Cost-utility analysis of community occupational therapy in dementia (COTiD-UK) versus usual care: Results from VALID, a multi-site randomised controlled trial in the UK.

BACKGROUND: A community-based occupational therapy intervention for people with mild to moderate dementia and their family carers: the Community Occupational Therapy in Dementia-UK version (COTiD-UK); and Treatment as usual (TAU) were randomly assigned to 468 pairs (each comprising a person with dementia and a family carer) in the Valuing Active Life in Dementia (VALID) randomised controlled trial (RCT). OBJECTIVES: To compare the cost-utility of the COTiD-UK intervention compared to TAU, using data from the VALID RCT. METHODS: We performed a cost-utility analysis estimating mean costs and quality adjusted life years (QALYs) per person with dementia and carer for both treatments over a 26 weeks' time horizon based on resource use data and utility values collected in the trial. RESULTS: Taking the National Health Service and Personal Social Services perspective, including costs and benefits to the person with dementia only, measuring Health Related Quality of Life based on Dementia Quality of Life scale (DEMQOL), accounting for missing data and adjusting for baseline values, there was a significant difference in costs between COTiD-UK and TAU (mean incremental cost for COTiD-UK £784 (95% CI £233 to £1334)), but no significant difference in outcomes (mean QALYs gained 0.00664 (95% CI -0.00404, 0.01732)). The Incremental Net Monetary Benefit (INMB) for COTiD-UK versus TAU was negative at a maximum willingness to pay for a QALY of £20000 (mean -£651, 95% CI -£878 to -£424) or £30000 (mean -£585, 95% CI -£824 to -£345). Extensive sensitivity analyses confirmed the results. CONCLUSIONS: This community-based occupational therapy intervention has a very low probability of being cost-effective.

Community Occupational Therapy for people with dementia and family carers (COTiD-UK) versus treatment as usual (Valuing Active Life in Dementia [VALID]) study: A single-blind, randomised controlled trial.

BACKGROUND: We aimed to estimate the clinical effectiveness of Community Occupational Therapy for people with dementia and family carers-UK version (Community Occupational Therapy in Dementia-UK version [COTiD-UK]) relative to treatment as usual (TAU). We hypothesised that COTiD-UK would improve the ability of people with dementia to perform activities of daily living (ADL), and family carers' sense of competence, compared with TAU. METHODS AND FINDINGS: The study design was a multicentre, 2-arm, parallel-group, assessor-masked, individually randomised controlled trial (RCT) with internal pilot. It was conducted in 15 sites across England from September 2014 to January 2018. People with a diagnosis of mild to moderate dementia living in their own home were recruited in pairs with a family carer who provided domestic or personal support for at least 4 hours per week. Pairs were randomised to either receive COTiD-UK, which comprised 10 hours of occupational therapy delivered over 10 weeks in the person with dementia's home or TAU, which comprised the usual local service provision that may or may not include standard occupational therapy. The primary outcome was the Bristol Activities of Daily Living Scale (BADLS) score at 26 weeks. Secondary outcomes for the person with dementia included the following: the BADLS scores at 52 and 78 weeks, cognition, quality of life, and mood; and for the family carer: sense of competence and mood; plus the number of social contacts and leisure activities for both partners. Participants were analysed by treatment allocated. A total of 468 pairs were recruited: people with dementia ranged from 55 to 97 years with a mean age of 78.6 and family carers ranged from 29 to 94 with a mean of 69.1 years. Of the people with dementia, 74.8% were married and 19.2% lived alone. Of the family carers, 72.6% were spouses, and 22.2% were adult children. On randomisation, 249 pairs were assigned to COTiD-UK (62% people with dementia and 23% carers were male) and 219 to TAU (52% people with dementia and 32% carers were male). At the 26 weeks follow-up, data were available for 364 pairs (77.8%). The BADLS score at 26 weeks did not differ significantly between groups (adjusted mean difference estimate 0.35, 95% CI -0.81 to 1.51; p = 0.55). Secondary outcomes did not differ between the groups. In total, 91% of the activity-based goals set by the pairs taking part in the COTiD-UK intervention were fully or partially achieved by the final COTiD-UK session. Study limitations include the following: Intervention fidelity was moderate but varied across and within sites, and the reliance on primarily proxy data focused on measuring the level of functional or cognitive impairment which may not truly reflect the actual performance and views of the person living with dementia. CONCLUSIONS: Providing community occupational therapy as delivered in this study did not improve ADL performance, cognition, quality of life, or mood in people with dementia nor sense of competence or mood in family carers. Future research should consider measuring person-centred outcomes that are more meaningful and closely aligned to participants' priorities, such as goal achievement or the quantity and quality of activity engagement and participation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10748953.

Taking part in the community occupational therapy in dementia UK intervention from the perspective of people with dementia, family carers and occupational therapists: A qualitative study.

AIM: Community Occupational Therapy in Dementia (COTiD-UK) is a manualised intervention delivered to the person with dementia and their identified family carer primarily in their own home. The focus is on enabling both the person with dementia and their family carer to engage in personally meaningful activities. This qualitative study examines the experiences of people with mild to moderate dementia, their family carers and occupational therapists, of taking part in the COTiD-UK intervention. METHOD: A purposive sample of 22 pairs of people with dementia and a family carer and seven occupational therapists took part in semi-structured interviews that were audio recorded, transcribed and inductively analysed using thematic analysis. FINDINGS: Themes from the occupational therapist interviews relate to the COTiD-UK intervention philosophy and content, aspects of delivering it in practice and thinking ahead to it becoming usual practice. Themes from the pair interviews relate to the focus of COTiD-UK sessions on meaningful occupation and working together and a sense of being able to plan to live well with dementia in the short- and longer-term as a result of the intervention. CONCLUSION: This person-centred occupation-focussed intervention was highly valued by people with dementia and their family carers and the occupational therapists delivering it.

Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease.

BACKGROUND/AIM: The natural history of the renal microvasculature changes in PKD is not known. The aim of this study was to test the hypothesis that angiogenesis is coupled with kidney cyst expansion, and the loss of peritubular capillary networks precedes the onset of interstitial fibrosis. METHODS: The renal microvasculature (RECA-1 and CD34) was evaluated in groups of Lewis polycystic kidney (LPK) rats and juvenile cystic kidney (jck) mice during the early, mid and late stage of disease. In addition, LPK rats and jck mice received sirolimus to determine if the reduction in renal cyst growth is in part mediated by the suppression of angiogenesis. RESULTS: In LPK rats, the loss of peritubular capillaries occurred in early-stage disease and paralleled cyst formation whereas in jck mice it was delayed to the mid stage. In both models, vasa recta were displaced by growing cysts and regressed in LPK rats with disease progression but lengthened in jck mice. Cortical and medullary capillary neoangiogenesis occurred during the early stage in both models and persisted with progression. Treatment with sirolimus reduced cyst enlargement but did not alter the progression of renal microvasculature changes in either model. CONCLUSION: Regression of peritubular capillaries and disruption of vasa recta occur in parallel with angiogenesis and the progressive enlargement of kidney cysts. These data suggest that the regrowth of peritubular capillaries together with inhibition of angiogenesis are potential strategies to be considered in the treatment of PKD.

Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease.

A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2 is a key regulator of cell proliferation, but its specific role in PKD remains unknown. The aim of this study was to test the hypothesis that Cdk2 deficiency reduces renal cyst growth in PKD. Three studies were undertaken: (i) a time course (days 28, 56, and 84) of cyclin and Cdk activity was examined in jck mice and compared with wild-type mice; (ii) the progression was compared in jck mice with or without Cdk2 ablation from birth; and (iii) the effect of sirolimus (an antiproliferative agent) on Cdk2 activity in jck mice was investigated. Renal disease in jck mice was characterized by diffuse tubular cyst growth, interstitial inflammation and fibrosis, and renal impairment, peaking on day 84. Renal cell proliferation peaked during earlier stages of disease (days 28-56), whereas the expression of Cdk2-cyclin partners (A and E) and Cdk1 and 2 activity, was maximal in the later stages of disease (days 56-84). Cdk2 ablation did not attenuate renal disease progression and was associated with persistent Cdk1 activity. In contrast, the postnatal treatment of jck mice with sirolimus reduced both Cdk2 and Cdk1 activity and reduced renal cyst growth. In conclusion, (i) the kinetics of Cdk2 and Cdk2-cyclin partners did not correlate with proliferation in jck mice; and (ii) the absence of Cdk2 did not alter renal cyst growth, most likely due to compensation by Cdk1. Taken together, these data suggest that Cdk2 is dispensable for the proliferation of cystic epithelial cells and progression of PKD.

Measuring fidelity of delivery of the Community Occupational Therapy in Dementia-UK intervention.

BACKGROUND: Interpreting data about intervention effectiveness requires an understanding of which intervention components were delivered and whether they were delivered as planned (fidelity of delivery). These studies aimed to develop a reliable measure for assessing fidelity of delivery of the Community Occupational Therapy in Dementia-UK intervention (COTiD-UK) (Study 1) and measure fidelity of delivery of COTiD-UK across sessions, sites and occupational therapists (Study 2). METHODS: The studies used a longitudinal observational design nested within a multi-site randomised controlled trial. Where practicable, all intervention sessions were audio-recorded. Fidelity checklists and coding guidelines were developed, piloted and refined until good agreement was achieved between two coders. Ten percent of sessions were purposively sampled from 12 sites and 31 occupational therapists. Transcripts were coded using checklists developed in Study 1; 10% of sets of intervention session transcripts were double coded to ensure that agreement was maintained. Percentages of components that were delivered were calculated for each session, site and occupational therapist. RESULTS: A reliable measure of fidelity of delivery for COTiD-UK was developed after several rounds of piloting and amendments. COTiD-UK was delivered with moderate fidelity across all six sessions (range: 52.4-75.5%). The mean range of fidelity varied across sites (26.7-91.2%) and occupational therapists (26.7-94.1%). CONCLUSIONS: A reliable, systematic method for measuring fidelity of delivery of COTiD-UK was developed and applied, and can be adapted for use in similar interventions. As COTiD-UK was delivered with moderate fidelity, there is a reasonable degree of confidence that intervention effects were attributable to COTiD-UK.

Recruiting hard to reach populations to studies: breaking the silence: an example from a study that recruited people with dementia.

OBJECTIVE: To share the challenges of recruiting people with dementia to studies, using experiences from one recently completed trial as an exemplar. BACKGROUND: Research publications always cite participant numbers but the effort expended to achieve the sample size is rarely reported, even when the study involved recruiting a hard to reach population. A multisite study of a psychosocial intervention for people with dementia illustrates the challenges. This study recruited 468 'dyads' (a person with dementia and a family carer together) from 15 sites but the time taken to achieve this was longer than originally estimated. This led to a study extension and the need for additional sites. Recruitment data revealed that certain sites were more successful than others, but why? Can the knowledge gained be used to inform other studies? METHODS: Secondary analysis of routinely collected recruitment data from three purposefully selected sites was examined to understand the strategies used and identify successful approaches. FINDINGS: At all three sites, the pool of potential recruits funnelled to a few participants. It took two sites 18 months longer than the third to achieve recruitment numbers despite additional efforts. Explanations given by potential participants for declining to take part included ill health, reporting they were 'managing', time constraints, adjusting to a diagnosis of dementia and burden of study procedures. CONCLUSIONS: Successful recruitment of people with dementia to studies, as one example of a hard to reach group, requires multiple strategies and close working between researchers and clinical services. It requires a detailed understanding of the needs and perspectives of the specific population and knowledge about how individuals can be supported to participate in research. Experiences of recruitment should be disseminated so that knowledge generated can be used to inform the planning and implementation of future research studies.

Changes in Oral Health Behaviors Associated With a Nursing Intervention in Primary Care.

Objective. To describe changes in oral health behaviors following implementation of a nursing intervention targeting children at risk for early childhood caries at an urban 2-site primary care practice. Methods. Nurses used a proprietary Nursing Caries Assessment Tool (N-CAT) to identify behaviors associated with early childhood caries risk, then provided brief focused dental education, fluoride varnish applications, and dental referrals to children without a dental home. We used generalized estimating equation logistic regression models, adjusted for age at visit, to analyze changes in oral health behaviors over time including the following: (1) tooth brushing frequency, (2) use of fluoride toothpaste, and (3) adult help with brushing among children younger than 5 years of age who had at least 2 N-CATs documented during well care visits between April 2013 and June 2015. We also evaluated dietary habits including going to bed with a bottle or sippy cup and sugar-sweetened beverage consumption, as secondary study outcomes during the same time frame. Results. A total of 2097 children with a mean age of 15.8 (SD 7.6) months at the initial visit were included in the analysis; 51% were boys; 28% were black, 36% Hispanic/Latino, 5% white, 2% Asian, and 19% other; 75% were publicly insured. During the study period, significant (P < .05) improvements were noted across the 3 oral health behaviors studied among children younger than 18 months. Conclusion. Nursing interventions show promise for promoting preventive dental care in primary care settings and deserve further study.

Establishment and Operation of a Third-Party Virus-Specific T Cell Bank within an Allogeneic Stem Cell Transplant Program.

Hematopoietic stem cell transplantation (HSCT) donor-generated virus-specific T cells (VSTs) can provide effective treatment for viral infection post-HSCT but are not readily accessible to all patients. Off-the-shelf cryopreserved VSTs suitable for treatment of multiple patients are an attractive alternative. We generated a bank of 17 cytomegalovirus (CMV)-, 14 Epstein-Barr virus (EBV)-, and 15 adenovirus (AdV)-specific T cell products from 30 third-party donors. Donors were selected for expression of 6 core HLA antigens expressed at high frequency in the local transplant population. T cells were generated by co-culturing venous blood or mobilized hematopoietic stem cell (HSC)-derived mononuclear cells with monocyte-derived dendritic cells pulsed with overlapping peptides covering CMV pp65, AdV5 hexon, or EBV BZLF1/LMP2A/EBNA1 proteins. Addition of a CD14+ selection step instead of plate adherence to isolate monocytes before culture initiation significantly improved expansion in cultures from HSC material. Phenotyping showed the CD8+ subset to have significantly higher numbers of terminal effector T cells (CD45RA+62L-) and lower numbers of effector memory T cells (CD45RA-62L-) when compared with the CD4+ subset. Increased expression of the immunoinhibitory markers PD-1 and TIM-3 was noted on CD4+ but not CD8+ cells when compared with the control group. VST showed antiviral activity restricted through a variety of common HLAs, and modelling suggested a suitably HLA-matched product would be available for >90% of HSCT patients. Only a small number of carefully selected third-party donors are required to generate a VST bank of broad coverage, indicating the feasibility of local banking integrated into existing allogeneic HSCT programs.

Adjuvant Peptide Pulsed Dendritic Cell Vaccination in Addition to T Cell Adoptive Immunotherapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Adoptive cellular immunotherapy has been shown to be effective in the management of cytomegalovirus (CMV) reactivation and disease. Whether adjuvant dendritic cell (DC) vaccination will provide additional benefit in prophylaxis or treatment of CMV in hematoietic cell transplantation (HSCT) recipients is unknown. In this study, we administered prophylactic CMV-peptide specific T cell infusions, followed by 2 doses of intradermal CMV peptide-pulsed DC vaccine, to 4 HSCT recipients. There were no immediate adverse events associated with T cell infusion or DC vaccinations. One of the 4 patients developed grade III acute gut graft-versus-host disease. Immune reconstitution against CMV was detected in all 4 patients. Patients receiving CMV peptide-specific T cells and DC vaccination had peak immune reconstitution at least 10 days after the second DC vaccination. In summary, combining DC vaccine with T cell infusion appears feasible, although further study is required to ascertain its safety and efficacy in augmenting the effects of infusing donor-derived CMV-specific T cells.

Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells.

Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells (VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant (HSCT) patients with persistent or recurrent cytomegalovirus (CMV) (n = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo-expanded VSTs (total = 50 infusions) at a median of 75 days post-HSCT (range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specific T-cell immunity rose significantly and coincided with a rise in CD8+ terminal effector cells. PD-1 expression was elevated on CD8+ lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD8+ effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718.

Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immunotherapy in patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Virus-specific T-cell immunotherapy is emerging as a promising management strategy for virus infections in patients after hematopoietic stem cell transplant (HSCT). Here we present outcomes of 10 adult patients who received multi-virus-specific T cells prophylactically after HSCT. METHODS: Donor-derived cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)-, adenoviral- and varicella zoster virus (VZV)-specific T cells were generated in a single culture and administered to HSCT patients at a dose of 2 × 10(7)/m(2) virus-specific T cells at a median of 63 days post-transplant. Patients were monitored for 12 months for evidence of viral reactivation and graft-versus-host disease. RESULTS: There was no acute infusion-related toxicity. Six patients developed CMV reactivation after T-cell infusion with a median peak CMV DNA titer of 600 copies per milliliter, and 1 received CMV-specific pharmacotherapy post-infusion. No EBV, adenoviral or VZV reactivation or disease was reported. Using interferon-γ Elispot analysis on post-infusion samples, we identified anti-viral immunity against all viruses including VZV. Three patients (30%) developed grade II-IV acute graft-versus-host disease. CONCLUSIONS: This is the first description of the use of a multi-virus-specific T-cell product containing cells specific for VZV after allogeneic HSCT. The T-cell product appears safe in the setting of HSCT and confirms our previous findings regarding CMV control and treatment. A larger study with longer follow-up is required to determine the efficacy of VZV-specific T cells given prophylactically in controlling episodes of herpes zoster and disseminated varicella infection after cessation of prophylactic anti-viral treatment.

The role of evidence and context for implementing a multimodal intervention to increase HIV testing.

BACKGROUND: Increasing the use of routine preventive care such as HIV testing is important, yet implementation of such evidence-based clinical care is complex. The Promoting Action on Research Implementation in Health Services (PARiHS) model for implementation posits that implementation will be most successful when the evidence, context, and facilitation strategies are strong for the clinical practice. We evaluated the relative importance of perceived evidence, context, and facilitation of HIV testing during the implementation of a multimodal intervention in US Department of Veterans Affairs primary care clinics. METHODS: A multimodal intervention including clinical reminders (CRs), academic detailing--providing education sessions for providers--and social marketing to improve HIV testing was implemented in 15 VA primary care clinics in three regions. We conducted qualitative formative and process evaluations using semi-structured interviews with HIV lead clinicians, primary care lead clinicians, nurse managers, and social workers. Interviews were analyzed thematically to identify barriers and facilitators to implementation of HIV testing and how these were addressed by the intervention. Sites were then rated high, medium, or low on the dimensions of perceived evidence and the context for testing. We then assessed the relationship of these ratings to improvements in HIV testing rates found in earlier quantitative analyses. RESULTS: Sites that showed greatest improvements in HIV testing rates also rated high on evidence and context. Conversely, sites that demonstrated the poorest improvements in testing rates rated low on both dimensions. Perceptions of evidence and several contextual aspects resulted in both barriers and facilitators to implementing testing. Evidence barriers included provider perceptions of evidence for routine testing as irrelevant to their population. Contextual barriers included clinical reminder overload, insufficient resources, onerous consent processes, stigma, provider discomfort, and concerns about linking individuals who test positive to HIV treatment. While most barriers were ameliorated by the intervention, HIV stigma in particular regions and concerns about linkage to care persisted. CONCLUSIONS: Interventions to implement evidence-based practices such as HIV testing can be successful when utilizing proven quality improvement techniques. However, it is critical to address providers' perceptions of evidence and consider aspects of the local context in order to fully implement new routine clinical practices such as HIV testing.

Central implementation strategies outperform local ones in improving HIV testing in Veterans Healthcare Administration facilities.

BACKGROUND: Pilot data suggest that a multifaceted approach may increase HIV testing rates, but the scalability of this approach and the level of support needed for successful implementation remain unknown. OBJECTIVE: To evaluate the effectiveness of a scaled-up multi-component intervention in increasing the rate of risk-based and routine HIV diagnostic testing in primary care clinics and the impact of differing levels of program support. DESIGN: Three arm, quasi-experimental implementation research study. SETTING: Veterans Health Administration (VHA) facilities. PATIENTS: Persons receiving primary care between June 2009 and September 2011 INTERVENTION: A multimodal program, including a real-time electronic clinical reminder to facilitate HIV testing, provider feedback reports and provider education, was implemented in Central and Local Arm Sites; sites in the Central Arm also received ongoing programmatic support. Control Arm sites had no intervention MAIN MEASURES: Frequency of performing HIV testing during the 6 months before and after implementation of a risk-based clinical reminder (phase I) or routine clinical reminder (phase II). KEY RESULTS: The adjusted rate of risk-based testing increased by 0.4 %, 5.6 % and 10.1 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). During phase II, the adjusted rate of routine testing increased by 1.1 %, 6.3 % and 9.2 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). At study end, 70-80 % of patients had been offered an HIV test. CONCLUSIONS: Use of clinical reminders, provider feedback, education and social marketing significantly increased the frequency at which HIV testing is offered and performed in VHA facilities. These findings support a multimodal approach toward achieving the goal of having every American know their HIV status as a matter of routine clinical practice.

Cytomegalovirus-specific cytotoxic T lymphocytes can be efficiently expanded from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell products ex vivo and safely transferred to stem cell transplantation recipients to facilitate immune reconstitution.

Uncontrolled cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation causes significant morbidity and mortality. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) is a promising therapy to treat reactivation and prevent viral disease. In this article, we describe the generation of clinical-grade CMV-specific CTLs directly from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell (G-HPC) products collected for transplantation. This method requires less than 2.5% of a typical G-HPC product to reproducibly expand CMV-specific CTLs ex vivo. Comparison of 11 CMV CTL lines generated from G-HPC products with 52 CMV CTL lines generated from nonmobilized peripheral blood revealed similar expansion kinetics and phenotype. G-HPC-derived CTLs produced IFN-γ after reexposure to CMVpp65 antigen and exhibited CMV-directed cytotoxicity but no alloreactivity against transplantation recipient-derived cells. Seven patients received CMV-specific CTL lines expanded from G-HPC products in a prophylactic adoptive immunotherapy phase I/II clinical trial. Use of G-HPC products will facilitate integration of CTL generation into established quality systems of transplantation centers and more rapid inclusion of T cell therapies into routine clinical care.

Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation.

We investigated the use of adoptively transferred donor-derived cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) as immune reconstitution postallogeneic transplant in a phase 2 study. Fifty patients were infused with a single dose of 2 × 10(7)cells/m(2) after day 28 post-transplant. Twenty-six patients reactivated CMV posttransplant (only 5 post-CTL infusion) and 9 required therapy with ganciclovir or foscarnet (only 1 post-CTL infusion). There was 1 case of fatal CMV disease, attributable to high levels of antithymocyte globulin at the time of T cell infusion. We compared the patients in the phase 2 study with a group of contemporaneous controls also treated at the trial centers. There was no increase in acute or chronic graft-versus-host disease attributable to CTL infusion; overall and progression-free survival were similar in both groups. There was a reduction in the percentage of patients who required CMV directed antiviral therapy (17% vs 36%, P = .01) and in the total number of treatment days in the cohort receiving CTL (3.4 days vs 8.9 days, P = .03) without a reduction in CMV reactivation rates. We postulate that adoptively transferred cells are able to expand in response to viral antigen, limit viral replication, and prevent progression to tissue infection. This study was registered on the Australian Clinical Trial Registry as #ACTRN12605000213640 and #ACTRN12607000224426.

Cultural adaptation of an evidence-based nursing intervention to improve medication adherence among people living with HIV/AIDS (PLWHA) in China.

BACKGROUND: Adapting nursing interventions to suit the needs and culture of a new population (cultural adaptation) is an important early step in the process of implementation and dissemination. While the need for cultural adaptation is widely accepted, research-based strategies for doing so are not well articulated. Non-adherence to medications for chronic disease is a global problem and cultural adaptation of existing evidence-based interventions could be useful. OBJECTIVES: This paper aims to describe the cultural adaptation of an evidence-based nursing intervention to improve medication adherence among people living with HIV/AIDS and to offer recommendations for adaptation of interventions across cultures and borders. SITE: The intervention, which demonstrated efficacy in a randomized controlled trial in North America, was adapted for the cultural and social context of Hunan Province, in south central China. SOURCES OF DATA: The adaptation process was undertaken by intervention stakeholders including the original intervention study team, the proposed adaptation team, and members of a Community Advisory Board, including people living with HIV/AIDS, family members, and health care workers at the target clinical sites. PROCEDURES: The adaptation process was driven by quantitative and qualitative data describing the new population and context and was guided by principles for cultural adaptation drawn from prevention science research. RESULTS: The primary adaptation to the intervention was the inclusion of family members in intervention activities, in response to the cultural and social importance of the family in rural China. In a pilot test of the adapted intervention, self-reported medication adherence improved significantly in the group receiving the intervention compared to the control group (p=0.01). Recommendations for cultural adaptation of nursing interventions include (1) involve stakeholders from the beginning; (2) assess the population, need, and context; (3) evaluate the intervention to be adapted with attention to details of the original studies that demonstrated efficacy; (4) compare important elements of the original intervention with those of the proposed new population and context to identify primary points for adaptation; (5) explicitly identify sources of tension between intervention fidelity and cultural adaptive needs; (6) document the process of adaptation, pilot the adapted intervention, and evaluate its effectiveness before moving to dissemination and implementation on a large scale.

Pre-clinical model of composite foetal pig pancreas fragment/renal xenotransplantation to treat renal failure and diabetes.

UNLABELLED: BACKGROUND: Development of a limitless source of ß cells for xenotransplantation into patients suffering type 1 diabetes and renal failure that can control their diabetes and provide normal renal function in one procedure would be a major achievement. For the islet tissue to survive transplantation, as an islet-kidney composite graft this would have significant advantages. It would simplify the surgical procedure; remove the complications caused by the exocrine pancreas whilst reversing diabetes and uraemia. It was our hypothesis that a composite foetal porcine pancreas fragment (FPPF)/renal graft could achieve these objectives in a large pre-clinical animal model as a means to establish whether this would be feasible before moving to the clinic. METHODS: Inbred 'Westran' pig FPPF were transplanted under the kidney capsule of syngeneic Westran pig recipients without immunosuppression. Following maturation of the FPPF under the renal subcapsular space of this recipient, this kidney bearing the composite FPPF piggyback graft was removed and transplanted into another nephrectomized and pancreatectomized recipient to demonstrate function. RESULTS: Under the kidney capsule of the first transplant group (n = 6), the FPPF-transplanted tissue developed and matured to form islet cell nests. These composite FPPF/renal grafts were then successfully removed and transplanted into the second functional assessment recipient group. This second group of six composite FPPF/renal-grafted pigs had normal renal function for more than 44 days and normal glucose homoeostasis without exogenous insulin as assessed by normal glucose tolerance tests, K values and normal glucagon secretion. Histological analysis showed despite the ischaemic insult during the composite kidney transplant procedure, there was appropriate development of islet-like structures up to and beyond 224 days after the original transplantation under the kidney capsule. CONCLUSIONS: This study shows that the use of composite FPPF/renal grafts can cure both diabetes and renal failure with a single-transplant procedure. Using such composite grafts for xenotransplantation would simplify the surgical procedure and protect the islet graft from the immediate innate immune response.

Subcapsular fetal pig pancreas fragment transplantation provides normal blood glucose control in a preclinical model of diabetes.

OBJECTIVE: Identifying a limitless source of ß-cells that survive transplantation into a neovascularised site and provide normal blood glucose control remains an important goal in the development of pancreatic islet xenotransplantation. It was our hypothesis that fetal porcine pancreas fragments could achieve these objectives, and this was tested in a large preclinical animal model. RESEARCH DESIGN AND METHODS: Inbred "Westran Pig" fetal porcine pancreas fragments were transplanted beneath the splenic capsule into syngeneic Westran Pig recipients without immunosuppression, and 3 months later, a total native pancreatectomy was performed to demonstrate function. RESULTS: Histologic analysis showed appropriate development of islet-like structures up to and beyond 120 days after transplantation. After native pancreatectomy, recipients survived more than 100 days without exogenous insulin and with normal glucose homeostasis as assessed by normal glucose tolerance tests, K values, and normal glucagon secretion. CONCLUSIONS: This study confirms that fetal pig islet tissue has the potential to mature and function normally in a neovascularised site, hence, avoiding the innate immune destruction that occurs when islet tissue is exposed directly to the circulation.