A rapid realist review of clinical neuropsychology rehabilitation programmes to improve psychological wellbeing and quality of life for people with acquired brain injuries.

Approximately 20% of acquired brain injury (ABI) survivors experience reduced psychological wellbeing (PWB). Neuropsychological rehabilitation (NPR) is one approach supporting people with ABI to participate meaningfully in activities despite challenges. Although literature supports NPR effectiveness, little is known about change mechanisms. This systematic realist review identifies what NPR programmes have been designed, delivered, and evaluated for people with ABI to improve PWB and/or quality of life (QOL), as well as providing a context-relevant understanding of what NPR includes and how NPR might lead to positive outcomes. A rapid realist review was conducted in three phases: (1) structured retrieval and evidence extraction; (2) stakeholder consultation; (3) analysis and synthesis. Searches were completed, and findings from 35 publications and one stakeholder consultation were synthesized into a refined logic model. Six context-mechanism-outcome chains (CMOCs) were identified. Participants' relationships to internal experiences, and feelings of self-worth, mastery, and connection appeared to be mechanisms that led to improved PWB and QOL. Adaptation and individualized programmes were also key mechanisms to explain successful NPR. Embedding CMOCs into NPR could improve PWB and/or QOL for people with ABI. The logic model will inform ongoing development of a new online, group-based, NPR programme.

Enhancing the immunogenicity of cancer vaccines by harnessing CLEC9A.

Dendritic cell (DC) vaccines are a safe and effective means of inducing tumor immune responses, however, a better understanding of DC biology is required in order to realize their full potential. Recent advances in DC biology have identified a crucial role for cDC1 in tumor immune responses, making this DC subset an attractive vaccine target. Human cDC1 exclusively express the C-type-lectin-like receptor, CLEC9A (DNGR-1) that plays an important role in cross-presentation, the process by which effective CD8+ T cell responses are generated. CLEC9A antibodies deliver antigen specifically to cDC1 for the induction of humoral, CD4+ and CD8+ T cell responses and are therefore promising candidates to develop as vaccines for infectious diseases and cancer. The development of human CLEC9A antibodies now facilitates their application as vaccines for cancer immunotherapy. Here we discuss the recent advances in CLEC9A targeting antibodies as vaccines for cancer and their translation to the clinic.

The application of triple aim framework in the context of primary healthcare: A systematic literature review.

The Triple Aim framework is an increasingly popular tool for designing and assessing quality improvements in the health care sector. We systematically reviewed the empirical evidence on the application of the Triple Aim framework within primary healthcare settings since its inception almost a decade ago. Results show that primary healthcare providers varied in their interpretation of the Triple Aim framework and generally struggled with a lack of guidance and an absence of composite sets of measures for performance assessment. Greater clarity around application of the Triple Aim framework in primary healthcare is needed, especially around the selection and implementation of purposeful measures from locally available data. This review highlights areas for improvement and makes recommendations intended to guide future applications of the Triple Aim in the context of primary healthcare.

Intergenerational care: an exploration of consumer preferences and willingness to pay for care.

OBJECTIVES: To identify feasible models of intergenerational care programmes, that is, care of children and older people in a shared setting, to determine consumer preferences and willingness to pay. METHOD: Feasible models were constructed in extensive consultations with a panel of experts using a Delphi technique (n = 23) and were considered based on their practical implementation within an Australian setting. This informed a survey tool that captured the preferences and willingness to pay for these models by potential consumers, when compared to the status quo. Information collected from the surveys (n = 816) was analysed using regression analysis to identify fundamental drivers of preferences and the prices consumers were willing to pay for intergenerational care programmes. RESULTS: The shared campus and visiting models were identified as feasible intergenerational care models. Key attributes of these models included respite day care; a common educational pedagogy across generations; screening; monitoring; and evaluation of participant outcomes. Although parents were more likely to take up intergenerational care compared to the status quo, adult carers reported a higher willingness to pay for these services. Educational attainment also influenced the likely uptake of intergenerational care. CONCLUSIONS: The results of this study show that there is demand for the shared campus and the visiting campus models among the Australian community. The findings support moves towards consumer-centric models of care, in line with national and international best practice. This consumer-centric approach is encapsulated in the intergenerational care model and enables greater choice of care to match different consumer demands.

Speech and swallow rehabilitation in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. The disease itself and the treatment can have far reaching effects on speech and swallow function, which are consistently prioritised by survivors as an area of concern. This paper provides recommendations on the assessments and interventions for speech and swallow rehabilitation in this patient group. Recommendations • All multidisciplinary teams should have rehabilitation patient pathways covering all stages of the patient's journey including multidisciplinary and pre-treatment clinics. (G) • Clinicians treating head and neck cancer patients should consult the National Cancer Rehabilitation Pathway for head and neck cancers. (G) • All head and neck cancer patients should have a pre-treatment assessment of speech and swallowing. (G) • A programme of prophylactic exercises and the teaching of swallowing manoeuvres can reduce impairments, maintain function and enable a speedier recovery. (R) • Continued speech and language therapist input is important in maintaining voice and safe and effective swallow function following head and neck cancer treatment. (R) • Disease recurrence must be ruled out in the management of stricture and/or stenosis. (R) • Continuous radial expansion balloons offer a safe, effective dilation method with advantages over gum elastic bougies. (R) • Site, length and completeness of strictures as well as whether they are in the presence of the larynx or not, need to be assessed when establishing the likelihood of surgically improved outcome. (G) • Primary surgical voice restoration should be offered to all patients undergoing laryngectomy. (R) • Attention to surgical detail and long-term speech and language therapist input is required to optimise speech and swallowing after laryngectomy. (G) • Patients should commence wearing heat and moisture exchange devices as soon as possible after laryngectomy. (R).

Histone deacetylase activity and recurrent bacterial bronchitis in severe eosinophilic asthma.

An increase in P13 Kinase activity and an associated reduction in histone deacetylase activity may contribute to both relative steroid insensitivity in patients with severe eosinophilic asthma and impaired macrophage scavenger function and susceptibility to recurrent infective bronchitis that may, in turn, contribute to further steroid insensitivity.

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

BACKGROUND: In severe asthmatics with persistent airway eosinophilia, blockade of interleukin-5 has significant steroid-sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics. OBJECTIVES: In a cross-sectional study, the number and growth potential of eosinophil-lineage-committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, eight COPD patients and eight normal subjects. The effect of anti-IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (substudy of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n = 9) or placebo (n = 8), as six monthly subcutaneous injections. RESULTS: Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony-forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP numbers consistent with blockade of systemic eosinophilopoiesis. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose. CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg subcutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5-driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma.

The effects of an epithelial barrier protective cationic aerosol on allergen-induced airway inflammation in asthma: a randomized, placebo-controlled clinical trial.

Inhaled cationic airway lining modulator (iCALM) is a cationic aerosol therapy comprised of 1.29% calcium chloride dissolved in 0.9% isotonic saline that enhances the biophysical barrier function of the airway lining fluid and primes the host defense response. It's ability to attenuate bronchitis caused by inhaled particles was investigated using an allergen-inhalation model in a proof-of-concept study. In a randomized, double-blind, placebo-controlled cross-over trial of 6 mild atopic steroid-naïve asthmatic subjects, 3 doses of iCALM were well tolerated and they attenuated allergen-induced increase in sputum eosinophils, and levels of IL-5, MCP-1 and eotaxin. This study provides an opportunity to investigate the role of enhancing epithelial barrier to decrease airway inflammation provoked by inhaled particles in a variety of airway diseases.

Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia.

BACKGROUND: Sputum eosinophilia has been shown to be a predictor of response to anti-eosinophil therapies in patients with airway diseases. However, quantitative cell counts and differentials of sputum are labor intensive. The objective of this study was to validate a novel ELISA-based assay of eosinophil peroxidase (EPX) in sputum as a rapid and reliable marker of airway eosinophils. METHODS: The utility of EPX-based ELISA as an eosinophil-specific assay was achieved through comparisons with sputum eosinophil differential counts in freshly prepared and archived patient samples from a variety of clinical settings. RESULTS: EPX levels in sputum correlated with eosinophil percentage (r(s) = 0.84) in asthma patients with varying degrees of airway eosinophilia. Significantly, unlike assays of other eosinophil granule proteins (e.g., ECP and EDN), which often detect the presence of these proteins even in asthma patients with neutrophilic bronchitis, EPX-based ELISA levels are not increased in this subset of asthma patients or in COPD patients lacking evidence of an airway eosinophilia. Moreover, sputum EPX was a surrogate marker of airway eosinophilia in other patient studies (e.g., allergen inhalation and treatment trials the anti-(IL-5) therapeutic Mepolizumab™). Finally, EPX levels in cytocentrifuged prepared sputum supernatants correlated with those from rapidly prepared noncentrifuged filtrates of sputum (r(s) = 0.94). CONCLUSION AND CLINICAL IMPLICATION: EPX-based ELISA is a valid, reliable, repeatable, and specific surrogate marker of eosinophils and/or eosinophil degranulation in the sputum of respiratory patients. The novel EPX assay is a valid and reproducible eosinophil-specific assay that can potentially be developed into a point-of-care assessment of eosinophil activity in airway secretions.

Inter-rater reliability of the Nottingham Neurological Driving Assessment for people with dementia - a preliminary evaluation.

OBJECTIVE: The purpose was to examine the inter-rater reliability of the Nottingham Neurological Driving Assessment. PARTICIPANTS: Six drivers with dementia (mean age 78 years, 5 men). INTERVENTIONS: Participants were assessed for their safety to drive on a set route while being observed by two driving assessors, who were experienced in assessing safety to drive in people with dementia. MAIN MEASURES: Performance was rated in terms of overall safety to drive and 25 items were recorded as correct, minor error (not compromising safety) and major error (compromising safety). RESULTS: Four drivers were found to be probably safe to drive and two definitely unsafe to drive. There was perfect agreement in the overall decisions about safety to drive. There were significant discrepancies between correct or minor error and major error on six of the 25 items of the road test involving three participants. CONCLUSIONS: Two experienced driving assessors agreed on the overall safety to drive of six participants with dementia. There were discrepancies about safety on six out of 150 observations (4%).

Human airway smooth muscle promotes eosinophil differentiation.

INTRODUCTION: Human airway smooth muscle (HASM) cells in culture synthesize cytokines and chemokines that may orchestrate the tissue homing and in situ differentiation of haemopoietic progenitor cells from the peripheral circulation. OBJECTIVE: To study the effect of a supernatant from cultured HASM cells on the differentiative and transmigrational responses of haemopoietic progenitor cells. METHODS: HASM cells were grown to confluence and stimulated with a cytomix of TNF-alpha, IL-1beta and IFN-gamma. Peripheral blood-derived progenitors from atopic asthmatics (n=12) and non-atopic controls (n=11) were grown in a methylcellulose culture with a supernatant from stimulated HASM cells to assess clonogenic potential. The ability of HASM cells to stimulate directional migration and adhesion to fibronectin of blood progenitors was also investigated. RESULTS: HASM cells stimulated significant growth of eosinophil/basophil colony forming units (Eo/B CFUs) from blood progenitor cells from both groups of subjects. This activity was significantly attenuated in the presence of anti-IL-5 and anti-granulocyte macrophage-colony forming factor blocking antibodies and by pre-treatment with SB202190 [p38 mitogen-activated protein kinase (MAPK) inhibitor]. An src kinase (srcK) inhibitor (Pyrazolopyrimidine 1) was less effective at attenuating IL-5- and HASM-stimulated Eo/B CFU growth from both groups of subjects. Examination of the phosphorylation of these kinases in CD34(+) cells following co-incubation with the major constituents of HASM showed activation of p38 MAPK but not that of the srcK pathway. The HASM supernatant had no significant effect on the migrational and adhesive responses of haemopoietic progenitor cells in vitro. CONCLUSION: We have shown that HASM cell-derived cytokines promote eosinophil differentiation that is dependent on p38 MAPK but not on the srcK pathway. This study shows that a major structural cell of the lungs, airway smooth muscle, has the capability to direct eosinophil differentiation and maturation from progenitor cells, which in turn may perpetuate an eosinophilic inflammation and consequently tissue remodelling in patients with chronic asthma.

Education for secondary prevention of foot ulcers in people with diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: This observer-blind, randomised controlled trial was designed to determine the effect of a foot care education programme in the secondary prevention of foot ulcers. METHODS: People with newly healed foot ulcers attending one of three specialist clinics were allocated to receive either targeted, one-to-one education or usual care, using a computer-generated random allocation sequence that had been prepared in advance but which was concealed from the clinical researcher. The primary outcome was ulcer incidence at 12 months. Secondary outcomes were ulcer incidence at 6 months and incidence of amputation, mood (Hospital Anxiety and Depression Scale) and quality of life (Diabetic Foot Ulcer Scale) at 6 and 12 months. Protective foot care behaviours (Nottingham Assessment of Functional Footcare) were assessed at 12 months. RESULTS: There were 87 (mean [SD] age 63.5 [12.1] years) patients in the intervention group and 85 control patients (mean [SD] age 64.9 [10.9] years). The groups were comparable at baseline. No significant differences (p > 0.05) were observed between groups in ulcer incidence at either 6 months (intervention 30%, control 21%) or 12 months (intervention 41%, control 41%). Recommended foot care behaviours at 12 months were better in the intervention than in the control group (p = 0.03), but education had no significant (p > 0.05) effect on mood, quality of life or amputations. CONCLUSIONS/INTERPRETATION: Even though the intervention was associated with improved foot care behaviour, there was no evidence that this programme of targeted education was associated with clinical benefit in this population when compared with usual care. The usefulness and optimal delivery of education to such a high-risk group requires further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00729456 FUNDING: Diabetes UK project grant RD02/0002535.

Somatosensory impairment after stroke: frequency of different deficits and their recovery.

OBJECTIVE: To investigate the frequency of somatosensory impairment in stroke patients within different somatosensory modalities and different body areas, and their recovery. DESIGN: Prospective observational study. SETTING: Two stroke rehabilitation units. SUBJECTS: Seventy patients with a first stroke (36 men, 34 women; average age, 71, SD 10.00 years; average time since stroke onset, 15 days) were assessed on admission and two, four and six months after stroke. INTERVENTIONS: Not applicable. MAIN MEASURE: Nottingham Sensory Assessment. RESULTS: Somatosensory impairment was common after stroke; 7-53% had impaired tactile sensations, 31-89% impaired stereognosis, and 34-64% impaired proprioception. When comparing somatosensory modalities within body areas the kappa values were low (kappa values<0.54). Recovery occurred over time, though not significantly in lower limb tactile sensations. Stroke severity was the main factor influencing initial somatosensory impairment, but accounted for a small amount of the variance (21-41%). Initial somatosensory impairment was significantly related to somatosensory ability at six months, accounting for 46-71% of the variance. CONCLUSIONS: Proprioception and stereognosis were more frequently impaired than tactile sensations. The different somatosensory modalities showed only slight agreement between impairment within the same body areas, suggesting that the modalities are independent of each other and all should be assessed. High agreements were found between different body areas for each somatosensory modality. Somatosensory impairment was associated with stroke severity, however low variance indicated other factors were involved.

Cognitive abilities as predictors of safety to drive in people with multiple sclerosis.

Cognitive impairments resulting from multiple sclerosis (MS) may affect driving performance. The purpose was to determine whether cognitive tests predict safety to drive in people with MS. Participants were recruited from people referred to Derby Regional Mobility Centre for assessment of their fitness to drive. They were assessed on tests of cognitive abilities related to driving including: the Stroke Drivers Screening Assessment, Paced Auditory Serial Addition Test, Stroop, Motor Impersistence and Adult Memory and Information Processing Battery (AMIPB). Participants' safety to drive on the public road was tested by an approved driving instructor blind to the results of the cognitive assessment. There were 34 participants with MS, 17 were men, mean age 46 (SD 10.4) years. Safe and unsafe drivers were compared. Significant differences were found on tests of executive function (Road Sign Recognition, P<0.01), visual memory (Design Learning Interference, P<0.05) Information Processing (AMIPB Task A, P<0.05 and B, P<0.05), concentration (Dot Cancellation false positive errors, P<0.01) and visuospatial abilities (AMIPB Figure copy). An equation was generated using discriminant function analysis with an overall predictive accuracy of 88% (Sensitivity for pass 90%, Specificity 90%). Cognitive abilities were predictors of safety to drive in people with MS.

Lung transplantation for cystic fibrosis: current concepts and one center's experience.

BACKGROUND: Although new approaches to the treatment of patients with cystic fibrosis (CF) are significantly prolonging their lives, most patients will eventually develop respiratory failure due to progressive bronchiectasis caused by chronic lung infection and inflammation and die from to respiratory failure. We examined our center's (University of Wisconsin Hospital and Clinics) experience with lung transplantation for patients with CF and reviewed the literature to examine current and evolving approaches to transplantation for this indication. METHODS: We reviewed all published literature pertaining to lung transplantation for CF through 2006, and we reviewed all aspects of transplantation for patients with CF at our institution from 1994 to 2005. RESULTS: Major complications following lung transplantation include acute rejection, bacterial infection, and bronchiolitis obliterans. Five-year survival at UWHC (Kaplan-Meier) is 67%, and survival was not adversely affected by transplanting patients receiving mechanical ventilation. The major cause of death for transplant recipients was bronchiolitis obliterans syndrome (BOS). CONCLUSIONS: Lung transplantation for CF is associated with acceptable survival rates and can improve quality of life. Lung transplant should be offered to all patients with advanced CF lung disease if they meet currently accepted inclusion and exclusion criteria.

Person-centred dementia services are feasible, but can they be sustained?

BACKGROUND: we evaluated a specialist community-based dementia service to establish whether high quality care was being delivered and the conditions for doing so. The service was in an urban part of Rushcliffe Primary Care Trust, Nottinghamshire, United Kingdom. The service comprised an assessment team of an occupational therapist, a community psychiatric nurse and a community care officer, supported by 235 h per week of care delivered by a team of specially trained community care workers. METHODS: a qualitative study was performed using non-participant observation, semi-structured interviews and focus groups, and analysed using a thematic framework approach. There were 2 focus groups involving staff, 11 interviews of staff and stakeholders, and interviews of 15 carers of people with dementia. RESULTS: the care provided was appreciated by carers, and the service was approved by staff and stakeholders. Care was delivered using a rehabilitative style that aimed to maintain personhood, rather than to promote independence. Clients were usually referred with the object of preventing unwanted admission to institutional care but, over time, moving into an institution ceased to be a uniformly undesirable outcome. The service's resources were reduced during the evaluation period, in part to meet mental health needs in intermediate care services. CONCLUSIONS: an appropriately resourced and constructed specialist service using an adaptive rehabilitation approach aimed at maintaining personhood can deliver good individualised care to people with dementia, but specific and appropriate commissioning for these services is needed to nurture them.

Extracellular matrix regulates human airway smooth muscle cell migration.

Extracellular matrix proteins regulate the survival and proliferation of smooth muscle cells. Their effect on airway smooth muscle cell migration is not known. Their role in leukotriene-primed (0.1 microM leukotriene E4) chemotaxis of cultured human airway smooth muscle cells towards platelet-derived growth factor BB (1 ng.mL(-1)) was investigated. Migration of cells was greater on membranes coated with collagens III and V and fibronectin compared to collagen I, elastin and laminin (all 10 microg.mL(-1)). Concentration-dependent promotion of migration was observed on collagen I (1,000>10 microg.mL(-1)), which was associated with increased phosphorylation of Src kinase. This was not observed on laminin or elastin. The role of Src kinase was further confirmed by demonstrating that its inhibitor, PP1 analogue (1 microM), inhibited chemotaxis. Collagen I itself was not a chemoattractant; however, haptokinesis was observed when cells were primed with leukotriene E4, and haptotaxis when cells were primed with platelet-derived growth factor. The priming effect of leukotrienes on chemotaxis was not elicited by promoting adhesion, increasing surface expression of beta1, alphav and alpha5 integrin, or Src kinase phosphorylation. These experiments demonstrate that the extracellular matrix, along with growth factors and cysteinyl leukotrienes, can regulate human airway smooth muscle cell migration. This may be relevant in the remodelling process in chronic airway diseases, such as asthma.

A UK multi-centre pilot study of speech and swallowing outcomes following head and neck cancer.

Speech and swallowing are important components of health-related quality of life following head and neck cancer treatment. The aim of this study was to demonstrate the value of prospective multi-centre evaluation by Speech and Language Therapists and to compare health-related quality of life with speech and swallowing impairments. The University of Washington Head and Neck questionnaire version 4 (UW-QOL) and Therapy Outcome Measures (TOM) were rated before and 6 months after cancer treatment in 95 patients from 12 centres. There was deterioration in TOM scores at 6 months. Pretreatment UW-QOL swallowing was ranked equal first, with speech fourth. At 6 months speech was first and swallowing second. There were positive correlations between UW-QOL swallowing and TOM dysphagia and between UW-QOL speech and TOM laryngectomy, voice, phonology and dysarthria disorders. Both outcome measures are suitable for routine practice. Adaptation of TOM scales for use with head and neck cancer patients may improve sensitivity, validity and therapist compliance.

Validation of the stroke drivers screening assessment for people with traumatic brain injury.

Cognitive impairments resulting from brain injury affect driving performance. The question of fitness to drive often arises during rehabilitation. Healthcare professionals need reliable criteria against which decisions about driving fitness can be made. Nouri et al. developed the Stroke Drivers Screening Assessment (SDSA), which was found predictive of on-road driving performance in stroke patients. The purpose of this study was to determine whether the SDSA, either alone or combined with other tests, predicted fitness to drive in brain injured people. Fifty-two participants were assessed on the SDSA plus additional cognitive tests. Their fitness to drive was examined on the public road. The SDSA predictions based on equations developed for stroke patients were not an accurate predictor of road test performance. Discriminant analysis was used to identify tests predictive of fitness to drive. Results indicated that a combination of the SDSA, the Stroop and the AMIPB Information Processing tasks correctly classified 87% of cases and may be useful predictors of driving fitness following brain injury. However, cross-validation on an independent sample of people with brain injury is required.