The Cost of Living with Inherited Ataxia in Ireland.

Inherited ataxias are a heterogenous group of neurodegenerative disorders characterised by progressive impairment of balance and coordination, typically leading to permanent and progressive disability. Diagnosis and management of these disorders incurs a range of direct and indirect financial costs. The aim of this study was to collect individual ataxia-related healthcare resources in a large cohort of individuals with different subtypes of inherited ataxia and calculate the associated cost of illness in the Republic of Ireland. One hundred twenty-nine respondents completed a cross-sectional study on healthcare resource utilisation for progressive ataxia in Ireland. Costs were calculated using a prevalence-based approach and bottom-up methodology. The COI for inherited ataxia in 2016 was €59,993 per person per year. Results were similar between participants with Friedreich's ataxia (FRDA, n = 56), non-FRDA (n = 18) and those with undetermined ataxia (n = 55). Indirect costs, based on productivity losses by participants or caregivers, accounted for 52% of the cost of illness. Inherited ataxia is associated with significant health and social care costs. Further funding for inherited ataxia to ease the financial burden on patients, caregivers and healthcare system and improve standards of care compliance is warranted.

CRISPR-delivery particles targeting nuclear receptor-interacting protein 1 (Nrip1) in adipose cells to enhance energy expenditure.

RNA-guided, engineered nucleases derived from the prokaryotic adaptive immune system CRISPR-Cas represent a powerful platform for gene deletion and editing. When used as a therapeutic approach, direct delivery of Cas9 protein and single-guide RNA (sgRNA) could circumvent the safety issues associated with plasmid delivery and therefore represents an attractive tool for precision genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fatty acid oxidation, and secretion of bioactive factors through a "browning" process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed "CRISPR-delivery particles," denoted CriPs, composed of nano-size complexes of Cas9 protein and sgRNA that are coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9-mediated gene deletion of ectopically expressed GFP by CriPs was achieved in multiple cell types, including a macrophage cell line, primary macrophages, and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP-expressing mice following intraperitoneal injection of CriPs containing Gfp-targeting sgRNA. Furthermore, disruption of a nuclear co-repressor of catabolism, the Nrip1 gene, in white adipocytes by CriPs enhanced adipocyte browning with a marked increase of uncoupling protein 1 (UCP1) expression. Of note, the CriP-mediated Nrip1 deletion did not produce detectable off-target effects. We conclude that CriPs offer an effective Cas9 and sgRNA delivery system for ablating targeted gene products in cultured cells and in vivo, providing a potential therapeutic strategy for metabolic disease.

Eight-Day Temporal Stability of the Automated Neuropsychological Assessment Metric (ANAM) in a Deployment Environment.

Automated neurocognitive tests are commonly used by military providers for making clinical decisions about the recovery of postconcussive cognitive sequelae. This practice often utilizes baseline assessments that precede the concussive injury. As such, investigating and establishing the psychometrics of an instrument is necessary to minimize confounds for interpreting assessment scores. Test-retest reliability (TRR) values for an 8.3 ± 2-day retest window for the Automated Neuropsychological Assessment Metrics-Version 4 (ANAM) were calculated in 86 healthy U.S. Army soldiers deployed to Iraq. After removal of outliers, all but 1 subtest, Simple Reaction Time, had adequate or greater TRR values (intraclass correlation coefficient = 0.72-0.86). The findings suggest that overall, the ANAM has good temporal stability when the retesting intertrial interval is less than 11 days while in a deployed environment.

An evaluation of the effectiveness of a multi-modal intervention in frail and pre-frail older people with type 2 diabetes--the MID-Frail study: study protocol for a randomised controlled trial.

BACKGROUND: Diabetes, a highly prevalent, chronic disease, is associated with increasing frailty and functional decline in older people, with concomitant personal, social, and public health implications. We describe the rationale and methods of the multi-modal intervention in diabetes in frailty (MID-Frail) study. METHODS/DESIGN: The MID-Frail study is an open, randomised, multicentre study, with random allocation by clusters (each trial site) to a usual care group or an intervention group. A total of 1,718 subjects will be randomised with each site enrolling on average 14 or 15 subjects. The primary objective of the study is to evaluate, in comparison with usual clinical practice, the effectiveness of a multi-modal intervention (specific clinical targets, education, diet, and resistance training exercise) in frail and pre-frail subjects aged ≥70 years with type 2 diabetes in terms of the difference in function 2 years post-randomisation. Difference in function will be measured by changes in a summary ordinal score on the short physical performance battery (SPPB) of at least one point. Secondary outcomes include daily activities, economic evaluation, and quality of life. DISCUSSION: The MID-Frail study will provide evidence on the clinical, functional, social, and economic impact of a multi-modal approach in frail and pre-frail older people with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01654341.

Cohort profile: the Caerphilly health and social needs electronic cohort study (E-CATALyST).

The Caerphilly Health and Social Needs study was established to inform and support collaborative multiagency working on reducing inequalities in health and to investigate neighbourhood influences on mental health. Initially, we collated a robust small-area multiagency dataset of contextual health determinants and outcomes from routine sources and sharing of data between the National Health Service and Caerphilly county borough council. These data were widely used in local joint planning to improve health and reduce health inequalities. Secondly, we carried out a baseline population questionnaire survey, collecting data from 10 892 (60.6%) respondents aged 18-74 years on a wide range of socio-economic, lifestyle, health and housing factors and perceptions of the local neighbourhood, including access to services, social cohesion and neighbourhood quality. We carried out wave 2 of the survey after 7 years with responses from 4558 (50.2%) participants to the same range of questions. We developed the study into an electronic cohort, linking all 17 979 sampled participants aged 18-74 years to mortality and hospital admission records with 10-year follow-up and full recording of migration both within and out of the borough. Readers with an interest in collaborative use of the data should contact Professor David Fone, Principal Investigator.

Collaboration between local health and local government agencies for health improvement.

BACKGROUND: In many countries, national, regional and local inter- and intra-agency collaborations have been introduced to improve health outcomes. Evidence is needed on the effectiveness of locally developed partnerships which target changes in health outcomes and behaviours. OBJECTIVES: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes in any population or age group. SEARCH METHODS: We searched the Cochrane Public Health Group Specialised Register, AMED, ASSIA, CENTRAL, CINAHL, DoPHER, EMBASE, ERIC, HMIC, IBSS, MEDLINE, MEDLINE In-Process, OpenGrey, PsycINFO, Rehabdata, Social Care Online, Social Services Abstracts, Sociological Abstracts, TRoPHI and Web of Science from 1966 through to January 2012. 'Snowballing' methods were used, including expert contact, citation tracking, website searching and reference list follow-up. SELECTION CRITERIA: Randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before-and-after studies (CBAs) and interrupted time series (ITS) where the study reported individual health outcomes arising from interagency collaboration between health and local government agencies compared to standard care. Studies were selected independently in duplicate, with no restriction on population subgroup or disease. DATA COLLECTION AND ANALYSIS: Two authors independently conducted data extraction and assessed risk of bias for each study. MAIN RESULTS: Sixteen studies were identified (28,212 participants). Only two were considered to be at low risk of bias. Eleven studies contributed data to the meta-analyses but a narrative synthesis was undertaken for all 16 studies. Six studies examined mental health initiatives, of which one showed health benefit, four showed modest improvement in one or more of the outcomes measured but no clear overall health gain, and one showed no evidence of health gain. Four studies considered lifestyle improvements, of which one showed some limited short-term improvements, two failed to show health gains for the intervention population, and one showed more unhealthy lifestyle behaviours persisting in the intervention population. Three studies considered chronic disease management and all failed to demonstrate health gains. Three studies considered environmental improvements and adjustments, of which two showed some health improvements and one did not.Meta-analysis of three studies exploring the effect of collaboration on mortality showed no effect (pooled relative risk of 1.04 in favour of control, 95% CI 0.92 to 1.17). Analysis of five studies (with high heterogeneity) looking at the effect of collaboration on mental health resulted in a standardised mean difference of -0.28, a small effect favouring the intervention (95% CI -0.51 to -0.06). From two studies, there was a statistically significant but clinically modest improvement in the global assessment of function symptoms score scale, with a pooled mean difference (on a scale of 1 to 100) of -2.63 favouring the intervention (95% CI -5.16 to -0.10).For physical health (6 studies) and quality of life (4 studies) the results were not statistically significant, the standardised mean differences were -0.01 (95% CI -0.10 to 0.07) and -0.08 (95% CI -0.44 to 0.27), respectively. AUTHORS' CONCLUSIONS: Collaboration between local health and local government is commonly considered best practice. However, the review did not identify any reliable evidence that interagency collaboration, compared to standard services, necessarily leads to health improvement. A few studies identified component benefits but these were not reflected in overall outcome scores and could have resulted from the use of significant additional resources. Although agencies appear enthusiastic about collaboration, difficulties in the primary studies and incomplete implementation of initiatives have prevented the development of a strong evidence base. If these weaknesses are addressed in future studies (for example by providing greater detail on the implementation of programmes; using more robust designs, integrated process evaluations to show how well the partners of the collaboration worked together, and measurement of health outcomes) it could provide a better understanding of what might work and why. It is possible that local collaborative partnerships delivering environmental Interventions may result in health gain but the evidence base for this is very limited.Evaluations of interagency collaborative arrangements face many challenges. The results demonstrate that collaborative community partnerships can be established to deliver interventions but it is important to agree goals, methods of working, monitoring and evaluation before implementation to protect programme fidelity and increase the potential for effectiveness.

Assessment of acute concussion in the combat environment.

Despite the prevalence of concussion in soldiers deployed to Iraq and Afghanistan, neuropsychological tests used to assist in concussion management have not been validated on the battlefield. This study evaluated the validity of the Automated Neuropsychological Assessment Metrics (ANAM) in the combat environment. Cases meeting criteria for concussion, healthy controls, and injured controls were assessed. Soldiers were administered the ANAM, traditional neuropsychological tests, and a background questionnaire. Cases were enrolled within 72 h of concussion. Cases exhibited poorer performance than controls on all ANAM subtests, with significant differences on simple reaction time (SRT), procedural reaction time (PRT), code substitution, and matching to sample (p<.001). Discriminant ability of scores on SRT and PRT subtests was 71%, which improved to 76% when pre-deployment baseline scores were available. An exploratory clinical decision tool incorporating ANAM scores and symptoms improved discriminant ability to 81%. Results provide initial validation of the ANAM for detecting acute effects of battlefield concussion.

Personality Assessment Inventory profiles of deployed combat troops: an empirical investigation of normative performance.

The present study examined the normative scores and psychometric properties of the Personality Assessment Inventory (PAI; Morey, 1991) within a non-treatment-seeking sample of soldiers deployed to combat zones in Iraq, compared with a sample of community adults matched with respect to age and gender. Results indicate the scores and properties of the PAI scales were generally quite similar in the Iraq and community samples, with modest differences emerging on only 3 subscales addressing antisocial behavior, issues with close relationships, and interpersonal vigilance. These results suggest that standard normative interpretation of PAI scales is appropriate even when the instrument is administered in a combat zone. In comparison with prior research, the results may suggest that documented mental health issues among combat veterans, when present, may be particularly likely to emerge postdeployment.

The need to improve the interface between in-hours and out-of-hours GP care, and between out-of-hours care and self-care.

BACKGROUND: considerable changes have occurred over the last 5 years in the organization of out-of-hours care in the UK. Users' experiences of their care are an important part of 'quality of care' and are valuable for identifying areas for improvement. AIM: to identify strengths and weaknesses of out-of hours service provision in Wales. The design of the study is a cross-sectional survey. The setting of the study is nine GP services, three Accident and Emergency units and NHS Direct in Wales. METHOD: survey using the validated Out-of-Hours questionnaire. We identified the four most and least favourably rated items regarding users' experience of care. These were analysed by type of care provided, telephone advice, treatment centre and home visit groups. RESULTS: eight hundred and fifty-five of 3250 users responded (26% response rate). Across providers and types of care, consistent strengths were the 'manner of treatment by call operator' and the 'explanation of the next step by call operator'. Consistent weaknesses were the 'speed of call back by the clinician', the 'information provided by the GP', 'getting medication after the consultation' and 'when to contact the (in-hours) GP'. CONCLUSIONS: users of out-of-hours care identify clear and consistent strengths and weaknesses of service provision across Wales. Specific areas for improvement concern the interface between in-hours care and out-of-hours care and between out-of-hours care and self-care. GP surgeries need to give better information on how to access the out-of-hours services. Out-of-hours providers should improve their advice on how and when to access in-hours surgeries and also improve the availability of medicines after out-of-hours consultations.

Evaluating cutpoints for the MHI-5 and MCS using the GHQ-12: a comparison of five different methods.

BACKGROUND: The Mental Health Inventory (MHI-5) and the Mental Health Component Summary score (MCS) derived from the Short Form 36 (SF-36) instrument are well validated and reliable scales. A drawback of their construction is that neither has a clinically validated cutpoint to define a case of common mental disorder (CMD). This paper aims to produce cutpoints for the MHI-5 and MCS by comparison with the General Health Questionnaire (GHQ-12). METHODS: Data were analysed from wave 9 of the British Household Panel Survey (2000), providing a sample size of 14,669 individuals. Receiver Operating Characteristic (ROC) curves were used to compare the scales and define cutpoints for the MHI-5 and MCS, using the following optimisation criteria: the Youden Index, the point closest to (0,1) on the ROC curve, minimising the misclassification rate, the minimax method, and prevalence matching. RESULTS: For the MHI-5, the Youden Index and the (0,1) methods both gave a cutpoint of 76, minimising the misclassification rate gave a cutpoint of 60 and the minimax method and prevalence matching gave a cutpoint of 68. For the MCS, the Youden Index and the (0,1) methods gave cutpoints of 51.7 and 52.1 respectively, minimising the error rate gave a cutpoint of 44.8 and both the minimax method and prevalence matching gave a cutpoint of 48.9. The correlation between the MHI-5 and the MCS was 0.88. CONCLUSION: The Youden Index and (0,1) methods are most suitable for determining a cutpoint for the MHI-5, since they are least dependent on population prevalence. The choice of method is dependent on the intended application. The MHI-5 performs remarkably well against the longer MCS.