Evaluating PET-CT in the detection and management of recurrent cervical cancer: Systematic reviews of diagnostic accuracy and subjective elicitation

Background: Positron emission tomography-computed tomography (PET-CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer. Objective: To evaluate diagnostic accuracy of additional whole body PET-CT compared with CT/magnetic resonance imaging (MRI) alone in women with suspected recurrent/persistent cervical cancer and in asymptomatic women as surveillance. Design: Systematic reviews. Subjective elicitation to supplement diagnostic information. Search strategy/Selection criteria/Data collection and analysis: Searches of electronic databases were performed to June 2013. Studies in women with suspected recurrent/persistent cervical cancer and in asymptomatic women undergoing follow up with sufficient numeric data were included. We calculated sensitivity, specificity and corresponding 95% confidence intervals. Meta-analyses employed a bivariate model that included a random-effects term for between-study variations (CT studies) and univariate random effects meta-analyses (PET-CT studies) for sensitivity and specificity separately. Subjective elicitation: Prevalence of recurrence and the accuracy of imaging elicited using the allocation of points technique. Coherence of elicited subjective probabilities with estimates in the literature examined. Results: We identified 15 relevant studies; none directly compared additional PET-CT with MRI or CT separately. Most CT and MRI studies used older protocols and the majority did not distinguish between asymptomatic and symptomatic women. Meta-analysis of nine PET-CT studies in mostly symptomatic women showed sensitivity of 94.8 (95% CI 91.2-96.9), and specificity of 86.9% (95% CI 82.2-90.5). The summary estimate of the sensitivity of CT for detection of recurrence was 89.64% (95% CI 81.59-94.41) and specificity was 76% (95% CI 43.68-92.82). Meta-analysis for MRI test accuracy studies was not possible because of clinical heterogeneity. The sensitivity and specificity of MRI in pelvic recurrence varied between 82 and 100% and between 78 and 100%, respectively. Formal statistical comparisons of the accuracy of index tests were not possible. Subjective elicitation provided estimates comparable to the literature. Subjective estimates of the increase in accuracy from the addition of PET-CT were less than elicited increases required to justify the use in PET-CT for surveillance. Conclusion: Evidence to support additional PET-CT is scarce, of average quality and does not distinguish between application for surveillance and diagnosis. Guidelines recommending PET-CT in recurrent cervical cancer need to be reconsidered in the light of the existing evidence base

Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling.

© Queen’s Printer and Controller of HMSO 2013. This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising.Cancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging.National Institute for Health Research Health Technology Assessment programm

Views of commissioners, managers and healthcare professionals on the NHS Health Check programme: a systematic review.

OBJECTIVE: To synthesise data concerning the views of commissioners, managers and healthcare professionals towards the National Health Service (NHS) Health Check programme in general and the challenges faced when implementing it in practice. DESIGN: A systematic review of surveys and interview studies with a descriptive analysis of quantitative data and thematic synthesis of qualitative data. DATA SOURCES: An electronic literature search of MEDLINE, Embase, Health Management Information Consortium, Cumulative Index of Nursing and Allied Health Literature, Global Health, PsycInfo, Web of Science, OpenGrey, the Cochrane Library, NHS Evidence, Google Scholar, Google, ClinicalTrials.gov and the International Standard Randomised Controlled Trial Number registry from 1 January 1996 to 9 November 2016 with no language restriction and manual screening of reference lists of all included papers. INCLUSION CRITERIA: Primary research reporting views of commissioners, managers or healthcare professionals on the NHS Health Check programme and its implementation in practice. RESULTS: Of 18 524 citations, 15 articles met the inclusion criteria. There was evidence from both quantitative and qualitative studies that some commissioners and general practice (GP) healthcare professionals were enthusiastic about the programme, whereas others raised concerns around inequality of uptake, the evidence base and cost-effectiveness. In contrast, those working in pharmacies were all positive about programme benefits, citing opportunities for their business and staff. The main challenges to implementation were: difficulties with information technology and computer software, resistance to the programme from some GPs, the impact on workload and staffing, funding and training needs. Inadequate privacy was also a challenge in pharmacy and community settings, along with difficulty recruiting people eligible for Health Checks and poor public access to some venues. CONCLUSIONS: The success of the NHS Health Check Programme relies on engagement by those responsible for its commissioning, management and delivery. Recognising and addressing the challenges identified in this review, in particular the concerns of GPs, are important for the future of the programme

NHS Health Check Programme rapid evidence synthesis

Background: The NHS Health Check programme is the largest current prevention initiative in England. Since its introduction in 2009 a growing literature has been published evaluating the first eight years of the programme. These have been summarised in reports published by Public Health England but, to date, no synthesis has been performed. There is, therefore, a need for an independent, comprehensive, rapid evidence synthesis to identify what has been learnt about the NHS Health Check programme so far. Aims and Objectives: To provide a rapid synthesis of the published research evidence on NHS Health Checks, specifically addressing the six research questions posed by Public Health England: 1. Who is and who is not having an NHS Health Check? 2. What are the factors that increase take-up among the population and sub-groups? 3. Why do people not take up an offer of an NHS Health Check? 4. How is primary care managing people identified as being at risk of cardiovascular disease or with abnormal risk factor results? 5. What are patients’ experiences of having an NHS Health Check? 6. What is the effect of the NHS Health Check on disease detection, changing behaviours, referrals to local risk management services, reductions in individual risk factor prevalence, reducing cardiovascular disease risk and on statin and antihypertensive prescribing? Design: A systematic review with descriptive synthesis of quantitative data and thematic synthesis of qualitative data. Data sources: Medline, PubMed, Embase, Health Management Information Consortium (HMIC), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Global Health, PsycInfo, Web of Science, the Cochrane Library, NHS Evidence, Google Scholar, Google, OpenGrey, Clinical Trials.gov, the ISRCTN registry, and article reference lists. Study selection: Studies identified by the searches were selected for inclusion in the review by two reviewers in a two-step process. First, studies relevant to the NHS Health Check were identified. These were then screened against predefined inclusion and exclusion criteria for each of the six research questions. Data extraction: At least two researchers assessed eligibility, extracted data, and assessed the quality of the included studies. Key findings: Coverage varies substantially across regions and in different settings. Multiple definitions used interchangeably make comparisons difficult. It is consistently higher in older people, females and more deprived populations but this may reflect targeting. Outreach services in the community can reach particular socio-demographic groups but better descriptions and robust evaluations are needed. There is a lack of national level studies reporting the characteristics of those who take-up the invitation to an NHS Health Check. Regional studies report uptake between 27% and 53%, similar to national reported uptake (48.3%). Older people, women in younger age groups and men in older age groups, and those from least deprived areas are more likely to take up invitations. Promising methods to increase uptake are modifications to the invitation (3-4% increase), and text message invites or reminders (up to 9% increase). There is a lack of quantitative evidence for the effect of community settings on uptake but qualitative evidence highlights their convenience and the value of community ambassadors. People do not take up the offer of an NHS Health Check due to lack of awareness or knowledge, competing priorities, misunderstanding the purpose, an aversion to preventive medicine, difficulty getting an appointment with a GP, and concerns about privacy and confidentiality of pharmacies. Amongst attendees there are high levels of satisfaction (over 80%). Some reported attendance had acted as a wake-up call and precipitant for lifestyle changes. Others were left with feelings of unmet expectations, were confused about or unable to remember their risk scores, and found lifestyle advice too simplistic and un-personalised. There are wide variations in the process, delivery and content of NHS Health Checks across the country, in part due to different local implementation. Regardless of region or setting those delivering NHS Health Checks reported challenges with workload, IT, funding, and training. Amongst general practice professionals there were concerns about inequality of uptake and doubts about the evidence underpinning the programme and the cost-effectiveness. NHS Health Checks are associated with small increases in disease detection. There is very little data on behaviour change or referrals to lifestyle services. NHS Health Checks are associated with a 3-4% increase in prescribing of statins

Dementia Care Mapping™ to reduce agitation in care home residents with dementia: the EPIC cluster RCT

Background The quality of care for people with dementia in care homes is of concern. Interventions that can improve care outcomes are required. Objective To investigate the clinical effectiveness and cost-effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation and improving care outcomes for people living with dementia in care homes, versus usual care. Design A pragmatic, cluster randomised controlled trial with an open-cohort design, follow-up at 6 and 16 months, integrated cost-effectiveness analysis and process evaluation. Clusters were not blinded to allocation. The primary end point was completed by staff proxy and independent assessors. Setting Stratified randomisation of 50 care homes to the intervention and control groups on a 3 : 2 ratio by type, size, staff exposure to dementia training and recruiting hub. Participants Fifty care homes were randomised (intervention, n = 31; control, n = 19), with 726 residents recruited at baseline and a further 261 recruited after 16 months. Care homes were eligible if they recruited a minimum of 10 residents, were not subject to improvement notices, had not used DCM in the previous 18 months and were not participating in conflicting research. Residents were eligible if they lived there permanently, had a formal diagnosis of dementia or a score of 4+ on the Functional Assessment Staging Test of Alzheimer’s Disease, were proficient in English and were not terminally ill or permanently cared for in bed. All homes were audited on the delivery of dementia and person-centred care awareness training. Those not reaching a minimum standard were provided training ahead of randomisation. Eighteen homes took part in the process evaluation. Intervention Two staff members from each intervention home were trained to use DCM and were asked to carry out three DCM cycles; the first was supported by an external expert. Main outcome measures The primary outcome was agitation (Cohen-Mansfield Agitation Inventory), measured at 16 months. Secondary outcomes included resident behaviours and quality of life. Results There were 675 residents in the final analysis (intervention, n = 388; control, n = 287). There was no evidence of a difference in agitation levels between the treatment arms. The adjusted mean difference in Cohen-Mansfield Agitation Inventory score was –2.11 points, being lower in the intervention group than in the control (95% confidence interval –4.66 to 0.44; p = 0.104; adjusted intracluster correlation coefficient: control = 0, intervention = 0.001). The sensitivity analyses results supported the primary analysis. No differences were detected in any of the secondary outcomes. The health economic analyses indicated that DCM was not cost-effective. Intervention adherence was problematic; only 26% of homes completed more than their first DCM cycle. Impacts, barriers to and facilitators of DCM implementation were identified. Limitations The primary completion of resident outcomes was by staff proxy, owing to self-report difficulties for residents with advanced dementia. Clusters were not blinded to allocation, although supportive analyses suggested that any reporting bias was not clinically important. Conclusions There was no benefit of DCM over control for any outcomes. The implementation of DCM by care home staff was suboptimal compared with the protocol in the majority of homes. Future work Alternative models of DCM implementation should be considered that do not rely solely on leadership by care home staff. Trial registration Current Controlled Trials ISRCTN82288852. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 16. See the NIHR Journals Library website for further project information

Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting ‘autophagy receptors’ in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF–TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling

Characterization of the Rabbit Neonatal Fc Receptor (FcRn) and Analyzing the Immunophenotype of the Transgenic Rabbits That Overexpresses FcRn

The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, takes an active role in phagocytosis, and delivers antigen for presentation. We have previously shown that overexpression of FcRn in transgenic mice significantly improves the humoral immune response. Because rabbits are an important source of polyclonal and monoclonal antibodies, adaptation of our FcRn overexpression technology in this species would bring significant advantages. We cloned the full length cDNA of the rabbit FcRn alpha-chain and found that it is similar to its orthologous analyzed so far. The rabbit FcRn - IgG contact residues are highly conserved, and based on this we predicted pH dependent interaction, which we confirmed by analyzing the pH dependent binding of FcRn to rabbit IgG using yolk sac lysates of rabbit fetuses by Western blot. Using immunohistochemistry, we detected strong FcRn staining in the endodermal cells of the rabbit yolk sac membrane, while the placental trophoblast cells and amnion showed no FcRn staining. Then, using BAC transgenesis we generated transgenic rabbits carrying and overexpressing a 110 kb rabbit genomic fragment encoding the FcRn. These transgenic rabbits – having one extra copy of the FcRn when hemizygous and two extra copies when homozygous - showed improved IgG protection and an augmented humoral immune response when immunized with a variety of different antigens. Our results in these transgenic rabbits demonstrate an increased immune response, similar to what we described in mice, indicating that FcRn overexpression brings significant advantages for the production of polyclonal and monoclonal antibodies

Evaluating the effectiveness and cost-effectiveness of Dementia Care Mapping™ to enable person-centred care for people with dementia and their carers (DCM-EPIC) in care homes: study protocol for a randomised controlled trial

Background Up to 90 % of people living with dementia in care homes experience one or more behaviours that staff may describe as challenging to support (BSC). Of these agitation is the most common and difficult to manage. The presence of agitation is associated with fewer visits from relatives, poorer quality of life and social isolation. It is recommended that agitation is treated through psychosocial interventions. Dementia Care Mapping™ (DCM™) is an established, widely used observational tool and practice development cycle, for ensuring a systematic approach to providing person-centred care. There is a body of practice-based literature and experience to suggests that DCM™ is potentially effective but limited robust evidence for its effectiveness, and no examination of its cost-effectiveness, as a UK health care intervention. Therefore, a definitive randomised controlled trial (RCT) of DCM™ in the UK is urgently needed. Methods/design A pragmatic, multi-centre, cluster-randomised controlled trial of Dementia Care Mapping (DCM™) plus Usual Care (UC) versus UC alone, where UC is the normal care delivered within the care home following a minimum level of dementia awareness training. The trial will take place in residential, nursing and dementia-specialist care homes across West Yorkshire, Oxfordshire and London, with residents with dementia. A random sample of 50 care homes will be selected within which a minimum of 750 residents will be registered. Care homes will be randomised in an allocation ratio of 3:2 to receive either intervention or control. Outcome measures will be obtained at 6 and 16 months following randomisation. The primary outcome is agitation as measured by the Cohen-Mansfield Agitation Inventory, at 16 months post randomisation. Key secondary outcomes are other BSC and quality of life. There will be an integral cost-effectiveness analysis and a process evaluation. Discussion The protocol was refined following a pilot of trial procedures. Changes include replacement of a questionnaire, whose wording caused some residents distress, to an adapted version specifically designed for use in care homes, a change to the randomisation stratification factors, adaption in how the staff measures are collected to encourage greater compliance, and additional reminders to intervention homes of when mapping cycles are due, via text message. Trial registration Current Controlled Trials ISRCTN82288852. Registered on 16 January 2014. Full protocol version and date: v7.1: 18 December 2015

Impact of laboratory test use strategies in a Turkish hospital

Objectives: Eliminating unnecessary laboratory tests is a good way to reduce costs while maintain patient safety. The aim of this study was to define and process strategies to rationalize laboratory use in Ankara Numune Training and Research Hospital (ANH) and calculate potential savings in costs. Methods: A collaborative plan was defined by hospital managers; joint meetings with ANHTA and laboratory professors were set; the joint committee invited relevant staff for input, and a laboratory efficiency committee was created. Literature was reviewed systematically to identify strategies used to improve laboratory efficiency. Strategies that would be applicable in local settings were identified for implementation, processed, and the impact on clinical use and costs assessed for 12 months. Results: Laboratory use in ANH differed enormously among clinics. Major use was identified in internal medicine. The mean number of tests per patient was 15.8. Unnecessary testing for chloride, folic acid, free prostate specific antigen, hepatitis and HIV testing were observed. Test panel use was pinpointed as the main cause of overuse of the laboratory and the Hospital Information System test ordering page was reorganized. A significant decrease (between 12.6-85.0%) was observed for the tests that were taken to an alternative page on the computer screen. The one year study saving was equivalent to 371,183 US dollars. Conclusion: Hospital-based committees including laboratory professionals and clinicians can define hospital based problems and led to a standardized approach to test use that can help clinicians reduce laboratory costs through appropriate use of laboratory test