bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study
Authors: Dackus Gwen MHE , ter Hoeve Natalie D , Opdam Mark , Vreuls Willem , Varga Zsuzsanna , Koop Esther , Willems Stefan M , Van Deurzen Carolien HM , Groen Emilie J , Cordoba Alicia , Bart Jos , Mooyaart Antien L , van den Tweel Jan G , Zolota Vicky , Wesseling Jelle , Sapino Anna , Chmielik Ewa , Ryska Ales , Amant Frederic , Broeks Annegien , Kerkhoven Ron , Stathonikos Nikolas , Veta Mitko , Voogd Adri , Jozwiak Katarzyna , Hauptmann Michael , Hoogstraat Marlous , Schmidt Marjanka K , Sonke Gabe , van der Wall Elsken , Siesling Sabine , van Diest Paul J , Linn Sabine C 
Published: November 2017

IntroductionCurrently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient’s prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged≤40 years.Methods and analysisAll young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle.Ethics and disseminationObservational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a ‘non-WMO’ declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.
MONITOR-IC study, a mixed methods prospective multicentre controlled cohort study assessing 5-year outcomes of ICU survivors and related healthcare costs: a study protocol
Authors: Geense Wytske , Zegers Marieke , Vermeulen Hester , van den Boogaard Mark , van der Hoeven Johannes 
Published: November 2017

IntroductionDue to advances in critical care medicine, more patients survive their critical illness. However, intensive care unit (ICU) survivors often experience long-term physical, cognitive and mental problems, summarised as post-intensive care syndrome (PICS), impacting their health-related quality of life (HRQoL). In what frequency PICS occurs, and to what extent this influences ICU survivors’ HRQoL, is mostly unknown. The aims of this study are therefore to study the: (1) 5-year patient outcomes, (2) predictors for PICS, (3) ratio between HRQoL of ICU survivors and healthcare-related costs, and (4) care and support needs.MethodsThe MONITOR-IC study is a multicentre prospective controlled cohort study, carried out in ICUs in four Dutch hospitals. Patients will be included between July 2016 and July 2021 and followed for 5 years. We estimated to include 12000 ICU patients. Outcomes are the HRQoL, physical, cognitive and mental symptoms, ICU survivors’ care and support needs, healthcare use and related costs. A control cohort of otherwise seriously ill patients will be assembled to compare long-term patient-reported outcomes. We will use a mixed methods design, including questionnaires, medical data from patient records, cost data from health insurance companies and interviews with patients and family members.Ethics and disseminationInsights from this study will be used to inform ICU patients and their family members about long-term consequences of ICU care, and to develop prediction and screening instruments to detect patients at risk for PICS. Subsequently, tailored interventions can be developed and implemented to prevent and mitigate long-term consequences. Additionally, insights into the ratio between HRQoL of ICU patients and related healthcare costs during 5 years after ICU admission can be used to discuss the added value of ICU care from a community perspective. The study has been approved by the research ethics committee of the Radboud University Medical Center (2016-2724).Clinical trial registrationNCT03246334
Impact of improved insulation and heating on mortality risk of older cohort members with prior cardiovascular or respiratory hospitalisations
Authors: Preval Nicholas , Keall Michael , Telfar-Barnard Lucy , Grimes Arthur , Howden-Chapman Philippa 
Published: November 2017

ObjectivesWe carried out an evaluation of a large-scale New Zealand retrofit programme using administrative data that provided the statistical power to assess the effect of insulation and/or heating retrofits on cardiovascular and respiratory-related mortality in people aged 65 and over with prior respiratory or circulatory hospitalisations.DesignQuasi-experimental cohort study based on administrative data.SettingNew Zealand.ParticipantsFrom a larger study cohort of over 900 000 people, we selected two subcohorts: 3287 people who were aged 65 and over and had experienced pretreatment period cardiovascular-related hospitalisation (ICD-10 chapter 9), and 1561 people aged 65 and over who had experienced pretreatment respiratory-related hospitalisation (ICD-10 chapter 10).InterventionsTreatment group individuals lived in a home that received insulation and/or heating retrofits under the Warm Up New Zealand: Heat Smart programme. Control group individuals lived in a home that was matched to a treatment home based on physical characteristics and location.Primary and secondary outcome measuresHR for all-cause mortality for treatment with insulation, heating, or insulation and heating relative to control group.ResultsPeople with pretreatment circulatory hospitalisation who occupied a household that received only insulation had an HR for all-cause mortality of 0.673 (95% CI 0.535 to 0.847) (p<0.001) relative to control group members. Individuals with a pretreatment respiratory hospitalisation who occupied a household that received only an insulation retrofit had an HR for all-cause mortality of 0.830 (95% CI 0.655 to 1.051) (p=0.122) relative to control group members. There was no evidence of an additional benefit from receiving heating.ConclusionsWe interpret the hazard rate observed for cardiovascular subcohort individuals who received insulation as evidence of a protective effect, reducing the risk of mortality for vulnerable older adults. There is suggestive evidence of a protective effect of insulation for the respiratory subcohort.
Healthcare providers’ gestational weight gain counselling practises and the influence of knowledge and attitudes: a cross-sectional mixed methods study
Authors: Morris Jill , Nikolopoulos Hara , Berry Tanya , Jain Venu , Vallis Michael , Piccinini-Vallis Helena , Bell Rhonda C 
Published: November 2017

ObjectiveTo understand current gestational weight gain (GWG) counselling practices of healthcare providers, and the relationships between practices, knowledge and attitudes.DesignConcurrent mixed methods with data integration: cross-sectional survey and semistructured interviews.ParticipantsPrenatal healthcare providers in Canada: general practitioners, obstetricians, midwives, nurse practitioners and registered nurses in primary care settings.ResultsTypically, GWG information was provided early in pregnancy, but not discussed again unless there was a concern. Few routinely provided women with individualised GWG advice (21%), rate of GWG (16%) or discussed the risks of inappropriate GWG to mother and baby (20% and 19%). More routinely discussed physical activity (46%) and food requirements (28%); midwives did these two activities more frequently than all other disciplines (P<0.001). Midwives interviewed noted a focus on overall wellness instead of weight, and had longer appointment times which allowed them to provide more in-depth counselling. Regression results identified that the higher priority level that healthcare providers place on GWG, the more likely they were to report providing GWG advice and discussing risks of GWG outside recommendations (β=0.71, P<0.001) and discussing physical activity and food requirements (β=0.341, P<0.001). Interview data linked the priority level of GWG to length of appointments, financial compensation methods for healthcare providers and the midwifery versus medical model of care.ConclusionsInterventions for healthcare providers to enhance GWG counselling practices should consider the range of factors that influence the priority level healthcare providers place on GWG counselling.
What Happens After Menopause? (WHAM): protocol for a prospective, multicentre, age-matched cohort trial of risk-reducing bilateral salpingo-oophorectomy in high-risk premenopausal women
Authors: Hickey Martha , Trainer Alison , Braat Sabine , Davey Mary-Ann , Krejany Efrosinia , Wark John 
Published: November 2017

IntroductionWomen at high inherited risk of ovarian cancer are advised to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) at age 40–45 years or when their families are complete. Most women are premenopausal at this age, so RRBSO will induce surgical menopause. Despite the clear benefits of RRBSO for cancer risk reduction, much less is known about the impact on non-cancer outcomes that contribute to health and well-being and inform surveillance and management strategies.Methods and analysisThis will be a multicentre, prospective cohort study of 105 premenopausal high-risk women undergoing RRBSO and an age-matched comparison group of 105 premenopausal women not planning oophorectomy or pregnancy in the next 2 years. The aim of this study is to measure the impact of RRBSO on sexual function (primary outcome) at 24 months in high-risk premenopausal women compared with the comparison group. Secondary outcomes include menopausal symptoms and menopause-related quality of life, mood, sleep quality, markers of cardiovascular disease and pre-diabetes, bone density and markers of bone turnover, and the impact of hormone replacement therapy use on these outcomes. Data analysis methods will include logistic and linear regression using general estimating equations accounting for the repeated outcome measurements within each participant.Ethics and disseminationThe study has been approved by institutional ethics committees at each participating centre. Findings will be disseminated through peer-reviewed publications and conference presentations, and national and international networks of centres managing high-risk women, and will inform national and international clinical guidelines.Trial registration numberThe pre-results protocol for this trial is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; registration no: ACTRN12615000082505).
Challenges in delivering computed tomography coronary angiography as the first-line test for stable chest pain
Authors: Dreisbach John G , Nicol Edward D , Roobottom Carl A , Padley Simon , Roditi Giles 
Published: November 2017

ObjectiveThe National Institute for Health and Care Excellence (NICE) clinical guidelines ‘chest pain of recent onset: assessment and diagnosis’ (update 2016) state CT coronary angiography (CTCA) should be offered as the first-line investigation for patients with stable chest pain. However, the current provision in the UK is unknown. We aimed to evaluate this and estimate the requirements for full implementation of the guidelines including geographical variation. Ancillary aims included surveying the number of CTCA-capable scanners and accredited practitioners in the UK.MethodsThe number of CTCA scans performed annually was surveyed across the National Health Service (NHS). The number of percutaneous coronary interventions performed for stable angina in the NHS in 2015 was applied to a model based on SCOT-HEART (CTCA in patients with suspected angina due to coronary heart disease: an open-label, parallel-group, multicentre trial) data to estimate the requirement for CTCA, for full guideline implementation. Details of CTCA-capable scanners were obtained from manufacturers and formally accredited practitioner details from professional societies.ResultsAn estimated 42 340 CTCAs are currently performed annually in the UK. We estimate that 350 000 would be required to fully implement the guidelines. 304 CTCA-capable scanners and 198 accredited practitioners were identified. A marked geographical variation between health regions was observed.ConclusionsThis study provides insight into the scale of increase in the provision of CTCA required to fully implement the updated NICE guidelines. A small specialist workforce and limited number of CTCA-capable scanners may present challenges to service expansion.
Rapid diagnosis of pulmonary tuberculosis and detection of drug resistance by combined simultaneous amplification testing and reverse dot blot
Authors: Chen Yiwen , Zhang Lahong , Hong Liquan , Luo Xian , Chen Juping , Tang Leiming , Chen Jiahuan , Liu Xia , Chen Zhaojun 
Published: November 2017

AimsMaking a correct and rapid diagnosis is essential for managing pulmonary tuberculosis (PTB), particularly multidrug-resistant tuberculosis. We aimed to evaluate the efficacy of the combination of simultaneous amplification testing (SAT) and reverse dot blot (RDB) for the rapid detection ofMycobacterium tuberculosis(MTB) and drug-resistant mutants in respiratory samples.Methods225 suspected PTB and 32 non-TB pulmonary disease samples were collected. All sputum samples were sent for acid-fast bacilli smear, SAT, culture and drug susceptibility testing (DST) by the BACTECTMMGITTM960 system. 53 PTB samples were tested by both RDB and DNA sequencing to identify drug resistance genes and mutated sites.ResultsThe SAT positive rate (64.9%) was higher than the culture positive rate (55.1%), with a coincidence rate of 83.7%. The sensitivity and specificity of SAT for diagnosing PTB were 66.7% and 100%, respectively, while those for culture were 53.9% and 84.2%, respectively. RDB has high sensitivity and specificity in identifying drug resistance genes and mutated sites. The results of RDB correlated well with those of DST and DNA sequencing, with coincidence rates of 92.5% and 98.1%, respectively.ConclusionsThe combination of SAT and RDB is promising for rapidly detecting PTB and monitoring drug resistance in clinical laboratories.
A tale of two velocities: Threading versus slicing
Authors: Gharechahi Razieh , Nouri-Zonoz Mohammad , Tavanfar Alireza 
Published: November 2017

One of the important quantities in cosmology and astrophysics is the 3-velocity of an object. Specifically, when the gravitational fields are strong, one should require the employment of general relativity both in its definition and measurement. Looking into the literature for GR-based definitions of 3-velocity, one usually finds different ad hoc definitions applied according to the case under consideration. Here, we introduce and analyze systematically the two principal definitions of 3-velocity assigned to a test particle following the timelike trajectories in stationary spacetimes. These definitions are based on the [Formula: see text] (threading) and [Formula: see text] (slicing) spacetime decomposition formalisms and defined relative to two different sets of observers. After showing that Synge’s definition of spatial distance and 3-velocity is equivalent to those defined in the [Formula: see text] (threading) formalism, we exemplify the differences between these two definitions by calculating them for particles in circular orbits in axially symmetric stationary spacetimes. Illustrating its geometric nature, the relative linear velocity between the corresponding observers is obtained in terms of the spacetime metric components. Circular particle orbits in the Kerr spacetime, as the prototype and the most well known of stationary spacetimes, are examined with respect to these definitions to highlight their observer-dependent nature. We also examine the Kerr-NUT spacetime in which the NUT parameter, contributing to the off-diagonal terms in the metric, is mainly interpreted not as a rotation parameter but as a gravitomagnetic monopole charge. Finally, in a specific astrophysical setup which includes rotating black holes, it is shown how the local velocity of an orbiting star could be related to its spectral line shifts measured by distant observers.
Energy-Efficient Compilation of Irregular Task-Parallel Loops
Authors: Shrivastava Rahul , Nandivada V. Krishna 
Published: November 2017

Energy-efficient compilation is an important problem for multi-core systems. In this context, irregular programs with task-parallel loops present interesting challenges: the threads with lesser work-loads (
non-critical
-threads) wait at the join-points for the thread with maximum work-load (
critical
-thread); this leads to significant energy wastage. This problem becomes more interesting in the context of multi-socket-multi-core (MSMC) systems, where different sockets may run at different frequencies, but all the cores connected to a socket run at a single frequency. In such a configuration, even though the load-imbalance among the cores may be significant, an MSMC-oblivious technique may miss the opportunities to reduce energy consumption, if the load-imbalance across the sockets is minimal. This problem becomes further challenging in the presence of mutual-exclusion, where scaling the frequencies of a socket executing the non-critical-threads can impact the execution time of the critical-threads. In this article, we propose a scheme (X10Ergy) to obtain energy gains with minimal impact on the execution time, for task-parallel languages, such as X10, HJ, and so on. X10Ergy takes as input a loop-chunked program (parallel-loop iterations divided into chunks and each chunk is executed by a unique thread). X10Ergy follows a mixed compile-time + runtime approach that (i) uses static analysis to efficiently compute the work-load of each chunk at runtime, (ii) computes the “remaining” work-load of the chunks running on the cores of each socket at regular intervals and tunes the frequency of the sockets accordingly, (iii) groups the threads into different sockets (based on the remaining work-load of their respective chunks), and (iv) in the presence of atomic-blocks, models the effect of frequency-scaling on the critical-thread. We implemented X10Ergy for X10 and have obtained encouraging results for the IMSuite kernels.
Phase I Study of Chimeric Antigen Receptor–Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers
Authors: Guo Yelei , Feng Kaichao , Liu Yang , Wu Zhiqiang , Dai Hanren , Yang Qingming , Wang Yao , Jia Hejin , Han Weidong 
Published: November 2017

Abstract
Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor–engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC).
Experimental Design: Patients with EGFR-positive (&gt;50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100–250 mg/m2) and cyclophosphamide (15–35 mg/kg).
Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 × 106/kg; range, 0.8–4.1 × 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5–22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome.
Conclusions: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277–86. ©2017 AACR.
See related commentary by Kalos, p. 1246
Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2
Authors: Chen Qun , Cai Jinquan , Wang Qixue , Wang Yunfei , Liu Mingyang , Yang Jingxuan , Zhou Junhu , Kang Chunsheng , Li Min , Jiang Chuanlu 
Published: November 2017

Abstract
Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but their mechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found that NEAT1 was a potential oncogene. We systematically analyzed the clinical significance and mechanism of NEAT1 in glioblastoma.
Experimental Design: Initially, we evaluated whether NEAT1 expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect of NEAT1 on the WNT/β-catenin pathway and its target binding gene. The animal model supported the experimental findings.
Results: We found that NEAT1 levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFκB (p65) downstream of the EGFR pathway. Moreover, we found that NEAT1 was critical for glioma cell growth and invasion by increasing β-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found that NEAT1 could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters. NEAT1 depletion also inhibited GBM cell growth and invasion in the intracranial animal model.
Conclusions: The EGFR/NEAT1/EZH2/β-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma. Clin Cancer Res; 24(3); 684–95. ©2017 AACR.