Gene therapy for the treatment of cystic fibrosis.

Gene therapy is being developed as a novel treatment for cystic fibrosis (CF), a condition that has hitherto been widely-researched yet for which no treatment exists that halts the progression of lung disease. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator (CFTR) DNA to the epithelial cells in the airways. The cloning of the CFTR gene in 1989 led to proof-of-principle studies of CFTR gene transfer in vitro and in animal models. The earliest clinical trials in CF patients were conducted in 1993 and used viral and non-viral gene transfer agents in both the nasal and bronchial airway epithelium. To date, studies have focused largely on molecular or bioelectric (chloride secretion) outcome measures, many demonstrating evidence of CFTR expression, but few have attempted to achieve clinical efficacy. As CF is a lifelong disease, turnover of the airway epithelium necessitates repeat administration. To date, this has been difficult to achieve with viral gene transfer agents due to host recognition leading to loss of expression. The UK Cystic Fibrosis Gene Therapy Consortium (Imperial College London, University of Edinburgh and University of Oxford) is currently working on a large and ambitious program to establish the clinical benefits of CF gene therapy. Wave 1, which has reached the clinic, uses a non-viral vector. A single-dose safety trial is nearing completion and a multi-dose clinical trial is shortly due to start; this will be powered for clinically-relevant changes. Wave 2, more futuristically, will look at the potential of lentiviruses, which have long-lasting expression. This review will summarize the current status of translational research in CF gene therapy.

Overview of the PROVE studies evaluating the use of telaprevir in chronic hepatitis C genotype 1 patients.

Current treatment for genotype 1 HCV infection with pegylated interferon (PEG IFN) and ribavirin (RBV) is effective in less than 50% of patients. The advent of direct-acting antiviral agents that target replication of HCV promises to improve therapy for the disease. Telaprevir is a new peptidomimetic serine protease inhibitor that specifically targets the NS3/4a HCV serine protease to cause rapid reduction in HCV RNA levels. Three Phase II Protease Inhibition for Viral Evaluation (PROVE) studies have assessed the efficacy and safety of telaprevir in genotype 1 patients. The studies examined sustained virological response (SVR) rates and also the adverse events related to the use of this drug in different groups. The results of these studies suggested that the addition of this specific protease inhibitor to PEG IFN alfa-2a and RBV can significantly improve the results of treatment in patients affected with chronic HCV infection with genotype 1, when compared with the standard treatment, PEG IFN alfa-2a and RBV alone. The key observations in these Phase II trials of telaprevir were higher rate of SVR above current standard of care (61-69% for T12PR24 treatment-naive patients compared with 46-48% for standard of care in naive patients). Low rates of relapse were observed in T12PR24-treated patients (2-14% vs 22-23%). The studies suggest that the duration of treatment could be reduced for rapidly responsive naive patients from 48 to 24 weeks while maintaining improved SVR rates. RBV remains an essential component of treatment with protease inhibitors combined with PEG IFN. The main adverse reactions of note with its use were rashes, anemia and nausea.

Mechanical ventilators in US acute care hospitals.

OBJECTIVE: The supply and distribution of mechanical ventilation capacity is of profound importance for planning for severe public health emergencies. However, the capability of US health systems to provide mechanical ventilation for children and adults remains poorly quantified. The objective of this study was to determine the quantity of adult and pediatric mechanical ventilators at US acute care hospitals. METHODS: A total of 5,752 US acute care hospitals included in the 2007 American Hospital Association database were surveyed. We measured the quantities of mechanical ventilators and their features. RESULTS: Responding to the survey were 4305 (74.8%) hospitals, which accounted for 83.8% of US intensive care unit beds. Of the 52,118 full-feature mechanical ventilators owned by respondent hospitals, 24,204 (46.4%) are pediatric/neonatal capable. Accounting for nonrespondents, we estimate that there are 62,188 full-feature mechanical ventilators owned by US acute care hospitals. The median number of full-feature mechanical ventilators per 100,000 population for individual states is 19.7 (interquartile ratio 17.2-23.1), ranging from 11.9 to 77.6. The median number of pediatric-capable device full-feature mechanical ventilators per 100,000 population younger than 14 years old is 52.3 (interquartile ratio 43.1-63.9) and the range across states is 22.1 to 206.2. In addition, respondent hospitals reported owning 82,755 ventilators other than full-feature mechanical ventilators; we estimate that there are 98,738 devices other than full-feature ventilators at all of the US acute care hospitals. CONCLUSIONS: The number of mechanical ventilators per US population exceeds those reported by other developed countries, but there is wide variation across states in the population-adjusted supply. There are considerably more pediatric-capable ventilators than there are for adults only on a population-adjusted basis.