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Journal Cover   The Lancet
  [SJR: 11.563]   [H-I: 514]   [1353 followers]  Follow
    
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   ISSN (Print) 0140-6736 - ISSN (Online) 1474-547X
   Published by Elsevier Homepage  [2812 journals]
  • Genetics and neonatal diabetes: towards precision medicine
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Leif Groop



      PubDate: 2015-07-31T20:52:10Z
       
  • The effect of early, comprehensive genomic testing on clinical care in
           neonatal diabetes: an international cohort study
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Elisa De Franco, Sarah E Flanagan, Jayne AL Houghton, Hana Lango Allen, Deborah JG Mackay, I Karen Temple, Sian Ellard, Andrew T Hattersley
      Background Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. Methods In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. Findings Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001). Interpretation Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. Funding Wellcome Trust and Diabetes UK.


      PubDate: 2015-07-31T20:52:10Z
       
  • A novel total artificial heart: search for haemocompatibility
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Alexander Stepanenko, Friedrich Kaufmann



      PubDate: 2015-07-31T20:52:10Z
       
  • Legionnaires' disease
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Burke A Cunha, Almudena Burillo, Emilio Bouza
      Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella, and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease.


      PubDate: 2015-07-31T20:52:10Z
       
  • Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a
           randomised, multicentre, placebo-controlled trial
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): John D Grainger, Franco Locatelli, Thirachit Chotsampancharoen, Elena Donyush, Bunchoo Pongtanakul, Patcharee Komvilaisak, Darintr Sosothikul, Guillermo Drelichman, Nongnuch Sirachainan, Susanne Holzhauer, Vladimir Lebedev, Richard Lemons, Dagmar Pospisilova, Ugo Ramenghi, James B Bussel, Kalpana K Bakshi, Malini Iyengar, Geoffrey W Chan, Karen D Chagin, Dickens Theodore, Lisa M Marcello, Christine K Bailey
      Background The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. Methods PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1–17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 109 per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12–17 years, 6–11 years, and 1–5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1–5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6–17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1–5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 109 per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. Findings Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 109 per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3–140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12–17 years, 42% vs 0% for patients aged 6–11 years, and 36% vs 0% for patients aged 1–5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1–4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2–4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 109 per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. ...
      PubDate: 2015-07-31T20:52:10Z
       
  • Thrombopoietin-receptor agonists in children with immune thrombocytopenia
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Cindy E Neunert, Rachael F Grace



      PubDate: 2015-07-31T20:52:10Z
       
  • First clinical use of a bioprosthetic total artificial heart: report of
           two cases
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Alain Carpentier, Christian Latrémouille, Bernard Cholley, David M Smadja, Jean-Christian Roussel, Elodie Boissier, Jean-Noël Trochu, Jean-Pierre Gueffet, Michèle Treillot, Philippe Bizouarn, Denis Méléard, Marie-Fazia Boughenou, Olivier Ponzio, Marc Grimmé, Antoine Capel, Piet Jansen, Albert Hagège, Michel Desnos, Jean-Noël Fabiani, Daniel Duveau
      Background The development of artificial hearts in patients with end-stage heart disease have been confronted with the major issues of thromboembolism or haemorrhage. Since valvular bioprostheses are associated with a low incidence of these complications, we decided to use bioprosthetic materials in the construction of a novel artificial heart (C-TAH). We report here the device characteristics and its first clinical applications in two patients with end-stage dilated cardiomyopathy. The aim of the study was to evaluate safety and feasibility of the CARMAT TAH for patients at imminent risk of death from biventricular heart failure and not eligible for transplant. Methods The C-TAH is an implantable electro-hydraulically actuated pulsatile biventricular pump. All components, batteries excepted, are embodied in a single device positioned in the pericardial sac after excision of the native ventricles. We selected patients admitted to hospital who were at imminent risk of death, having irreversible biventricular failure, and not eligible for heart transplantation, from three cardiac surgery centres in France. Findings The C-TAH was implanted in two male patients. Patient 1, aged 76 years, had the C-TAH implantation on Dec 18, 2013; patient 2, aged 68 years, had the implantation on Aug 5, 2014. The cardiopulmonary bypass times for C-TAH implantation were 170 min for patient 1 and 157 min for patient 2. Both patients were extubated within the first 12 postoperative hours and had a rapid recovery of their respiratory and circulatory functions as well as a normal mental status. Patient 1 presented with a tamponade on day 23 requiring re-intervention. Postoperative bleeding disorders prompted anticoagulant discontinuation. The C-TAH functioned well with a cardiac output of 4·8–5·8 L/min. On day 74, the patient died due to a device failure. Autopsy did not detect any relevant thrombus formation within the bioprosthesis nor the different organs, despite a 50-day anticoagulant-free period. Patient 2 experienced a transient period of renal failure and a pericardial effusion requiring drainage, but otherwise uneventful postoperative course. He was discharged from the hospital on day 150 after surgery with a wearable system without technical assistance. After 4 months at home, the patient suffered low cardiac output. A change of C-TAH was attempted but the patient died of multiorgan failure. Interpretation This preliminary experience could represent an important contribution to the development of total artificial hearts using bioprosthetic materials. Funding CARMAT SA.


      PubDate: 2015-07-31T20:52:10Z
       
  • Can we model a cognitive footprint of interventions and policies to help
           to meet the global challenge of dementia?
    • Abstract: Publication date: Available online 29 July 2015
      Source:The Lancet
      Author(s): Martin Rossor, Martin Knapp



      PubDate: 2015-07-31T20:52:10Z
       
  • 50 years of Medicare
    • Abstract: Publication date: Available online 29 July 2015
      Source:The Lancet
      Author(s): Susan Jaffe



      PubDate: 2015-07-31T20:52:10Z
       
  • Is crowdfunding a viable source of clinical trial research funding'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Abhinav Sharma, James Khan, Phillip J Devereaux



      PubDate: 2015-07-28T20:48:53Z
       
  • Against age discrimination
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Timo Strandberg, Sirpa Pietikäinen, Stefania Maggi, Marian Harkin, Jean Petermans



      PubDate: 2015-07-28T20:48:53Z
       
  • Polio vaccination in Pakistan
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Muhammad Umair Khan, Akram Ahmad



      PubDate: 2015-07-28T20:48:53Z
       
  • Levi Watkins
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Geoff Watts



      PubDate: 2015-07-28T20:48:53Z
       
  • Greek financial crisis and child mental health
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Gerasimos Kolaitis, George Giannakopoulos



      PubDate: 2015-07-28T20:48:53Z
       
  • Management of disease outbreak in Nepal
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Rabindra Karki



      PubDate: 2015-07-28T20:48:53Z
       
  • Is precision medicine the route to a healthy world'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Denis Horgan, Angelo Paradiso, Gordon McVie, Ian Banks, Tom Van der Wal, Angela Brand, Mark Lawler



      PubDate: 2015-07-28T20:48:53Z
       
  • Global Health Film Festival: media, impact, and social change
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Joseph Robert Fitchett, Lalitha Bhagavatheeswaran, Gerri McHugh



      PubDate: 2015-07-28T20:48:53Z
       
  • Mood vibrations
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Jason Socrates Bardi



      PubDate: 2015-07-28T20:48:53Z
       
  • A fictional avatar
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Jonathan Barnes



      PubDate: 2015-07-28T20:48:53Z
       
  • Signing the US Medicare Act: a long political struggle
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Elizabeth Fee



      PubDate: 2015-07-28T20:48:53Z
       
  • Augmentation treatment for α1 antitrypsin deficiency
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Ronald G Crystal



      PubDate: 2015-07-28T20:48:53Z
       
  • Climate and health: mortality attributable to heat and cold
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Keith Dear, Zhan Wang



      PubDate: 2015-07-28T20:48:53Z
       
  • Offline: Why the unity of life matters for our planetary health
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Richard Horton



      PubDate: 2015-07-28T20:48:53Z
       
  • The World Bank under Jim Kim
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Sam Loewenberg



      PubDate: 2015-07-28T20:48:53Z
       
  • What's your poison'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Sean Cleghorn



      PubDate: 2015-07-28T20:48:53Z
       
  • Safeguarding children and improving their care in the UK
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): David Low, Damian Roland, Gillian Baird, Cyril Chantler



      PubDate: 2015-07-28T20:48:53Z
       
  • Ureteric colic: evidence empowers responsible treatment
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Jean de la Rosette, M Pilar Laguna



      PubDate: 2015-07-28T20:48:53Z
       
  • Withdrawal from methadone in US prisons: cruel and unusual'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): M-J Milloy, Evan Wood



      PubDate: 2015-07-28T20:48:53Z
       
  • Financing global health: the poverty of nations
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): The Lancet



      PubDate: 2015-07-28T20:48:53Z
       
  • New guidelines for idiopathic pulmonary fibrosis
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): The Lancet



      PubDate: 2015-07-28T20:48:53Z
       
  • Ending institutionalisation of children
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): The Lancet



      PubDate: 2015-07-28T20:48:53Z
       
  • Mortality risk attributable to high and low ambient temperature: a
           multicountry observational study
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Antonio Gasparrini, Yuming Guo, Masahiro Hashizume, Eric Lavigne, Antonella Zanobetti, Joel Schwartz, Aurelio Tobias, Shilu Tong, Joacim Rocklöv, Bertil Forsberg, Michela Leone, Manuela De Sario, Michelle L Bell, Yue-Liang Leon Guo, Chang-fu Wu, Haidong Kan, Seung-Muk Yi, Micheline de Sousa Zanotti Stagliorio Coelho, Paulo Hilario Nascimento Saldiva, Yasushi Honda, Ho Kim, Ben Armstrong
      Background Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures. Methods We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature–mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5th temperature percentiles. Findings We analysed 74 225 200 deaths in various periods between 1985 and 2012. In total, 7·71% (95% empirical CI 7·43–7·91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80–90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7·29%, 7·02–7·49) than by heat (0·42%, 0·39–0·44). Extreme cold and hot temperatures were responsible for 0·86% (0·84–0·87) of total mortality. Interpretation Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios. Funding UK Medical Research Council.


      PubDate: 2015-07-28T20:48:53Z
       
  • Estimating the global prevalence of hepatitis B
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Jennifer H MacLachlan, Stephen Locarnini, Benjamin C Cowie



      PubDate: 2015-07-28T20:48:53Z
       
  • Plaque-type glomuvenous malformations in a child
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Riccardo Cavalli, Gregorio P Milani, Cristina Chelleri, Stefano Donelli, Emilio F Fossali



      PubDate: 2015-07-28T20:48:53Z
       
  • ADVICE on adenosine to improve atrial fibrillation ablation
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Tomás Datino



      PubDate: 2015-07-28T20:48:53Z
       
  • Postmenopausal breast cancer: a best endocrine strategy'
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Erica L Mayer, Harold J Burstein



      PubDate: 2015-07-28T20:48:53Z
       
  • Bisphosphonates, bone, and breast cancer recurrence
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Adam Brufsky, Aju Mathew



      PubDate: 2015-07-28T20:48:53Z
       
  • Aromatase inhibitors versus tamoxifen in early breast cancer:
           patient-level meta-analysis of the randomised trials
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
      Background The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2–3 years of tamoxifen then aromatase inhibitor to year 5; and of 2–3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). Findings In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0–1 (RR 0·64, 95% CI 0·52–0·78) and 2–4 (RR 0·80, 0·68–0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75–0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2–3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0–1 (RR 0·74, 0·62–0·89) but not while both groups received aromatase inhibitors during years 2–4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81–0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78–1·03; 2p=0·11). In the comparison of 2–3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2–4 (RR 0·56, 0·46–0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64–0·77), but not significantly thereafter (RR 0·93, 0·86–1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67–0·92), and subsequently (RR 0·89, 0·81–0·99), and for all periods combined (RR 0·86, 0·80–0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82–0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21–0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28–1·57); non-breast-cancer mortality was similar. Interpretation Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Funding Cancer Research UK, Medical Research Council.


      PubDate: 2015-07-28T20:48:53Z
       
  • Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of
           individual patient data from randomised trials
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
      Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.


      PubDate: 2015-07-28T20:48:53Z
       
  • The World Heart Federation's vision for worldwide cardiovascular disease
           prevention
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Salim Yusuf, David Wood, Johanna Ralston, K Srinath Reddy



      PubDate: 2015-07-28T20:48:53Z
       
  • Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal
           atrial fibrillation: an international, multicentre, randomised superiority
           trial
    • Abstract: Publication date: Available online 23 July 2015
      Source:The Lancet
      Author(s): Laurent Macle, Paul Khairy, Rukshen Weerasooriya, Paul Novak, Atul Verma, Stephan Willems, Thomas Arentz, Isabel Deisenhofer, George Veenhuyzen, Christophe Scavée, Pierre Jaïs, Helmut Puererfellner, Sylvie Levesque, Jason G Andrade, Lena Rivard, Peter G Guerra, Marc Dubuc, Bernard Thibault, Mario Talajic, Denis Roy, Stanley Nattel
      Background Catheter ablation is increasingly used to manage atrial fibrillation, but arrhythmia recurrences are common. Adenosine might identify pulmonary veins at risk of reconnection by unmasking dormant conduction, and thereby guide additional ablation to improve arrhythmia-free survival. We assessed whether adenosine-guided pulmonary vein isolation could prevent arrhythmia recurrence in patients undergoing radiofrequency catheter ablation for paroxysmal atrial fibrillation. Methods We did this randomised trial at 18 hospitals in Australia, Europe, and North America. We enrolled patients aged older than 18 years who had had at least three symptomatic atrial fibrillation episodes in the past 6 months, and for whom treatment with an antiarrhythmic drug failed. After pulmonary vein isolation, intravenous adenosine was administered. If dormant conduction was present, patients were randomly assigned (1:1) to additional adenosine-guided ablation to abolish dormant conduction or to no further ablation. If no dormant conduction was revealed, randomly selected patients were included in a registry. Patients were masked to treatment allocation and outcomes were assessed by a masked adjudicating committee. Patients were followed up for 1 year. The primary outcome was time to symptomatic atrial tachyarrhythmia after a single procedure in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01058980. Findings Adenosine unmasked dormant pulmonary vein conduction in 284 (53%) of 534 patients. 102 (69·4%) of 147 patients with additional adenosine-guided ablation were free from symptomatic atrial tachyarrhythmia compared with 58 (42·3%) of 137 patients with no further ablation, corresponding to an absolute risk reduction of 27·1% (95% CI 15·9–38·2; p<0·0001) and a hazard ratio of 0·44 (95% CI 0·31–0·64; p<0·0001). Of 115 patients without dormant pulmonary vein conduction, 64 (55·7%) remained free from symptomatic atrial tachyarrhythmia (p=0·0191 vs dormant conduction with no further ablation). Occurrences of serious adverse events were similar in each group. One death (massive stroke) was deemed probably related to ablation in a patient included in the registry. Interpretation Adenosine testing to identify and target dormant pulmonary vein conduction during catheter ablation of atrial fibrillation is a safe and highly effective strategy to improve arrhythmia-free survival in patients with paroxysmal atrial fibrillation. This approach should be considered for incorporation into routine clinical practice. Funding Canadian Institutes of Health Research, St Jude Medical, Biosense-Webster, and M Lachapelle (Montreal Heart Institute Foundation).


      PubDate: 2015-07-28T20:48:53Z
       
  • The science of early adversity: is there a role for large institutions in
           the care of vulnerable children'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Anne E Berens, Charles A Nelson
      It has been more than 80 years since researchers in child psychiatry first documented developmental delays among children separated from family environments and placed in orphanages or other institutions. Informed by such findings, global conventions, including the 1989 UN Convention on the Rights of the Child, assert a child's right to care within a family-like environment that offers individualised support. Nevertheless, an estimated 8 million children are presently growing up in congregate care institutions. Common reasons for institutionalisation include orphaning, abandonment due to poverty, abuse in families of origin, disability, and mental illness. Although the practice remains widespread, a robust body of scientific work suggests that institutionalisation in early childhood can incur developmental damage across diverse domains. Specific deficits have been documented in areas including physical growth, cognitive function, neurodevelopment, and social-psychological health. Effects seem most pronounced when children have least access to individualised caregiving, and when deprivation coincides with early developmental sensitive periods. Offering hope, early interventions that place institutionalised children into families have afforded substantial recovery. The strength of scientific evidence imparts urgency to efforts to achieve deinstitutionalisation in global child protection sectors, and to intervene early for individual children experiencing deprivation.


      PubDate: 2015-07-28T20:48:53Z
       
  • Osteoarthritis
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): S Glyn-Jones, A J R Palmer, R Agricola, A J Price, T L Vincent, H Weinans, A J Carr
      Osteoarthritis is a major source of pain, disability, and socioeconomic cost worldwide. The epidemiology of the disorder is complex and multifactorial, with genetic, biological, and biomechanical components. Aetiological factors are also joint specific. Joint replacement is an effective treatment for symptomatic end-stage disease, although functional outcomes can be poor and the lifespan of prostheses is limited. Consequently, the focus is shifting to disease prevention and the treatment of early osteoarthritis. This task is challenging since conventional imaging techniques can detect only quite advanced disease and the relation between pain and structural degeneration is not close. Nevertheless, advances in both imaging and biochemical markers offer potential for diagnosis and as outcome measures for new treatments. Joint-preserving interventions under development include lifestyle modification and pharmaceutical and surgical modalities. Some show potential, but at present few have proven ability to arrest or delay disease progression.


      PubDate: 2015-07-28T20:48:53Z
       
  • Intravenous augmentation treatment and lung density in severe α1
           antitrypsin deficiency (RAPID): a randomised, double-blind,
           placebo-controlled trial
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Kenneth R Chapman, Jonathan G W Burdon, Eeva Piitulainen, Robert A Sandhaus, Niels Seersholm, James M Stocks, Berend C Stoel, Liping Huang, Zhenling Yao, Jonathan M Edelman, Noel G McElvaney
      Background The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. Methods The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35–70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). Findings Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). Interpretation Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. Funding CSL Behring.


      PubDate: 2015-07-28T20:48:53Z
       
  • Methadone continuation versus forced withdrawal on incarceration in a
           combined US prison and jail: a randomised, open-label trial
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Josiah D Rich, Michelle McKenzie, Sarah Larney, John B Wong, Liem Tran, Jennifer Clarke, Amanda Noska, Manasa Reddy, Nickolas Zaller
      Background Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. Methods In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care—forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from incarceration and time to engagement with methadone maintenance treatment, by intention-to-treat and as-treated analyses, which we established in a follow-up interview with the participants at 1 month after their release from incarceration. Our study paid for 10 weeks of methadone treatment after release if participants needed financial help. This trial is registered with ClinicalTrials.gov, number NCT01874964. Findings Between June 14, 2011, and April 3, 2013, we randomly assigned 283 prisoners to our study, 142 to continued methadone treatment, and 141 to forced withdrawal from methadone. Of these, 60 were excluded because they did not fit the eligibility criteria, leaving 114 in the continued-methadone group and 109 in the forced-withdrawal group (usual care). Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2·04, 95% CI 1·48–2·80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively. Interpretation Although our study had several limitations—eg, it only included participants incarcerated for fewer than 6 months, we showed that forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release. Continuation of methadone maintenance during incarceration could contribute to greater treatment engagement after release, which could in turn reduce the risk of death from overdose and risk behaviours. Funding National Institute on Drug Abuse and the Lifespan/Tufts/Brown Center for AIDS Research from the National Institutes of Health.
      ...
      PubDate: 2015-07-28T20:48:53Z
       
  • Medical expulsive therapy in adults with ureteric colic: a multicentre,
           randomised, placebo-controlled trial
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Robert Pickard, Kathryn Starr, Graeme MacLennan, Thomas Lam, Ruth Thomas, Jennifer Burr, Gladys McPherson, Alison McDonald, Kenneth Anson, James N'Dow, Neil Burgess, Terry Clark, Mary Kilonzo, Katie Gillies, Kirsty Shearer, Charles Boachie, Sarah Cameron, John Norrie, Samuel McClinton
      Background Meta-analyses of previous randomised controlled trials concluded that the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage for people managed expectantly for ureteric colic, but emphasised the need for high-quality trials with wide inclusion criteria. We aimed to fulfil this need by testing effectiveness of these drugs in a standard clinical care setting. Methods For this multicentre, randomised, placebo-controlled trial, we recruited adults (aged 18–65 years) undergoing expectant management for a single ureteric stone identified by CT at 24 UK hospitals. Participants were randomly assigned by a remote randomisation system to tamsulosin 400 μg, nifedipine 30 mg, or placebo taken daily for up to 4 weeks, using an algorithm with centre, stone size (≤5 mm or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation covariates. Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, analysed in a modified intention-to-treat population defined as all eligible patients for whom we had primary outcome data. This trial is registered with the European Clinical Trials Database, EudraCT number 2010-019469-26, and as an International Standard Randomised Controlled Trial, number 69423238. Findings Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167 participants, 1136 (97%) of whom were included in the primary analysis (17 were excluded because of ineligibility and 14 participants were lost to follow-up). 303 (80%) of 379 participants in the placebo group did not need further intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group (adjusted risk difference 1·3% [95% CI −5·7 to 8·3]; p=0·73) and 304 (80%) of 379 in the nifedipine group (0·5% [–5·6 to 6·5]; p=0·88). No difference was noted between active treatment and placebo (p=0·78), or between tamsulosin and nifedipine (p=0·77). Serious adverse events were reported in three participants in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one had malaise, headache, and chest pain; and one had severe chest pain, difficulty breathing, and left arm pain) and in one participant in the placebo group (headache, dizziness, lightheadedness, and chronic abdominal pain). Interpretation Tamsulosin 400 μg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic. Funding UK National Institute for Health Research Health Technology Assessment Programme.


      PubDate: 2015-07-28T20:48:53Z
       
  • Legal preparedness and Ebola vaccines
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): John Monahan, Sam Halabi



      PubDate: 2015-07-28T20:48:53Z
       
  • Another step change for tobacco control in China'
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): Yong Hu, Xiaoyang Sun, Zhenshan Yuan, Weixin Dong, Jiao Zhang



      PubDate: 2015-07-28T20:48:53Z
       
  • Data donation after death
    • Abstract: Publication date: 25–31 July 2015
      Source:The Lancet, Volume 386, Issue 9991
      Author(s): David M Shaw, Julianne V Gross, Thomas C Erren



      PubDate: 2015-07-28T20:48:53Z
       
  • Estimations of worldwide prevalence of chronic hepatitis B virus
           infection: a systematic review of data published between 1965 and 2013
    • Abstract: Publication date: Available online 28 July 2015
      Source:The Lancet
      Author(s): Aparna Schweitzer, Johannes Horn, Rafael T Mikolajczyk, Gérard Krause, Jördis J Ott
      Background The quantification of the burden of disease attributable to hepatitis B virus (HBV) infection and the adaptation of prevention and control measures requires knowledge on its prevalence in the general population. For most countries such data are not routinely available. We estimated the national, regional, and global prevalence of chronic HBV infection. Methods For this systematic review and pooled analysis, we searched for data on prevalence of chronic HBV infection published between Jan 1, 1965, and Oct 23, 2013, in the databases Medline, Embase, CAB s (Global health), Popline, and Web of Science. We included studies reporting the hepatitis B surface antigen (HBsAg) serological marker of chronic HBV infection in non-high-risk groups and extracted data into a customised database. For each country, we calculated HBsAg prevalence estimates and 95% CIs weighted by study size. We extrapolated prevalence estimates to population sizes in 2010 to obtain the number of individuals with chronic HBV infection. Findings Of the 17 029 records screened, 1800 report on the prevalence of HBsAg covering 161 countries were included. HBsAg seroprevalence was 3·61% (95% CI 3·61–3·61) worldwide with highest endemicity in countries of the African region (total 8·83%, 8·82–8·83) and Western Pacific region (total 5·26%, 5·26–5·26). Within WHO regions, prevalence ranged from 0·20% (0·19–0·21; Mexico) to 13·55% (9·00–19·89; Haiti) in the Americas, to 0·48% (0·12–1·90; the Seychelles) to 22·38% (20·10–24·83; South Sudan) in the African region. We estimated that in 2010, globally, about 248 million individuals were HBsAg positive. Interpretation This first global assessment of country-level population prevalence of chronic HBV infection found a wide variation between countries and highlights the need for continued prevention and control strategies and the collection of reliable epidemiologic data using standardised methodology. Funding World Health Organization.


      PubDate: 2015-07-28T20:48:53Z
       
 
 
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