsic motivator’ and ‘independence from family’); two barrier sub‐themes (‘obstructive behaviours’ and ‘limited capacity for family support’); and one equivocal behaviours subtheme (‘regular reminders and/or nagging’).

Conclusion

While most family behaviours are unambiguously perceived by adults with Type 2 diabetes to act as facilitators of or barriers to self‐management, some behaviours were perceived as being neither clear facilitators nor barriers; these were termed ‘equivocal behaviours’. If the concept of ‘equivocal behaviours’ is confirmed, it may be possible to encourage the adult living with Type 2 diabetes to reframe these behaviours so that they are perceived as enabling their diabetes self‐management.
Cost‐effectiveness of the psycho‐educational blended (group and online) intervention HypoAware compared with usual care for people with Type 1 and insulin‐treated Type 2 diabetes with problematic hypoglycaemia: analyses of a cluster‐randomized controlled trial
Authors: de Wit M. , Rondags S. M. P. A. , van Tulder M. W. , Snoek F. J. , Bosmans J. E.
Published: November 2017

Aims

To evaluate the cost‐effectiveness of HypoAware, a blended (group and online) psycho‐educational intervention based on the evidence‐based Blood Glucose Awareness Training, in comparison with usual care in people with Type 1 and Type 2 diabetes with a high risk of severe hypoglycaemia.

Methods

We performed an economic evaluation, from a societal and healthcare perspective, that used data from a 6‐month, multicentre, cluster‐randomized controlled trial (n = 137).

Results

The proportion of people with at least one severe hypoglycaemic event per 6 months was 0.22 lower (95% CI –0.39 to –0.06) and the proportion of people with impaired hypoglycaemia awareness was 0.16 lower (95% CI –0.34 to 0.02) in the HypoAware group. There was no difference in quality‐adjusted life‐years (–0.0; 95% CI –0.05 to 0.05). The mean total societal costs in the HypoAware group were EUR708 higher than in the usual care group (95% CI –951 to 2298). The mean incremental cost per severe hypoglycaemic event prevented was EUR2,233. At a willingness‐to‐pay threshold of EUR20,000 per event prevented, the probability that HypoAware was cost‐effective in comparison with usual care was 54% from a societal perspective and 55% from a healthcare perspective. For quality‐adjusted life‐years the incremental cost‐effectiveness ratio was EUR119,360/quality‐adjusted life‐year gained and the probability of cost‐effectiveness was low at all ceiling ratios.

Conclusions

Based on the present study, we conclude that HypoAware is not cost‐effective compared to usual care. Further research in less well‐resourced settings and more severely affected patients is warranted.

(Clinical Trials Registry no: Dutch Trial Register NTR4538.)
The first case of “locked‐in leaflet” after transcatheter aortic valve replacement in a patient with bicuspid aortic stenosis
Authors: Shibata Nao , Matsumoto Kensuke , Toba Takayoshi , Mori Shumpei , Shimoyama Shinsuke , Tanaka Hidekazu , Shinke Toshiro , Hirata Ken‐ichi
Published: November 2017

This case report is about an 85‐year‐old woman with bicuspid aortic stenosis (AS). Although preoperative multimodality imaging showed challenging anatomical aspects, transcatheter aortic valve replacement (TAVR) was selected to be performed as a less invasive alternative treatment approach, owing to her comorbidity. Postoperative transesophageal echocardiography and multidetector‐row computed tomography revealed the presence of “locked‐in leaflet” caused by stent distortion due to pinching by calcified native leaflets, with nodular calcification preventing the full expansion of the valve, which resulted in moderate perivalvular leakage. This is the first reported case of bicuspid AS treated with TAVR that eventually resulted in “locked‐in leaflet.”
Misperceiving inequality
Authors: Gimpelson Vladimir , Treisman Daniel
Published: November 2017

A vast literature suggests that economic inequality has important consequences for politics and public policy. Higher inequality is thought to increase demand for income redistribution in democracies and to discourage democratization and promote class conflict and revolution in dictatorships. Most such arguments crucially assume that ordinary people know how high inequality is, how it has been changing, and where they fit in the income distribution. Using a variety of large, cross‐national surveys, we show that, in recent years, ordinary people have had little idea about such things. What they think they know is often wrong. Widespread ignorance and misperceptions emerge robustly, regardless of data source, operationalization, and measurement method. Moreover, perceived inequality—not the actual level—correlates strongly with demand for redistribution and reported conflict between rich and poor. We suggest that most theories about political effects of inequality need to be reframed as theories about effects of perceived inequality.
Colletotrichum theobromicola causing anthracnose on butia fruits in Brazil
Authors: Dorneles K. R. , Eloy J. , Dallagnol L. J.
Published: November 2017

Native fruits of Brazil have received more attention recently due to their organoleptic properties and as sources of secondary metabolites that improve human health. Amongst the native fruit species are Butia spp palms, the fruits of which are consumed raw or processed into juices, jams, liquor and ice cream. In this work, anthracnose was found on fruits from Butia odorata plants. Fruits heavily affected by this condition are considered inappropriate for consumption of raw or use in processed foods. The fungus was identified using morphological and molecular methods as Colletotrichum gloeosporioides, phylogenetically close to Colletotrichum theobromicola. To the best of our knowledge, this is the first report of C. theobromicola causing anthracnose in Butia species.
Thalamic volume reduction in drug‐naive patients with new‐onset genetic generalized epilepsy
Authors: Perani Suejen , Tierney Tim M. , Centeno Maria , Shamshiri Elhum A. , Yaakub Siti N. , O'Muircheartaigh Jonathan , Carmichael David W. , Richardson Mark P.
Published: November 2017

Objective

Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED‐naive patients with GGE at disease onset. We hypothesize that drug‐naive patients at disease onset have gray matter changes compared to age‐matched healthy controls.

Methods

We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED‐naive patients with new‐onset GGE and compared them to 32 age‐matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups.

Results

The thalamus was the only structure to show reduced gray matter volume in AED‐naive patients with new‐onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions.

Significance

Structural abnormalities in the thalamus are present at the initial onset of GGE in AED‐naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.