Is it feasible to deliver a complex intervention to improve the outcome of falls in people with dementia? A protocol for the DIFRID feasibility study

Background: People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed-methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups, and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods: People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED; facilitated discharge services; rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life–Alzheimer’s Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL-AD Proxy and a Health Utilisation Questionnaire (HUQ), The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion: The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination: The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration: International Standard Randomised Controlled Trial Registry Registration number: ISRCTN41760734 Date of registration: 16/11/201

Robust acinar cell transgene expression of CreErT via BAC recombineering

Pancreatic acinar cells are critical in gastrointestinal physiology and pancreatitis and may be involved in pancreatic cancer. Previously, a short rat pancreatic elastase promoter has been widely utilized to control acinar cell transgene expression. However, this partial sequence does not confer robust and stable expression. In this study, we tested the hypothesis that a transgene employing bacterial-artificial-chromosome (BAC) technology to express a tamoxifen-regulated Cre recombinase from a full-length mouse elastase gene (BAC-Ela-CreErT) would be more robust and stable. When founders were crossed with Rosa26 reporter mice nearly 100% of acini expressed Β-galactosidase after tamoxifen treatment. The expression was specific for pancreatic acinar cells and these characteristics have remained stable for 2 years. However, because of high levels of expression in differentiated acinar cells, this construct is tamoxifen independent in ∼50% of adult acinar cells. This model of pancreatic acinar specific Cre expression is a powerful tool for future transgenic and knockout studies. genesis 46:390–395, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60895/1/20411_ftp.pd

Tumor-Infiltrating Mast Cells Confer Resistance to Immunotherapy in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltration correlated with human PDAC progression, and genetic or pharmacological mast cell depletion reduced tumor growth and desmoplasia while enhancing survival in mouse PDAC models. Mechanistically, mast cell-derived IL-10 promoted PDAC progression. Strikingly, combining an agonistic anti-OX40 immunotherapy with mast cell blockade synergistically elicited durable anti-tumor immunity, marked by increased infiltration of CD

Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC

Cognitive behavioural therapy (CBT) for anxiety in people with dementia: study protocol for a randomised controlled trial

Background Many people with dementia experience anxiety, which can lead to decreased independence, relationship difficulties and increased admittance to care homes. Anxiety is often treated with antipsychotic medication, which has limited efficacy and serious side effects. Cognitive behavioural therapy (CBT) is widely used to treat anxiety in a range of populations, yet no RCTs on CBT for anxiety in dementia exist. This study aims to develop a CBT for anxiety in dementia manual and to determine its feasibility in a pilot RCT. Methods/design Phase I involves the development of a CBT for anxiety in dementia manual, through a process of (1) focus groups, (2) comprehensive literature reviews, (3) expert consultation, (4) a consensus conference and (5) field testing. Phase II involves the evaluation of the manual with 50 participants with mild to moderate dementia and anxiety (and their carers) in a pilot, two-armed RCT. Participants will receive either ten sessions of CBT or treatment as usual. Primary outcome measures are anxiety and costs. Secondary outcome measures are participant quality of life, behavioural disturbance, cognition, depression, mood and perceived relationship with the carer, and carer mood and perceived relationship with the person with dementia. Measures will be administered at baseline, 15 weeks and 6 months. Approximately 12 qualitative interviews will be used to gather service-users' perspectives on the intervention. Discussion This study aims to determine the feasibility of CBT for people with anxiety and dementia and provide data on the effect size of the intervention in order to conduct a power analysis for a definitive RCT. The manual will be revised according to qualitative and quantitative findings. Its publication will enable its availability throughout the NHS and beyond. Trial registration ISRCTN6480685

Improving care for people with dementia: development and initial feasibility study for evaluation of life story work in dementia care

Background: Improving dementia care quality is an urgent priority nationally and internationally. Life story work (LSW) is an intervention that aims to improve individual outcomes and care for people with dementia and their carers. LSW gathers information and artefacts about the person, their history and interests, and produces a tangible output: the ‘life story’. Objective: To establish whether or not full evaluation of LSW was feasible. Design: Mixed-methods feasibility study. Methods: In-depth interviews and focus groups explored experiences of LSW and best practice with people with dementia, family members and dementia care staff. A systematic review explored best practice and theories of change for LSW. These stages helped to identify the outcomes and resources to explore in the feasibility study. A representative sample survey of health and social care dementia care providers in England established LSW practice in different settings. A survey of a self-selected sample of family members of people with dementia explored how LSW is experienced. Two small outcome studies (stepped-wedge study in six care homes and pre-test post-test study in inpatient specialist dementia care wards) explored the feasibility of full evaluation of LSW in these settings. Settings: Survey: generalist and specialist care homes; NHS dementia care settings; and community dementia services. Feasibility study: care homes and NHS inpatient dementia care wards. Participants: NHS and social care services, people with dementia, family carers, care home staff and NHS staff. Interventions: LSW. Main outcome measures: Spread of LSW and good practice, quality of life (QoL) for the person with dementia and carers, relationships between people with dementia and family carers, staff attitudes about dementia, staff burnout, resource use and costs. Review methods: Narrative review and synthesis, following Centre for Review and Dissemination guidelines. Results: Good practice in LSW is identifiable, as are theories of change about how it might affect given outcomes. Indicators of best practice were produced. LSW is spreading but practice and use vary between care settings and are not always in line with identified good practice. Two different models of LSW are evident; these are likely to be appropriate at different stages of the dementia journey. The feasibility study showed some positive changes in staff attitudes towards dementia and, for some people with dementia, improvements in QoL. These may be attributable to LSW but these potential benefits require full evaluation. The feasibility work established the likely costs of LSW and highlighted the challenges of future evaluation in care homes and inpatient dementia care settings. Limitations: There was insufficient evidence in the literature to allow estimation of outcome size. We did not carry out planned Markov chain modelling to inform decisions about carrying out future evaluation because of the dearth of outcome data in the literature; low levels of data return for people with dementia in the hospital settings; lack of detected effect for most people with dementia; and questions about implementation in the research settings. Conclusions: LSW is used across different health and social care settings in England, but in different ways, not all of which reflect ‘good practice’. This large, complex study identified a wide range of challenges for future research, but also the possibility that LSW may help to improve care staff attitudes towards dementia and QoL for some people with dementia. Future work: Full evaluation of LSW as an intervention to improve staff attitudes and care is feasible with researchers based in or very close to care settings to ensure high-quality data collection. Funding: The National Institute for Health Research Health Services and Delivery Research programme. Keywords

Challenge Demcare: management of challenging behaviour in dementia at home and in care homes:Development, evaluation and implementation of an online individualised intervention for care homes; and a cohort study of specialist community mental health care for families

Background: Dementia with challenging behaviour (CB) causes significant distress for caregivers and the person with dementia. It is associated with breakdown of care at home and disruption in care homes. Challenge Demcare aimed to assist care home staff and mental health practitioners who support families at home to respond effectively to CB. Objectives: To study the management of CB in care homes (ResCare) and in family care (FamCare). Following a conceptual overview, two systematic reviews and scrutiny of clinical guidelines, we (1) developed and tested a computerised intervention; (2) conducted a cluster randomised trial (CRT) of the intervention for dementia with CB in care homes; (3) conducted a process evaluation of implementation of the intervention; and (4) conducted a longitudinal observational cohort study of the management of people with dementia with CB living at home, and their carers. Review methods: Cochrane review of randomised controlled trials; systematic meta-ethnographic review of quantitative and qualitative studies. Design: ResCare – survey, CRT, process evaluation and stakeholder consultations. FamCare – survey, longitudinal cohort study, participatory development design process and stakeholder consultations. Comparative examination of baseline levels of CB in the ResCare trial and the FamCare study participants. Settings: ResCare – 63 care homes in Yorkshire. FamCare – 33 community mental health teams for older people (CMHTsOP) in seven NHS organisations across England. Participants: ResCare – 2386 residents and 861 staff screened for eligibility; 555 residents with dementia and CB; 277 ‘other’ residents; 632 care staff; and 92 staff champions. FamCare – every new referral (n = 5360) reviewed for eligibility; 157 patients with dementia and CB, with their carer; and 26 mental health practitioners. Stakeholder consultations – initial workshops with 83 practitioners and managers from participating organisations; and 70 additional stakeholders using eight group discussions and nine individual interviews. Intervention: An online application for case-specific action plans to reduce CB in dementia, consisting of e-learning and bespoke decision support care home and family care e-tools. Main outcome measures: ResCare – survey with the Challenging Behaviour Scale; measurement of CB with the Neuropsychiatric Inventory (NPI) and medications taken from prescriptions; implementation with thematic views from participants and stakeholders. FamCare – case identification from all referrals to CMHTsOP; measurement of CB with the Revised Memory and Behaviour Problems Checklist and NPI; medications taken from prescriptions; and thematic views from stakeholders. Costs of care calculated for both settings. Comparison of the ResCare trial and FamCare study participants used the NPI, Clinical Dementia Rating and prescribed medications. Results: ResCare – training with group discussion and decision support for individualised interventions did not change practice enough to have an impact on CB in dementia. Worksite e-learning opportunities were not readily taken up by care home staff. Smaller homes with a less hierarchical management appear more ready than others to engage in innovation. FamCare – home-dwelling people with dementia and CB are referred to specialist NHS services, but treatment over 6 months, averaging nine contacts per family, had no overall impact on CB. Over 60% of people with CB had mild dementia. Families bear the majority of the care costs of dementia with CB. A care gap in the delivery of post-diagnostic help for families supporting relatives with dementia and significant CB at home has emerged. Higher levels of CB were recorded in family settings; and prescribing practices were suboptimal in both care home and family settings. Limitations: Functionality of the software was unreliable, resulting in delays. This compromised the feasibility studies and undermined delivery of the intervention in care homes. A planned FamCare CRT could not proceed because of insufficient referrals. Conclusions: A Cochrane review of individualised functional analysis-based interventions suggests that these show promise, although delivery requires a trained dementia care workforce. Like many staff training interventions, our interactive e-learning course was well received by staff when delivered in groups with facilitated discussion. Our e-learning and decision support e-tool intervention in care homes, in its current form, without ongoing review of implementation of recommended action plans, is not effective at reducing CB when compared with usual care. This may also be true for staff training in general. A shift in priorities from early diagnosis to early recognition of dementia with clinically significant CB could bridge the emerging gap and inequities of care to families. Formalised service improvements in the NHS, to co-ordinate such interventions, may stimulate better opportunities for practice models and pathways. Separate services for care homes and family care may enhance the efficiency of delivery and the quality of research on implementation into routine care. Future work: There is scope for extending functional analysis-based interventions with communication and interaction training for carers. Our clinical workbooks, video material of real-life episodes of CB and process evaluation tool resources require further testing. There is an urgent need for evaluation of interventions for home-dwelling people with dementia with clinically significant CB, delivered by trained dementia practitioners. Realist evaluation designs may illuminate how the intervention might work, and for whom, within varying service contexts

Identification of a Specific Vimentin Isoform That Induces an Antibody Response in Pancreatic Cancer

Pancreatic cancer has a poor prognosis, in part due to lack of early detection. The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis. We have used a proteomic approach to identify proteins that commonly induce a humoral response in pancreatic cancer. Proteins from a pancreatic adenocarcinoma cell line (Panc-1) were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for autoantibodies. Sera from 36 newly diagnosed patients with pancreatic cancer, 18 patients with chronic pancreatitis and 15 healthy subjects were analyzed. Autoantibodies were detected against a protein identified by mass spectrometry as vimentin, in sera from 16/36 patients with pancreatic cancer (44.4%). Only one of 18 chronic pancreatitis patients and none of the healthy controls exhibited reactivity against this vimentin isoform. Interestingly, none of several other isoforms of vimentin detectable in 2-D gels exhibited reactivity with patient sera. Vimentin protein expression levels were investigated by comparing the integrated intensity of spots visualized in 2-D PAGE gels of various cancers. Pancreatic tumor tissues showed greater than a 3-fold higher expression of total vimentin protein than did the lung, colon, and ovarian tumors that were analyzed. The specific antigenic isoform was found at 5–10 fold higher levels. The detection of autoantibodies to this specific isoform of vimentin may have utility for the early diagnosis of pancreatic cancer

Human Pancreatic Acinar Cells Do Not Respond to Cholecystokinin

Pancreatic secretion can be influenced by cholecystokinin (CCK) either directly via actions on acinar cells or indirectly via actions on nerves. The presence and functional roles of CCK receptors on human pancreatic acinar cells remains unclear. In the current study human pancreatic acini were isolated and then treated with CCK-8, gastrin and/or carbachol. Functional parameters were measured including intracellular [Ca2+] and amylase secretion. It was observed that human acini did not respond to CCK agonists but did respond to carbachol with robust increases in functional parameters. Adenoviral-mediated gene transfer of CCK1 or CCK2 receptors to the human cells resulted in cell responses to CCK agonists. In order to determine the reason for the lack of responsiveness of the human acini, expression of receptor mRNAs was determined using quantitative RT-PCR and localized by in situ hybridization. mRNA levels for CCK1 receptors were ∼30 times lower than those of CCK2 receptors, which were ∼10 times lower than those of m3 Ach receptors as measured by quantitative PCR. Neither CCK1 nor CCK2 receptors were localized in adult human pancreas by i n situ hybridization. These results indicate that human pancreatic acinar cells do not respond directly to CCK receptor activation and this is likely due to an insufficient level of receptor expression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73903/1/j.1600-0773.2002.910610.x.pd