Hot off the presses! Feb 11 LANCET

The Feb 11 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:

• Natural disasters—taking a longer term view
  - LANCET 377(9764):439 (2011)
  
• Looking forward to new hypertension guidelines
  - LANCET 377(9764):440 (2011)
  
• Supporting the Global Fund to fight fraud
  - LANCET 377(9764):440 (2011)
  
• CRP: star trekking the galaxy of risk markers
  - LANCET 377(9764):441-442 (2011)
  
• Combination therapy for visceral leishmaniasis
  - LANCET 377(9764):443-444 (2011)
  
• A prototype assay to detect vCJD-infected blood
  - LANCET 377(9764):444-446 (2011)
  
• Restricted elimination diet for ADHD: the INCA study
  - LANCET 377(9764):446-448 (2011)
  
• Universal health care in India: the time is right
  - LANCET 377(9764):448-449 (2011)
  
• Rethinking health-care systems: a focus on chronicity
  - LANCET 377(9764):450-451 (2011)
  
• Offline: Prime Ministers and Presidents
  - LANCET 377(9764):452 (2011)
  
• GAVI takes steps to address funding woes
  - LANCET 377(9764):453 (2011)
  
• Doctors in distress
  - LANCET 377(9764):454-455 (2011)
  
• Progress patchy on health-worker crisis
  - LANCET 377(9764):456 (2011)
  
• Facing up to medical error
  - LANCET 377(9764):457-458 (2011)
  
• The tyranny of tradition
  - LANCET 377(9764):458 (2011)
  
• Dagfinn Høybråten—new Board Chair of GAVI Alliance
  - LANCET 377(9764):459 (2011)
  
• Narrative epileptology
  - LANCET 377(9764):460-461 (2011)
  
• Richard Bing
  - LANCET 377(9764):462 (2011)
  
• Stronger guidance needed on lifelong care for chronic diseases
  - LANCET 377(9764):463 (2011)
  
• Health and societal effects of alcohol
  - LANCET 377(9764):463-464 (2011)
  
• Putting teeth into chronic diseases
  - LANCET 377(9764):464 (2011)
  
• Anticoagulation: improve care quality or use new alternatives?
  - LANCET 377(9764):464-465 (2011)
  
• Anticoagulation: improve care quality or use new alternatives? – Author's reply
  - LANCET 377(9764):465 (2011)
  
• Phenotyping and treatment of phenylketonuria
  - LANCET 377(9764):465 (2011)
  
• Phenotyping and treatment of phenylketonuria – Authors' reply
  - LANCET 377(9764):466 (2011)
  
• Founding of the MDG-15 Young Professionals Forum
  - LANCET 377(9764):466-467 (2011)
  
• Requests for euthanasia and palliative care in France
  - LANCET 377(9764):467-468 (2011)
  
• Empowering whom? Neuroethics at its limits
  - LANCET 377(9764):468 (2011)
  
• Department of Error
  - LANCET 377(9764):468 (2011)
  
• C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20 536 patients in the Heart Protection Study
  - LANCET 377(9764):469-476 (2011)
  Background It has been suggested that inflammation status, as assessed by C-reactive protein (CRP) concentration, modifies the vascular protective effects of statin therapy. In particular, there have been claims that statins might be more beneficial in people with raised CRP concentrations, and might even be ineffective in people with low concentrations of both CRP and LDL cholesterol. This study aimed to test this hypothesis. Methods In 69 UK hospitals, 20 536 men and women aged 40–80 years at high risk of vascular events were randomly assigned to simvastatin 40 mg daily versus matching placebo for a mean of 5·0 years. Patients were categorised into six baseline CRP groups (<1·25, 1·25–1·99, 2·00–2·99, 3·00–4·99, 5·00–7·99, and ≥8·00 mg/L). The primary endpoint for subgroup analyses was major vascular events, defined as the composite of coronary death, myocardial infarction, stroke, or revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN48489393. Findings Overall, allocation to simvastatin resulted in a significant 24% (95% CI 19–28) proportional reduction in the incidence of first major vascular event after randomisation (2033 [19·8%] allocated simvastatin vs 2585 [25·2%] allocated placebo). There was no evidence that the proportional reduction in this endpoint, or its components, varied with baseline CRP concentration (trend p=0·41). Even in participants with baseline CRP concentration less than 1·25 mg/L, major vascular events were significantly reduced by 29% (99% CI 12–43, p<0·0001; 239 [14·1%] vs 329 [19·4%]). No significant heterogeneity in the relative risk reduction was recorded between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP (p=0·72). In particular, there was clear evidence of benefit in those with both low LDL cholesterol and low CRP (27% reduction, 99% CI 11–40, p<0·0001; 295 [15·6%] vs 400 [20·9%]). Interpretation Evidence from this large-scale randomised trial does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially. Funding UK Medical Research Council, British Heart Foundation, Merck, Roche Vitamins, and GlaxoSmithKline.
• Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial
  - LANCET 377(9764):477-486 (2011)
  Background Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. Methods Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5–60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention ! to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. Findings Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5–96·3) for amphotericin B, 156 (97·5%; 93·3–99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24–99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1–99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. Interpretation Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. Funding Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.
• Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay
  - LANCET 377(9764):487-493 (2011)
  Background Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder originating from exposure to bovine-spongiform-encephalopathy-like prions. Prion infections are associated with long and clinically silent incubations. The number of asymptomatic individuals with vCJD prion infection is unknown, posing risk to others via blood transfusion, blood products, organ or tissue grafts, and contaminated medical instruments. We aimed to establish the sensitivity and specificity of a blood-based assay for detection of vCJD prion infection. Methods We developed a solid-state binding matrix to capture and concentrate disease-associated prion proteins and coupled this method to direct immunodetection of surface-bound material. Quantitative assay sensitivity was assessed with a serial dilution series of 10−7 to 10−10 of vCJD prion-infected brain homogenate into whole human blood, with a baseline control of normal human brain homogenate in whole blood (10−6). To establish the sensitivity and specificity of the assay for detection of endogenous vCJD, we analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic CJD, 42 with other neurological diseases, and 100 normal controls. Samples were masked and numbered by individuals independent of the assay and analysis. Each sample was tested twice in independent assay runs; only samples that were reactive in both runs were scored as positive overall. Findings We were able to distinguish a 10−10 dilution of exogenous vCJD prion-infected brain from a 10−6 dilution of normal brain (mean chemiluminescent signal, 1·3×105 [SD 1·1×104] for vCJD vs 9·9×104 [4·5×103] for normal brain; p<0·0001)—an assay sensitivity that was orders of magnitude higher than any previously reported. 15 samples in the masked panel were scored as positive. All 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71·4% (95% CI 47·8–88·7) and a specificity of 100% (95% CIs between 97·8% and 100%). Interpretation These initial studies provide a prototype blood test for diagnosis of vCJD in symptomatic individuals, which could allow development of large-scale screening tests for asymptomatic vCJD prion infection. Funding UK Medical Research Council.
• Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial
  - LANCET 377(9764):494-503 (2011)
  Background The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children. Methods The Impact of Nutrition on Children with ADHD (INCA) study was a randomised controlled trial that consisted of an open-label phase with masked measurements followed by a double-blind crossover phase. Patients in the Netherlands and Belgium were enrolled via announcements in medical health centres and through media announcements. Randomisation in both phases was individually done by random sampling. In the open-label phase (first phase), children aged 4–8 years who were diagnosed with ADHD were randomly assigned to 5 weeks of a restricted elimination diet (diet group) or to instructions for a healthy diet (control group). Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child's individual IgG blood test results) were added to the diet. During ! the first phase, only the assessing paediatrician was masked to group allocation. During the second phase (challenge phase), all persons involved were masked to challenge allocation. Primary endpoints were the change in ARS score between baseline and the end of the first phase (masked paediatrician) and between the end of the first phase and the second phase (double-blind), and the abbreviated Conners' scale (ACS) score (unmasked) between the same timepoints. Secondary endpoints included food-specific IgG levels at baseline related to the behaviour of the diet group responders after IgG-based food challenges. The primary analyses were intention to treat for the first phase and per protocol for the second phase. INCA is registered as an International Standard Randomised Controlled Trial, number ISRCTN 76063113. Findings Between Nov 4, 2008, and Sept 29, 2009, 100 children were enrolled and randomly assigned to the control group (n=50) or the diet group (n=50). Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23·7 (95% CI 18·6–28·8; p<0·0001) according to the masked ratings. The difference between groups in the mean ACS score between the same timepoints was 11·8 (95% CI 9·2–14·5; p<0·0001). The ARS total score increased in clinical responders after the challenge by 20·8 (95% CI 14·3–27·3; p<0·0001) and the ACS score increased by 11·6 (7·7–15·4; p<0·0001). In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels. There were no harms or adverse events reported in both phases. Interpretation A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged. Funding Foundation of Child and Behaviour, Foundation Nuts Ohra, Foundation for Children's Welfare Stamps Netherlands, and the KF Hein Foundation.
• Valsalva haemorrhagic retinopathy after push-ups
  - LANCET 377(9764):504 (2011)
  
• Health care and equity in India
  - LANCET 377(9764):505-515 (2011)
  In India, despite improvements in access to health care, inequalities are related to socioeconomic status, geography, and gender, and are compounded by high out-of-pocket expenditures, with more than three-quarters of the increasing financial burden of health care being met by households. Health-care expenditures exacerbate poverty, with about 39 million additional people falling into poverty every year as a result of such expenditures. We identify key challenges for the achievement of equity in service provision, and equity in financing and financial risk protection in India. These challenges include an imbalance in resource allocation, inadequate physical access to high-quality health services and human resources for health, high out-of-pocket health expenditures, inflation in health spending, and behavioural factors that affect the demand for appropriate health care. Use of equity metrics in monitoring, assessment, and strategic planning; investment in development o! f a rigorous knowledge base of health-systems research; development of a refined equity-focused process of deliberative decision making in health reform; and redefinition of the specific responsibilities and accountabilities of key actors are needed to try to achieve equity in health care in India. The implementation of these principles with strengthened public health and primary-care services will help to ensure a more equitable health care for India's population.
• Maternal, neonatal, and child health in southeast Asia: towards greater regional collaboration
  - LANCET 377(9764):516-525 (2011)
  Although maternal and child mortality are on the decline in southeast Asia, there are still major disparities, and greater equity is key to achieve the Millennium Development Goals. We used comparable cross-national data sources to document mortality trends from 1990 to 2008 and to assess major causes of maternal and child deaths. We present inequalities in intervention coverage by two common measures of wealth quintiles and rural or urban status. Case studies of reduction in mortality in Thailand and Indonesia indicate the varying extents of success and point to some factors that accelerate progress. We developed a Lives Saved Tool analysis for the region and for country subgroups to estimate deaths averted by cause and intervention. We identified three major patterns of maternal and child mortality reduction: early, rapid downward trends (Brunei, Singapore, Malaysia, and Thailand); initially high declines (sustained by Vietnam but faltering in the Philippines and Ind! onesia); and high initial rates with a downward trend (Laos, Cambodia, and Myanmar). Economic development seems to provide an important context that should be coupled with broader health-system interventions. Increasing coverage and consideration of the health-system context is needed, and regional support from the Association of Southeast Asian Nations can provide increased policy support to achieve maternal, neonatal, and child health goals.
• Mind the gap! An unusual metabolic acidosis
  - LANCET 377(9764):526 (2011)