Implementing public involvement standards in cerebral palsy register research

BACKGROUND: In 2018, the National Institute for Health Research launched Draft Standards for Public Involvement in Research. The Northern Ireland Cerebral Palsy Register (NICPR) was competitively selected as a “test-bed” project to pilot the Draft Standards over a one-year period. AIM: This perspective paper aims to describe the NICPR's experience of piloting the Draft Standards for Public Involvement in Research, highlighting successes and challenges. METHOD: Three of the six Draft Standards were piloted from April 2018 to April 2019: Standard 2 “working together”, Standard 4 “communications” and Standard 5, “impact”. RESULTS: Implementation of Standard 2 resulted in formation of a dedicated Public Involvement Group. Standard 4 was implemented by revision of the NICPR's Privacy Notice and development of the NICPR website. Standard 5 was not implemented during the test-bed pilot period. DISCUSSION: Benefits of use of the Draft Standards in cerebral palsy register research included development of relationships, improving quality, accessibility and relevance of NICPR materials, increasing skills and confidence, networking opportunities, advocating for others and feeling empowered to shape cerebral palsy research. Challenges included administrative issues, absence of dedicated and sustained funding, limitations in the availability and applicability of public involvement training and the time required for meaningful public involvement. CONCLUSIONS: Standards for Public Involvement provide a useful framework for structuring and embedding meaningful public involvement. Sustained, authentic public involvement in cerebral palsy register research ensures that people affected by the condition are empowered to engage, inform, develop and lead research that meets their needs

Work-life imbalance: informal care and paid employment

In the United Kingdom informal carers are people who look after relatives or friends who need extra support because of age, physical or learning disability or illness. The majority of informal carers are women and female carers also care for longer hours and for longer durations than men. Thus women and older women in particular, shoulder the burden of informal care. We consider the costs of caring in terms of the impact that these kinds of caring responsibilities have on employment. The research is based on the responses of informal carers to a dedicated questionnaire and in-depth interviews with a smaller sub-sample of carers. Our results indicate that the duration of a caring episode as well as the hours carers commit to caring impact on their employment participation. In addition carers’ employment is affected by financial considerations, the needs of the person they care for, carers’ beliefs about the compatibility of informal care and paid work and employers’ willingness to accommodate carers’ needs. Overall, the research confirms that informal carers continue to face difficulties when they try to combine employment and care in spite of recent policy initiatives designed to help them

Sleep Medication Use by people with Cerebral Palsy: A Population Level DataLinkage Study

Objectives To (1) compare proportions of the population dispensed sleep medication, and rate (dispensations/month) and amount (milligrams/month) of dispensed sleep medication, in individuals with and without cerebral palsy (CP); and (2) describe dispensation of sleep medication within CP and non-CP cohorts with respect to sociodemographic and clinical characteristics. Approach Individuals aged 6 -36 years (aligning with those known to the Northern Ireland CP Register [NICPR]), registered with a general practitioner at 01-January-2018, were identified within the National Health Application and Infrastructure System.  Sleep medications dispensed 01-January-2018 to 31-December-2019 were extracted from the Enhanced Prescribing Database.  Analysis was limited to melatonin due to small counts in other medications.  Routine healthcare data was sourced from the Honest Broker Service (HBS).  NICPR clinical data (CP-type, Gross Motor Function Classification System (GMFCS), gestation and birthweight) were linked to routine healthcare data using the Health and Care Number by HBS. Descriptive statistics are presented. Results Complete matching was achieved between NICPR and healthcare data using the HCN.  Final cohorts consisted of 1,598 individuals with CP and 790,097 without CP. A greater proportion of those with CP were dispensed melatonin compared to those without CP (4.6% vs 1.0%).  The CP cohort were also dispensed melatonin at a greater rate (median(IQR) CP 0.33(0.71) vs non-CP 0.25(0.54) dispensations/month) and in greater amounts (median(IQR) CP 30(74.7) vs non-CP 17.5(55.0) mg/month).  Within the CP cohort, differences in melatonin dispensation were observed across sociodemographic groups (male 5.1% vs female 3.9%; children 8.2% vs young adults 2.2%; urban 6.5% vs rural 5.0%); deprived 5.1% vs affluent 4.2%).  Clinical characteristics associated with greatest dispensation of melatonin were non-spastic CP (6.83%), GMFCS IV&V (5.29%), or extremely premature birth (6.85%). Conclusion Individuals with CP, particularly children, are more likely to be dispensed sleep medications compared to the general population.  Awareness of this disparity could encourage further research on assessment and management of sleep in CP and facilitate discussions between healthcare providers and families on underlying causes of sleep problems

Chemotherapy vs supportive care alone for relapsed gastric, gastroesophageal junction, and oesophageal adenocarcinoma: a meta-analysis of patient-level data.

BACKGROUND: Second-line chemotherapy treatment of patients with relapsed gastric and oesophageal cancers in comparison with supportive care (SC) alone has been supported by recent phase 3 clinical trials, but a meta-analysis of patient-level data is lacking. METHODS: We searched Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Web of Science for phase 3 clinical trials that compared second-line chemotherapy with SC alone for gastric and oesophageal cancers. A meta-analysis of the comprehensive patient-level data from the three identified trials was performed. RESULTS: A total of 410 patients with gastric (n=301), gastroesophageal junction (n=76), or oesophageal (n=33) adenocarcinoma were identified. In all, 154 patients received single-agent docetaxel and 84 patients received single-agent irinotecan, each with SC. SC alone was given to 172 patients. Chemotherapy significantly reduced the risk of death (hazard ratio (HR)=0.63, 95% confidence interval (CI)=0.51-0.77, P<0.0001). This effect was observed for treatment with docetaxel (HR=0.71, 95% CI=0.56-0.89, P=0.003) and irinotecan (HR=0.49, 95% CI=0.36-0.67, P<0.001). Overall survival (OS) benefit was greatest for patients who progressed 3-6 months following first-line chemotherapy (HR=0.39, 95% CI=0.26-0.59, P<0.0001). Performance status (PS) 0-1 compared with PS 2 (HR=0.66, 95% CI=0.46-0.94, P=0.02), locally advanced disease compared with metastatic disease (HR=0.41, 95% CI=0.25-0.67, P=0.0004) and older age (HR=0.94 per 5 years, 95% CI=0.90-0.99, P=0.01) were significant predictors of improved OS. Progression of disease during first-line treatment (HR=1.24, 95% CI=0.96-1.59) or within the first 3 months of completion of first-line treatment (HR=1.42, 95% CI=1.09-1.83) were predictors of an increased risk of death compared with progression between 3 and 6 months (P=0.03). Health-related quality of life outcomes were reported in only one of the three trials, precluding meta-analysis of these parameters. CONCLUSIONS: This meta-analysis of patient-level data confirms that second-line chemotherapy treatment results in significantly better OS compared with SC alone in patients with platinum and fluoropyrimidine refractory gastric and oesphageal adenocarcinoma. Health-related quality of life outcomes should be included in future trials in this setting.TJ and CC were supported by the Wellcome Trust Translational Medicine and Therapeutics programme and the National Institute for Health Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/bjc.2015.45

p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015). We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1) to 0.03 pfu/cell (TOV21G). Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials

Implementing biomarkers to predict motor recovery after stroke

BACKGROUND: There is growing interest in using biomarkers to predict motor recovery and outcomes after stroke. The PREP2 algorithm combines clinical assessment with biomarkers in an algorithm, to predict upper limb functional outcomes for individual patients. To date, PREP2 is the first algorithm to be tested in clinical practice, and other biomarker-based algorithms are likely to follow. PURPOSE: This review considers how algorithms to predict motor recovery and outcomes after stroke might be implemented in clinical practice. FINDINGS: There are two tasks: first the prediction information needs to be obtained, and then it needs to be used. The barriers and facilitators of implementation are likely to differ for these tasks. We identify specific elements of the Consolidated Framework for Implementation Research that are relevant to each of these two tasks, using the PREP2 algorithm as an example. These include the characteristics of the predictors and algorithm, the clinical setting and its staff, and the healthcare environment. CONCLUSIONS: Active, theoretically underpinned implementation strategies are needed to ensure that biomarkers are successfully used in clinical practice for predicting motor outcomes after stroke, and should be considered in parallel with biomarker developmen

Separating the anti-apoptotic and mitotic roles of survivin

Survivin is a bifunctional protein that acts as a suppressor of apoptosis and has an essential role in mitosis. To date whether these two functions can be divorced has not been addressed. Here we show that the linker region between the BIR (baculovirus inhibitor of apoptosis repeat) domain of survivin and COOH-terminal alpha helix may be the key to separating its roles. When overexpressed survivin is present in interphase cells and shuttles between the cytoplasm and nucleus. Here we identify a rev-like nuclear exportation signal (NES) in the central domain of survivin and demonstrate that point mutations within this region cause accumulation of survivin in the nucleus. Interestingly cells expressing NES mutants exhibit reduced survival after X-irradiation. Moreover, cells expressing survivin(L98A)-green fluorescent protein (GFP) showed increased poly(ADP-ribose) polymerase-cleavage and caspase-3 activity after tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment compared with cells expressing full-length survivin-green fluorescent protein. These data suggest a direct link between the interphase localization of survivin and cellular responsiveness to apoptotic stimuli. Using a cell proliferation assay, we also found that ectopic expression of NES mutants can complement for depletion of endogenous survivin, indicating that they can execute the mitotic duties of survivin. Thus we demonstrate for the first time that 1) survivin has a functional NES; 2) nuclear accumulation of overexpressed survivin correlates with increased sensitivity of cells to ionising radiation; and 3) the anti-apoptotic and mitotic roles of survivin can be separated through mutation of its NES. Separating these two functions of survivin could open up new possibilities for therapeutic strategies aimed at eliminating cancer cells yet preserving normal cell viability

Early relapse on adjuvant gemcitabine associated with an exceptional response to 2nd line capecitabine chemotherapy in a patient with pancreatic adenosquamous carcinoma with strong intra-tumoural expression of cytidine deaminase: a case report

Funder: Cambridge Experimental Medicine InitiativeFunder: Cancer Research United KingdomAbstract: Background: Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown. Case presentation: We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour. Conclusions: This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient’s disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice

Appropriate disclosure of a diagnosis of dementia : identifying the key behaviours of 'best practice'

Background: Despite growing evidence that many people with dementia want to know their diagnosis, there is wide variation in attitudes of professionals towards disclosure. The disclosure of the diagnosis of dementia is increasingly recognised as being a process rather than a one-off behaviour. However, the different behaviours that contribute to this process have not been comprehensively defined. No intervention studies to improve diagnostic disclosure in dementia have been reported to date. As part of a larger study to develop an intervention to promote appropriate disclosure, we sought to identify important disclosure behaviours and explore whether supplementing a literature review with other methods would result in the identification of new behaviours. Methods: To identify a comprehensive list of behaviours in disclosure we conducted a literature review, interviewed people with dementia and informal carers, and used a consensus process involving health and social care professionals. Content analysis of the full list of behaviours was carried out. Results: Interviews were conducted with four people with dementia and six informal carers. Eight health and social care professionals took part in the consensus panel. From the interviews, consensus panel and literature review 220 behaviours were elicited, with 109 behaviours over-lapping. The interviews and consensus panel elicited 27 behaviours supplementary to the review. Those from the interviews appeared to be self-evident but highlighted deficiencies in current practice and from the panel focused largely on balancing the needs of people with dementia and family members. Behaviours were grouped into eight categories: preparing for disclosure; integrating family members; exploring the patient's perspective; disclosing the diagnosis; responding to patient reactions; focusing on quality of life and well-being; planning for the future; and communicating effectively. Conclusion: This exercise has highlighted the complexity of the process of disclosing a diagnosis of dementia in an appropriate manner. It confirms that many of the behaviours identified in the literature (often based on professional opinion rather than empirical evidence) also resonate with people with dementia and informal carers. The presence of contradictory behaviours emphasises the need to tailor the process of disclosure to individual patients and carers. Our combined methods may be relevant to other efforts to identify and define complex clinical practices for further study.This project is funded by UK Medical Research Council, Grant reference number G0300999

Conflict in Mens Experiences With Antidepressants

While men’s experiences of depression and help-seeking are known to be shaped by gender there is little research which examines their experience of using antidepressants to treat this. This study is based on in-depth, narrative style interviews with 20 New Zealand men who had used antidepressants. The analysis identified a number of areas of conflict in the men’s accounts of using this medication. Conflict centered on the way taking antidepressants was seen as undermining personal control while also allowing users to take charge of their problems; facilitating general functioning while undermining sexual functioning; relieving emotional distress while undermining emotional vitality; and the tension participants felt between making autonomous judgements about the value of antidepressants or relying the ‘expertise’ of others. Participants negotiated these conflicts in a variety of ways. In some cases antidepressants were positioned as being able to affirm aspects of traditional masculinity while a smaller number of participants managed these conflicts by redefining aspects of their own masculinity in ways that contrasted with dominant constructions. This research is limited by the sample of older, more privileged men in the context of New Zealand culture which favors macho forms of masculinity. In similar contexts mental health practitioners should be mindful of the conflicts that men might experience in relation to their antidepressant use. Facilitating men’s exploration of these issues may enable them to make better decisions about treatment options or to provide more effective support to those who have opted for antidepressant treatment