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  • 1
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    American Society of Hematology (ASH)
    In: Blood
    Publication Date: 2018-01-26
    Description: Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.
    Keywords: How I Treat, Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-02-09
    Description: Introduction Patient-reported outcomes (PROs) are increasingly included within cancer clinical trials. If appropriately collected, analysed and transparently reported, these data might provide invaluable evidence to inform patient care. However, there is mounting indication that the design and reporting of PRO data in cancer trials may be suboptimal. This programme of research will establish via three interlinked studies whether these findings are applicable to UK cancer trials, and if so, how to best enhance the way PROs are assessed, managed and reported in clinical trials. This study will explore with key stakeholders factors that influence optimal PRO protocol content, implementation and reporting and make recommendations for training and guidance. Methods and analysis Semistructured interviews will be conducted with members of key stakeholder groups. The purposive sample of up to 48 participants will include: (1) trial chief investigators, trial management group members, statisticians and research nurses of cancer trials including primary or secondary PRO recruited via the National Cancer Research Institute (NCRI) Clinical Studies Group and Consumer Liaison Group and the UK Clinical Research Collaboration Registered UK Clinical Trial Unit Network; (2) NCRI Consumer Liaison Group members; (3) international experts in PRO oncology trial design; and (4) journal editors and funding bodies. Data will be analysed using directed thematic analysis employing a coding frame and modified as analysis progresses. Formal triangulation of coding and member checking will be employed to enhance credibility. Ethics and dissemination This study was approved by the University of Birmingham Ethics Committee (Ref: ERN_17–0085). Findings will be disseminated via conference presentations, peer-reviewed journals, patient groups and social media (@CPROR_UoB; http://www.birmingham.ac.uk/cpror ). PROSPERO registration number CRD42016036533.
    Keywords: Open access, Oncology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 3
    Publication Date: 2018-09-18
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 4
    Publication Date: 2018-10-16
    Description: Joel M. Brown and Maria J. Garcia-Garcia Neural tube closure relies on the apical constriction of neuroepithelial cells. Research in frog and fly embryos has found links between the levels of intracellular calcium, actomyosin dynamics and apical constriction. However, genetic evidence for a role of calcium in apical constriction during mammalian neurulation is still lacking. Secretory pathway calcium ATPase (SPCA1) regulates calcium homeostasis by pumping cytosolic calcium into the Golgi apparatus. Loss of function in Spca1 causes cranial exencephaly and spinal cord defects in mice, phenotypes previously ascribed to apoptosis. However, our characterization of a novel allele of Spca1 revealed that neurulation defects in Spca1 mutants are not due to cell death, but rather to a failure of neuroepithelial cells to apically constrict. We show that SPCA1 influences cell contractility by regulating myosin II localization. Furthermore, we found that loss of Spca1 disrupts actin dynamics and the localization of the actin remodeling protein cofilin 1. Taken together, our results provide evidence that SPCA1 promotes neurulation by regulating the cytoskeletal dynamics that promote apical constriction and identify cofilin 1 as a downstream effector of SPCA1 function.
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 5
    Publication Date: 2018-01-28
    Description: Introduction Australia’s National Cervical Screening Program (NCSP) currently recommends 2-year cytology in women aged 18–69 years. Following a review of the NCSP prompted by the implementation of human papillomavirus (HPV) vaccination, the programme will transition in 2017 to 5-year primary HPV screening with partial genotyping for HPV16/18 in women aged 25–74 years. Compass is a sentinel experience for the renewed NCSP and the first prospectively randomised trial of primary HPV screening compared with cytology to be conducted in a population with high uptake of HPV vaccination. This protocol describes the main Compass trial, which commenced after a pilot study of ~5000 women completed recruitment. Methods and analysis Women aged 25–69 years will be randomised at a 1:2 allocation to (1) 2.5-year image-read, liquid-based cytology (LBC) screening with HPV triage of low-grade smears (active control Arm A) or (2) 5-year HPV screening with partial genotyping and referral of HPV16/18-positive women to colposcopy (intervention Arm B). Women in Arm B positive for other oncogenic HPV (not 16/18) will undergo secondary randomisation at a 1:1 allocation to either LBC or dual-stained (p16 INK4a and Ki-67) cytology testing (dual-stained cytology). The primary outcome is cumulative CIN3+ (CIN3, adenocarcinoma in situ and invasive cervical cancer) following a 5-year HPV exit testing round in both arms, in women randomised to the HPV arm versus women randomised to the LBC arm, based on an intention-to-treat analysis. The primary outcome will first be tested for non-inferiority and if declared, the primary outcome will be tested for superiority. A total of 36 300 women in birth cohorts not offered vaccination and 84 700 women in cohorts offered vaccination will be recruited, bringing the final sample size to 121 000. The trial is powered for the secondary outcome of cumulative CIN3+ in screen-negative women, adjusted for censoring after CIN2+ treatment and hysterectomy. Ethics and dissemination Approved by the Bellberry Ethics Committee (2014-11-592). Findings will be reported in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT02328872 ; Pre-results.
    Keywords: Open access, Public health
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 6
    Publication Date: 2018-03-24
    Description: Introduction For patients with advanced cancer, research shows that pain is frequent, burdensome and undertreated. Evidence-based approaches to support cancer pain management have been developed but have not been implemented within the context of the UK National Health Service. This protocol is for a pragmatic multicentre randomised controlled trial (RCT) to assess feasibility, acceptability, effectiveness and cost-effectiveness for a multicomponent intervention for pain management in patients with advanced cancer. Methods and analysis This trial will assess the feasibility of implementation and uptake of evidence-based interventions, developed and piloted as part of the Improving the Management of Pain from Advanced Cancer in the Community Programme grant, into routine clinical practice and determine whether there are potential differences with respect to patient-rated pain, patient pain knowledge and experience, healthcare use, quality of life and cost-effectiveness. 160 patients will receive either the intervention (usual care plus supported self-management) delivered within the oncology clinic and palliative care services by locally assigned community palliative care nurses, consisting of a self-management educational intervention and eHealth intervention for routine pain assessment and monitoring; or usual care. The primary outcomes are to assess implementation and uptake of the interventions, and differences in terms of pain severity. Secondary outcomes include pain interference, participant pain knowledge and experience, and cost-effectiveness. Outcome assessment will be blinded and patient-reported outcome measures collected via post at 6 and 12 weeks following randomisation. Ethics and dissemination This RCT has the potential to significantly influence National Health Service delivery to community-based patients with pain from advanced cancer. We aim to provide definitive evidence of whether two simple interventions delivered by community palliative care nurse in palliative care that support-self-management are clinically effective and cost-effective additions to standard community palliative care. Trial registration number ISRCTN18281271 ; Pre-results.
    Keywords: Palliative care, Open access, Palliative care
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 7
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    American Society of Hematology (ASH)
    In: Blood
    Publication Date: 2018-04-27
    Keywords: Free Research Articles
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-02-23
    Description: Introduction Acute colorectal surgery forms a significant proportion of emergency admissions within the National Health Service. There is limited evidence to suggest minimally invasive surgery may be associated with improved clinical outcomes in this cohort of patients. Consequently, there is a need to assess the clinical effectiveness and cost-effectiveness of laparoscopic surgery in the acute colorectal setting. However,emergency colorectal surgical trials have previously been difficult to conduct due to issues surrounding recruitment and equipoise. The LaCeS (randomised controlled trial of Laparoscopic versus open Colorectal Surgery in the acute setting) feasibility trial will determine the feasibility of conducting a definitive, phase III trial of laparoscopic versus open acute colorectal resection. Methods and analysis The LaCeS feasibility trial is a prospective, multicentre, single-blinded, parallel group, pragmatic randomised controlled feasibility trial. Patients will be randomised on a 1:1 basis to receive either laparoscopic or open surgery. The trial aims to recruit at least 66 patients from five acute general surgical units across the UK. Patients over the age of 18 with a diagnosis of acute colorectal pathology requiring resection on clinical and radiological/endoscopic investigations, with a National Confidential Enquiry into Patient Outcome and Death classification of urgent will be considered eligible for participation. The primary outcome is recruitment. Secondary outcomes include assessing the safety profile of laparoscopic surgery using intraoperative and postoperative complication rates, conversion rates and patient-safety indicators as surrogate markers. Clinical and patient-reported outcomes will also be reported. The trial will contain an embedded qualitative study to assess clinician and patient acceptability of trial processes. Ethics and dissemination The LaCeS feasibility trial is approved by the Yorkshire and The Humber, Bradford Leeds Research Ethics Committee (REC reference: 15/ YH/0542). The results from the trial will be presented at national and international colorectal conferences and will be submitted for publication to peer-reviewed journals. Trial registration number ISRCTN15681041 ; Pre-results.
    Keywords: Clinical trials (epidemiology), Open access, Surgery
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 9
    Publication Date: 2018-02-15
    Description: In budding yeast meiosis, homologous chromosomes become linked by chiasmata and then move back and forth on the spindle until they are bioriented, with the kinetochores of the partners attached to microtubules from opposite spindle poles. Certain mutations in the conserved kinase, Mps1, result in catastrophic meiotic segregation errors but mild mitotic defects. We tested whether Dam1, a known substrate of Mps1, was necessary for its critical meiotic role. We found that kinetochore–microtubule attachments are established even when Dam1 is not phosphorylated by Mps1, but that Mps1 phosphorylation of Dam1 sustains those connections. But the meiotic defects when Dam1 is not phosphorylated are not nearly as catastrophic as when Mps1 is inactivated. The results demonstrate that one meiotic role of Mps1 is to stabilize connections that have been established between kinetochores and microtubles by phosphorylating Dam1.
    Print ISSN: 1059-1524
    Electronic ISSN: 1939-4586
    Topics: Biology
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  • 10
    Publication Date: 2018-01-28
    Description: Objectives Sickness absence (SA) among healthcare workers is associated with occupational and non-occupational risk factors and impacts employee health, healthcare delivery and patient health. At the same time, healthcare is one of the employment sectors with the highest rates of work-related ill health in the UK. Musculoskeletal (MSK) and mental health (MH) issues are leading causes of SA, but there is a lack of research on how certain MSK/MH conditions impact on SA duration. The study aim is to determine differences in SA duration by MH and MSK disorders in healthcare employees. Methods Survival analyses were used to estimate SA duration due to MSK and MH problems over 6 years, and Cox’s proportional hazards models to determine the HRs of returning to work, using a bespoke Scottish health board database with over 53 000 SA events. SA duration and time to return-to-work (RTW) were estimated for employees by age, gender, job and health conditions. Results MSK and MH conditions accounted for 27% and 6% of all SA events and 23.7% and 19.5% of all days lost, respectively. Average SA duration was 43.5 days for MSK and 53.9 days for MH conditions. For MSK conditions, employees with low back or neck pain had the fastest RTW (median P 50 : 7 days), whereas employees absent due to depression took the longest (P 50 : 54 days). The most influential sociodemographic variables affecting RTW were age, gender and job category. Conclusions Using a unique and rich database, we found significant differences in SA duration by presenting condition in healthcare workers. MH conditions, and depression specifically, accounted for the most working days’ absence. Significant variations in duration were also observed for MSK conditions. Our findings can inform public health practitioners and healthcare managers of the most significant factors impacting MSK-related and MH-related SA to develop and implement tailored and targeted workplace interventions.
    Keywords: Open access, Occupational and environmental medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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