bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empowering the health of retired professional footballers: the systematic development of an After Career Consultation and its feasibility
Authors: Gouttebarge Vincent , Goedhart Edwin , Kerkhoffs Gino 
Published: December 2018

ObjectivesThis article describes (1) the systematic development of the intervention and (2) the assessment of its feasibility (in terms of relevancy, suitability, satisfaction and added value).MethodsThe intervention was developed based on the first four steps of the Intervention Mapping and Knowledge Transfer Scheme processes. Subsequently, a qualitative research based on a one-group post-test cross-sectional design was conducted. Eight retired professional footballers underwent the developed intervention and its feasibility (operationalised in relevancy, suitability, satisfaction and added value) was assessed by means of a questionnaire and interview.ResultsAn After Career Consultation (ACC) was developed with a focus on five main domains: (1) detraining from professional football; (2) remission of osteoarthritis; (3) promotion of healthy lifestyle; (4) preventing mental and cognitive health problems; and (5) employment and education. The ACC relies on three components: (1) raising self-awareness about potential physical, mental and social health problems after a career in professional football; (2) medical examination (60 min) with thorough medical history and general physical examination; and (3) follow-up during 3 months (if necessary) about optimal skills and strategies to empower physical, mental and social health and quality of life. The relevancy, suitability, satisfaction and added value of the ACC were positively evaluated by the retired professional footballers.ConclusionThe ACC was developed with a focus on five main health-related domains. The feasibility of the ACC was positively assessed by retired professional footballers, while the suggestion was made to repeat the ACC in the initial years after football retirement.
Stochastic modelling of flow sequences for improved prediction of fluvial flood hazards
Authors: Patidar Sandhya , Allen Deonie , Haynes Rick , Haynes Heather 
Published: December 2018

Abstract
The availability of historical streamflow data of the desired length is often limited and, in these situations, the ability to synthetically generate statistically significant datasets becomes important. We previously developed a highly efficient stochastic modelling approach for the synthetic generation of daily streamflow sequences using the systematic combination of a hidden Markov model with the generalized Pareto distribution (the HMM-GP model). Daily streamflow sequences provide limited information on various significant small duration flooding events exceeding the peak over threshold values, but these are averaged out in the daily datasets. These small duration intense flooding events are often capable of causing significant damage and are important in conducting thorough flood risk management and flood risk assessment studies. This paper presents upgrades to our HMM-GP stochastic modelling approach and examines its efficiency in simulating streamflow at a temporal resolution of 15 minutes. The potential of the HMM-GP model in simulating a synthetic 15-minute streamflow series is investigated by comparing various statistical characteristics (e.g. percentiles, the probability density distribution and the autocorrelation function) of the observed streamflow records with 100 synthetically simulated streamflow time series. The proposed modelling schematics are robustly validated across case studies in four UK rivers (the Don, Nith, Dee and Tweed).
Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1
Authors: Yang Feng , Fang Erhu , Mei Hong , Chen Yajun , Li Huanhuan , Li Dan , Song Huajie , Wang Jianqun , Hong Mei , Xiao Wenjing , Wang Xiaojing , Huang Kai , Zheng Liduan , Tong Qiangsong 
Published: December 2018

Abstract

Circular RNAs (circRNA), a subclass of noncoding RNA characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. However, the functions and underlying mechanisms of circRNA in regulating Wnt/β-catenin signaling and cancer progression remain elusive. Here, we screen cis-acting circRNA generated by β-catenin (CTNNB1)/transcription factor 7–like 2 genes and identify one intronic circRNA derived from CTNNB1 (circ-CTNNB1) as a novel driver of cancer progression. Circ-CTNNB1 was predominantly expressed in the nucleus, upregulated in cancer tissues and cell lines, and associated with unfavorable outcomes in patients with cancer. Circ-CTNNB1 promoted β-catenin activation, growth, invasion, and metastasis in cancer cells. Circ-CTNNB1 bound DEAD-box polypeptide 3 (DDX3) to facilitate its physical interaction with transcription factor Yin Yang 1 (YY1), resulting in the transactivation of YY1 and transcriptional alteration of downstream genes associated with β-catenin activation and cancer progression. Preclinically, administration of lentivirus-mediated short hairpin RNA targeting circ-CTNNB1 or a cell-penetrating inhibitory peptide blocking the circ-CTNNB1–DDX3 interaction inhibited downstream gene expression, tumorigenesis, and aggressiveness in cancer cells. Taken together, these results demonstrate cis-acting circ-CTNNB1 as a mediator of β-catenin signaling and cancer progression through DDX3-mediated transactivation of YY1.

Significance:
These findings reveal the oncogenic functions of a cis-acting circular RNA in β-catenin activation and cancer progression, with potential value as a therapeutic target for human cancers.
Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia
Authors: Takam Kamga Paul , Dal Collo Giada , Midolo Martina , Adamo Annalisa , Delfino Pietro , Mercuri Angela , Cesaro Simone , Mimiola Elda , Bonifacio Massimiliano , Andreini Angelo , Chilosi Marco , Krampera Mauro 
Published: December 2018

Abstract
Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in B-ALL chemosensitivity. We observed significant Notch receptor and ligand expression in B-ALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of B-ALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-κB, and ERK expression. In NOG-mouse-based xenograft models of B-ALL, co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with B-ALL.
Significance: Inhibition of Notch signaling enhances the chemosensitivity of B-ALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with B-ALL.
Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer
Authors: Blagden Sarah P. , Hamilton Anne L. , Mileshkin Linda , Wong Shirley , Michael Agnieszka , Hall Marcia , Goh Jeffrey C. , Lisyanskaya Alla S. , DeSilvio Michelle , Frangou Eleni , Stronach Euan A. , Gopalakrishna Prashanth , Meniawy Tarek M. , Gabra Hani 
Published: December 2018

Abstract

Purpose:
Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC).

Patients and Methods:
Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50–150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II).

Results:
Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9–52.4] by RECIST 1.1 and 52% (95% CI, 31.3–72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3–9.0 months).

Conclusions:
Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.
Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function
Authors: Bieber Michael , Schuhmann Michael K. , Volz Julia , Kumar Gangasani Jagadeesh , Vaidya Jayathirtha Rao , Nieswandt Bernhard , Pham Mirko , Stoll Guido , Kleinschnitz Christoph , Kraft Peter 
Published: December 2018

Background and Purpose—
Acetylsalicylic acid and clopidogrel are the 2 main antithrombotic drugs for secondary prevention in patients with ischemic stroke (IS) without indication for anticoagulation. Because of their limited efficacy and potential side effects, novel antiplatelet agents are urgently needed. Cilostazol, a specific phosphodiesterase (PDE)-3 inhibitor, protected from IS in clinical studies comprising mainly Asian populations. Nevertheless, the detailed mechanistic role of PDE-3 inhibitors in IS pathophysiology is hardly understood. In this project, we analyzed the efficacy and pathophysiologic mechanisms of a novel and only recently described PDE-3 inhibitor (substance V) in a mouse model of focal cerebral ischemia.

Methods—
Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in 6- to 8-week-old male C57Bl/6 wild-type mice receiving substance V or vehicle 1 hour after ischemia induction. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, as well as the extent of local inflammatory response and cell death, was determined.

Results—
Inhibition of PDE-3 by pharmacological blockade with substance V significantly reduced infarct volumes and improved neurological outcome on day 1 and 7 after experimental cerebral ischemia. Reduced blood-brain barrier damage, attenuated brain tissue inflammation, and decreased local cell death could be identified as potential mechanisms. PDE-3 inhibitor treatment did neither increase the number of intracerebral hemorrhages nor affect platelet function.

Conclusions—
The novel PDE-3 inhibitor substance V protected mice from IS independent from platelet function. Pharmaceutical inactivation of PDE-3 might become a promising therapeutic approach to combat IS via inhibition of thromboinflammatory mechanisms and stabilization of the blood-brain barrier.
The context of litigation in evaluating physical and psychological outcomes from pain management programmes
Authors: Twiddy Hannah , Brown Richard J , Waheed Hasan 
Published: December 2018

Objectives: There has been extensive research in evaluating chronic pain in the context of litigation while considering the implications that it can have on healthcare outcomes and rehabilitation progress. The aim of this article is to present retrospective observational data about the levels of disability and distress reported by patients with ongoing litigation at the start and following a UK-based multi-disciplinary pain management programme (PMP) when compared with those without litigation. Method: Between June 2014 and September 2017, 859 patients attended and completed a 16-day PMP at a tertiary-level National Health Service (UK) pain clinic. Patients were split into two groups: (1) litigation (n = 110) and (2) non-litigation (n = 749). As a part of the assessment procedure, the patients were given a battery of psychological and physical measures to complete over two time points. Results: Patients with litigation are statistically significantly more distressed at assessment but make comparable clinically meaningful change in PMP intervention when compared with a non-litigation sample. A very small proportion of the variance in depression scores post-treatment is accounted for by the context of litigation (0.5%), which may be accounted for by employment status. There was no effect of litigation on physical outcome post-intervention. Discussion: This article concludes that it is not appropriate to merely assume that the context of litigation results in limited positive psychological and physical outcomes post-PMP. There are some limitations to the clinical sample presented in respect to the conclusions.
HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment
Authors: Rimando Joseph , Slade Michael , DiPersio John F. , Westervelt Peter , Gao Feng , Liu Chang , Romee Rizwan 
Published: December 2018

Abstract
HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet–derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell–replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.
Didactic lectures versus simulation training: a randomised pilot evaluation of its impact on surgical skill
Authors: Supramaniam Prasanna Raj , Mittal Monica , Davies Rebecca , Lim Lee Nai , Arambage Kirana 
Published: December 2018

Abstract
Background
The Bristol enquiry and national surveys have highlighted medicolegal concerns, reduction in training time available for trainees and the change from trainees performing procedures for the first time on patients. The Royal Colleges have taken an active role in advocating the use of simulation training prior to doctors undertaking operative procedures in real time. This study compares didactic lecture-based teaching to simulation training using a quantitative assessment tool.

Method
Randomised pilot study including 20 trainees within their first and second year of Obstetrics and Gynaecology training. The participants were randomised to one of two groups. Group A were taken through the 10 steps to perform a diagnostic laparoscopy with a lecture, followed by an assessment using a laparoscopic pelvic box trainer. Group B were given the same didactic lecture, followed by simulation training in a dry lab, prior to undergoing the same assessment as group A.

Findings
The study demonstrates a statistically significant improvement in the overall OSATS score for trainees undertaking a hands-on simulation training session prior to completing the diagnostic laparoscopy assessment (p = 0.023).

Conclusions
This study clearly demonstrates that exposure to simulation training is superior compared to didactic lecture-based teaching for the acquisition of surgical skills.
Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance
Authors: Hattori Sachiko 
Published: December 2018

Abstract
Background
Inflammation might be a pathological mediator of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk.

Methods
We investigated whether empagliflozin (EMPA) exerts anti-inflammatory effects that are reflected in decreased high-sensitivity C-reactive protein (hsCRP) values. Patients were allocated to receive a placebo (n = 51) or EMPA (n = 51) as an add-on treatment. Fasting blood samples were collected before and every 3 months after this intervention for 1 year.

Results
Empagliflozin tended to elicit reductions in BMI, HbA1c, aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase compared with the placebo, but the differences did not reach statistical significance. Levels of LDL-cholesterol, HDL-cholesterol, and triglycerides were unaltered, significantly increased, and decreased, respectively, by EMPA, but the differences were not statistically significant compared with the placebo. Empagliflozin for 12 months notably reduced the homeostatic model assessment of insulin resistance (HOMA-IR), remnant-like particle cholesterol (RLP-C), and hsCRP by 43%, 52% and 54%, respectively. The time courses of these reductions significantly differed from those of the placebo. Systolic and diastolic blood pressure were also significantly reduced by EMPA compared with the placebo. We applied multiple linear regression analysis to determine which factors were associated with changes in hsCRP induced by EMPA. The results revealed that alterations in hsCRP values (log [hsCRP at 12 months] minus log [hsCRP at month 0]) were significantly associated with changes in HOMA-IR, RLP-C, systolic blood pressure, HDL-C and ALT.

Conclusion
Empagliflozin decreased hs-CRP and lowered levels of remnant related lipoproteins probably via ameliorating insulin resistance. The cardiovascular benefits conferred by EMPA might be driven at least partly by anti-inflammatory effects, and this mechanism might cooperate with other EMPA-induced changes including reduced blood pressure, to achieve the degree of cardioprotection revealed by the EMPA-REG OUTCOME trial.
Trial registration UMIN Clinical Registry (UMIN000021552). Registered 21 March 2016, https://upload.umin.ac.jp/UMIN000021552
A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis
Authors: Turer Emre E. , San Miguel Miguel , Wang Kuan-wen , McAlpine William , Ou Feiya , Li Xiaohong , Tang Miao , Zang Zhao , Wang Jianhui , Hayse Braden , Evers Bret , Zhan Xiaoming , Russell Jamie , Beutler Bruce 
Published: December 2018

ABSTRACT
Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.
What does ‘routine post-op neuro obs’ really mean? Establishing a guideline
Authors: Lynch Claire , Gwynn Chloe , Holland Katie , Swift Amelia 
Published: December 2018

Background: Neurosurgery carries a risk of post-operative deterioration that can be detected using neurological observations (NO). NO are frequently requested by surgeons using the phrase ‘routine post-op neuro obs’. There is no agreed definition of what this means. Aims: To identify the range of possible interpretations of the phrase ‘routine post-op neuro obs’ by nurses and surgeons. Method: National policy analysis, literature review, notes audit and survey methods were used to identify national and local practice. Data were analysed descriptively using Excel. Findings: Two out of 15 policies contained observation guidance. Fifteen surgeons used five terms to describe post-operative observations. ‘Routine’ was used to describe observation frequency anywhere between every 15 minutes and every 4 hours. Nurses varied in their interpretation, and frequency was based on clinical judgement. Conclusion: Post-operative instructions and nursing practice vary. There is a need and desire for clear evidence-based guidelines to ensure consistency and patient safety.