bluuebunny/crossref_metadata_2025_split huggingface dataset:
D‐dimer Interval Likelihood Ratios for Pulmonary Embolism
Authors: Kohn Michael A. , Klok Frederikus A. , van Es Nick 
Published: April 2017

AbstractObjectiveThe objective was to estimate D‐dimer interval likelihood ratios (iLRs) for diagnosing pulmonary embolism (PE).MethodsThe authors used pooled patient‐level data from five PE diagnostic management studies to estimate iLRs for the eight D‐dimer intervals with boundaries 250, 500, 750, 1,000, 1,500, 2,500, and 5,000 ng/mL. Logistic regression was used to fit the data so that an interval increase corresponds to increasing the likelihood ratio by a constant factor.ResultsThe iLR for the D‐dimer interval 1,000–1,499 ng/mL was essentially 1.0 (0.98 with 95% confidence interval [CI] = 0.82–1.18). In the logistic regression model, the constant between‐interval factor was 2.0 (95% CI = 1.9–2.1). Using these iLR estimates, if the pre–D‐dimer probability of PE is 15%, only a D‐dimer less than 500 ng/mL will result in a posttest probability below 3%; if the pretest probability is 5%, the threshold for a “negative” D‐dimer is 1,000 ng/mL.ConclusionsA decision strategy based on these approximate iLRs agrees with several published strategies.
Ivabradine: Current and Future Treatment of Heart Failure
Authors: Thorup Lene , Simonsen Ulf , Grimm Daniela , Hedegaard Elise R. 
Published: April 2017

AbstractIn heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end‐diastolic pressure. Current treatments for HF with reduced ejection fraction (HFrEF) include angiotensin‐converting enzyme (ACE) inhibitors, angiotension receptor type 1 (AT1) antagonists, β‐adrenoceptor antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT1 receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate (HR) above 70 bpm. Here, we review the evidence regarding the use of ivabradine for lowering HR in HF. Ivabradine is a blocker of an I funny current (I(f)) channel and causes rate‐dependent inhibition of the pacemaker activity in the sinoatrial node. In clinical trials of HFrEF, treatment with ivabradine seems to improve clinical outcome, for example improved ejection fraction (EF) and less readmission for hospital, but the effect appears most pronounced in patients with HRs above 70 bpm, while the effect on cardiovascular death appears less consistent. The adverse effects of ivabradine include bradycardia, atrial fibrillation and visual disturbances, but ivabradine avoids the negative inotrope effects observed with β‐adrenoceptor antagonists. In conclusion, in patients with stable HFrEF with EF<35% and HR above 70 bpm, ivabradine improves the outcome and might be a first choice of therapy, if beta‐adrenoceptor antagonists are not tolerated. Further studies must show whether that can be extended to HF patients with preserved EF.
Targeting Tankyrase to Fight WNT‐dependent Tumours
Authors: Thorvaldsen Tor Espen 
Published: April 2017

AbstractAberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multi‐protein β‐catenin destruction complex promote excessive amounts of the main transcriptional activator β‐catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN. Indeed, tankyrase inhibitors (TNKSi) have emerged as promising therapeutics by restoring functional signal‐limiting destruction complexes in CRCs. Furthermore, as TNKSi‐induced destruction complexes (so‐called degradasomes) can be visualized by microscopy, they have served as a valuable experimental model system to address unresolved aspects regarding the structure, function and composition of the β‐catenin destruction complex. This MiniReview provides an overview of the current knowledge on the regulatory mechanisms and interactions that govern the β‐catenin destruction complex activity. It further highlights the potential of TNKSi as anticancer drugs and as a novel research tool to dissect the WNT signalling pathway.
The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis
Authors: Schinnerling K , Aguillón J C , Catalán D , Soto L 
Published: April 2017

SummaryTherapeutic blockage of cytokine signalling in autoimmune diseases has improved our understanding of the role of these cytokines in triggering, shaping and perpetuating autoimmune responses. In rheumatoid arthritis (RA), immunopathology is driven by a predominance of arthritogenic T helper cells secreting interferon-γ [T helper type 1 (Th1)] and interleukin (IL)-17 (Th17) over regulatory T cells (Treg). The pleiotropic cytokine IL-6 is crucial to the differentiation of Th17 cells and the balance between pathogenic Th17 and protective Treg. Targeting the IL-6 receptor (IL-6R) by humanized antibodies improves signs and symptoms of RA, and has provided new insights into the mechanisms of inflammation and immune regulation. Here we review current evidence on the role of IL-6 in the pathogenesis of RA and the molecular consequences of IL-6R blockage in disease, with special focus on the Th17/Treg balance and plasticity.
Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, sub-Saharan Africa: implications for the susceptibility to meningococcal disease
Authors: Franco-Jarava C , Comas D , Orren A , Hernández-González M , Colobran R 
Published: April 2017

SummaryComplement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5–2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area.
Hearing optimisation in neurofibromatosis type 2: A systematic review
Authors: Lloyd S.K.W. , King A.T. , Rutherford S.A. , Hammerbeck‐Ward C.L. , Freeman S.R.M. , Mawman D.J. , O'Driscoll M. , Evans D.G. 
Published: April 2017

BackgroundIt is common for patients with neurofibromatosis type 2 to develop bilateral profound hearing loss hearing loss, and this is one of the main determinants of quality of life in this patient group.ObjectivesThe aim of this systematic review was to review the current literature regarding hearing outcomes of treatments for vestibular schwannomas in neurofibromatosis type 2 including conservative and medical management, radiotherapy, hearing preservation surgery and auditory implantation in order to determine the most effective way of preserving or rehabilitating hearing.Search strategyA MESH search in PubMed using search terms ((‘Neurofibromatosis 2’ [Mesh]) AND ‘Neuroma, Acoustic’[Mesh]) AND ‘Hearing Loss’ [Mesh] was performed. A search using keywords was also performed. Studies with adequate hearing outcome data were included. With the exception of the cochlear implant studies (cohort size was very small), case studies were excluded.Evaluation methodThe GRADE system was used to assess quality of publication. Formal statistical analysis of data was not performed because of very heterogenous data reporting.ResultsConservative management offers the best chance of hearing preservation in stable tumours. The use of bevacizumab probably improves the likelihood of hearing preservation in growing tumours in the short term and is probably more effective than hearing preservation surgery and radiotherapy in preserving hearing. Of the hearing preservation interventions, hearing preservation surgery probably offers better hearing preservation rates than radiotherapy for small tumours but recurrence rates for hearing preservation surgery were high. For patients with profound hearing loss, cochlear implantation provides significantly better auditory outcomes than auditory brainstem implantation. Patients with untreated stable tumours are likely to achieve the best outcomes from cochlear implantation. Those who have had their tumours treated with surgery or radiotherapy do not gain as much benefit from cochlear implantation than those with untreated tumours.ConclusionsThis review summarises the current literature related to hearing preservation/rehabilitation in patients with NF2. Whilst it provides indicative data, the quality of the data was low and should be interpreted with care. It is also important to consider that the management of vestibular schwannomas in NF2 is complex and decision‐making is determined by many factors, not just the need to preserve hearing.
Comparing characteristics and clinical and echocardiographic outcomes in low‐flow vs normal‐flow severe aortic stenosis with preserved ejection fraction in an Asian population
Authors: Ngiam Jinghao Nicholas , Tan Benjamin Yong‐Qiang , Sia Ching‐Hui , Lee Glenn K.M. , Kong William K.F. , Chan Yiong‐Huak , Poh Kian‐Keong 
Published: April 2017

Background/ObjectivesIn severe aortic stenosis (AS), deterioration of left ventricular ejection fraction (LVEF) to <50% is an AHA/ACC class I indication for valve replacement, regardless of symptoms. Controversy surrounds prognosis of low‐flow AS compared to normal‐flow, and no study has examined LVEF deterioration. We compared factors associated with LVEF deterioration (to <50%) and clinical outcomes.MethodsConsecutive subjects with low‐flow (stroke volume index <35 mL/m2, n=56) and normal‐flow (n=72) severe AS (aortic valve area <1 cm2) with preserved LVEF (>50%) and with paired echocardiography were studied. Univariate and multivariate analyses identified factors associated with LVEF deterioration. Clinical outcomes were determined on follow‐up for more than 5 years.ResultsSignificant LVEF deterioration (to <50%) was seen in 18% of low‐flow (initial LVEF 63±8% to 32±9%) and 18% of normal‐flow AS (61±7% to 31±12%). Independent factors in low‐flow AS were hypertension (OR: 30.7, 95% CI: 2.0–467.6, P=.014) and higher end‐systolic wall stress (OR: 1.086, 95% CI: 1.022–1.153, P=.008), compared to normal‐flow, which were hypertension (OR: 15.9, 95% CI: 3.1–81.9, P=.001), higher septal E/E′ ratio (OR: 1.16, 95% CI: 1.01–1.35, P=.043), lower septal S′ velocity (OR: 0.204, 95% CI: 0.061–0.682, P=.010), and higher end‐systolic wall stress (OR: 1.051, 95% CI: 1.001–1.104, P=.047). Overall, a third of the cohort experienced MACE, regardless of flow (log‐rank 0.048, P=.827). However, aortic valve replacement (AVR) rates were lower in low‐flow AS (20% vs 43%, P=.005).ConclusionsLow‐flow AS despite normal LVEF appears similar to normal‐flow in terms of LVEF deterioration and clinical outcomes in our Asian population. AVR rate was lower even though low‐flow may not reflect less severe disease.
Regional right ventricular remodeling and function in children with idiopathic pulmonary arterial hypertension vs those with pulmonary valve stenosis: Insights into mechanics of right ventricular dysfunction
Authors: Driessen Mieke M.P. , Meijboom Folkert J. , Hui Wei , Dragulescu Andreea , Mertens Luc , Friedberg Mark K. 
Published: April 2017

BackgroundRight ventricular (RV) pressure overload in the context of pulmonary stenosis (PS) has a much better prognosis than in the context of idiopathic pulmonary arterial hypertension (iPAH), which may be related to differences in global and regional RV remodeling and systolic function. We compared RV mechanics in children with PS to those with iPAH, aiming to identify mechanisms and markers of RV dysfunction.MethodsEighteen controls, 18 iPAH and 16 PS patients were retrospectively studied. Age, BSA, and sex distribution were comparable. Two‐dimensional echocardiography, blood flow and tissue Doppler, and longitudinal RV deformation were analyzed. ANCOVA—including RV systolic pressure (RVSP) and length as covariates—was used to compare patient groups.ResultsRV systolic pressure was higher in iPAH vs PS (96.8±25.4 vs 75.4±18.9 mm Hg, P=.011). Compared to controls, PS patients showed mild dilation (P<.01) and decreased longitudinal deformation (P<.001) at the RV apex. Compared to both PS and controls, iPAH patients showed marked spherical RV dilation (P<.001), reduced global, RV free wall and septal longitudinal deformation (iPAH −22.07%±4.35% vs controls −28.18%±1.69%; −9.98%±4.30% vs −17.45%±2.52%; P<.001) and RV postsystolic shortening (P<.001). RV transverse shortening (radial performance) was increased in PS (31.75%±10.35%; P<.001) but reduced in iPAH (−1.62%±11.11% vs controls 12.00%±7.74%; P<.001).ConclusionChildren with iPAH demonstrate adverse global and regional RV remodeling and mechanics compared to those with PS. Mechanisms of RV systolic dysfunction in iPAH include decreased longitudinal deformation, decreased or absent transverse shortening, and postsystolic shortening. These markers may be useful to identify children at risk of RV failure.
Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy
Authors: Kobayashi Yukari , Wheeler Matthew , Finocchiaro Gherardo , Ariyama Miyuki , Kobayashi Yuhei , Perez Marco V. , Liang David , Kuznetsova Tatiana , Schnittger Ingela , Ashley Euan , Haddad Francois 
Published: April 2017

BackgroundFew studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.MethodsFrom Stanford Cardiomyopathy Registry, we randomly selected 50 age‐/sex‐matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.ResultsThe mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m2 in controls, 32.2±13.3 mL/m2 in HCM 1, 42.0±12.9 mL/m2 in HCM 2, 52.4±15.2 mL/m2 for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (−18.5±1.9% in controls, −14.5±1.9% in HCM 1, −13.3±1.8% in HCM 2, −11.6±2.3% in HCM 3, and P<.05 all between groups).ConclusionsLA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.
Genetic and epigenetic variation in Spartina alterniflora following the Deepwater Horizon oil spill
Authors: Robertson Marta , Schrey Aaron , Shayter Ashley , Moss Christina J , Richards Christina 
Published: April 2017

AbstractCatastrophic events offer unique opportunities to study rapid population response to stress in natural settings. In concert with genetic variation, epigenetic mechanisms may allow populations to persist through severe environmental challenges. In 2010, the Deepwater Horizon oil spill devastated large portions of the coastline along the Gulf of Mexico. However, the foundational salt marsh grass, Spartina alterniflora, showed high resilience to this strong environmental disturbance. Following the spill, we simultaneously examined the genetic and epigenetic structure of recovering populations of S. alterniflora to oil exposure. We quantified genetic and DNA methylation variation using amplified fragment length polymorphism and methylation sensitive fragment length polymorphism (MS‐AFLP) to test the hypothesis that response to oil exposure in S. alterniflora resulted in genetically and epigenetically based population differentiation. We found high genetic and epigenetic variation within and among sites and found significant genetic differentiation between contaminated and uncontaminated sites, which may reflect nonrandom mortality in response to oil exposure. Additionally, despite a lack of genomewide patterns in DNA methylation between contaminated and uncontaminated sites, we found five MS‐AFLP loci (12% of polymorphic MS‐AFLP loci) that were correlated with oil exposure. Overall, our findings support genetically based differentiation correlated with exposure to the oil spill in this system, but also suggest a potential role for epigenetic mechanisms in population differentiation.
Catalase is a determinant of the colonization and transovarial transmission of Rickettsia parkeri in the Gulf Coast tick Amblyomma maculatum
Authors: Budachetri K. , Kumar D. , Karim S. 
Published: April 2017

AbstractThe Gulf Coast tick (Amblyomma maculatum) has evolved as a competent vector of the spotted‐fever group rickettsia, Rickettsia parkeri. In this study, the functional role of catalase, an enzyme responsible for the degradation of toxic hydrogen peroxide, in the colonization of the tick vector by R. parkeri and transovarial transmission of this pathogen to the next tick generation, was investigated. Catalase gene (CAT) expression in midgut, salivary glands and ovarian tissues exhibited a 2–11‐fold increase in transcription level upon R. parkeri infection. Depletion of CAT transcripts using an RNA‐interference approach significantly reduced R. parkeri infection levels in midgut and salivary gland tissues by 53–63%. The role of CAT in transovarial transmission of R. parkeri was confirmed by simultaneously blocking the transcript and the enzyme by injecting double‐stranded RNA for CAT and a catalase inhibitor (3‐amino‐1,2,4‐triazole) into gravid females. Simultaneous inhibition of the CAT transcript and the enzyme significantly reduced the egg conversion ratio with a 44% reduction of R. parkeri transovarial transmission. These data suggest that catalase is required for rickettsial colonization of the tick vector and transovarial transmission to the next generation.
Constructing a positive identity: A qualitative study of the driving forces of peer workers in mental health‐care systems
Authors: Vandewalle Joeri , Debyser Bart , Beeckman Dimitri , Vandecasteele Tina , Deproost Eddy , Van Hecke Ann , Verhaeghe Sofie 
Published: April 2017

AbstractThere is growing recognition in mental health for the perspective of individuals with lived experience of mental health problems and mental health service use. As peer workers, these individuals can use their specific experience to benefit and support peers and professional caregivers, and to participate at all levels of mental health‐care systems. The aim of the present study was to develop a conceptual framework representing the driving forces of peer workers to fullfil their position in mental health‐care systems. A qualitative interview approach was employed using principles of grounded theory. Over a period of 5 months in 2014–2015, semistructured interviews were conducted with 14 peer workers in residential and community mental health‐care systems. The emerged conceptual framework reveals that peer workers strive towards constructing a positive identity. This process is powered by driving forces reflecting a desire for normalization and an urge for self‐preservation. Peer workers realize a meaningful employment by using their lived experience perspective as an asset, liberating themselves out of restrictive role patterns, and by breaking down stigma and taboo. As a precondition to engage in these normalization processes, peer workers perceive they need to secure their self‐preservation by balancing the emergence of adverse emotional fluctuations. The conceptual framework can inform the development of work contexts in which peer workers have an authentic and meaningful contribution, while being offered sufficient support and learning opportunities to manage their well‐being.
Impact of demographic and clinical variables on the oral health‐related quality of life among five‐year‐old children: a population‐based study using self‐reports
Authors: Abanto Jenny , Panico Claudia , Bönecker Marcelo , Frazão Paulo 
Published: April 2017

BackgroundAlthough SOHO‐5 has been validated, there is no study testing this instrument in population‐based samples.AimsTo evaluate the impact of demographic and oral clinical variables on the oral health‐related quality of life (OHRQoL) in 5‐year‐old children from a socially deprived Brazilian area using selfreports.DesignData from 588 children were analyzed. Examinations included untreated dental caries and occlusal deviations. Children answered the Brazilian SOHO‐5 version and interviewers collected demographic characteristics of the child (sex and skin color). Robust Poisson regression associated outcome and exposures.ResultsGeneral, the oral impacts were reported by 71.1% of children. The mean and standard deviation total score of the Brazilian SOHO‐5 were 3.51 and 3.82, respectively. Children with untreated dental caries (PR = 1.28; P = 0.004) and increased overjet (PR = 1.35; P = 0.002) experienced a worse OHRQoL. Dark and mixed skin color children did not have a good impact on their OHRQoL (PR = 1.53; P = 0.006 and PR = 1.44; P < 0.000, respectively) compared to light ones.ConclusionsUntreated dental caries and increased overjet were independently associated with worst OHRQoL in 5‐year‐old children. As an indication of social deprivation, dark and mixed skin color children compared to light ones presented higher probability for reporting worst OHRQoL independently of the oral clinical conditions.