bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of repeated self-measurements of maximum step length and gait speed by community-dwelling older persons
Authors: Bongers Kim T J , Schoon Yvonne , Olde Rikkert Marcel G M 
Published: August 2016

ObjectivesSelf-management of mobility and fall risk can be important in fall prevention; however, it remains unstudied. Therefore, the current study assessed whether community-dwelling older persons were able to repeatedly self-assess maximum step length (MSL) and gait speed (GS) in their own home for a 6-month period, how these tests changed during this period and if these changes were related to falling.DesignThis is a prospective study.SettingThis study was conducted at home.ParticipantsA total of 56 community-dwelling older adults (24 women (43%), mean age 76.2 (SD 3.9) years) entered the study; of which, 45 completed the study.MethodsParticipants performed MSL and GS once a week in their own home during a 6-month period.Primary and secondary outcomesRepeated MSL and GS measurements were the primary outcomes. Falls, self-management and mobility were the secondary outcomes.ResultsSelf-assessment of MSL and GS by older persons is feasible. Compliance of repeatedly self-measuring MSL and GS was good; the median number of weekly measurements was 23.0 (88%) and 21.0 (81%) for MSL and GS, respectively. Drop-outs showed less self-management abilities compared to the participants who completed the study (p=0.049). Linear mixed models showed a small significant improvement in MSL and GS over time (p<0.001), without an influence on falling.ConclusionsMost community-dwelling older persons are able and willing to repeatedly assess their MSL and GS. Self-managing mobility and fall risk did not increase fall occurrence. The fact that older persons can be actively involved in their own healthcare is clinically relevant. Further studies are needed to examine the (cost-)effectiveness of self-management in fall prevention interventions.
Estimating the economic burden of cardiovascular events in patients receiving lipid-modifying therapy in the UK
Authors: Danese Mark D , Gleeson Michelle , Kutikova Lucie , Griffiths Robert I , Azough Ali , Khunti Kamlesh , Seshasai Sreenivasa Rao Kondapally , Ray Kausik K 
Published: August 2016

ObjectivesTo characterise the costs to the UK National Health Service of cardiovascular (CV) events among individuals receiving lipid-modifying therapy.DesignRetrospective cohort study using Clinical Practice Research Datalink records from 2006 to 2012 to identify individuals with their first and second CV-related hospitalisations (first event and second event cohorts). Within-person differences were used to estimate CV-related outcomes.SettingPatients in the UK who had their first CV event between January 2006 and March 2012.ParticipantsPatients ≥18 years who had a CV event and received at least 2 lipid-modifying therapy prescriptions within 180 days beforehand.Primary and secondary outcome measuresDirect medical costs (2014 £) were estimated in 3 periods: baseline (pre-event), acute (6 months afterwards) and long-term (subsequent 30 months). Primary outcomes included incremental costs, resource usage and total costs per period.ResultsThere were 24 093 patients in the first event cohort of whom 5274 were included in the second event cohort. The mean incremental acute CV event costs for the first event and second event cohorts were: coronary artery bypass graft/percutaneous transluminal coronary angioplasty (CABG/PTCA) £5635 and £5823, myocardial infarction £4275 and £4301, ischaemic stroke £3512 and £4572, heart failure £2444 and £3461, unstable angina £2179 and £2489 and transient ischaemic attack £1537 and £1814. The mean incremental long-term costs were: heart failure £848 and £2829, myocardial infarction £922 and £1385, ischaemic stroke £973 and £682, transient ischaemic attack £705 and £1692, unstable angina £328 and £677, and CABG/PTCA £−368 and £599. Hospitalisation accounted for 95% of acute and 61% of long-term incremental costs. Higher comorbidity was associated with higher long-term costs.ConclusionsRevascularisation and myocardial infarction were associated with the highest incremental costs following a CV event. On the basis of real-world data, the economic burden of CV events in the UK is substantial, particularly among those with greater comorbidity burden.
Nutritional route in oesophageal resection trial II (NUTRIENT II): study protocol for a multicentre open-label randomised controlled trial
Authors: Berkelmans Gijs H K , Wilts Bas J W , Kouwenhoven Ewout A , Kumagai Koshi , Nilsson Magnus , Weijs Teus J , Nieuwenhuijzen Grard A P , van Det Marc J , Luyer Misha D P 
Published: August 2016

IntroductionEarly start of an oral diet is safe and beneficial in most types of gastrointestinal surgery and is a crucial part of fast track or enhanced recovery protocols. However, the feasibility and safety of oral intake directly following oesophagectomy remain unclear. The aim of this study is to investigate the effects of early versus delayed start of oral intake on postoperative recovery following oesophagectomy.Methods and analysisThis is an open-label multicentre randomised controlled trial. Patients undergoing elective minimally invasive or hybrid oesophagectomy for cancer are eligible. Further inclusion criteria are intrathoracic anastomosis, written informed consent and age 18 years or older. Inability for oral intake, inability to place a feeding jejunostomy, inability to provide written consent, swallowing disorder, achalasia, Karnofsky Performance Status <80 and malnutrition are exclusion criteria. Patients will be randomised using online randomisation software. The intervention group (direct oral feeding) will receive a liquid oral diet for 2 weeks with gradually expanding daily maximums. The control group (delayed oral feeding) will receive enteral feeding via a jejunostomy during 5 days and then start the same liquid oral diet. The primary outcome measure is functional recovery. Secondary outcome measures are 30-day surgical complications; nutritional status; need for artificial nutrition; need for additional interventions; health-related quality of life. We aim to recruit 148 patients. Statistical analysis will be performed according to an intention to treat principle. Results are presented as risk ratios with corresponding 95% CIs. A two-tailed p<0.05 is considered statistically significant.Ethics and disseminationOur study protocol has received ethical approval from the Medical research Ethics Committees United (MEC-U). This study is conducted according to the principles of Good Clinical Practice. Verbal and written informed consent is required before randomisation. All data will be collected using an online database with adequate security measures.Trial registration numbersNCT02378948 and Dutch trial registry: NTR4972; Pre-results.
Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways
Authors: Hill Jonathan C , Kang Sujin , Benedetto Elena , Myers Helen , Blackburn Steven , Smith Stephanie , Dunn Kate M , Hay Elaine , Rees Jonathan , Beard David , Glyn-Jones Sion , Barker Karen , Ellis Benjamin , Fitzpatrick Ray , Price Andrew 
Published: August 2016

ObjectivesCurrent musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ).SettingA consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics.ParticipantsStakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients).Outcome measuresOutcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test–retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM).ResultsMusculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be ‘highly relevant’ and ‘easy to understand’. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test–retest reliability was excellent, and convergent validity was strong (correlations 0.81–0.88).ConclusionsA new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test–retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis.
Avoiding costly hospitalisation at end of life: findings from a specialist palliative care pilot in residential care for older adults
Authors: Chapman Michael , Johnston Nikki , Lovell Clare , Forbat Liz , Liu Wai-Man 
Published: August 2016

ObjectivesSpecialist palliative care is not a standardised component of service delivery in nursing home care in Australia. Specialist palliative care services can increase rates of advance care planning, decrease hospital admissions and improve symptom management in such facilities. New approaches are required to support nursing home residents in avoiding unnecessary hospitalisation and improving rates of dying in documented preferred place of death. This study examined whether the addition of a proactive model of specialist palliative care reduced resident transfer to the acute care setting, and achieved a reduction in hospital deaths.MethodsA quasi-experimental design was adopted, with participants at 4 residential care facilities. The intervention involved a palliative care nurse practitioner leading ‘Palliative Care Needs Rounds’ to support clinical decision-making, education and training. Participants were matched with historical decedents using propensity scores based on age, sex, primary diagnosis, comorbidities and the Aged Care Funding Instrument rating. Outcome measures included participants’ hospitalisation in the past 3 months of life and the location of death.ResultsThe data demonstrate that the intervention is associated with a substantial reduction in the length of hospital stays and a lower incidence of death in the acute care setting. While rates of hospitalisation were unchanged on average, length of admission was reduced by an average of 3.22 days (p<0.01 and 95% CI −5.05 to −1.41), a 67% decrease in admitted days.ConclusionsThe findings have significant implications for promoting quality outcomes through models of palliative care service delivery in residential facilities.
The transition to clinical expert: enhanced decision making for children aged less than 5 years attending the paediatric ED with acute respiratory conditions
Authors: Bowen Leah , Shaw Alison , Lyttle Mark D , Purdy Sarah 
Published: August 2016

BackgroundRates of unplanned paediatric admissions are persistently high. Many admissions are short-stay events, lasting less than 48 hours.ObjectiveThis qualitative research explores factors that influence clinical decision making in the paediatric ED (PED) for children under 5 attending with acute respiratory conditions, focusing on how management decisions adapt with increasing experience.MethodSemi-structured interviews were conducted with 15 PED clinicians (doctors, emergency nurse practitioners and registered nurses) with varying levels of experience in paediatric emergency medicine (PEM), emergency medicine or paediatrics. Audio-recorded interviews were transcribed and analysed thematically.ResultsThere were clear differences in decision-making approaches between experienced clinicians and junior staff. The latter were more risk adverse, relying heavily on guidelines, set admission criteria, clinical theory and second opinions. This was particularly true for doctors. ‘Informal’ learning was apparent in accounts from less-experienced doctors and nurses, whereby tacit knowledge and risk management played an increasing role in the development of clinical intuition that permitted rapid assessment and treatment of young patients.ConclusionsThe emergence of intuition entwined with approaches to risk management and the role of these skills in clinical decision making, carry implications for the development of training programmes for clinicians working in PEM. Enhanced training for such groups to permit development of the supplementary skills described in this study could have the ability to improve care delivery and even reduce paediatric admissions.
Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17
Authors: Hu Dong G. , Selth Luke A. , Tarulli Gerard A. , Meech Robyn , Wijayakumara Dhilushi , Chanawong Apichaya , Russell Roslin , Caldas Carlos , Robinson Jessica L.L. , Carroll Jason S. , Tilley Wayne D. , Mackenzie Peter I. , Hickey Theresa E. 
Published: August 2016

Abstract
Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3′ to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα+ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881–93. ©2016 AACR.
PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis
Authors: Xu Hai-Tao , Lai Wai-Lung , Liu Heong-Fai , Wong Leo Lap-Yan , Ng Irene Oi-Lin , Ching Yick Pang 
Published: August 2016

Abstract
PAK4 kinase contributes to signaling pathways controlling cancer cell transformation, invasion, and survival, but its clinicopathological impact has begun to emerge only recently. Here we report that PAK4 overexpression in hepatocellular carcinoma (HCC) conveys aggressive metastatic properties. A novel nuclear splice isoform of PAK4 lacking exon 2 sequences was isolated as part of our studies. By stably overexpressing or silencing PAK4 in HCC cells, we showed that it was critical for their migration. Mechanistic investigations in this setting revealed that PAK4 directly phosphorylated p53 at S215, which not only attenuated transcriptional transactivation activity but also inhibited p53-mediated suppression of HCC cell invasion. Taken together, our results showed how PAK4 overexpression in HCC promotes metastatic invasion by regulating p53 phosphorylation. Cancer Res; 76(19); 5732–42. ©2016 AACR.
Nestin Mediates Hedgehog Pathway Tumorigenesis
Authors: Li Peng , Lee Eric H. , Du Fang , Gordon Renata E. , Yuelling Larra W. , Liu Yongqiang , Ng Jessica M.Y. , Zhang Hao , Wu Jinhua , Korshunov Andrey , Pfister Stefan M. , Curran Tom , Yang Zeng-jie 
Published: August 2016

Abstract
The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem–like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway–driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573–83. ©2016 AACR.
A BRCA1/2 Mutational Signature and Survival in Ovarian High-Grade Serous Carcinoma
Authors: Dong Fei , Davineni Phani K. , Howitt Brooke E. , Beck Andrew H. 
Published: August 2016

Abstract
Background: Mutational signatures have been identified by the broad sequencing of cancer genomes and reflect underlying processes of mutagenesis. The clinical application of mutational signatures is not well defined. Here we aim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma.
Methods: Open access data of 15,439 somatic mutations of 310 ovarian high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) are used to construct a Bayesian model to classify each cancer as either having or lacking a BRCA1/2 mutational signature. We evaluate the association of the BRCA1/2 signature with overall survival on the TCGA dataset and on an independent cohort of 92 ovarian high-grade serous carcinomas from the Australian Ovarian Cancer Study (AOCS).
Results: Patients from TCGA with tumors harboring the BRCA1/2 mutational signature have improved survival (55.2 months vs. 38.0 months), which is independent of BRCA1/2 gene mutation status, age, stage, and grade (HR = 0.64; P = 0.02). In the AOCS dataset, the BRCA1/2 mutational signature is also associated with improved overall survival (46.3 months vs. 23.6 months) independent of age and stage (HR = 0.52; P = 0.007).
Conclusions: A BRCA1/2 mutational signature is a prognostic marker in ovarian high-grade serous carcinoma. Mutational signature analysis of ovarian cancer genomes may be useful in addition to testing for BRCA1/2 mutations.
Impact: This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian high-grade serous carcinoma. Cancer Epidemiol Biomarkers Prev; 25(11); 1511–6. ©2016 AACR.
Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages
Authors: Wang Don-Hong , Lee Hyun-Sung , Yoon David , Berry Gerald , Wheeler Thomas M. , Sugarbaker David J. , Kheradmand Farrah , Engleman Edgar , Burt Bryan M. 
Published: August 2016

Abstract
Purpose: Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors.
Experimental Design: To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs.
Results: EGFR oncogene–dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR-targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma.
Conclusions: Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778–88. ©2016 AACR.