Saturday, December 10, 2011

Hot off the presses! Dec 16 The Lancet

The Dec 16 issue of the The Lancet is now up on Pubget (About The 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:

  • December 10â€"16, 2011
    - The Lancet 378(9808):i (2011)
  • Health in Afghanistan: hope and future
    - The Lancet 378(9808):1975 (2011)
  • Lessons from Lipitor and the broken blockbuster drug model
    - The Lancet 378(9808):1976 (2011)
  • What constitutes full access to data in industry-funded trials?
    - The Lancet 378(9808):1976 (2011)
  • Bioartificial tissues and organs: are we ready to translate?
    - The Lancet 378(9808):1977-1978 (2011)
  • mTOR inhibitor therapy for patients with carcinoid
    - The Lancet 378(9808):1978-1980 (2011)
  • Statins and safety: can we finally be reassured?
    - The Lancet 378(9808):1980-1981 (2011)
  • Keep it clean: hospital-acquired infections in children
    - The Lancet 378(9808):1982-1983 (2011)
  • Postgraduate medical education in England: 100 years of solitude
    - The Lancet 378(9808):1984-1985 (2011)
  • Offline: Nightmare on Downing Street
    - The Lancet 378(9808):1986 (2011)
  • India grapples with its child marriage challenge
    - The Lancet 378(9808):1987-1988 (2011)
  • The Lancet Technology: December, 2011
    - The Lancet 378(9808):1989 (2011)
  • Still life
    - The Lancet 378(9808):1990 (2011)
  • Anand Grover: leading the defence of human rights
    - The Lancet 378(9808):1991 (2011)
  • Franklin A Neva
    - The Lancet 378(9808):1992 (2011)
  • Dietary salt and cardiovascular disease
    - The Lancet 378(9808):1993 (2011)
  • Dietary salt and cardiovascular disease
    - The Lancet 378(9808):1993 (2011)
  • Dietary salt and cardiovascular disease
    - The Lancet 378(9808):1993-1994 (2011)
  • Dietary salt and cardiovascular disease â€" Authors' reply
    - The Lancet 378(9808):1994 (2011)
  • Sharing of research data
    - The Lancet 378(9808):1994-1995 (2011)
  • Sharing of research data
    - The Lancet 378(9808):1995 (2011)
  • Access to data in industry-sponsored trials
    - The Lancet 378(9808):1995-1996 (2011)
  • Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study
    - The Lancet 378(9808):1997-2004 (2011)
    Background Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. Methods A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 μg/kg) and epoetin beta (40 000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. Findings We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. Interpretation Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome. Funding European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, StratRegen, Vinnova Foundation, Radiumhemmet, Clinigene EU Network of Excellence, Swedish Cancer Society, Centre for Biosciences (The Live Cell imaging Unit), and UCL Business.
  • Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study
    - The Lancet 378(9808):2005-2012 (2011)
    Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at, number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Funding Novartis Pharmaceuticals.
  • Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20 536 high-risk individuals: a randomised controlled trial
    - The Lancet 378(9808):2013-2020 (2011)
    Background Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods. Methods 20 536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393. Findings During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19–28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89–1·02]) or vascular mortality (0·98 [0·90–1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92–1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92–1·11]) or to non-vascular causes (0·96 [0·89–1·03]). Interpretation More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment. Funding UK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.
  • Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: a prospective cohort study
    - The Lancet 378(9808):2021-2027 (2011)
    Background In sub-Saharan Africa, community-acquired bacteraemia is an important cause of illness and death in children. Our aim was to establish the magnitude and causes of hospital-acquired (nosocomial) bacteraemia in African children. Methods We reviewed prospectively collected surveillance data of 33 188 admissions to Kilifi District Hospital, Kenya, between April 16, 2002, and Sept 30, 2009. We defined bacteraemia as nosocomial if it occurred 48 h or more after admission. We estimated the per-admission risk, daily rate, effect on mortality, and microbial cause of nosocomial bacteraemia and analysed risk factors by multivariable Cox regression. The effect on morbidity was measured as the increase in hospital stay by comparison with time-matched patients without bacteraemia. Findings The overall risk of nosocomial bacteraemia during this period was 5·9/1000 admissions (95% CI 5·2–6·9) but we recorded an underlying rise in risk of 27% per year. The incidence was 1·0/1000 days in hospital (0·87–1·14), which is about 40 times higher than that of community-acquired bacteraemia in the same region. Mortality in patients with nosocomial bacteraemia was 53%, compared with 24% in community-acquired bacteraemia and 6% in patients without bacteraemia. In survivors, nosocomial bacteraemia lengthened hospital stay by 10·1 days (3·0–17·2). Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter spp, group D streptococci, and Pseudomonas aeruginosa accounted for three-quarters of nosocomial infections. Nosocomial bacteraemia was significantly associated with severe malnutrition (hazard ratio 2·52, 95% CI 1·79–3·57) and blood transfusion in children without severe anaemia (4·99; 3·39–7·37). Interpretation Our findings show that although nosocomial bacteraemia is rare, it has serious effects on morbidity and mortality, and the microbiological causes are distinct from those of community-acquired bacteraemia. Nosocomial infections are largely unrecognised or undocumented as a health risk in low-income countries, but they are likely to become public health priorities as awareness of their occurrence increases and as other prominent childhood diseases are progressively controlled. Funding Wellcome Trust.
  • Sudden unexpected death in epilepsy
    - The Lancet 378(9808):2028-2038 (2011)
    Sudden unexpected death in epilepsy (SUDEP) refers to the sudden death of a seemingly healthy individual with epilepsy, usually occurring during, or immediately after, a tonic-clonic seizure. The frequency of SUDEP varies depending on the severity of the epilepsy, but overall the risk of sudden death is more than 20 times higher than that in the general population. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. Data from a pooled analysis of risk factors indicate that the higher the frequency of tonic-clonic seizures, the higher the risk of SUDEP; furthermore, risk of SUDEP is also elevated in male patients, patients with long-duration epilepsy, and those on antiepileptic polytherapy. SUDEP usually occurs when the seizures are not witnessed and often at night. In this Seminar, we provide advice to clinicians on ways to minimise the ! risk of SUDEP, information to pass on to patients, and medicolegal aspects of these deaths.
  • Spider bite
    - The Lancet 378(9808):2039-2047 (2011)
    Spiders are a source of intrigue and fear, and several myths exist about their medical effects. Many people believe that bites from various spider species cause necrotic ulceration, despite evidence that most suspected cases of necrotic arachnidism are caused by something other than a spider bite. Latrodectism and loxoscelism are the most important clinical syndromes resulting from spider bite. Latrodectism results from bites by widow spiders (Latrodectus spp) and causes local, regional, or generalised pain associated with non-specific symptoms and autonomic effects. Loxoscelism is caused by Loxosceles spp, and the cutaneous form manifests as pain and erythema that can develop into a necrotic ulcer. Systemic loxoscelism is characterised by intravascular haemolysis and renal failure on occasion. Other important spiders include the Australian funnel-web spider (Atrax spp and Hadronyche spp) and the armed spider (Phoneutria spp) from Brazil. Antivenoms are an important tr! eatment for spider envenomation but have been less successful than have those for snake envenomation, with concerns about their effectiveness for both latrodectism and loxoscelism.
  • Routine blood tests? Helping you live(r) longer!
    - The Lancet 378(9808):2048 (2011)
  • Is health still global? A new approach from the UK Government
    - The Lancet 378(9808):e19-e20 (2011)
  • Students' perspective on rooting out causes of health injustice
    - The Lancet 378(9808):e20-e21 (2011)

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