bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and factors associated with medication adherence among patients with hypertension in sub-Saharan Africa: protocol for a systematic review and meta-analysis
Authors: Agbor Valirie Ndip , Takah Noah Fongwen , Aminde Leopold Ndemnge 
Published: March 2018

IntroductionHypertension is the leading cardiovascular risk factor globally, associated with a high morbidity and mortality. The high prevalence of hypertension in sub-Saharan Africa (SSA) is associated with contrastingly low awareness, treatment and control rates. Adherence to medication remains a major determinant of optimal blood pressure control. This systematic review aims to determine the prevalence, and factors associated with adherence to antihypertensive pharmacotherapy among patients with hypertension in SSA.Methods and analysisWe will include studies published in Africa up to 31 December 2017. The following databases will be searched: PubMed, Embase, SCOPUS and Web of Science to identify potential studies without language restriction. To minimise chances of missing studies, resources specific to African literature such as WHO AFROLIB, African Index Medicus and African Journals Online will also be searched. Two reviewers will independently screen studies, extract data and critically appraise included studies for risk of bias, and a third reviewer will resolve discrepancies. A random-effects meta-analysis is planned to pool study-specific estimates to obtain a summary measure presented in Forest plots. Heterogeneity of included studies will be assessed using the χ2test on Cochrane’s Q statistic and quantified using I2. Publication bias will be assessed using the Egger’s test and funnel plots. This protocol has been prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Protocols 2015 statement.Ethical and disseminationAn ethical approval is not required for the proposed study, as it will be based on already published data. The end report will be presented at conferences and published in a peer-reviewed journal.PROSPERO registration numberCRD42017079838.
Development of an intervention to stimulate physical activity in hard-to-reach physically disabled people and design of a pilot implementation: an intervention mapping approach
Authors: Krops Leonie A , Dekker Rienk , Geertzen Jan H B , Dijkstra Pieter U 
Published: March 2018

IntroductionPhysically disabled people are less physically active compared with healthy people. Existing physical activity (PA) interventions are limited in reach, since they are primarily rehabilitation or school based. The current study aims to develop a community-based intervention for stimulating PA in hard-to-reach physically disabled people.Methods and analysisTo systematically develop a PA-stimulating intervention, intervention mapping (six steps) was applied. PA level and health-related quality of life of patients after rehabilitation was determined using questionnaires (step 1). Qualitative research was performed to study professionals’ and physically disabled people’s ideas about intervention objectives, determinants and design (steps 2 and 3). Since experts expressed no need for a new intervention, the existing intervention ‘Activity coach’ was adapted to the specific target population. The adapted intervention ‘Activity coach+’ composes a network of intermediate organisations that refers participants to an activity coach, who coaches participants during 1 year. After a preintervention physical assessment by a physiotherapist, participants will be individually guided to existing organised or non-organised activities. An activity tracker will be used to monitor and stimulate PA in daily life (step 4). To support adoption and implementation, meetings between involved parties are organised (step 5). ‘Activity coach+’ is implemented in community in March 2017, and will be evaluated using a mixed-method analysis. Quantitative evaluation of intervention effects on PA, health and social participation takes place after 0, 2, 4, 6 and 12 months. The implementation process and experiences with the intervention will be determined using qualitative research (step 6).Ethics and disseminationInsights from this study will be used for dissemination and further development of the intervention. The Medical Ethical Committee of the University Medical Center Groningen confirmed that formal ethical approval was not required (METc 2016/630).Trial registration numberNTR6858.
Inter-rater and intrarater reliability of the South African Triage Scale in low-resource settings of Haiti and Afghanistan
Authors: Dalwai Mohammed , Tayler-Smith Katie , Twomey Michèle , Nasim Masood , Popal Abdul Qayum , Haqdost Waliul Haq , Gayraud Olivia , Cheréstal Sophia , Wallis Lee , Valles Pola 
Published: March 2018

ObjectiveThe South African Triage Scale (SATS) has demonstrated good validity in the EDs of Médecins Sans Frontières (MSF)-supported sites in Afghanistan and Haiti; however, corresponding reliability in these settings has not yet been reported on. This study set out to assess the inter-rater and intrarater reliability of the SATS in four MSF-supported EDs in Afghanistan and Haiti (two trauma-only EDs and two mixed (including both medical and trauma cases) EDs).MethodsUnder classroom conditions between December 2013 and February 2014, ED nurses at each site assigned triage ratings to a set of context-specific vignettes (written case reports of ED patients). Inter-rater reliability was assessed by comparing triage ratings among nurses; intrarater reliability was assessed by asking the nurses to retriage 10 random vignettes from the original set and comparing these duplicate ratings. Inter-rater reliability was calculated using the unweighted kappa, linearly weighted kappa and quadratically weighted kappa (QWK) statistics, and the intraclass correlation coefficient (ICC). Intrarater reliability was calculated according to the percentage of exact agreement and the percentage of agreement allowing for one level of discrepancy in triage ratings. The correlation between years of nursing experience and reliability of the SATS was assessed based on comparison of ICCs and the respective 95% CIs.ResultsA total of 67 nurses agreed to participate in the study: In Afghanistan there were 19 nurses from Kunduz Trauma Centre and nine from Ahmed Shah Baba; in Haiti, there were 20 nurses from Martissant Emergency Centre and 19 from Tabarre Surgical and Trauma Centre. Inter-rater agreement was moderate across all sites (ICC range: 0.50–0.60; QWK range: 0.50–0.59) apart from the trauma ED in Haiti where it was moderate to substantial (ICC: 0.58; QWK: 0.61). Intrarater agreement was similar across the four sites (68%–74% exact agreement); when allowing for a one-level discrepancy in triage ratings, intrarater reliability was near perfect across all sites (96%–99%). No significant correlation was found between years of nursing experience and reliability.ConclusionThe SATS has moderate reliability in different EDs in Afghanistan and Haiti. These findings, together with concurrent findings showing that the SATS has good validity in the same settings, provide evidence to suggest that SATS is suitable in trauma-only and mixed EDs in low-resource settings.
Nusinersen for SMA: expanded access programme
Authors: Farrar Michelle A , Teoh Hooi Ling , Carey Kate A , Cairns Anita , Forbes Robin , Herbert Karen , Holland Sandra , Jones Kristi J , Menezes Manoj P , Morrison Margot , Munro Kate , Villano Daniella , Webster Richard , Woodcock Ian R , Yiu Eppie M , Sampaio Hugo , Ryan Monique M 
Published: March 2018

BackgroundSpinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1.MethodsAn Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed.ResultsA total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, P<0.05). Management shifts included proactive nutritional and pulmonary support in all newly diagnosed patients with increased complexity of decision making. Supplemental nutrition with or without nocturnal non-invasive ventilation was implemented during follow-up in new diagnoses with age of onset <3 months and 2 SMN2 copies.ConclusionsThe nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.
Brain microstructural injury occurs in patients with RRMS despite ‘no evidence of disease activity’
Authors: Harel Asaff , Sperling Dylan , Petracca Maria , Ntranos Achillefs , Katz-Sand Ilana , Krieger Stephen , Lublin Fred , Wang Zichen , Liu Yangbo , Inglese Matilde 
Published: March 2018

ObjectivesThe accuracy of ‘no evidence of disease activity’ (NEDA) in predicting long-term clinical outcome in patients with relapsing remitting multiple sclerosis (RRMS) is unproven, and there is growing evidence that NEDA does not rule out disease worsening. We used diffusion tensor imaging (DTI) to investigate whether ongoing brain microstructural injury occurs in patients with RRMS meeting NEDA criteria.MethodsWe performed a retrospective study to identify patients with RRMS visiting our centre over a 3-month period who had undergone prior longitudinal DTI evaluation at our facility spanning ≥2 years. Patients meeting NEDA criteria throughout the evaluation period were included in the NEDA group, and those not meeting NEDA criteria were included in an ‘evidence of disease activity’ (EDA) group. Fractional anisotropy (FA) and mean diffusivity (MD) maps were created, and annual rates of change were calculated.ResultsWe enrolled 85 patients, 39 meeting NEDA criteria. Both NEDA and EDA groups showed longitudinal DTI worsening. Yearly FA decrease was lower in the NEDA group (0.5%, p<0.0001) than in the EDA group (1.2%, p=0.003), while yearly MD increase was similar in both groups (0.8% for NEDA and EDA, both p<0.01). There was no statistical difference in deterioration within and outside of T2 lesions. DTI parameters correlated with disability scores and fatigue complaints.ConclusionsWhite matter microstructural deterioration occurs in patients with RRMS over short-term follow-up in patients with NEDA, providing further evidence of the limitations of conventional measures and arguing for DTI in monitoring of the disease process.
Hemodynamic characteristics of stable and unstable vertebrobasilar dolichoectatic and fusiform aneurysms
Authors: Brinjikji Waleed , Chung Bongjae , Yong-Hong Ding , Wald John T , Mut Fernando , Kadirvel Ramanathan , Kallmes David F , Rouchaud Aymeric , Lanzino Giuseppe , Cebral Juan R 
Published: March 2018

Background and purposeVertebrobasilar dolichoectatic and fusiform aneurysms (VBDAs) are known to have a poor natural history, with high rates of growth, rupture, and stroke. The purpose of this study was to identify hemodynamic characteristics that differ between VBDAs associated with growth, rupture, and stroke.Materials and methodsVBDAs with CT angiography or MR angiography followed longitudinally without treatment were studied. Unstable aneurysms were defined as those that grew or ruptured during follow-up. Aneurysms associated with stroke were defined as those associated with posterior circulation infarct at follow-up. Baseline data, including demographics, comorbidities, and aneurysm morphology and size were collected. Image based computational fluid dynamics models were created and run under pulsatile flow conditions. Relevant hemodynamic and geometric variables were calculated and compared between groups (stable vs unstable and no stroke vs stroke) using the Wilcoxon test.ResultsA total of 37 VBDAs were included (24 stable, 13 unstable; 30 no stroke, 7 stroke). Unstable aneurysms had lower shear rates (P=0.05), blood flow velocity (P=0.03), and lower vorticity (P=0.049) than stable aneurysms. In addition, unstable aneurysms had higher mean oscillatory shear indices (P=0.001). There were no differences in the hemodynamic characteristics of aneurysms in the stroke group compared with the non-stroke group.ConclusionThis small study suggests there may be hemodynamic differences between unstable and stable VBDAs. Unstable VBDAs appear to be under lower flow conditions with lower velocity, vorticity, and shear rates, and have more oscillatory flow. There was no difference in the hemodynamic characteristics of aneurysms in the stroke and no stroke group.
Inflammatory and structural changes in vertebral bodies and posterior elements of the spine in axial spondyloarthritis: construct validity, responsiveness and discriminatory ability of the anatomy-based CANDEN scoring system in a randomised placebo-controlled trial
Authors: Krabbe Simon , Sørensen Inge J , Jensen Bente , Møller Jakob M , Balding Lone , Madsen Ole R , Lambert Robert G W , Maksymowych Walter P , Pedersen Susanne J , Østergaard Mikkel 
Published: March 2018

BackgroundThe Canada-Denmark (CANDEN) definitions of spinal MRI lesions allow a detailed anatomy-based evaluation of inflammatory and structural lesions in vertebral bodies and posterior elements of the spine in patients with axial spondyloarthritis (axSpA). The objective was to examine the reliability, responsiveness and discrimination of scores for spinal inflammation, fat, bone erosion and new bone formation based on the CANDEN system and to describe patterns of inflammatory and structural lesions and their temporal development.Methods49 patients with axSpA from an investigator-initiated, randomised, placebo-controlled trial of adalimumab underwent spinal MRI at weeks 0/6/24/48. MR images were scored according to the CANDEN system and the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Total scores, and various subscores, were created by summing individual lesion scores.ResultsThe CANDEN spine inflammation score had high responsiveness, similar to the SPARCC MRI spine index (Guyatt’s responsiveness index 1.88 and 1.67, respectively), and discriminated between adalimumab and placebo treatment already at 6 weeks’ follow-up (P=0.03). Anterior/posterior corner inflammation subscores showed similar responsiveness. Inter-reader reliability for the CANDEN spine inflammation and fat scores was good to very good for status and change scores (intraclass correlation coefficient (ICC)=0.71–0.92). Reliability for CANDEN new bone formation and erosion scores was good to very good for status scores (ICC=0.61–0.75) but, due to minimal progression, poor for change scores (ICC≤0.40).ConclusionsThe CANDEN spine inflammation score showed good responsiveness, discrimination between active treatment and placebo and reliability. The CANDEN spine structural scores had good cross-sectional reliability, but longer studies are needed to investigate their sensitivity to change.Trial registration numberNCT01029847; Results.
Sedimentary processes and facies on a high-latitude passive continental margin, Wilkes Land, East Antarctica
Authors: Passchier Sandra , Ciarletta Daniel J. , Henao Victor , Sekkas Vicky 
Published: March 2018

Abstract
The impact of high-latitude physical processes on the sedimentary geology of a passive continental margin is addressed using a sediment record from the Wilkes Land margin of Antarctica. We present sequence stratigraphic models based on analytical data and genetic interpretations of sedimentary facies assemblages observed in drill cores collected by the Integrated Ocean Drilling Program. The examination of drill cores within a previously published seismostratigraphic context enhances the resolution of the sequence stratigraphic interpretations. Weaker tidal forcing, a stronger Coriolis effect and more pronounced seasonality are some of the physical processes that affect erosion and sedimentation at high latitudes, even if ice sheets are absent. In addition, the presence of an ice sheet affects erosion rates, crustal motion, and atmospheric and ocean circulation, with major implications for the development of depositional systems. As a result, high-latitude, ice-covered, passive margins show distinct sedimentary facies associations and their interpretation requires the application of a different suite of sequence stratigraphic models from those applied to low-latitude continental margins.
Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells
Authors: Hall Amelia Weber , Battenhouse Anna M. , Shivram Haridha , Morris Adam R. , Cowperthwaite Matthew C. , Shpak Max , Iyer Vishwanath R. 
Published: March 2018

Abstract
Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene-regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and CTCF binding as well as gene expression in primary gliomas and identified chromatin states that define distinct regulatory elements across the tumor genome. Enhancers in mesenchymal and classical tumor subtypes drove gene expression associated with cell migration and invasion, whereas enhancers in proneural tumors controlled genes associated with a less aggressive phenotype in GBM. We identified bivalent domains marked by activating and repressive chromatin modifications. Interestingly, the gene interaction network from common (subtype-independent) bivalent domains was highly enriched for homeobox genes and transcription factors and dominated by SHH and Wnt signaling pathways. This subtype-independent signature of early neural development may be indicative of poised dedifferentiation capacity in glioblastoma and could provide potential targets for therapy.
Significance: Enhancers and bivalent domains in glioblastoma are regulated in a subtype-specific manner that resembles gene regulation in glioma stem cells. Cancer Res; 78(10); 2463–74. ©2018 AACR.
Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer
Authors: Segal Neil H. , He Aiwu R. , Doi Toshihiko , Levy Ronald , Bhatia Shailender , Pishvaian Michael J. , Cesari Rossano , Chen Ying , Davis Craig B. , Huang Bo , Thall Aron D. , Gopal Ajay K. 
Published: March 2018

Abstract
Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.
Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.
Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (&lt;10% of patients). Only one (1.8%) patient experienced a grade 3–4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%–13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.
Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816–23. ©2018 AACR.
Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer
Authors: Camblin Adam J. , Pace Emily A. , Adams Sharlene , Curley Michael D. , Rimkunas Victoria , Nie Lin , Tan Gege , Bloom Troy , Iadevaia Sergio , Baum Jason , Minx Charlene , Czibere Akos , Louis Chrystal U. , Drummond Daryl C. , Nielsen Ulrik B. , Schoeberl Birgit , Pipas J. Marc , Straubinger Robert M. , Askoxylakis Vasileios , Lugovskoy Alexey A. 
Published: March 2018

Abstract
Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.
Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.
Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo.
Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.