Hot off the presses! Oct 22 LANCET

The Oct 22 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:

• A critical look at critical care
  - LANCET 376(9749):1273 (2010)
  
• The Global Fund: a bleak future ahead
  - LANCET 376(9749):1274 (2010)
  
• Mental health: WHO minds the GAP
  - LANCET 376(9749):1274 (2010)
  
• Intensive care medicine: a specialty coming to LIFE
  - LANCET 376(9749):1275-1276 (2010)
  
• Kidneys donated after cardiac death are acceptable
  - LANCET 376(9749):1276-1278 (2010)
  
• Response to antiplatelet treatment: from genes to outcome
  - LANCET 376(9749):1278-1281 (2010)
  
• Preventing HIV infection: turning the tide for young women
  - LANCET 376(9749):1281-1282 (2010)
  
• Time for a bold new vision at the Stop TB Partnership
  - LANCET 376(9749):1283-1284 (2010)
  
• Rural MBBS degree in India
  - LANCET 376(9749):1284-1285 (2010)
  
• Offline: Being relaxed about yachts
  - LANCET 376(9749):1286 (2010)
  
• First reduce harm: tackling HIV in Ukraine
  - LANCET 376(9749):1287-1288 (2010)
  
• Nuclear tests leave Kazakhstan still searching for answers
  - LANCET 376(9749):1289-1290 (2010)
  
• Anders Sparrman—masterful tale of a scientific vagabond
  - LANCET 376(9749):1291-1292 (2010)
  
• Exhibition Corporeal art
  - LANCET 376(9749):1292 (2010)
  
• Robert Edwards: Nobel Prize for father of in-vitro fertilisation
  - LANCET 376(9749):1293 (2010)
  
• Empowering brain science with neuroethics
  - LANCET 376(9749):1294-1295 (2010)
  
• Trevor Cory Beard
  - LANCET 376(9749):1296 (2010)
  
• Editorials about home birth—proceed with caution
  - LANCET 376(9749):1297 (2010)
  
• Editorials about home birth—proceed with caution
  - LANCET 376(9749):1297 (2010)
  
• Editorials about home birth—proceed with caution
  - LANCET 376(9749):1297-1298 (2010)
  
• Editorials about home birth—proceed with caution
  - LANCET 376(9749):1298 (2010)
  
• High-dose allopurinol in patients with stable angina pectoris
  - LANCET 376(9749):1298 (2010)
  
• High-dose allopurinol in patients with stable angina pectoris
  - LANCET 376(9749):1298-1299 (2010)
  
• High-dose allopurinol in patients with stable angina pectoris
  - LANCET 376(9749):1299 (2010)
  
• High-dose allopurinol in patients with stable angina pectoris – Authors' reply
  - LANCET 376(9749):1299-1300 (2010)
  
• Was it really hepatic hydrothorax?
  - LANCET 376(9749):1300 (2010)
  
• Was it really hepatic hydrothorax? – Authors' reply
  - LANCET 376(9749):1300-1301 (2010)
  
• Testiculopathy and vitamin D insufficiency
  - LANCET 376(9749):1301 (2010)
  
• Putting patients above politics
  - LANCET 376(9749):1301-1302 (2010)
  
• Can we increase male involvement in AIDS treatment?
  - LANCET 376(9749):1302 (2010)
  
• Department of Error
  - LANCET 376(9749):1302 (2010)
  
• Department of Error
  - LANCET 376(9749):1302 (2010)
  
• Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study
  - LANCET 376(9749):1303-1311 (2010)
  Background A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. Methods We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged ≥18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). Findings 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1·01, 95% CI 0·83 to 1·19, p=0·97), or in eGFR at 1–5 years after transplantation (at 12 months −0·36 mL/min per 1·73 m2, 95% CI −2·00 to 1·27, p=0·66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. Interpretation Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. Funding UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.
• Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis
  - LANCET 376(9749):1312-1319 (2010)
  Background Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON–TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. Methods We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON–TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. Findings In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22–2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38–2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly asso ciated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. Interpretation Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. Funding Daiichi Sankyo Company Ltd and Eli Lilly and Company.
• Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial
  - LANCET 376(9749):1320-1328 (2010)
  Background In the PLATO trial of ticagrelor versus clopidogrel for treatment of acute coronary syndromes, ticagrelor reduced the composite outcome of cardiovascular death, myocardial infarction, and stroke, but increased events of major bleeding related to non-coronary artery bypass graft (CABG). CYP2C19 and ABCB1 genotypes are known to influence the effects of clopidogrel. In this substudy, we investigated the effects of these genotypes on outcomes between and within treatment groups. Methods DNA samples obtained from patients in the PLATO trial were genotyped for CYP2C19 loss-of-function alleles (*2, *3, *4, *5, *6, *7, and *8), the CYP2C19 gain-of-function allele *17, and the ABCB1 single nucleotide polymorphism 3435C→T. For the CYP2C19 genotype, patients were stratified by the presence or absence of any loss-of-function allele, and for the ABCB1 genotype, patients were stratified by predicted gene expression (high, intermediate, or low). The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke after up to 12 months' treatment with ticagrelor or clopidogrel. Findings 10 285 patients provided samples for genetic analysis. The primary outcome occurred less often with ticagrelor versus clopidogrel, irrespective of CYP2C19 genotype: 8·6% versus 11·2% (hazard ratio 0·77, 95% CI 0·60–0·99, p=0·0380) in patients with any loss-of-function allele; and 8·8% versus 10·0% (0·86, 0·74–1·01, p=0·0608) in those without any loss-of-function allele (interaction p=0·46). For the ABCB1 genotype, event rates for the primary outcome were also consistently lower in the ticagrelor than in the clopidogrel group for all genotype groups (interaction p=0·39; 8·8% vs 11·9%; 0·71, 0·55–0·92 for the high-expression genotype). In the clopidogrel group, the event rate at 30 days was higher in patients with than in those without any loss-of-function CYP2C19 alleles (5·7% vs 3·8%, p=0·028), leading to earlier separation of event rates between treatment groups in patients with loss-of-function alleles. Patients on clopidogrel who had any gain-of -function CYP2C19 allele had a higher frequency of major bleeding (11·9%) than did those without any gain-of-function or loss-of-function alleles (9·5%; p=0·022), but interaction between treatment and genotype groups was not significant for any type of major bleeding. Interpretation Ticagrelor is a more efficacious treatment for acute coronary syndromes than is clopidogrel, irrespective of CYP2C19 and ABCB1 polymorphisms. Use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment. Funding AstraZeneca.
• PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial
  - LANCET 376(9749):1329-1337 (2010)
  Background Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. Methods Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO 2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. Findings We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation. Interpretation Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. Funding UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.
• Stroke, infective endocarditis and a blood filled cyst
  - LANCET 376(9749):1338 (2010)
  
• Critical care and the global burden of critical illness in adults
  - LANCET 376(9749):1339-1346 (2010)
  Critical care has evolved from treatment of poliomyelitis victims with respiratory failure in an intensive care unit to treatment of severely ill patients irrespective of location or specific technology. Population-based studies in the developed world suggest that the burden of critical illness is higher than generally appreciated and will increase as the population ages. Critical care capacity has long been needed in the developing world, and efforts to improve the care of the critically ill in these settings are starting to occur. Expansion of critical care to handle the consequences of an ageing population, natural disasters, conflict, inadequate primary care, and higher-risk medical therapies will be challenged by high costs at a time of economic constraint. To meet this challenge, investigators in this discipline will need to measure the global burden of critical illness and available critical-care resources, and develop both preventive and therapeutic intervention s that are generalisable across countries.
• Ethics and end-of-life care for adults in the intensive care unit
  - LANCET 376(9749):1347-1353 (2010)
  The intensive care unit (ICU) is where patients are given some of the most technologically advanced life-sustaining treatments, and where difficult decisions are made about the usefulness of such treatments. The substantial regional variability in these ethical decisions is a result of many factors, including religious and cultural beliefs. Because most critically ill patients lack the capacity to make decisions, family and other individuals often act as the surrogate decision makers, and in many regions communication between the clinician and family is central to decision making in the ICU. Elsewhere, involvement of the family is reduced and that of the physicians is increased. End-of-life care is associated with increased burnout and distress among clinicians working in the ICU. Since many deaths in the ICU are preceded by a decision to withhold or withdraw life support, high-quality decision making and end-of-life care are essential in all regions, and can improve pa tient and family outcomes, and also retention of clinicians working in the ICU. To make such a decision requires adequate training, good communication between the clinician and family, and the collaboration of a well functioning interdisciplinary team.
• Critical care: advances and future perspectives
  - LANCET 376(9749):1354-1361 (2010)
  Intensive care offers a standard of monitoring, intervention, and organ support that cannot be readily delivered in a general ward. Its expansion in the past few decades, including the creation of emergency and outreach teams, emphasises that intensive care has an increasingly prominent role within the hospital. Although outcomes are clearly improving, intensive care remains a nascent specialty in which we are still learning how to harness a powerful ability to manipulate physiology, biochemistry, and immunology to achieve best outcomes for the patient. The results of many multicentre studies have not lent support to, or have even confounded, expectations, drawing attention to several issues related to patient heterogeneity, trial design, and elucidation of underlying pathophysiological processes. However, these results have generated constructive introspection and reappraisal of treatments and management strategies that have benefited the patient. In addition to the me dical, financial, and logistical challenges in the future, exciting opportunities will arise as new developments in diagnostic tests, therapeutic interventions, and technology are used to exploit an increasing awareness of how critical illness should be managed.
• Delirious deficiency
  - LANCET 376(9749):1362 (2010)