Hot off the presses! Mar 18 LANCET

The Mar 18 issue of the LANCET is now up on Pubget (About LANCET): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A breath of fresh air please
  - LANCET 377(9769):875 (2011)
  
• "A very severe physical trial"
  - LANCET 377(9769):876 (2011)
  
• Preventing elder abuse: can we learn from child protection?
  - LANCET 377(9769):876 (2011)
  
• Quadruple or triple therapy to eradicate H pylori
  - LANCET 377(9769):877-878 (2011)
  
• EMBRACE, eribulin, and new realities of advanced breast cancer
  - LANCET 377(9769):878-880 (2011)
  
• Ultra-long-acting insulins for a lifestyle-related pandemic
  - LANCET 377(9769):880-881 (2011)
  
• Genital infection with HPV in men: research into practice
  - LANCET 377(9769):881-883 (2011)
  
• Universal health care in India: missing core determinants
  - LANCET 377(9769):883-885 (2011)
  
• A stormy future for population health in southeast Asia?
  - LANCET 377(9769):885-886 (2011)
  
• Patients' safety for global health
  - LANCET 377(9769):886-887 (2011)
  
• Offline: Where are the optimists?
  - LANCET 377(9769):888 (2011)
  
• US bioethics commission hears expert testimonies
  - LANCET 377(9769):889 (2011)
  
• Mediator scandal rocks French medical community
  - LANCET 377(9769):890-892 (2011)
  
• Seamus Heaney—digging deep into prehistory
  - LANCET 377(9769):893-894 (2011)
  
• Between two worlds
  - LANCET 377(9769):894 (2011)
  
• Somebody's mother
  - LANCET 377(9769):895 (2011)
  
• Drew Berry
  - LANCET 377(9769):895 (2011)
  
• Virtue and vice in health and illness: the idea that wouldn't die
  - LANCET 377(9769):896-897 (2011)
  
• Herschel Weldon Leibowitz
  - LANCET 377(9769):898 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium
  - LANCET 377(9769):899 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium
  - LANCET 377(9769):899 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium
  - LANCET 377(9769):899-900 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium
  - LANCET 377(9769):900 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium
  - LANCET 377(9769):900-901 (2011)
  
• Cholinesterase inhibitor treatment in patients with delirium – Authors' reply
  - LANCET 377(9769):901 (2011)
  
• New drug development
  - LANCET 377(9769):901-902 (2011)
  
• New drug development
  - LANCET 377(9769):902 (2011)
  
• Benefits of medical treatment of obesity
  - LANCET 377(9769):903 (2011)
  
• What would Shaw do?
  - LANCET 377(9769):903 (2011)
  
• The dynamics of collective human behaviour
  - LANCET 377(9769):903-904 (2011)
  
• No increased risk of febrile convulsions after seasonal influenza immunisation in UK
  - LANCET 377(9769):904 (2011)
  
• Department of Error
  - LANCET 377(9769):904 (2011)
  
• Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial
  - LANCET 377(9769):905-913 (2011)
  Background Helicobacter pylori is associated with benign and malignant diseases of the upper gastrointestinal tract, and increasing antibiotic resistance has made alternative treatments necessary. Our aim was to assess the efficacy and safety of a new, single-capsule treatment versus the gold standard for H pylori eradication. Methods We did a randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe, comparing the efficacy and safety of 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline (quadruple therapy) versus 7 days of omeprazole, amoxicillin, and clarithromycin (standard therapy) in adults with recorded H pylori infection. Patients were randomly assigned treatment according to a predetermined list independently generated by Quintiles Canada (Ville St-Laurent, QC, Canada). Our study was designed as a non-inferiority trial but was powered to detect superiority. Our primary outcome was H pylori eradication, established by two negative 13C urea breath tests at a minimum of 28 and 56 days after the end of treatment. Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment for superiority in the intention-to-treat population (ie, all participants! randomly assigned treatment). This study is registered with ClinicalTrials.gov, number NCT00669955. Findings 12 participants were lost to follow-up and 101 were excluded from the per-protocol analysis. In the per-protocol population (n=339), the lower bound of the CI for treatment with quadruple therapy was greater than the pre-established non-inferiority margin of −10% (95% CI 15·1–32·3; p<0·0001). In the intention-to-treat population (n=440), eradication rates were 80% (174 of 218 participants) in the quadruple therapy group versus 55% (123 of 222) in the standard therapy group (p<0·0001). Safety profiles for both treatments were similar; main adverse events were gastrointestinal and CNS disorders. Interpretation Quadruple therapy should be considered for first-line treatment in view of the rising prevalence of clarithromycin-resistant H pylori, especially since quadruple therapy provides superior eradication with similar safety and tolerability to standard therapy. Funding Axcan Pharma Inc.
• Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study
  - LANCET 377(9769):914-923 (2011)
  Background Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments. Methods In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m2 administered intravenously during 2–5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. Findings 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8–14·3) compared with TPC (10·6 months, 9·3–12·5; hazard ratio 0·81, 95% CI 0·66–0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients. Interpretation Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. Funding Eisai.
• Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial
  - LANCET 377(9769):924-931 (2011)
  Background Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs. Methods In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18–75 years with type 2 diabetes and glycosylated haemoglobin (HbA1C) of 7·0–11·0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer-generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA1C after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884. Findings Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA1C levels were much the same across treatment groups, at 7·3% (SD 1·1), 7·4% (1·0), 7·5% (1·1), and 7·2% (0·9), respectively. Estimated mean HbA1C treatment differences from insulin degludec by comparison with insulin glargine were 0·08% (95% CI −0·23 to 0·40) for the three dose per week schedule, 0·17% (−0·15 to 0·48) for group A, and 0·28% (−0·04 to 0·59) for group B. Few participants had hypoglycaemia and the number of adverse events was much the same across groups, with no apparent treat! ment-specific pattern. Interpretation Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile. Funding Novo Nordisk.
• Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study
  - LANCET 377(9769):932-940 (2011)
  Background Human papillomaviruses (HPVs) cause genital warts and cancers in men. The natural history of HPV infection in men is largely unknown, and that information is needed to inform prevention strategies. The goal in this study was to estimate incidence and clearance of type-specific genital HPV infection in men, and to assess the associated factors. Methods Men (aged 18–70 years), residing in Brazil, Mexico, and the USA, who were HIV negative and reported no history of cancer were recruited from the general population, universities, and organised health-care systems. They were assessed every 6 months for a median follow-up of 27·5 months (18·0–31·2). Specimens from the coronal sulcus, glans penis, shaft, and scrotum were obtained for the assessment of the status of HPV genotypes. Findings In 1159 men, the incidence of a new genital HPV infection was 38·4 per 1000 person months (95% CI 34·3–43·0). Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners (hazard ratio 2·40, 1·38–4·18, for at least 50 partners vs not more than one partner), and number of male anal-sexual partners (2·57, 1·46–4·49, for at least three male partners vs no recent partners). Median duration of HPV infection was 7·52 months (6·80–8·61) for any HPV and 12·19 months (7·16–18·17) for HPV 16. Clearance of oncogenic HPV infection decreased in men with a high number of lifetime female partners (0·49, 0·31–0·76, for at least 50 female partners vs not more than one partner), and in men in Brazil (0·71, 0·56–0·91) and Mexico (0·73, 0·57–0·94) compared with the USA. Clearance of oncogenic HPV was more rapid with increasing age (1·02, 1·01–1·03). Interpretation The data from this study are useful for the development of realistic cost-effectiveness models for male HPV vaccination internationally. Funding National Cancer Institute.
• Retroperitoneal liposarcoma with lamellar bone inside
  - LANCET 377(9769):941 (2011)
  
• Amyotrophic lateral sclerosis
  - LANCET 377(9769):942-955 (2011)
  Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading—from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.
• The health of prisoners
  - LANCET 377(9769):956-965 (2011)
  More than 10 million people are incarcerated worldwide; this number has increased by about a million in the past decade. Mental disorders and infectious diseases are more common in prisoners than in the general population. High rates of suicide within prison and increased mortality from all causes on release have been documented in many countries. The contribution of prisons to illness is unknown, although shortcomings in treatment and aftercare provision contribute to adverse outcomes. Research has highlighted that women, prisoners aged 55 years and older, and juveniles present with higher rates of many disorders than do other prisoners. The contribution of initiatives to improve the health of prisoners by reducing the burden of infectious and chronic diseases, suicide, other causes of premature mortality and violence, and counteracting the cycle of reoffending should be further examined.
• Rupture without warning
  - LANCET 377(9769):966 (2011)