Hot off the presses! Jan 13 The Lancet

The Jan 13 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:

• January 7â€"13, 2012
  - The Lancet 379(9810):i (2012)
  
• Translational research and experimental medicine in 2012
  - The Lancet 379(9810):1 (2012)
  
• Addictionâ€"a global problem with no global solution
  - The Lancet 379(9810):2 (2012)
  
• North Koreaâ€"who will help?
  - The Lancet 379(9810):2 (2012)
  
• Catheter-directed thrombolysis for acute DVT
  - The Lancet 379(9810):3-4 (2012)
  
• Treatment of prostate cancer metastases: more than semantics
  - The Lancet 379(9810):4-6 (2012)
  
• The control of non-communicable diseases in rural Iran
  - The Lancet 379(9810):6-7 (2012)
  
• Contracts with patients in clinical practice
  - The Lancet 379(9810):7-9 (2012)
  
• Human security and universal health insurance
  - The Lancet 379(9810):9-10 (2012)
  
• The remaining smallpox stocks: the healthiest outcome
  - The Lancet 379(9810):10-12 (2012)
  
• Science and consensus for health policy making in Japan
  - The Lancet 379(9810):12-13 (2012)
  
• Offline: Rearranging the furniture
  - The Lancet 379(9810):14 (2012)
  
• Innovating for every woman and every child
  - The Lancet 379(9810):e1-e2 (2012)
  
• Commitment and action to boost health workforce
  - The Lancet 379(9810):e2-e4 (2012)
  
• Legalise assisted suicide, UK Commission urges
  - The Lancet 379(9810):15 (2012)
  
• Haiti prepares for cholera vaccination but concerns remain
  - The Lancet 379(9810):16 (2012)
  
• Prescription drug addiction: the treatment challenge
  - The Lancet 379(9810):17-18 (2012)
  
• Anatomy of an artist
  - The Lancet 379(9810):19 (2012)
  
• Creatively confronting addiction
  - The Lancet 379(9810):20 (2012)
  
• Louisa Degenhardt: hooked on addiction research
  - The Lancet 379(9810):21 (2012)
  
• The rise, fall, and revival of recovery in drug policy
  - The Lancet 379(9810):22-23 (2012)
  
• Paul Robert Epstein
  - The Lancet 379(9810):24 (2012)
  
• An open letter to Michael Ball, Chief Executive of Hospira Pharmaceuticals
  - The Lancet 379(9810):25 (2012)
  
• An open letter to Michael Ball, Chief Executive of Hospira Pharmaceuticals â€" Response from Hospira
  - The Lancet 379(9810):25 (2012)
  
• The new decade of vaccines
  - The Lancet 379(9810):25-26 (2012)
  
• The new decade of vaccines
  - The Lancet 379(9810):26 (2012)
  
• The new decade of vaccines â€" Authors' reply
  - The Lancet 379(9810):27 (2012)
  
• The new decade of vaccines â€" Authors' reply
  - The Lancet 379(9810):27 (2012)
  
• Global burden of disease in young people aged 10â€"24 years
  - The Lancet 379(9810):27-28 (2012)
  
• Global burden of disease in young people aged 10â€"24 years â€" Authors' reply
  - The Lancet 379(9810):28 (2012)
  
• Global burden of disease in young people aged 10â€"24 years â€" Authors' reply
  - The Lancet 379(9810):29 (2012)
  
• Misleading information concerning the University of Helsinki
  - The Lancet 379(9810):29 (2012)
  
• The NHS IT project: more than just a bad dream
  - The Lancet 379(9810):29-30 (2012)
  
• The unobtainable placebo: control of independent clinical research by industry?
  - The Lancet 379(9810):30 (2012)
  
• Department of Error
  - The Lancet 379(9810):30 (2012)
  
• Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial
  - The Lancet 379(9810):31-38 (2012)
  Background Conventional anticoagulant treatment for acute deep vein thrombosis (DVT) effectively prevents thrombus extension and recurrence, but does not dissolve the clot, and many patients develop post-thrombotic syndrome (PTS). We aimed to examine whether additional treatment with catheter-directed thrombolysis (CDT) using alteplase reduced development of PTS. Methods Participants in this open-label, randomised controlled trial were recruited from 20 hospitals in the Norwegian southeastern health region. Patients aged 18–75 years with a first-time iliofemoral DVT were included within 21 days from symptom onset. Patients were randomly assigned (1:1) by picking lowest number of sealed envelopes to conventional treatment alone or additional CDT. Randomisation was stratified for involvement of the pelvic veins with blocks of six. We assessed two co-primary outcomes: frequency of PTS as assessed by Villalta score at 24 months, and iliofemoral patency after 6 months. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00251771. Findings 209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months' follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41·1%, 95% CI 31·5–51·4) patients allocated additional CDT presented with PTS compared with 55 (55·6%, 95% CI 45·7–65·0) in the control group (p=0·047). The difference in PTS corresponds to an absolute risk reduction of 14·4% (95% CI 0·2–27·9), and the number needed to treat was 7 (95% CI 4–502). Iliofemoral patency after 6 months was reported in 58 patients (65·9%, 95% CI 55·5–75·0) on CDT versus 45 (47·4%, 37·6–57·3) on control (p=0·012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds. Interpretation Additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding. Funding South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo; Oslo University Hospital.
• Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
  - The Lancet 379(9810):39-46 (2012)
  Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial ! was registered at ClinicalTrials.gov, number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%)! on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
• Effectiveness of diabetes and hypertension management by rural primary health-care workers (Behvarz workers) in Iran: a nationally representative observational study
  - The Lancet 379(9810):47-54 (2012)
  Background Non-communicable diseases and their risk factors are leading causes of disease burden in Iran and other middle-income countries. Little evidence exists for whether the primary health-care system can effectively manage non-communicable diseases and risk factors at the population level. Our aim was to examine the effectiveness of the Iranian rural primary health-care system (the Behvarz system) in the management of diabetes and hypertension, and to assess whether the effects depend on the number of health-care workers in the community. Methods We used individual-level data from the 2005 Non-Communicable Disease Surveillance Survey (NCDSS) for fasting plasma glucose (FPG) and systolic blood pressure (SBP), body-mass index, medication use, and sociodemographic variables. Data for Behvarz-worker and physician densities were from the 2006 Population and Housing Census and the 2005 Outpatient Care Centre Mapping Survey. We assessed the effectiveness of treatment on FPG and SBP, and associations between FPG or SBP and Behvarz-worker density with two statistical approaches: a mixed-effects regression analysis of the full NCDSS sample adjusting for individual-level and community-level covariates and an analysis that estimated average treatment effect on data balanced with propensity score matching. Results NCDSS had data for 65 619 individuals aged 25 years or older (11 686 of whom in rural areas); of these, 64 694 (11 521 in rural areas) had data for SBP and 50 202 (9337 in rural areas) had data for FPG. Nationally, 39·2% (95% CI 37·7 to 40·7) of individuals with diabetes and 35·7% (34·9 to 36·5) of those with hypertension received treatment, with higher treatment coverage in women than in men and in urban areas than in rural areas. Treatment lowered mean FPG by an estimated 1·34 mmol/L (0·58 to 2·10) in rural areas and 0·21 mmol/L (−0·15 to 0·56) in urban areas. Individuals in urban areas with hypertension who received treatment had 3·8 mm Hg (3·1 to 4·5) lower SBP than they would have had if they had not received treatment; the treatment effect was 2·5 mm Hg (1·1 to 3·9) lower FPG in rural areas. Each additional Behvarz worker per 1000 adults was associated with a 0·09 mmol/L (0·01 to 0·18) lower district-level avera! ge FPG (p=0·02); for SBP this effect was 0·53 mm Hg (−0·44 to 1·50; p=0·28). Our findings were not sensitive to the choice of statistical method. Interpretation Primary care systems with trained community health-care workers and well established guidelines can be effective in non-communicable disease prevention and management. Iran's primary care system should expand the number and scope of its primary health-care worker programmes to also address blood pressure and to improve performance in areas with few primary care personnel. Funding None.
• Extent of illicit drug use and dependence, and their contribution to the global burden of disease
  - The Lancet 379(9810):55-70 (2012)
  This paper summarises data for the prevalence, correlates, and probable adverse health consequences of problem use of amphetamines, cannabis, cocaine, and opioids. We discuss findings from systematic reviews of the prevalence of illicit drug use and dependence, remission from dependence, and mortality in illicit drug users, and evidence for acute and chronic effects of illicit drug use. We outline the regional and global distribution of use and estimated health burden from illicit drugs. These distributions are likely to be underestimates because they have not included all adverse outcomes of drug use and exclude those of cannabis—the mostly widely used illicit drug. In high-income countries, illicit drug use contributes less to the burden of disease than does tobacco but a substantial proportion of that due to alcohol. The major adverse health effects of cannabis use are dependence and probably psychotic disorders and other mental disorders. The health-related harms! of cannabis use differ from those of amphetamine, cocaine, and opioid use, in that cannabis contributes little to mortality. Intelligent policy responses to drug problems need better data for the prevalence of different types of illicit drug use and the harms that their use causes globally. This need is especially urgent in high-income countries with substantial rates of illicit drug use and in low-income and middle-income countries close to illicit drug production areas.
• Drug policy and the public good: evidence for effective interventions
  - The Lancet 379(9810):71-83 (2012)
  Debates about which policy initiatives can prevent or reduce the damage that illicit drugs cause to the public good are rarely informed by scientific evidence. Fortunately, evidence-based interventions are increasingly being identified that are capable of making drugs less available, reducing violence in drug markets, lessening misuse of legal pharmaceuticals, preventing drug use initiation in young people, and reducing drug use and its consequences in established drug users. We review relevant evidence and outline the likely effects of fuller implementation of existing interventions. The reasoning behind the final decisions for action might be of a non-scientific nature, focused more on what the public and policy-makers deem of value. Nevertheless, important opportunities exist for science to inform these deliberations and guide the selection of policies that maximise the public good.
• How well do international drug conventions protect public health?
  - The Lancet 379(9810):84-91 (2012)
  The Single Convention on Narcotic Drugs in 1961 aimed to eliminate the illicit production and non-medical use of cannabis, cocaine, and opioids, an aim later extended to many pharmaceutical drugs. Over the past 50 years international drug treaties have neither prevented the globalisation of the illicit production and non-medical use of these drugs, nor, outside of developed countries, made these drugs adequately available for medical use. The system has also arguably worsened the human health and wellbeing of drug users by increasing the number of drug users imprisoned, discouraging effective countermeasures to the spread of HIV by injecting drug users, and creating an environment conducive to the violation of drug users' human rights. The international system has belatedly accepted measures to reduce the harm from injecting drug use, but national attempts to reduce penalties for drug use while complying with the treaties have often increased the number of drug users i! nvolved with the criminal justice system. The international treaties have also constrained national policy experimentation because they require nation states to criminalise drug use. The adoption of national policies that are more aligned with the risks of different drugs and the effectiveness of controls will require the amendment of existing treaties, the formulation of new treaties, or withdrawal of states from existing treaties and re-accession with reservations.
• Recurrent aspiration and upper lobe cavitation
  - The Lancet 379(9810):92 (2012)
  

Hot off the presses! Dec 09 The Lancet

The Dec 09 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 3â€"9, 2011
  - The Lancet 378(9807):i (2011)
  
• Championing good health for people with disabilities
  - The Lancet 378(9807):1895 (2011)
  
• The Global Fund and a new modus operandi
  - The Lancet 378(9807):1896 (2011)
  
• Political commitment for HIV/AIDS control in China
  - The Lancet 378(9807):1896 (2011)
  
• Assessment of the burden of influenza in children
  - The Lancet 378(9807):1897-1898 (2011)
  
• Tilting the AXIS towards therapeutic limits in renal cancer
  - The Lancet 378(9807):1898-1900 (2011)
  
• Polymer drug-eluting stents: is the future biodegradable?
  - The Lancet 378(9807):1900-1902 (2011)
  
• The Commission on Macroeconomics and Health: was it the right recipe?
  - The Lancet 378(9807):1902-1903 (2011)
  
• Africa's health and the Commission on Macroeconomics and Health
  - The Lancet 378(9807):1904-1905 (2011)
  
• Offline: Reasons to be disappointed
  - The Lancet 378(9807):1906 (2011)
  
• The Commission on Macroeconomics and Health: 10 years on
  - The Lancet 378(9807):1907-1908 (2011)
  
• Health policy: from the clinical to the economic gaze
  - The Lancet 378(9807):1909 (2011)
  
• Revolution in health care
  - The Lancet 378(9807):1910 (2011)
  
• Stephen Lawrie: PsySTAR trek, the next generation
  - The Lancet 378(9807):1911 (2011)
  
• Wilson Greatbatch
  - The Lancet 378(9807):1912 (2011)
  
• Role of acute infection in HIV transmission
  - The Lancet 378(9807):1913 (2011)
  
• Role of acute infection in HIV transmission
  - The Lancet 378(9807):1913-1914 (2011)
  
• Role of acute infection in HIV transmission â€" Authors' reply
  - The Lancet 378(9807):1914-1915 (2011)
  
• Bivalirudin for patients with ST-elevation myocardial infarction
  - The Lancet 378(9807):1915 (2011)
  
• Bivalirudin for patients with ST-elevation myocardial infarction â€" Authors' reply
  - The Lancet 378(9807):1915-1916 (2011)
  
• HPV vaccine in Rwanda: different disease, same double standard
  - The Lancet 378(9807):1916 (2011)
  
• Social accountability in health professionals' training
  - The Lancet 378(9807):e12-e13 (2011)
  
• Keeping women's and children's health at the forefront
  - The Lancet 378(9807):e13-e15 (2011)
  
• Primary health care and early childhood development
  - The Lancet 378(9807):e16 (2011)
  
• Parenting resources matter
  - The Lancet 378(9807):e16-e17 (2011)
  
• Advocacy training and social accountability of health professionals
  - The Lancet 378(9807):e17 (2011)
  
• Quality of care in Japan: an additional strategy
  - The Lancet 378(9807):e17 (2011)
  
• Spinal tuberculosis
  - The Lancet 378(9807):e18 (2011)
  
• Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis
  - The Lancet 378(9807):1917-1930 (2011)
  Background The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. Methods We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. Findings We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49–162 million) new cases of influenza (data from nine studies), 20 million (13–32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1–2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28 000–111 500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. Interpretation Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. Funding WHO; Bill & Melinda Gates Foundation.
• Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial
  - The Lancet 378(9807):1931-1939 (2011)
  Background The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. Methods We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. Findings A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. Interpretation Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. Funding Pfizer Inc.
• Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial
  - The Lancet 378(9807):1940-1948 (2011)
  Background The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. Methods We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. Findings 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7%) patients versus 192 (22·6%) patients (rate ratios [RR] 0·81, 95% CI 0·66–1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35–1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95% CI 0·06–0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51–1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (pinteraction=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint event! s associated with ST, the RR was 0·86 (0·41–1·80) during the first year and 0·17 (0·04–0·78) during subsequent years (pinteraction=0·049). Interpretation Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. Funding Biosensors Europe SA, Switzerland.
• Idiopathic pulmonary fibrosis
  - The Lancet 378(9807):1949-1961 (2011)
  Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we! review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.
• Serotype replacement in disease after pneumococcal vaccination
  - The Lancet 378(9807):1962-1973 (2011)
  Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial repl! acement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance.
• What a difference an egg makes
  - The Lancet 378(9807):1974 (2011)
  

Hot off the presses! Nov 25 The Lancet

The Nov 25 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:

• November 19â€"25, 2011
  - The Lancet 378(9805):i (2011)
  
• Politics and patient care
  - The Lancet 378(9805):1757 (2011)
  
• Breast cancer: old and new debates
  - The Lancet 378(9805):1758 (2011)
  
• CRASH-2 goes viral
  - The Lancet 378(9805):1758 (2011)
  
• Multiple sclerosisâ€"quenching the flames of inflammation
  - The Lancet 378(9805):1759-1760 (2011)
  
• Tackling domestic violence: is increasing referral enough?
  - The Lancet 378(9805):1760-1762 (2011)
  
• Community management of severe pneumonia in children
  - The Lancet 378(9805):1762-1764 (2011)
  
• The Global Fund: getting the reforms right
  - The Lancet 378(9805):1764-1765 (2011)
  
• The European Respiratory Roadmap
  - The Lancet 378(9805):1765-1767 (2011)
  
• Offline: Nursing, but not as you know it
  - The Lancet 378(9805):1768 (2011)
  
• Drug withdrawal sends critical care specialists back to basics
  - The Lancet 378(9805):1769 (2011)
  
• Health 2020: WHO's missing link?
  - The Lancet 378(9805):1770 (2011)
  
• Saving Chile's angelitos
  - The Lancet 378(9805):1771-1772 (2011)
  
• Book Lost words
  - The Lancet 378(9805):1772 (2011)
  
• Moving pictures of Parkinson's disease
  - The Lancet 378(9805):1773-1774 (2011)
  
• Effect of population-based screening on breast cancer mortality
  - The Lancet 378(9805):1775-1776 (2011)
  
• Leadership and public health
  - The Lancet 378(9805):1776 (2011)
  
• Leadership and public health
  - The Lancet 378(9805):1776 (2011)
  
• Leadership and public health
  - The Lancet 378(9805):1776-1777 (2011)
  
• Hydroxycarbamide use in young children with sickle-cell anaemia
  - The Lancet 378(9805):1777 (2011)
  
• Hydroxycarbamide use in young children with sickle-cell anaemia
  - The Lancet 378(9805):1777 (2011)
  
• Need to realign patient-oriented and commercial and academic research
  - The Lancet 378(9805):1777-1778 (2011)
  
• The forgotten psychosocial dimension of the obesity epidemic
  - The Lancet 378(9805):e8 (2011)
  
• Non-communicable diseases and surgery at the UN? “Fugetaboutit!”
  - The Lancet 378(9805):e8 (2011)
  
• Department of Error
  - The Lancet 378(9805):1778 (2011)
  
• Department of Error
  - The Lancet 378(9805):1778 (2011)
  
• Department of Error
  - The Lancet 378(9805):1778 (2011)
  
• Department of Error
  - The Lancet 378(9805):1778 (2011)
  
• Department of Error
  - The Lancet 378(9805):1778 (2011)
  
• Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial
  - The Lancet 378(9805):1779-1787 (2011)
  Background B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis. Methods We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18–55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 亮g) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an! intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00676715. Findings 218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68–97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89–99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0–4·4) patients in the placebo group, one of 55 (2%; 1·3–2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6–6·3) in the 2000 mg group, and two of 54 (4%; 3·0–4·4) in the interferon beta-1a group. Interpretation The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials. Funding F Hoffmann-La Roche Ltd, Biogen Idec Inc.
• Identification and Referral to Improve Safety (IRIS) of women experiencing domestic violence with a primary care training and support programme: a cluster randomised controlled trial
  - The Lancet 378(9805):1788-1795 (2011)
  Background Most clinicians have no training about domestic violence, fail to identify patients experiencing abuse, and are uncertain about management after disclosure. We tested the effectiveness of a programme of training and support in primary health-care practices to increase identification of women experiencing domestic violence and their referral to specialist advocacy services. Methods In this cluster randomised controlled trial, we selected general practices in two urban primary care trusts, Hackney (London) and Bristol, UK. Practices in which investigators from this trial were employed or those who did not use electronic records were excluded. Practices were stratified by proportion of female doctors, postgraduate training status, number of patients registered, and percentage of practice population on low incomes. Within every primary care trust area, we randomised practices with a computer-minimisation programme with a random component to intervention or control groups. The intervention programme included practice-based training sessions, a prompt within the medical record to ask about abuse, and a referral pathway to a named domestic violence advocate, who also delivered the training and further consultancy. The primary outcome was recorded referral of patients to domestic violence advocacy services. The prespecified secondary outcome was recorded iden! tification of domestic violence in the electronic medical records of the general practice. Poisson regression analyses accounting for clustering were done for all practices receiving the intervention. Practice staff and research associates were not masked and patients were not aware they were part of a study. This study is registered at Current Controlled Trials, ISRCTN74012786. Findings We randomised 51 (61%) of 84 eligible general practices in Hackney and Bristol. Of these, 24 received a training and support programme, 24 did not receive the programme, and three dropped out before the trial started. 1 year after the second training session, the 24 intervention practices recorded 223 referrals of patients to advocacy and the 24 control practices recorded 12 referrals (adjusted intervention rate ratio 22·1 [95% CI 11·5–42·4]). Intervention practices recorded 641 disclosures of domestic violence and control practices recorded 236 (adjusted intervention rate ratio 3·1 [95% CI 2·2–4·3). No adverse events were recorded. Interpretation A training and support programme targeted at primary care clinicians and administrative staff improved referral to specialist domestic violence agencies and recorded identification of women experiencing domestic violence. Our findings reduce the uncertainty about the benefit of training and support interventions in primary care settings for domestic violence and show that screening of women patients for domestic violence is not a necessary condition for improved identification and referral to advocacy services. Funding Health Foundation.
• Community case management of severe pneumonia with oral amoxicillin in children aged 2â€"59 months in Haripur district, Pakistan: a cluster randomised trial
  - The Lancet 378(9805):1796-1803 (2011)
  Background First dose oral co-trimoxazole and referral are recommended for WHO-defined severe pneumonia. Difficulties with referral compliance are reported in many low-resource settings, resulting in low access to appropriate treatment. The objective in this study was to assess whether community case management by lady health workers (LHWs) with oral amoxicillin in children with severe pneumonia was equivalent to current standard of care. Methods In Haripur district, Pakistan, 28 clusters were randomly assigned with stratification in a 1:1 ratio to intervention and control clusters by use of a computer-generated randomisation sequence. Children were included in the study if they were aged 2–59 months with WHO-defined severe pneumonia and living in the study area. In the intervention clusters, community-based LHWs provided mothers with oral amoxicillin (80–90 mg/kg per day or 375 mg twice a day for infants aged 2–11 months and 625 mg twice a day for those aged 12–59 months) with specific guidance on its use. In control clusters, LHWs gave the first dose of oral co-trimoxazole (age 2–11 months, sulfamethoxazole 200 mg plus trimethoprim 40 mg; age 12 months to 5 years, sulfamethoxazole 300 mg plus trimethoprim 60 mg) and referred the children to a health facility for standard of care. Participants, carers, and assessors were not masked to treatment assignment. The primary outcome was treatment failure by day 6! . Analysis was per protocol with adjustment for clustering within groups by use of generalised estimating equations. This study is registered, number ISRCTN10618300. Findings We assigned 1995 children to treatment in 14 intervention clusters and 1477 in 14 control clusters, and we analysed 1857 and 1354 children, respectively. Cluster-adjusted treatment failure rates by day 6 were significantly reduced in the intervention clusters (165 [9%] vs 241 [18%], risk difference −8·9%, 95% CI −12·4 to −5·4). Further adjustment for baseline covariates made little difference (−7·3%, −10·1 to −4·5). Two deaths were reported in the control clusters and one in the intervention cluster. Most of the risk reduction was in the occurrence of fever and lower chest indrawing on day 3 (−6·7%, −10·0 to −3·3). Adverse events were diarrhoea (n=4) and skin rash (n=1) in the intervention clusters and diarrhoea (n=3) in the control clusters. Interpretation Community case management could result in a standardised treatment for children with severe pneumonia, reduce delay in treatment initiation, and reduce the costs for families and health-care systems. Funding United States Agency for International Development (USAID).
• MRI for breast cancer screening, diagnosis, and treatment
  - The Lancet 378(9805):1804-1811 (2011)
  MRI is used widely both for screening women who are at increased risk of breast cancer and for treatment selection. Prospective studies confirm that MRI screening of women with known or suspected genetic mutation results in a higher sensitivity for cancer detection than does mammography. However, survival data are not available. In women with breast cancer, MRI detects cancer not identified with other types of screening. In two randomised trials, this increased sensitivity did not translate into improved selection of surgical treatment or a reduction in the number of operations. Data for longer-term outcomes such as ipsilateral breast tumour recurrence rates and contralateral breast cancer incidence are scarce, but to date do not show clear benefit for MRI. MRI is better than other methods of assessing the response to neoadjuvant chemotherapy, and is helpful in identifying the primary tumour in patients who present with axillary adenopathy.
• Gene expression profiling in breast cancer: classification, prognostication, and prediction
  - The Lancet 378(9805):1812-1823 (2011)
  Microarray-based gene expression profiling has had a major effect on our understanding of breast cancer. Breast cancer is now perceived as a heterogeneous group of different diseases characterised by distinct molecular aberrations, rather than one disease with varying histological features and clinical behaviour. Gene expression profiling studies have shown that oestrogen-receptor (ER)-positive and ER-negative breast cancers are distinct diseases at the transcriptomic level, that additional molecular subtypes might exist within these groups, and that the prognosis of patients with ER-positive disease is largely determined by the expression of proliferation-related genes. On the basis of these principles, a molecular classification system and prognostic multigene classifiers based on microarrays or derivative technologies have been developed and are being tested in randomised clinical trials and incorporated into clinical practice. In this review, we focus on the concep! tual effect and potential clinical use of the molecular classification of breast cancer, and discuss prognostic and predictive multigene predictors.
• A strange case of waitress headache
  - The Lancet 378(9805):1824 (2011)