RESUMO
New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.
Assuntos
Fumarato de Dimetilo , Distrofia Muscular de Duchenne , Animais , Camundongos , Camundongos Endogâmicos mdx , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Prednisona , Músculos/patologiaRESUMO
Objective Stroke telemedicine improves the provision of reperfusion therapies in regional hospitals, yet evidence of its cost-effectiveness using patient-level data is lacking. The aim of this study was to estimate the cost per quality-adjusted life year (QALY) gained from stroke telemedicine. Methods As part of the Victorian Stroke Telemedicine (VST) program, stroke telemedicine provided to 16 hospitals in regional Victoria was evaluated using a historical-control design. Patient-level costs from a societal perspective (2018 Australian dollars (A$)) and QALYs up to 12 months after stroke were estimated using data from medical records, surveys at 3 months and 12 months after stroke and multiple imputation. Multivariable regression models and bootstrapping were used to estimate differences between periods. Results Costs and health outcomes were estimated from 1024 confirmed strokes suffered by patients arriving at hospital within 4.5 h of stroke onset (median age 76 years, 55% male, 83% ischaemic stroke; 423 from the control period). Total costs to 12 months post stroke were estimated to be A$82 449 per person for the control period and A$82 259 in the intervention period (P = 0.986). QALYs at 12 months were estimated to be 0.43 per person for the control period and 0.5 per person in the intervention period (P = 0.02). Following 1000 iterations of bootstrapping, in comparison to the control period, the VST intervention was more effective and cost saving in 50.6% of iterations and cost-effective (A$0 and A$50 000 per QALY gained) in 10.4% of iterations. Conclusion The VST program was likely to be cost saving or cost-effective. Our findings provide confidence in supporting wider implementation of telemedicine for acute stroke care in Australia.
Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Telemedicina , Idoso , Análise Custo-Benefício , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/terapia , Telemedicina/métodos , VitóriaRESUMO
INTRODUCTION: Globally, the use of telestroke programmes for acute care is expanding. Currently, a standardised set of variables for enabling reliable international comparisons of telestroke programmes does not exist. The aim of the study was to establish a consensus-based, minimum dataset for acute telestroke to enable the reliable comparison of programmes, clinical management and patient outcomes. METHODS: An initial scoping review of variables was conducted, supplemented by reaching out to colleagues leading some of these programmes in different countries. An international expert panel of clinicians, researchers and managers (n = 20) from the Australasia Pacific region, USA, UK and Europe was convened. A modified-Delphi technique was used to achieve consensus via online questionnaires, teleconferences and email. RESULTS: Overall, 533 variables were initially identified and harmonised into 159 variables for the expert panel to review. The final dataset included 110 variables covering three themes (service configuration, consultations, patient information) and 12 categories: (1) details about telestroke network/programme (n = 12), (2) details about initiating hospital (n = 10), (3) telestroke consultation (n = 17), (4) patient characteristics (n = 7), (5) presentation to hospital (n = 5), (6) general clinical care within first 24 hours (n = 10), (7) thrombolysis treatment (n = 10), (8) endovascular treatment (n = 13), (9) neurosurgery treatment (n = 8), (10) processes of care beyond 24 hours (n = 7), (11) discharge information (n = 5), (12) post-discharge and follow-up data (n = 6). DISCUSSION: The acute telestroke minimum dataset provides a recommended set of variables to systematically evaluate acute telestroke programmes in different countries. Adoption is recommended for new and existing services.
Assuntos
Acidente Vascular Cerebral , Telemedicina , Assistência ao Convalescente , Humanos , Alta do Paciente , Encaminhamento e Consulta , Acidente Vascular Cerebral/tratamento farmacológico , Terapia TrombolíticaRESUMO
OBJECTIVES: To evaluate the impact of the Victorian Stroke Telemedicine (VST) program during its first 12 months on the quality of care provided to patients presenting with suspected stroke to hospitals in regional Victoria. DESIGN: Historical controlled cohort study comparing outcomes during a 12-month control period with those for the initial 12 months of full implementation of the VST program at each hospital. SETTING: 16 hospitals in regional Victoria that participated in the VST program between 1 January 2010 and 30 January 2016. PARTICIPANTS: Adult patients with suspected stroke presenting to the emergency departments of the participating hospitals. MAIN OUTCOME MEASURES: Indicators for key processes of care, including symptom onset-to-arrival, door-to-first medical review, and door-to-CT times; provision and timeliness of provision of thrombolysis to patients with ischaemic stroke. RESULTS: 2887 patients with suspected stroke presented to participating emergency departments during the control period, 3178 during the intervention period; the patient characteristics were similar for both periods. A slightly larger proportion of patients with ischaemic stroke who arrived within 4.5 hours of symptom onset received thrombolysis during the intervention than during the control period (37% v 30%). Door-to-CT scan time (median, 25 min [IQR, 13-49 min] v 34 min [IQR, 18-76 min]) and door-to-needle time for stroke thrombolysis (73 min [IQR, 56-96 min] v 102 min [IQR, 77-128 min]) were shorter during the intervention. The proportions of patients who received thrombolysis and had a symptomatic intracerebral haemorrhage (4% v 16%) or died in hospital (6% v 20%) were smaller during the intervention period. CONCLUSIONS: Telemedicine has provided Victorian regional hospitals access to expert care for emergency department patients with suspected acute stroke. Eligible patients with ischaemic stroke are now receiving stroke thrombolysis more quickly and safely.
Assuntos
Acessibilidade aos Serviços de Saúde/organização & administração , Acidente Vascular Cerebral/terapia , Telemedicina/organização & administração , Pesquisa Translacional Biomédica/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Acidente Vascular Cerebral/epidemiologia , Terapia Trombolítica/métodos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vitória/epidemiologiaRESUMO
BACKGROUND: Skeletal muscle undergoes significant atrophy in Type 2 diabetic patients and animal models. We aimed to determine if atrophy of Zucker rat skeletal muscle was due to the activation of intracellular damage pathways induced by excess reactive oxygen species production (specifically those associated with the peroxidation of lipid membranes) and calpain activity. 14 week old obese Zucker rats and littermate lean controls were injected with 1% Evan's Blue Dye. Animals were anaesthetised and extensor digitorum longus and soleus muscles were dissected, snap frozen and analysed for ROS-mediated F2-isoprostane production and calpain activation/autolysis. Contralateral muscles were histologically analysed for markers of muscle membrane permeability and atrophy. RESULTS: Muscle mass was lower in extensor digitorum longus and soleus of obese compared with lean animals, concomitant with reduced fibre area. Muscles from obese rats had a higher proportional area of Evan's Blue Dye fluorescence, albeit this was localised to the interstitium/external sarcolemma. There were no differences in F2-isoprostane production when expressed relative to arachidonic acid content, which was lower in the obese EDL and soleus muscles. There were no differences in the activation of either µ-calpain or calpain-3. CONCLUSIONS: This study highlights that atrophy of Zucker rat skeletal muscle is not related to sarcolemmal damage, sustained hyperactivation of the calpain proteases or excessive lipid peroxidation. As such, establishing the correct pathways involved in atrophy is highly important so as to develop more specific treatment options that target the underlying cause. This study has eliminated two of the potential pathways theorised to be responsible.