Hot off the presses! May 27 Lance

The May 27 issue of the Lance is now up on Pubget (About Lance): 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:

• HIV treatment as prevention—it works
  - Lance 377(9779):1719 (2011)
  
• A top-down approach to diabetes
  - Lance 377(9779):1720 (2011)
  
• It happened to me: responses to the Stillbirths Series
  - Lance 377(9779):1720 (2011)
  
• Brazil: towards sustainability and equity in health
  - Lance 377(9779):1721-1722 (2011)
  
• Brazil: structuring cooperation for health
  - Lance 377(9779):1722-1723 (2011)
  
• Brazil's health-care reform: social movements and civil society
  - Lance 377(9779):1724-1725 (2011)
  
• Do we need oncology trials tailored for the elderly or frail?
  - Lance 377(9779):1725-1727 (2011)
  
• Pirfenidone for idiopathic pulmonary fibrosis
  - Lance 377(9779):1727-1729 (2011)
  
• The mysteries of immunity to malaria
  - Lance 377(9779):1729-1730 (2011)
  
• The Mediterranean diet: a cultural journey
  - Lance 377(9779):1730-1731 (2011)
  
• Offline: The mid-life obituary
  - Lance 377(9779):1732 (2011)
  
• Health professionals under threat in Bahrain
  - Lance 377(9779):1733-1734 (2011)
  
• Growing up in Rio's favelas
  - Lance 377(9779):1735-1736 (2011)
  
• The life of a museum
  - Lance 377(9779):1737 (2011)
  
• Paulo Buss—a leader of public health and health policy in Brazil
  - Lance 377(9779):1738 (2011)
  
• Sonia Fleury—promoting social inclusion for better health in Brazil
  - Lance 377(9779):1739 (2011)
  
• Carlos Chagas: science, health, and national debate in Brazil
  - Lance 377(9779):1740-1741 (2011)
  
• Moacyr Scliar
  - Lance 377(9779):1742 (2011)
  
• Treatment of mild persistent asthma in children
  - Lance 377(9779):1743 (2011)
  
• Treatment of mild persistent asthma in children
  - Lance 377(9779):1743 (2011)
  
• Treatment of mild persistent asthma in children
  - Lance 377(9779):1743-1744 (2011)
  
• Treatment of mild persistent asthma in children – Authors' reply
  - Lance 377(9779):1744 (2011)
  
• Health research—Europe's future
  - Lance 377(9779):1744-1745 (2011)
  
• Lessons from the Netherlands for the Health and Social Care Bill
  - Lance 377(9779):1745 (2011)
  
• A deserving role for the National Center for Advancing Translational Sciences
  - Lance 377(9779):1745-1746 (2011)
  
• Cholera in Haiti: please do not forget zinc
  - Lance 377(9779):1746 (2011)
  
• Cholera in Haiti: please do not forget zinc – Authors' reply
  - Lance 377(9779):1746-1747 (2011)
  
• Violence against Chinese health-care workers
  - Lance 377(9779):1747 (2011)
  
• Violence against Chinese health-care workers
  - Lance 377(9779):1747 (2011)
  
• Joined-up thinking in reduction of cardiovascular risk
  - Lance 377(9779):1747-1748 (2011)
  
• HIV counselling and testing in South African schools
  - Lance 377(9779):1748 (2011)
  
• Department of Error
  - Lance 377(9779):1748 (2011)
  
• Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
  - Lance 377(9779):1749-1759 (2011)
  Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite ! measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predi! ctive of better OTU. Interpretation FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding Cancer Research UK and the Medical Research Council.
• Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials
  - Lance 377(9779):1760-1769 (2011)
  Background Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. Methods In two concurrent trials (004 and 006), patients (aged 40–80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716. Findings In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was −8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and −12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at! week 72 was −9·0% (SD 19·6) in the pirfenidone group and −9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, −3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. Interpretation The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. Funding InterMune.
• Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study
  - Lance 377(9779):1770-1776 (2011)
  Background We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers. Methods In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum. Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum. Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov, number NCT00757887. Findings Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency had adverse events similar to those in the control group. Interpretation Artificially induced immunity lasts longer than generally recorded after natural exposure; providing a new avenue of research into the mechanisms of malaria immunity. Funding Dioraphte Foundation.
• A painful cranial bulge
  - Lance 377(9779):1777 (2011)
  
• The Brazilian health system: history, advances, and challenges
  - Lance 377(9779):1778-1797 (2011)
  Brazil is a country of continental dimensions with widespread regional and social inequalities. In this report, we examine the historical development and components of the Brazilian health system, focusing on the reform process during the past 40 years, including the creation of the Unified Health System. A defining characteristic of the contemporary health sector reform in Brazil is that it was driven by civil society rather than by governments, political parties, or international organisations. The advent of the Unified Health System increased access to health care for a substantial proportion of the Brazilian population, at a time when the system was becoming increasingly privatised. Much is still to be done if universal health care is to be achieved. Over the past 20 years, there have been other advances, including investments in human resources, science and technology, and primary care, and a substantial decentralisation process, widespread social participation, a! nd growing public awareness of a right to health care. If the Brazilian health system is to overcome the challenges with which it is presently faced, strengthened political support is needed so that financing can be restructured and the roles of both the public and private sector can be redefined.
• Stillbirths: the vision for 2020
  - Lance 377(9779):1798-1805 (2011)
  Stillbirth is a common adverse pregnancy outcome, with nearly 3 million third-trimester stillbirths occurring worldwide each year. 98% occur in low-income and middle-income countries, and more than 1 million stillbirths occur in the intrapartum period, despite many being preventable. Nevertheless, stillbirth is practically unrecognised as a public health issue and few data are reported. In this final paper in the Stillbirths Series, we call for inclusion of stillbirth as a recognised outcome in all relevant international health reports and initiatives. We ask every country to develop and implement a plan to improve maternal and neonatal health that includes a reduction in stillbirths, and to count stillbirths in their vital statistics and other health outcome surveillance systems. We also ask for increased investment in stillbirth-related research, and especially research aimed at identifying and addressing barriers to the aversion of stillbirths within the maternal an! d neonatal health systems of low-income and middle-income countries. Finally, we ask all those interested in reducing stillbirths to join with advocates for the improvement of other pregnancy-related outcomes, for mothers and their offspring, so that a united front for improved pregnancy and neonatal care for all will become a reality.
• An accidental mass
  - Lance 377(9779):1806 (2011)