Hot off the presses! Nov 05 LANCET

The Nov 05 issue of the LANCET is now up on Pubget (About LANCET): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• UK health, science, and overseas aid: not what they seem
  - LANCET 376(9751):1437 (2010)
  
• GAVI's challenges: funding and leadership
  - LANCET 376(9751):1438 (2010)
  
• The UK's continued shameful neglect of migrants' health
  - LANCET 376(9751):1438 (2010)
  
• Increased resources for the Global Fund, but pledges fall short of expected demand
  - LANCET 376(9751):1439-1440 (2010)
  
• Curing hepatitis C with pills: a step toward global control
  - LANCET 376(9751):1441-1442 (2010)
  
• Celiprolol therapy for vascular Ehlers-Danlos syndrome
  - LANCET 376(9751):1443-1444 (2010)
  
• Improving aid for maternal, newborn, and child health
  - LANCET 376(9751):1444-1446 (2010)
  
• A counterfeit drug treaty: great idea, wrong implementation
  - LANCET 376(9751):1446-1448 (2010)
  
• Anecdotes in medicine—15 years of Lancet Case Reports
  - LANCET 376(9751):1448-1449 (2010)
  
• Offline: Doing a Blakemore
  - LANCET 376(9751):1450 (2010)
  
• Californian autism clusters leave researchers baffled
  - LANCET 376(9751):1451-1452 (2010)
  
• The parlous state of palliative care in the developing world
  - LANCET 376(9751):1453-1454 (2010)
  
• The FDA and the black arts of drug regulation
  - LANCET 376(9751):1455-1456 (2010)
  
• The birth of Facebook
  - LANCET 376(9751):1456 (2010)
  
• David Weatherall: Lasker Award for pioneer in molecular medicine
  - LANCET 376(9751):1457 (2010)
  
• Perspiration, inspiration, and the 10-year rule
  - LANCET 376(9751):1458-1459 (2010)
  
• William Harrison
  - LANCET 376(9751):1460 (2010)
  
• Mixed messages on systemic therapies for diabetic retinopathy
  - LANCET 376(9751):1461 (2010)
  
• Mixed messages on systemic therapies for diabetic retinopathy
  - LANCET 376(9751):1461 (2010)
  
• Mixed messages on systemic therapies for diabetic retinopathy – Authors' reply
  - LANCET 376(9751):1462 (2010)
  
• Intensive treatment of hyperglycaemia: what are the objectives?
  - LANCET 376(9751):1462-1463 (2010)
  
• Huntington's disease
  - LANCET 376(9751):1463 (2010)
  
• Huntington's disease
  - LANCET 376(9751):1463-1464 (2010)
  
• Huntington's disease
  - LANCET 376(9751):1464 (2010)
  
• New international consensus on health impact assessment
  - LANCET 376(9751):1464-1465 (2010)
  
• New international consensus on health impact assessment – Authors' reply
  - LANCET 376(9751):1465 (2010)
  
• Regulating medical tourism
  - LANCET 376(9751):1465-1466 (2010)
  
• Why are drug trials in Alzheimer's disease failing?
  - LANCET 376(9751):1466 (2010)
  
• Department of Error
  - LANCET 376(9751):1466 (2010)
  
• Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial
  - LANCET 376(9751):1467-1475 (2010)
  Background Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs—RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor—in patients with chronic HCV infection. Methods Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment alloca! tion. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255. Findings 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from −3·7 to −5·2 log10 IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was −5·1 log10 IU/mL (IQR −5·6 to −4·7) in treatment-naive patients and −4·9 log10 IU/mL in previous standard of care null responders (−5·2 to −4·5) compared with an increase of 0·1 log10 IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontin! uations. Interpretation This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV. Funding Roche Palo Alto.
• Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial
  - LANCET 376(9751):1476-1484 (2010)
  Background Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Methods Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg twice daily. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. Findings 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. Interpretation We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. Funding French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.
• Countdown to 2015: assessment of official development assistance to maternal, newborn, and child health, 2003–08
  - LANCET 376(9751):1485-1496 (2010)
  Background Achievement of high coverage of effective interventions and Millennium Development Goals (MDGs) 4 and 5A requires adequate financing. Many of the 68 priority countries in the Countdown to 2015 Initiative are dependent on official development assistance (ODA). We analysed aid flows for maternal, newborn, and child health for 2007 and 2008 and updated previous estimates for 2003–06. Methods We manually coded and analysed the complete aid activities database of the Organisation for Economic Co-operation and Development for 2007 and 2008 with methods that we previously developed to track ODA. By use of newly available data for donor disbursement and population estimates, we revised data for 2003–06. We analysed the degree to which donors target their ODA to recipients with the greatest maternal and child health needs and examined trends over the 6 years. Findings In 2007 and 2008, US$4·7 billion and $5·4 billion (constant 2008 US$), respectively, were disbursed in support of maternal, newborn, and child health activities in all developing countries. These amounts reflect a 105% increase between 2003 and 2008, but no change relative to overall ODA for health, which also increased by 105%. Countdown priority countries received $3·4 billion in 2007 and $4·1 billion in 2008, representing 71·6% and 75·6% of all maternal, newborn, and child health disbursements, respectively. Targeting of ODA to countries with high rates of maternal and child mortality improved over the 6-year period, although some of these countries persistently received far less ODA per head than did countries with much lower mortality rates and higher income levels. Funding from the GAVI Alliance and the Global Fund to Fight AIDS, Tuberculosis and Malaria exceeded core funding from multilateral institutions, and bilateral funding also increased substantially betwe! en 2003 and 2008, especially from the USA and the UK. Interpretation The increases in ODA to maternal, newborn, and child health during 2003–08 are to be welcomed, as is the somewhat improved targeting of ODA to countries with greater needs. Nonetheless, these increases do not reflect increased prioritisation relative to other health areas. Funding Partnership for Maternal, Newborn, and Child Health on behalf of the Countdown to 2015 Initiative.
• Inside out
  - LANCET 376(9751):1497 (2010)
  
• Antiphospholipid syndrome
  - LANCET 376(9751):1498-1509 (2010)
  The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency. Other clinical manifestations are cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, haemolytic anaemia, and cognitive impairment. Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. Of the different antiphospholipid antibodies, lupus anticoagulant is the strongest predictor of features related to antiphospholipid syndrome. Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thromboprophylaxis is recommended in patients with systemic lupus erythematosus and probably in purely obstetric antiphospholipid syndrome. Ob! stetric care is based on combined medical-obstetric high-risk management and treatment with aspirin and heparin. Hydroxychloroquine is a potential additional treatment for this syndrome. Possible future therapies for non-pregnant patients with antiphospholipid syndrome are statins, rituximab, and new anticoagulant drugs.
• Does instant access to compiled information undermine clinical cognition?
  - LANCET 376(9751):1510-1511 (2010)
  
• Puberty, stress, and sudden death
  - LANCET 376(9751):1512 (2010)