Hot off the presses! Oct 29 LANCET

The Oct 29 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:

• Progress and challenges in neglected tropical diseases
  - LANCET 376(9750):1363 (2010)
  
• Reflections on ADHD
  - LANCET 376(9750):1364 (2010)
  
• Implementing the US health-care reform bill
  - LANCET 376(9750):1364 (2010)
  
• September 11, a decade on: a call for papers
  - LANCET 376(9750):1365 (2010)
  
• Genomic risk prediction
  - LANCET 376(9750):1366-1367 (2010)
  
• Neuropsychiatric connections of ADHD genes
  - LANCET 376(9750):1367-1368 (2010)
  
• International donor assistance for health
  - LANCET 376(9750):1368-1370 (2010)
  
• Realising the benefits of genetics for health
  - LANCET 376(9750):1370-1371 (2010)
  
• Huntington's disease out of the closet?
  - LANCET 376(9750):1372-1373 (2010)
  
• NHS reform: untried remedies for misdiagnosed problems?
  - LANCET 376(9750):1373-1375 (2010)
  
• Global Health Metrics and Evaluation—a call for abstracts
  - LANCET 376(9750):1375 (2010)
  
• Offline: 41 Portland Place
  - LANCET 376(9750):1376 (2010)
  
• The ethics of direct-to-consumer genetic testing
  - LANCET 376(9750):1377-1378 (2010)
  
• Chilean miners see the light at last
  - LANCET 376(9750):1379-1380 (2010)
  
• Personal genomes
  - LANCET 376(9750):1381-1382 (2010)
  
• The missing link?
  - LANCET 376(9750):1382 (2010)
  
• Charles Rotimi: engaging Africa in human genomic research
  - LANCET 376(9750):1383 (2010)
  
• Bad seeds, bad science, and fairly black cats?
  - LANCET 376(9750):1384-1385 (2010)
  
• Robert Wayne McCollum
  - LANCET 376(9750):1386 (2010)
  
• Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
  - LANCET 376(9750):1387 (2010)
  
• Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
  - LANCET 376(9750):1387 (2010)
  
• Rosiglitazone plus metformin to prevent type 2 diabetes mellitus
  - LANCET 376(9750):1387-1388 (2010)
  
• Rosiglitazone plus metformin to prevent type 2 diabetes mellitus – Author's reply
  - LANCET 376(9750):1388 (2010)
  
• Maternal mortality for 181 countries, 1980–2008
  - LANCET 376(9750):1389 (2010)
  
• Maternal mortality for 181 countries, 1980–2008
  - LANCET 376(9750):1389 (2010)
  
• Maternal mortality for 181 countries, 1980–2008
  - LANCET 376(9750):1389-1390 (2010)
  
• Maternal mortality for 181 countries, 1980–2008
  - LANCET 376(9750):1390 (2010)
  
• Significant errors
  - LANCET 376(9750):1390-1391 (2010)
  
• Significant errors – Author's reply
  - LANCET 376(9750):1391 (2010)
  
• Web-surfers beware: know thy source
  - LANCET 376(9750):1391-1392 (2010)
  
• Antiretroviral therapy in low-resource settings
  - LANCET 376(9750):1392 (2010)
  
• Department of Error
  - LANCET 376(9750):1392 (2010)
  
• Department of Error
  - LANCET 376(9750):1392 (2010)
  
• A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses
  - LANCET 376(9750):1393-1400 (2010)
  Background Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design. Methods We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48 897 controls free of the disease) and a prospective cohort design including 30 725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression. Findings In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years' follow-up (IQR 6·7–13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35–2·04, p value for linear trend=7·3×10−10). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses. Interpretation Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined. Funding The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.
• Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis
  - LANCET 376(9750):1401-1408 (2010)
  Background Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. Methods We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5–17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autis! m or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35 243 Icelandic controls. Findings Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10−5). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10−6), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). Interpretation Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. Funding Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.
• Equity and adequacy of international donor assistance for global malaria control: an analysis of populations at risk and external funding commitments
  - LANCET 376(9750):1409-1416 (2010)
  Background Financing for malaria control has increased as part of international commitments to achieve the Millennium Development Goals (MDGs). We aimed to identify the unmet financial needs that would be biologically and economically equitable and would increase the chances of reaching worldwide malaria-control ambitions. Methods Populations at risk of stable Plasmodium falciparum or Plasmodium vivax transmission were calculated for 2007 and 2009 for 93 malaria-endemic countries to measure biological need. National per-person gross domestic product (GDP) was used to define economic need. An analysis of external donor assistance for malaria control was done for the period 2002–09 to compute overall and annualised per-person at-risk-funding commitments. Annualised malaria donor assistance was compared with independent predictions of funding needed to reach international targets of 80% coverage of best practices in case-management and effective disease prevention. Countries were ranked in relation to biological, economic, and unmet needs to examine equity and adequacy of support by 2010. Findings International financing for malaria control has increased by 166% (from $0·73 billion to $1·94 billion) since 2007 and is broadly consistent with biological needs. African countries have become major recipients of external assistance; however, countries where P vivax continues to pose threats to control ambitions are not as well funded. 21 countries have reached adequate assistance to provide a comprehensive suite of interventions by 2009, including 12 countries in Africa. However, this assistance was inadequate for 50 countries representing 61% of the worldwide population at risk of malaria—including ten countries in Africa and five in Asia that coincidentally are some of the poorest countries. Approval of donor funding for malaria control does not correlate with GDP. Interpretation Funding for malaria control worldwide is 60% lower than the US$4·9 billion needed for comprehensive control in 2010; this includes funding shortfalls for a wide range of countries with different numbers of people at risk and different levels of domestic income. More efficient targeting of financial resources against biological need and national income should create a more equitable investment portfolio that with increased commitments will guarantee sustained financing of control in countries most at risk and least able to support themselves. Funding Wellcome Trust.
• Phenylketonuria
  - LANCET 376(9750):1417-1427 (2010)
  Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20% of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom.! Possible future treatments include enzyme substitution with phenylalanine ammonia lyase, which degrades phenylalanine, and gene therapy to restore phenylalanine hydroxylase activity.
• Escherichia coli O157
  - LANCET 376(9750):1428-1435 (2010)
  Escherichia coli O157 is an uncommon but serious cause of gastroenteritis. This bacterium is noteworthy because a few, but significant, number of infected people develop the haemolytic uraemic syndrome, which is the most frequent cause of acute renal failure in children in the Americas and Europe. Many infections of E coli O157 could be prevented by the more effective application of evidence-based methods, which is especially important because once an infection has been established, no therapeutic interventions are available to lessen the risk of the development of the haemolytic uraemic syndrome. This Review takes into account the evolution and geographical distibution of E coli O157 (and its close pathogenic relatives); the many and varied routes of transmission from its major natural hosts, ruminant farm animals; and other aspects of its epidemiology, its virulence factors, the diagnosis and management of infection and their complications, the repercussions of infec! tion including costs, and prevention.
• The patient has the diagnosis
  - LANCET 376(9750):1436 (2010)