bluuebunny/crossref_metadata_2025_split huggingface dataset:
04 Paramedic perspectives towards gp referral schemes in north west england: a qualitative-observational study
Authors: Blodgett Joanna , Robertson Duncan , Ratcliffe David , Rockwood Kenneth 
Published: September 2017

BackgroundAn innovative policy developed and implemented by a UK Ambulance Service allows paramedics to refer patients to the GP Acute Visiting Service scheme. Initial evidence suggests that using this alternate route of care can decrease hospital admission rates, increase bed availability, decrease wait time in A and Es and provide substantial savings for the NHS. However, there are many unrecognised barriers to referral that have not been captured by the quantitative analysis. The goal of this qualitative-observational study was to gain insight into the GP referral scheme from a paramedic’s perspective.MethodsWe observed eight paramedics throughout full shifts of 8–12 hours. Data was collected using participant demographics, researcher observations and informal semi-structured interviews. All notes were transcribed, coded and analysed using a Grounded Theory approach to identify emerging themes.ResultsParamedics expressed a wide range of frustrations with the scheme, identifying the waiting time, the process and a lack of confidence, experience and training as the three major barriers to referrals. They described how they approached patients with the GP referral scheme in mind, identified common characteristics of referrals, described how the triage tool shaped their decision making and shared how they involved the patient in the decision making. They shared too their frustrations with some GP decision making, which they admitted then influenced their future decision making. Finally, they described what motivated them to refer and discussed the lack of awareness and understanding of the scheme’s impact and aims.ConclusionsThis study provided valuable insight into the paramedic’s perspective of the GP referral scheme. Maximising understanding of the scheme, investigating the GP’s perspective in decision making and ensuring knowledge and accountability of paramedics, GPs and the public were identified as solutions to strengthen and increase referral rates and scheme success.
05 Exploring why ‘primary care’ problems end up receiving ambulance treatment: early findings from a pre-hospital ethnographic study
Authors: Brooker Mathew , Barnes Rebecca , Heawood Alison , Purdy Sarah 
Published: September 2017

BackgroundAn increasing part of the Ambulance Service workload can more accurately be described as ‘urgent care’ cases, many of which could potentially be managed by timely contact with Primary Care. Previous work by this team and others has sought to define what constitutes a ‘primary care sensitive’ contact with Ambulance Services. The complex reasons driving the increase in such contacts remain unclear.MethodsThis study is utilising complementary qualitative methods to explore exemplar ‘primary care sensitive’ cases, identified by a GP accompanying front-line ambulance crews to calls across a range of shifts in a typical NHS Ambulance Trust. The study is on track to complete 160 hours of observation and recruit 50 cases. Detailed ethnographic field notes and reflexive diaries supplement semi-structured interviews with patients, carers and ‘in-the-moment’ purposful conversations with ambulance staff. Analysis of call recordings associated with each case, Document Analysis of Primary Care records and interviews with patients’ GPs provide additional triangulation.ResultsData collection and analysis are ongoing, but initial findings indicate that the process of seeking help on behalf of someone else can change the way uncertainty is handled and projected. There appears to be an emerging typology of ‘triggers’ that prompt contact with ambulance services for Primary Care problems. Some aspects of ambulance care are highly valued by patients and carers. These valued aspects may offset the practical limitations that the ambulance service faces in fully resolving the clinial situation. Both ambulance clinicians and Primary Care clinicians use similar strategies to manage expectations.ConclusionsWe discuss possible implications for both Primary Care and Ambulance providers in the ways patients and their carers can be supported to access services. As urgent care is increasingly being delivered in a range of settings, patients may be viewing their ‘route in’ to acute services as less important than the eventual outcome.
OP06 Multi-method development of new ambulance service quality and performance measures
Authors: Coster Joanne , Siriwardena A Niroshan , Turner Janette , Jacques Richard , Crum Annabel , Nicholl Jon 
Published: September 2017

BackgroundThe scope to measure the quality and performance of ambulance service care is limited by poor access to follow up patient information and lack of consensus about what to measure. The Prehospital Outcomes for Evidence Based Evaluation (PhOEBE) research programme aims to address these research gaps by identifying potentially important prehospital quality measures and testing these using a prehospital/linked subsequent health service dataset.MethodsWe undertook systematic reviews of published and aspirational measures, together with interviews with ambulance service users to identify potential measures. Measures identified from reviews and interviews were prioritised using a multi-stakeholder consensus conference. Measures identified as high priority were further refined and ranked through an expert Delphi method and a service user/patient public involvement workshop. High ranking measures were further assessed against criteria for good outcome measures, including feasibility, importance and relevance, to create a shortlist of measures.ResultsEight high-ranking measures were shortlisted following assessment against criteria for good outcome measures. These were:Mean reduction in pain scoreProportion of serious emergency conditions correctly identifiedAverage response time (mean/median)Proportion of non-conveyance decisions which resulted in admission or death within 3 days (hear and treat and see and treat)Proportion of patients with a low risk of death, who subsequently die within 3 days of an ambulance contactProportion of ambulance patients with a serious emergency condition who survive to admission, and to 7 days post-admissionProportion of unnecessary transports to EDProportion of cases with a specific condition treated in accordance with established protocols and guidelines, e.g. stroke, diabetes, fallsConclusionThese measures can be used to assess the impact of care provided by the ambulance service and to support quality improvement through monitoring, audit and service evaluation. Some measures are based on ambulance service data only whereas others require additional linked hospital data.
Risks of smoking and benefits of smoking cessation on hospitalisations for cardiovascular events and respiratory infection in patients with rheumatoid arthritis: a retrospective cohort study using the Clinical Practice Research Datalink
Authors: Joseph Rebecca M , Movahedi Mohammad , Dixon William G , Symmons Deborah PM 
Published: September 2017

ObjectivesTo investigate the associations between smoking status, smoking cessation and hospitalisations for cardiovascular events (CVE) and respiratory tract infections (RTI) in an inception cohort of patients with rheumatoid arthritis (RA).MethodsThe study was set within UK primary care electronic health records (the Clinical Practice Research Datalink) linked to hospital inpatient data (Hospital Episode Statistics). Patients with RA were followed from diagnosis to hospitalisation with a record of CVE or RTI, leaving their general practice, death, or 10 January 2012, whichever was earliest. Smoking status (never, current, former) was defined using primary care data and could vary over time. Survival analysis was performed using Cox regression (first event) and conditional risk set models (multiple RTIs).Results5677 patients were included in the cohort: 68% female, median age 61 years. The age-adjusted and sex-adjusted risks of hospitalisation for CVE or RTI were more than twice as high in current vs never smokers (CVE HR (95% CI) 2.19 (1.44 to 3.31); RTI 2.18 (1.71 to 2.78)). The risks for both outcomes were significantly higher in current compared with former smokers (CVE 1.51 (1.04 to 2.19), RTI 1.29 (1.04 to 1.61)). For each additional year of smoking cessation, the risk of first CVE and RTI hospitalisation fell significantly, approximately 25% and 15% respectively in the adjusted models.ConclusionsPatients with RA who smoke have an increased risk of hospitalisation with CVE or RTI compared with never and former smokers. The risk decreases for each additional year of smoking cessation. Patients with RA who smoke should be advised to stop smoking.
High variability impairs motor learning regardless of whether it affects task performance
Authors: Cardis Marco , Casadio Maura , Ranganathan Rajiv 
Published: September 2017

Motor variability plays an important role in motor learning, although the exact mechanisms of how variability affects learning are not well understood. Recent evidence suggests that motor variability may have different effects on learning in redundant tasks, depending on whether it is present in the task space (where it affects task performance) or in the null space (where it has no effect on task performance). We examined the effect of directly introducing null and task space variability using a manipulandum during the learning of a motor task. Participants learned a bimanual shuffleboard task for 2 days, where their goal was to slide a virtual puck as close as possible toward a target. Critically, the distance traveled by the puck was determined by the sum of the left- and right-hand velocities, which meant that there was redundancy in the task. Participants were divided into five groups, based on both the dimension in which the variability was introduced and the amount of variability that was introduced during training. Results showed that although all groups were able to reduce error with practice, learning was affected more by the amount of variability introduced rather than the dimension in which variability was introduced. Specifically, groups with higher movement variability during practice showed larger errors at the end of practice compared with groups that had low variability during learning. These results suggest that although introducing variability can increase exploration of new solutions, this may adversely affect the ability to retain the learned solution.NEW & NOTEWORTHY We examined the role of introducing variability during motor learning in a redundant task. The presence of redundancy allows variability to be introduced in different dimensions: the task space (where it affects task performance) or the null space (where it does not affect task performance). We found that introducing variability affected learning adversely, but the amount of variability was more critical than the dimension in which variability was introduced.
Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers
Authors: Yau Edwin H. , Kummetha Indrasena Reddy , Lichinchi Gianluigi , Tang Rachel , Zhang Yunlin , Rana Tariq M. 
Published: September 2017

Abstract
Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS (KRASMUT) colorectal cancers. Using pooled lentiviral single-guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human colorectal cancer cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory in vivo. In addition, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors. Cancer Res; 77(22); 6330–9. ©2017 AACR.
Mutational Analysis of Gene Fusions Predicts Novel MHC Class I–Restricted T-Cell Epitopes and Immune Signatures in a Subset of Prostate Cancer
Authors: Kalina Jennifer L. , Neilson David S. , Lin Yen-Yi , Hamilton Phineas T. , Comber Alexandra P. , Loy Emma M.H. , Sahinalp S. Cenk , Collins Colin C. , Hach Faraz , Lum Julian J. 
Published: September 2017

AbstractPurpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQ) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients.Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T-cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico–predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events.Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I–binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration.Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune cell infiltration within a subgroup of prostate cancer patients. Clin Cancer Res; 23(24); 7596–607. ©2017 AACR.
A Phase I, Dose Escalation Study of Oral ASP8273 in Patients with Non–small Cell Lung Cancers with Epidermal Growth Factor Receptor Mutations
Authors: Yu Helena A. , Spira Alexander , Horn Leora , Weiss Jared , West Howard , Giaccone Giuseppe , Evans Tracey , Kelly Ronan J. , Desai Bhardwaj , Krivoshik Andrew , Moran Diarmuid , Poondru Srinivasu , Jie Fei , Aoyama Kouji , Keating Anne , Oxnard Geoffrey R. 
Published: September 2017

Abstract
Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M.
Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25–500 mg) were administered once daily to non–small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint.
Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response–expansion (n = 36), RP2D (300 mg; n = 19) and food–effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%–44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5–10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.
Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467–73. ©2017 AACR.
Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma
Authors: Narayan Ravi S. , Gasol Ana , Slangen Paul L.G. , Cornelissen Fleur M.G. , Lagerweij Tonny , Veldman Hou Y.Y.E. , Dik Rogier , van den Berg Jaap , Slotman Ben J. , Würdinger Tom , Haas-Kogan Daphne A. , Stalpers Lukas J.A. , Baumert Brigitta G. , Westerman Bart A. , Theys Jan , Sminia Peter 
Published: September 2017

Abstract
Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. In vivo data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients. Mol Cancer Ther; 17(2); 347–54. ©2017 AACR.
See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
O Movimento Sanitarista no Brasil: a visão da doença como mal nacional e a saúde como redentora
Authors: Omena Tamano Luana Tieko 
Published: September 2017

Pretende-se, com este artigo, refletir acerca do movimento sanitarista no Brasil no decênio de 1910, por meio de uma análise histórica. Busca-se entender como a ideia de doença foi apresentada, pelos médicos sanitaristas, como um problema central que explicava o "atraso" nacional, o que, por sua vez, realocou a categoria de raça no discurso sobre o futuro do país. Almeja-se, ainda, compreender o que esse movimento significou para a saúde pública nacional, tencionando também demonstrar como os preceitos sanitários foram considerados de grande importância pela elite intelectual e política, resultando em sua propaganda e aplicação.
Gestational Age and Cardiorespiratory Fitness in Individuals Born At Term: A Life Course Study
Authors: Ferreira Isabel , Gbatu Pei T. , Boreham Colin A. 
Published: September 2017

Background

In contrast to the effects of preterm birth, the extent to which shorter gestational age affects the cardiorespiratory fitness (
CRF
) levels of individuals who were born at term (ie, between 37 and 42 weeks) is largely unknown. The aim of this study was to examine whether life‐course
CRF
levels varied across different gestational ages within the at‐term range.

Methods and Results

The association between gestational age (in weeks) obtained from Child Health Services records and
CRF
, estimated from field and laboratory tests and expressed by maximal oxygen uptake level through adolescence to young adulthood, was examined in 791 participants in the Northern Ireland Young Hearts Study, all singletons born at term. Longitudinal data were analyzed with generalized estimating equations, accounting for important potential confounders. Mean levels of
CRF
were 45.6, 43.7, and 33.0 mL/kg per minute when participants were aged 12, 15, and 22 years, respectively. After adjustment for confounders, each week increase in gestational age was associated with 0.46 mL/kg per minute (95%
confidence interval
, 0.14–0.79) in
CRF
. Compared with individuals born full term (39–40 weeks, n=533) or late term (41–42 weeks, n=148), those who were born early term (37–38 weeks, n=110) had a higher incidence of poor
CRF
(risk ratio, 1.57; 95%
confidence interval
, 1.14–2.16). The changes in
CRF
through adolescence to young adulthood were similar across groups, with those born early term consistently displaying the lowest CRF.

Conclusions

These findings suggest that early‐term births within the at‐term range are linked to poorer
CRF
through adolescence to young adulthood, and may have important clinical and public health implications for policies about (avoidable) early‐term deliveries given their recent increasing trends.
Pancreatic β-Cell Function and Prognosis of Nondiabetic Patients With Ischemic Stroke
Authors: Pan Yuesong , Chen Weiqi , Jing Jing , Zheng Huaguang , Jia Qian , Li Hao , Zhao Xingquan , Liu Liping , Wang Yongjun , He Yan , Wang Yilong 
Published: September 2017

Background and Purpose—
Pancreatic β-cell dysfunction is an important factor in the development of type 2 diabetes mellitus. This study aimed to estimate the association between β-cell dysfunction and prognosis of nondiabetic patients with ischemic stroke.

Methods—
Patients with ischemic stroke without a history of diabetes mellitus in the ACROSS-China (Abnormal Glucose Regulation in Patients with Acute Stroke across China) registry were included. Disposition index was estimated as computer-based model of homeostatic model assessment 2-β%/homeostatic model assessment 2-insulin resistance based on fasting C-peptide level. Outcomes included stroke recurrence, all-cause death, and dependency (modified Rankin Scale, 3–5) at 12 months after onset.

Results—
Among 1171 patients, 37.2% were women with a mean age of 62.4 years. At 12 months, 167 (14.8%) patients had recurrent stroke, 110 (9.4%) died, and 184 (16.0%) had a dependency. The first quartile of the disposition index was associated with an increased risk of stroke recurrence (adjusted hazard ratio, 3.57; 95% confidence interval, 2.13–5.99) and dependency (adjusted hazard ratio, 2.30; 95% confidence interval, 1.21–4.38); both the first and second quartiles of the disposition index were associated with an increased risk of death (adjusted hazard ratio, 5.09; 95% confidence interval, 2.51–10.33; adjusted hazard ratio, 2.42; 95% confidence interval, 1.17–5.03) compared with the fourth quartile. Using a multivariable regression model with restricted cubic spline, we observed an L-shaped association between the disposition index and the risk of each end point.

Conclusions—
In this large-scale registry, β-cell dysfunction was associated with an increased risk of 12-month poor prognosis in nondiabetic patients with ischemic stroke.