Hot off the presses! Aug 19 Lancet

The Aug 19 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:

• Health in the Horn of Africa: a collective response needed
  - Lancet 378(9791):541 (2011)
  
• Syphilis on the rise in the USA
  - Lancet 378(9791):542 (2011)
  
• The NHS IT nightmare
  - Lancet 378(9791):542 (2011)
  
• Hepatitis in drug users: time for attention, time for action
  - Lancet 378(9791):543-544 (2011)
  
• Folate and cardiovascular disease: one size does not fit all
  - Lancet 378(9791):544-546 (2011)
  
• Exon-skipping therapy for Duchenne muscular dystrophy
  - Lancet 378(9791):546-547 (2011)
  
• Ombudsman's ninth report
  - Lancet 378(9791):548-549 (2011)
  
• The last mile in global poliomyelitis eradication
  - Lancet 378(9791):549-552 (2011)
  
• World Hepatitis Day: a new era for hepatitis control
  - Lancet 378(9791):552-553 (2011)
  
• Offline: Listening to the voice of Paulo Freire
  - Lancet 378(9791):554 (2011)
  
• Humanitarian response inadequate in Horn of Africa crisis
  - Lancet 378(9791):555-558 (2011)
  
• The politics of data
  - Lancet 378(9791):559 (2011)
  
• A sense of the future
  - Lancet 378(9791):560 (2011)
  
• Alys Cole-King: a pioneer of suicide mitigation in the UK
  - Lancet 378(9791):561 (2011)
  
• Laughing to longevity—the work of elder clowns
  - Lancet 378(9791):562-563 (2011)
  
• Barbara Starfield
  - Lancet 378(9791):564 (2011)
  
• Priority actions for the non-communicable disease crisis
  - Lancet 378(9791):565 (2011)
  
• Priority actions for the non-communicable disease crisis
  - Lancet 378(9791):565 (2011)
  
• Priority actions for the non-communicable disease crisis – Authors' reply
  - Lancet 378(9791):565-566 (2011)
  
• Priority actions for the non-communicable disease crisis
  - Lancet 378(9791):566 (2011)
  
• Priority actions for the non-communicable disease crisis
  - Lancet 378(9791):566-567 (2011)
  
• Non-communicable diseases: beyond prevention and screening
  - Lancet 378(9791):567 (2011)
  
• Normal ranges of blood pressure in paediatric resuscitation guidelines
  - Lancet 378(9791):567-568 (2011)
  
• Normal ranges of blood pressure in paediatric resuscitation guidelines – Authors' reply
  - Lancet 378(9791):568 (2011)
  
• Cell-based tissue-engineered urethras
  - Lancet 378(9791):568-569 (2011)
  
• Cell-based tissue-engineered urethras – Authors' reply
  - Lancet 378(9791):569 (2011)
  
• Regulation of herbal medicines
  - Lancet 378(9791):569-570 (2011)
  
• Regulation of herbal medicines
  - Lancet 378(9791):570 (2011)
  
• Further response to Offline about Great Ormond Street Hospital
  - Lancet 378(9791):570 (2011)
  
• Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews
  - Lancet 378(9791):571-583 (2011)
  Background Injecting drug use is an important risk factor for transmission of viral hepatitis, but detailed, transparent estimates of the scale of the issue do not exist. We estimated national, regional, and global prevalence and population size for hepatitis C virus (HCV) and hepatitis B virus (HBV) in injecting drug users (IDUs). Methods We systematically searched for data for HBV and HCV in IDUs in peer-reviewed databases (Medline, Embase, and PsycINFO), grey literature, conference abstracts, and online resources, and made a widely distributed call for additional data. From 4386 peer-reviewed and 1019 grey literature sources, we reviewed 1125 sources in full. We extracted studies into a customised database and graded them according to their methods. We included serological reports of HCV antibodies (anti-HCV), HBV antibodies (anti-HBc), or HBV surface antigen (HBsAg) in studies of IDUs with more than 40 participants (<100% HIV-positive) and sampling frames that did not exclude participants on the basis of age or sex. With endorsed decision rules, we calculated prevalence estimates with anti-HCV and anti-HBc as proxies for exposure and HBsAg as proxy for current infection. We combined these estimates with IDU population sizes to calculate the number of IDUs with positive HBV or HCV statuses. Findings We located eligible reports with data for prevalence of anti-HCV in IDUs for 77 countries; midpoint prevalence estimates suggested 60–80% of IDUs had anti-HCV in 25 countries and more than 80% of IDUs did so in 12 countries. About 10.0 million (range 6.0–15.2) IDUs worldwide might be anti-HCV positive. China (1.6 million), USA (1.5 million), and Russia (1.3 million) had the largest such populations. We identified eligible HBsAg reports for 59 countries, with midpoint prevalence estimates of 5–10% in 21 countries and more than 10% in ten countries. Worldwide, we estimate 6.4 million IDUs are anti-HBc positive (2.3–9.7 million), and 1.2 million (0.3–2.7 million) are HBsAg positive. Interpretation More IDUs have anti-HCV than HIV infection, and viral hepatitis poses a key challenge to public health. Variation in the coverage and quality of existing research creates uncertainty around estimates. Improved and more complete data and reporting are needed to estimate the scale of the issue, which will inform efforts to prevent and treat HCV and HBV in IDUs. Funding WHO and US National Institutes of Health (NIDA R01 DA018609).
• Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials
  - Lancet 378(9791):584-594 (2011)
  Background The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low! folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. Interpretation In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. Funding Full funding sources listed at end of paper (see Acknowledgments).
• Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study
  - Lancet 378(9791):595-605 (2011)
  Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory in! filtrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. Funding UK Medical Research Council; AVI BioPharma.
• Hemifacial sweating after carotid artery dissection
  - Lancet 378(9791):606 (2011)
  
• Pancreatic cancer
  - Lancet 378(9791):607-620 (2011)
  Substantial progress has been made in our understanding of the biology of pancreatic cancer, and advances in patients' management have also taken place. Evidence is beginning to show that screening first-degree relatives of individuals with several family members affected by pancreatic cancer can identify non-invasive precursors of this malignant disease. The incidence of and number of deaths caused by pancreatic tumours have been gradually rising, even as incidence and mortality of other common cancers have been declining. Despite developments in detection and management of pancreatic cancer, only about 4% of patients will live 5 years after diagnosis. Survival is better for those with malignant disease localised to the pancreas, because surgical resection at present offers the only chance of cure. Unfortunately, 80–85% of patients present with advanced unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. Hence, we ne! ed to understand the biological mechanisms that contribute to development and progression of pancreatic tumours. In this Seminar we will discuss the most common and deadly form of pancreatic cancer, pancreatic ductal adenocarcinoma.
• Novel melatonin-based therapies: potential advances in the treatment of major depression
  - Lancet 378(9791):621-631 (2011)
  Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT2C) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving plac! ebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.
• Reflections on transplantation waiting lists
  - Lancet 378(9791):632-635 (2011)
  
• From a pimple to a crater
  - Lancet 378(9791):636 (2011)