RESUMO
BACKGROUND: As part of significant mental health reform, the Community Mental Health Rehabilitation Service (CMHRS) was implemented in rural South Australia. The CMHRS is a 10-bed mental health residential program offering rehabilitative mental health support to rural residents. AIM: To analyse the CMHRS service delivery model and its impact on recovery outcomes for consumers. METHODS: A mixed method, realist evaluation approach was utilised. A purposive sample of CMHRS staff (n = 6) and consumers (n = 8) were recruited. Consumer recovery was measured using the RAS-DS (on admission and discharge). Participants' perspectives of the service were gained via one staff focus group (n = 6) and individual semi-structured interviews (consumers n = 6; staff n = 2). Pre-post RAS-DS scores were analysed using paired t-tests/Wilcoxon paired-signed rank test, with qualitative data analysed thematically. RESULTS: Significant positive increases in RAS-DS total scores were observed at discharge, supported by the qualitative themes of (re)building relationships and social connections and recovering health and wellbeing. Contextual factors (e.g. staffing) and program mechanisms (e.g. scheduling) impacting on service implementation were identified. CONCLUSION: Maintaining a rehabilitation recovery-focused approach, balanced with an appropriately trained multi-disciplinary team, are vital for maximising positive consumer outcomes. SIGNIFICANCE: This realist evaluation identifies critical factors impacting rural mental health rehabilitation service delivery.
Assuntos
Serviços Comunitários de Saúde Mental , Saúde Mental , Serviços de Saúde Rural , Reforma dos Serviços de Saúde , Humanos , População Rural , Austrália do SulRESUMO
OBJECTIVES: Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). METHODS: Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. RESULTS: Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits NaV 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the NaV 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. CONCLUSION: Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in NaV 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. SIGNIFICANCE: Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the NaV 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in NaV 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls.
Assuntos
Anestésicos Locais/administração & dosagem , Eritromelalgia/genética , Eritromelalgia/fisiopatologia , Lidocaína/administração & dosagem , Limiar da Dor/efeitos dos fármacos , Canais de Sódio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eritromelalgia/complicações , Feminino , Temperatura Alta , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Nociceptores/efeitos dos fármacos , Dor/diagnóstico , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Adulto JovemRESUMO
In the last decade, there have been intensive efforts to invent, qualify and use novel biomarkers as a means to improve success rates in drug discovery and development. The biomarkers field is maturing and this article considers whether these research efforts have brought about the expected benefits. The characteristics of a clinically useful biomarker are described and the impact this area of research has had is evaluated by reviewing a few, key examples of emerging biomarkers. There is evidence that the impact has been genuine and is increasing in both the drug and the diagnostic discovery and development processes. Beneficial impact on patient health outcomes seems relatively limited thus far, with the greatest impact in oncology (again, both in terms of novel drugs and in terms of more refined diagnoses and therefore more individualized treatment). However, the momentum of research would indicate that patient benefits are likely to increase substantially and to broaden across multiple therapeutic areas. Even though this research was originally driven by a desire to improve the drug discovery and development process, and was therefore funded with this aim in mind, it seems likely that the largest impact may actually come from more refined diagnosis. Refined diagnosis will facilitate both better allocation of healthcare resources and the use of treatment regimens which are optimized for the individual patient. This article also briefly reviews emerging technological approaches and how they relate to the challenges inherent in biomarker discovery and validation, and discusses the role of public/private partnerships in innovative biomarker research.
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Biomarcadores/análise , Técnicas e Procedimentos Diagnósticos/tendências , Descoberta de Drogas/métodos , Biomarcadores Farmacológicos/análise , Descoberta de Drogas/tendências , Previsões , Marcadores Genéticos/genética , HumanosRESUMO
Multiple sclerosis (MS) is a chronic neurological disease affecting the central nervous system (CNS). The disease is characterised by demyelination and axonal loss caused by abnormal immunological responses resulting in accumulating neurological disabilities. MS is considered a complex disease, with both genetic and environmental factors contributing to the pathogenesis. In this study, we have investigated the genetic role of the myeloperoxidase (MPO) gene encoding myeloperoxidase in MS. MPO is an enzyme found in myeloid cells which catalyses the production of hypochlorus acid, a potent microbicidal agent. It also plays an important role in inflammatory processes, where migrating neutrophiles may release active MPO and cause tissue damage. In this study, we investigated two polymorphisms located in the promotor region of the MPO gene, known to influence the expression of MPO, in a large case/control material consisting of 871 Swedish MS patients and 532 Swedish healthy controls. No association was observed with risk of MS.
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Esclerose Múltipla/genética , Peroxidase/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Estudos de Coortes , Humanos , Esclerose Múltipla/enzimologia , Reação em Cadeia da Polimerase , Valores de Referência , SuéciaRESUMO
Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this two-stage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P<0.08) between patients and controls. After additional genotyping in stage two, two genes--each containing at least three significantly (P<0.05) associated SNPs--conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis--and, by extension, derangement of immune homeostasis--influence the risk of MS.
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Antígenos CD/genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Receptores de Interleucina-7/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Masculino , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.