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N Engl J Med [journal]
- Multidrug-resistant tuberculosis and culture conversion with bedaquiline. [Journal Article, Research Support, Non-U.S. Gov't]
- N Engl J Med 2014 Aug 21; 371(8):723-32.
Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks.In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline.Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).
- Oral GS-5806 activity in a respiratory syncytial virus challenge study. [Journal Article, Research Support, Non-U.S. Gov't]
- N Engl J Med 2014 Aug 21; 371(8):711-22.
Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).
- Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia. [JOURNAL ARTICLE]
- N Engl J Med 2014 Aug 21; 371(8):699-710.
Background Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. Methods In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. Results A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). Conclusions Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761 , and Current Controlled Trials number, ISRCTN52713285 .).
- The challenges of challenge experiments. [Journal Article]
- N Engl J Med 2014 Aug 21; 371(8):695-7.
- The impact and evolution of Medicare Part D. [Journal Article]
- N Engl J Med 2014 Aug 21; 371(8):693-5.
- Did Hospital Engagement Networks Actually Improve Care? [JOURNAL ARTICLE]
- N Engl J Med 2014 Aug 21; 371(8):691-693.
The Centers for Medicare and Medicaid Services claims its Partnership for Patients Program led to big improvements in patient outcomes. But weak study design and methods and a lack of transparency and rigor in evaluation make it hard to assess whether the program improved care.
- FDA approval of bedaquiline--the benefit-risk balance for drug-resistant tuberculosis. [Comment, Journal Article]
- N Engl J Med 2014 Aug 21; 371(8):689-91.
- Ebola 2014 - New Challenges, New Global Response and Responsibility. [JOURNAL ARTICLE]
- N Engl J Med 2014 Aug 20.
Since Ebola virus was first identified in 1976, no previous Ebola outbreak has been as large or persistent as the current epidemic, and none has spread beyond East and Central Africa.(1) To date, more than 1000 people, including numerous health care workers, have been killed by Ebola virus disease (EVD) in 2014, and the number of cases in the current outbreak now exceeds the number from all previous outbreaks combined. Indirect effects include disruption of standard medical care, including for common and deadly conditions such as malaria, and substantial economic losses, insecurity, and social disruption in countries that were already . . .
- Studying "Secret Serums" - Toward Safe, Effective Ebola Treatments. [JOURNAL ARTICLE]
- N Engl J Med 2014 Aug 20.
Ebola virus (EV), the cause of an ongoing deadly epidemic in West Africa, has been one of the world's most feared pathogens, causing catastrophic clinical disease and high mortality. Although the highest priority must be given to public health and infection-control measures that have contained past outbreaks, the current outbreak - the largest ever recorded - also highlights the need for effective treatment. The report that two seriously ill American volunteers, Kent Brantly and Nancy Writebol, received an experimental cocktail of three monoclonal antibodies, never before administered to humans, has raised questions around the globe. Dubbed "secret serum" by the . . .
- Ebola Virus Disease in West Africa - No Early End to the Outbreak. [JOURNAL ARTICLE]
- N Engl J Med 2014 Aug 20.
Many people have asked me why the outbreak of Ebola virus disease in West Africa is so large, so severe, and so difficult to contain. These questions can be answered with a single word: poverty. The hardest-hit countries, Guinea, Liberia, and Sierra Leone, are among the poorest in the world. They have only recently emerged from years of conflict and civil war that have left their health systems largely destroyed or severely disabled and, in some areas, left a generation of children without education. In these countries, only one or two doctors are available for every 100,000 people, and these . . .