bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals
Authors: Rehal Sunita , Morris Tim P , Fielding Katherine , Carpenter James R , Phillips Patrick P J 
Published: October 2016

ObjectiveTo assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines.DesignReview of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine,Archives Internal Medicine,PLOS Medicine,Annals of Internal Medicine,BMJ,JAMA,LancetandNew England Journal of Medicine).Data sourcesOvid (MEDLINE).MethodsWe searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used.ResultsA total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used.ConclusionsReporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice.
Hyaluronic Acid Binding Sperm Selection for assisted reproduction treatment (HABSelect): study protocol for a multicentre randomised controlled trial
Authors: Witt K D , Beresford L , Bhattacharya S , Brian K , Coomarasamy A , Hooper R , Kirkman-Brown J , Khalaf Y , Lewis S E , Pacey A , Pavitt S , West R , Miller D 
Published: October 2016

IntroductionThe selection of a sperm with good genomic integrity is an important consideration for improving intracytoplasmic sperm injection (ICSI) outcome. Current convention selects sperm by vigour and morphology, but preliminary evidence suggests selection based on hyaluronic acid binding may be beneficial. The aim of the Hyaluronic Acid Binding Sperm Selection (HABSelect) trial is to determine the efficacy of hyaluronic acid (HA)-selection of sperm versus conventionally selected sperm prior to ICSI on live birth rate (LBR). The mechanistic aim is to assess whether and how the chromatin state of HA-selected sperm corresponds with clinical outcomes—clinical pregnancy rate (CPR), LBR and pregnancy loss (PL).Methods and analysisCouples attending UK Centres will be approached, eligibility screening performed and informed consent sought. Randomisation will occur within 24 hours prior to ICSI treatment. Participants will be randomly allocated 1:1 to the intervention arm (physiological intracytoplasmic sperm injection, PICSI) versus the control arm using conventional methods (ICSI). The primary clinical outcome is LBR ≥37 weeks' gestation with the mechanistic study determining LBR's relationship with sperm DNA integrity. Secondary outcomes will determine this for CPR and PL. Only embryologists performing the procedure will be aware of the treatment allocation. Steps will be taken to militate against biases arising from embryologists being non-blinded. Randomisation will use a minimisation algorithm to balance for key prognostic variables. The trial is powered to detect a 5% difference (24–29%: p=0.05) in LBR ≥37 weeks' gestation. Selected residual sperm samples will be tested by one or more assays of DNA integrity.Ethics and disseminationHABSelect is a UK NIHR-EME funded study (reg no 11/14/34; IRAS REF. 13/YH/0162). The trial was designed in partnership with patient and public involvement to help maximise patient benefits. Trial findings will be reported as per CONSORT guidelines and will be made available in lay language via the trial web site (http://www.habselect.org.uk/).Trial registration numberISRCTN99214271; Pre-results.
Standardised tobacco packaging: a health policy case study of corporate conflict expansion and adaptation
Authors: Hatchard Jenny L , Fooks Gary J , Gilmore Anna B 
Published: October 2016

ObjectivesTo investigate opposition to standardised tobacco packaging in the UK. To increase understanding of how transnational corporations are adapting to changes in their access to policymakers precipitated by Article 5.3 of the Framework Convention on Tobacco Control (FCTC).DesignCase study web-based documentary analysis, using NVivo V.10. Examination of relationships between opponents of standardised packaging and transnational tobacco companies (TTCs) and of the volume, nature, transparency and timing of their activities.SettingUK standardised packaging policy debate 2011–2013.ParticipantsOrganisations selected on basis of opposition to, or facilitation thereof, standardised tobacco packaging in the UK; 422 associated documents.ResultsExcluding tobacco manufacturing and packaging companies (n=12), 109 organisations were involved in opposing standardised packaging, 82 (75%) of which had a financial relationship with 1 or more TTC. These 82 organisations (43 actively opposing the measure, 39 facilitating opposition) were responsible for 60% of the 404 activities identified, including the majority of public communications and research production. TTCs were directly responsible for 28% of total activities, predominantly direct lobbying, but also financially underwrote third party research, communication, mass recruitment and lobbying. Active organisations rarely reported any financial relationship with TTCs when undertaking opposition activities.ConclusionsThe multifaceted opposition to standardised packaging was primarily undertaken by third parties with financial relationships with major tobacco manufacturers. Low levels of transparency regarding these links created a misleading impression of diverse and widespread opposition. Countries should strengthen implementation of Article 5.3 of the FCTC by systematically requiring conflict of interest declarations from all organisations participating in political or media debates on tobacco control.
The iBRA-2 (immediate breast reconstruction and adjuvant therapy audit) study: protocol for a prospective national multicentre cohort study to evaluate the impact of immediate breast reconstruction on the delivery of adjuvant therapy
Authors: Dave Rajiv , O'Connell Rachel , Rattay Tim , Tolkien Zoe , Barnes Nicola , Skillman Joanna , Williamson Paula , Conroy Elizabeth , Gardiner Matthew , Harnett Adrian , O'Brien Ciara , Blazeby Jane , Potter Shelley , Holcombe Chris 
Published: October 2016

IntroductionImmediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy, but there are concerns that more complex surgery may delay the delivery of adjuvant oncological treatments and compromise long-term oncological outcomes. High-quality evidence, however, is lacking. iBRA-2 is a national prospective multicentre cohort study that aims to investigate the effect of IBR on the delivery of adjuvant therapy.Methods and analysisBreast and plastic surgery centres in the UK performing mastectomy with or without (±) IBR will be invited to participate in the study through the trainee research collaborative network. All women undergoing mastectomy ± IBR for breast cancer between 1 July and 31 December 2016 will be included. Patient demographics, operative, oncological and complication data will be collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR will be compared to determine the impact that IBR has on the time of delivery of adjuvant therapy. Prospective data on 3000 patients from ∼50 centres are anticipated.Ethics and disseminationResearch ethics approval is not required for this study. This has been confirmed using the online Health Research Authority decision tool. This novel study will explore whether IBR impacts the time to delivery of adjuvant therapy. The study will provide valuable information to help patients and surgeons make more informed decisions about their surgical options. Dissemination of the study protocol will be via the Mammary Fold Academic and Research Collaborative (MFAC) and the Reconstructive Surgery Trials Network (RSTN), the Association of Breast Surgery (ABS) and the British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS). Participating units will have access to their own data and collective results will be presented at relevant surgical conferences and published in appropriate peer-reviewed journals.
Assessment of proximal pulmonary arterial stiffness using magnetic resonance imaging: effects of technique, age and exercise
Authors: Weir-McCall Jonathan R , Kamalasanan Anu , Cassidy Deidre B , Struthers Allan D , Lipworth Brian J , Houston J Graeme 
Published: October 2016

IntroductionTo compare the reproducibility of pulmonary pulse wave velocity (PWV) techniques, and the effects of age and exercise on these.Methods10 young healthy volunteers (YHV) and 20 older healthy volunteers (OHV) with no cardiac or lung condition were recruited. High temporal resolution phase contrast sequences were performed through the main pulmonary arteries (MPAs), right pulmonary arteries (RPAs) and left pulmonary arteries (LPAs), while high spatial resolution sequences were obtained through the MPA. YHV underwent 2 MRIs 6 months apart with the sequences repeated during exercise. OHV underwent an MRI scan with on-table repetition. PWV was calculated using the transit time (TT) and flow area techniques (QA). 3 methods for calculating QA PWV were compared.ResultsPWV did not differ between the two age groups (YHV 2.4±0.3/ms, OHV 2.9±0.2/ms, p=0.1). Using a high temporal resolution sequence through the RPA using the QA accounting for wave reflections yielded consistently better within-scan, interscan, intraobserver and interobserver reproducibility. Exercise did not result in a change in either TT PWV (mean (95% CI) of the differences: −0.42 (−1.2 to 0.4), p=0.24) or QA PWV (mean (95% CI) of the differences: 0.10 (−0.5 to 0.9), p=0.49) despite a significant rise in heart rate (65±2 to 87±3, p<0.0001), blood pressure (113/68 to 130/84, p<0.0001) and cardiac output (5.4±0.4 to 6.7±0.6 L/min, p=0.004).ConclusionsQA PWV performed through the RPA using a high temporal resolution sequence accounting for wave reflections yields the most reproducible measurements of pulmonary PWV.
Effect of vedolizumab (anti-α4β7-integrin) therapy on histological healing and mucosal gene expression in patients with UC
Authors: Arijs Ingrid , De Hertogh Gert , Lemmens Bart , Van Lommel Leentje , de Bruyn Magali , Vanhove Wiebe , Cleynen Isabelle , Machiels Kathleen , Ferrante Marc , Schuit Frans , Van Assche Gert , Rutgeerts Paul , Vermeire Severine 
Published: October 2016

ObjectiveLymphocyte recruitment to the inflamed gut is increased in UC. Inhibition of this cell trafficking by vedolizumab (VDZ) was successful in inducing and maintaining remission and in induction of endoscopic mucosal healing. There are no data on histological healing with VDZ. We studied histological changes following VDZ therapy and compared gene expression in patients with UC before and after therapy.DesignForty-one patients with UC from GEMINI I and LTS were studied before and at three time points (weeks 6/12/52) following VDZ therapy. Colonic biopsies were scored using the Geboes index and correlated with Mayo endoscopic subscore. Gene expression was analysed using Affymetrix gene arrays.ResultsFifty-five per cent of patients achieving endoscopic healing (= Mayo endoscopic subscore 0–1) with VDZ at the studied time points also had histological healing (= Geboes grade 0–1). In most healers, some residual histological changes (eg, disturbed architecture and increased mononuclear cell infiltrate) were still observed, although this was less at week 52. VDZ restored expression of many inflammatory genes in patients with endoscopic healing only at week 52 and not before. In VDZ healers, the expression of many genes remained dysregulated at weeks 6/12/52 compared with controls.ConclusionsVDZ induces histological healing in >50% of patients with endoscopic healing, with maximal effect at week 52. VDZ also restored, although incompletely, the colonic expression of many immune-related genes in patients with UC achieving endoscopic healing at week 52. However, persistent histological and gene dysregulations did remain even in healers, suggesting that maintenance therapy will be necessary to control the intestinal inflammation.Trial registration numbers:NCT00783718 and NCT00790933; post-results.
Dissenting from care.data: an analysis of opt-out forms
Authors: Vezyridis Paraskevas , Timmons Stephen 
Published: October 2016

BackgroundCare.data was a programme of work led by NHS England for the extraction of patient-identifiable and coded information from general practitioner (GP) records for secondary uses. This study analyses the forms (on the websites of GP practices) which enabled patients to opt out.MethodsTheoretical sampling and summative content analysis were used to collect and analyse dissent forms used by patients to opt out from care.data. Domains included basic information about the programme, types of objections and personal details required for identification purposes.ResultsOne hundred opt-out forms were analysed. Fifty-four forms mentioned that this programme was run by NHS England. 81 forms provided two types of objections to data-sharing, and 15 provided only one objection. Only 26 forms mentioned that direct care would not be affected and 32 that patients maintain their right to opt back anytime. All but one of the opt-out forms we reviewed requested the name of the person wishing to opt out. 94 required a date of birth and 33 an NHS number. 82 required an address, 42 a telephone number and 7 an email address.ConclusionsNumbers of patients (not) opting out should be treated with caution, because the variability of information provided and the varied options for dissent may have caused confusion among patients. To ensure that dissent is in accordance with individual preferences and moral values, we recommend that well-designed information material and standardised opt-out forms be developed for such data-sharing initiatives.
Effectiveness and safety of TNF inhibitors in adults with juvenile idiopathic arthritis
Authors: Kearsley-Fleet Lianne , McErlane Flora , Foster Helen E , Lunt Mark , Watson Kath D , Symmons Deborah P M , Hyrich Kimme L 
Published: October 2016

IntroductionMany children with juvenile idiopathic arthritis (JIA) continue to have active disease into adulthood. Adults with JIA are a heterogeneous group, and the effects of tumour necrosis factor inhibitor (TNFi) therapies are not well described. This analysis aims to describe treatment outcomes among patients with JIA starting TNFi for the first time in adulthood.MethodsPatients with arthritis onset <16 years starting their first TNFi therapy were identified from the British Society of Rheumatology Biologics Register. Disease activity outcomes (using 28-joint Disease Activity Score (DAS28) and Health Assessment Questionnaire (HAQ)) are presented at 1 year after start of therapy according to disease pattern. Incidence rates (IR) of adverse events per 1000 person-years (pyrs) were calculated. Outcomes in patients with polyarticular JIA were compared with a cohort (weighted for age and gender) of patients with rheumatoid arthritis (RA).ResultsIn 443 adults with JIA starting a first TNFi, disease activity over 1 year improved across all measures. There were 58 first serious infections (IR 22.3/1000 pyrs); 4 cardiovascular events (IR 1.4/1000 pyrs); 11 uveitis events (IR 4.0/1000 pyrs) and 16 malignancies (IR 3.9/1000 pyrs). Compared with the weighted RA cohort, disease activity improvement was similar; malignancy rates were lower and uveitis rates much higher. While crude IR were similar, JIA patients had a lower risk of serious infection (HR 0.5 (95% CI 0.3 to 0.9)).ConclusionsThis is the largest study to describe disease activity and safety outcomes in adults with JIA receiving TNFi. Disease activity improved after 1 year in all disease patterns, suggesting TNFi is an effective therapy in this population.
Validation of risk scoring models for predicting stroke-associated pneumonia in patients with ischaemic stroke
Authors: Gong Siyin , Zhou Zhiwei , Zhou Muke , Lei Zhao , Guo Jian , Chen Ning , He Li 
Published: October 2016

ObjectiveVarious risk scoring models have been developed to predict stroke-associated pneumonia (SAP). We aim to determine whether these risk models could effectively predict SAP in Chinese patients with ischaemic stroke (IS).MethodsConsecutive patients with IS in West China hospital between January 2011 and September 2013 were included to assess the predictive performance of risk scoring models, including Chumbler's score, A2DS2and AISAPS. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the performance of each risk model in predicting pneumonia.ResultsA total of 1569 consecutive patients with IS within 30 days of onset in West China hospital were included. The incidence of pneumonia is 15.3%. The AUROC of Chumbler's score, A2DS2and AISAPS was 0.659, 0.728 and 0.758, respectively, and AISAPS had the highest AUROC.ConclusionsA2DS2and AISAPS had acceptable discriminatory abilities to predict SAP in Chinese patients with IS within 30 days of onset.
Electrochemotherapy as a single treatment or adjuvant treatment to surgery of cutaneous sarcoid tumours in horses: a 31‐case retrospective study
Authors: Tozon N. , Kramaric P. , Kos Kadunc V. , Sersa G. , Cemazar M. 
Published: October 2016

The aim of our study was to evaluate the efficacy of electrochemotherapy (ECT) with cisplatin as a single or adjuvant treatment for sarcoids in equids. Different treatment options with different success rates were proposed. Thirty‐one horses and one donkey with different clinical type, size and location of tumours were treated with ECT as a single treatment (18 animals with 52 tumour nodules) or as adjuvant treatment with marginal surgical excision (14 animals with 18 tumour nodules). In animals treated only with ECT with cisplatin, complete response was obtained in 48/52 (92.3 per cent) nodules and partial response in the other 4 nodules (7.7 per cent). In most cases, one to three sessions, only in two cases four and in one case five sessions, every 4 weeks were needed to obtain the measurable response. During the observation time, only in one case was the recurrence noted 60 months after treatment. Complete response in all 18 tumour nodules treated with surgery and adjuvant ECT was obtained and only one recurrence was noted after 14 months during the observation time. The results of this study show that ECT with cisplatin is an effective, safe, and simple local treatment of sarcoids in equids. According to the tumour size and location, single or combined treatment should be performed.
Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity
Authors: Lin Sheng-Chieh , Chou Yu-Ting , Jiang Shih Sheng , Chang Junn-Liang , Chung Chih-Hung , Kao Yu-Rung , Chang I-Shou , Wu Cheng-Wen 
Published: October 2016

Abstract
Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM–p21Cip1–cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036–48. ©2016 AACR.
E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia
Authors: Duque-Afonso Jesús , Lin Chiou-Hong , Han Kyuho , Wei Michael C. , Feng Jue , Kurzer Jason H. , Schneidawind Corina , Wong Stephen Hon-Kit , Bassik Michael C. , Cleary Michael L. 
Published: October 2016

AbstractThere is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%–7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCγ2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCγ2 and inhibited proliferation of human and mouse preBCR+/E2A-PBX1+ leukemias in vitro and in vivo. Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCγ2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937–49. ©2016 AACR.