The Lancet – Volume 377, Number 9759 (2011 - January - 1)

Editorial

A new year in medicine The change of year provides an opportunity for Januslike reflection on the matters that dominated health care in 2010 and challenges ahead for 2011. But how much really changes? To provide perspective, one might consider how 100 years ago, The Lancet, under the editorship of Squire Sprigge, welcomed the new decade in an editorial titled, “The promise of 1911”. The editorial would be familiar in tone and content to Lancet readers today. It cited progress against rabies, diphtheria, and the plague, and praised advances in surgery that would have seemed miraculous to a previous generation. Sprigge anticipated that history would regard the previous decade’s achievements of “wireless telegraphy,…the mechanically-propelled vehicle, and… aviation [as] among the most prominent feats of human ingenuity”. He lamented that advances in medicine moved more slowly, and that the “demon of tuberculosis” had not been exorcised in 1910, although he hoped that better understanding would one day result in mastery of the disease. There had been two general elections in the UK in 1910, so concern was expressed about the effect of political uncertainty on social issues, such as the health of disadvantaged people, the maintenance of charitable hospitals in a depressed economy, occupational health, and workers’ compensation for industrial accidents. In addressing the profession, legislation was urged against the “grasping charlatan and dangerous quack” (echoing a letter about homoeopathy in the correspondence section). He argued that the public would be best protected by better-educated doctors, referring to the issue’s lead Article, which attacked the contemporary curriculum in medical schools and absence of leadership for progress in education. While the eloquent prose and emphasis on syphilis of the Jan 7, 1911 issue seems dated, there is more of relevance to practice in 2011 than one might comfortably admit. Case reports from regional medical associations in the UK would be familiar today, as would reports “from our own correspondent”, which describe cocaine addiction in Montreal, Canada, and identified tuberculosis, measles, diarrhoea, and respiratory infection as leading causes of death in South Africa. The behaviour of expert medical witnesses and the reporting of medicine by the lay press also came under discussion, as did jurisprudence and anaesthesia, and even medical tourism. There was www.thelancet.com Vol 377 January 1, 2011

also complaint about philanthropists whose charity is excessive, poorly coordinated, and indiscriminate. In addition to medical education, which was the focus of The Lancet on Dec 4, 2010, three other topics are particularly timely. A discussion about the origin of cancer is a reminder of how much remains to be understood about this disease. How welcome, therefore, is the study by Peter Rothwell and colleagues in today’s issue of the potential protective benefit of aspirin against some cancers. A review of an 800-page textbook of paediatric surgery suggests a level of competency in 1911 that sits uncomfortably with the recent announcement by the Royal College of Surgeons that half of NHS district hospitals in England lack the facilities or staff to undertake emergency surgery on children. The correspondent from New York reported a crackdown on trade in rotten eggs. Food safety continues to threaten health, yet new food legislation in the USA seems uncertain because of cost. When Thomas Wakley founded The Lancet in 1823, he set out to inform, reform, and entertain. Sprigge’s Lancet was certainly an entertaining read that covered more than health. Writing a book review seems to have been a blood sport in 1911. In addition to medical books, the reviews included a book on Eastern religions and philosophies, diaries, medical journals, and literary and art magazines. Another section was devoted to The Lancet laboratory, in which new products were described. Peripheral articles included archaeology in Egypt, and the science of tea—in which the chemistry of Chateau Lafite is mentioned by way of comparison. History renders some content poignant. The review of A handbook for medical officers in the field foreshadowed the world war that would soon destroy the world that readers knew in 1911. A provincial UK hospital announced plans to acquire an x-ray machine, citing among other reasons that it could be used to treat ringworm; years later those treated would have higher risks of cancer. From Vienna came news about superior health among the city’s 180 000 Jewish people, whom a generation later would face lethal persecution. Between 1911 and 2011 there is much for medicine to be proud of—and also to be humble about. New years bring new promise and new opportunities, but some old demons remain. ■ The Lancet

See Articles page 31

For previous issues of The Lancet see http://www.sciencedirect. com/ For Health professionals for a new century: transforming education to strengthen health systems in an interdependent world see The Lancet Commissions 2010; 376: 1923–58

1

Editorial

Presidential Commission for the Study of Bioethical Issues

On synthetic biology

For The President’s Bioethics Commission see http:// bioethics.gov/ For the Commission’s report on synthetic biology see http:// bioethics.gov/documents/ synthetic-biology/PCSBISynthetic-BiologyReport-12.16.10.pdf For Creation of the first synthetic cell see http://www. sciencemag.org/content/329/ 5987/52.full?sid=db4dfc35f47d-4dcf-b1cb-53b130242cf7

On Dec 16, the 13-member US Presidential Commission for the Study of Bioethical Issues published a 188-page document entitled New Directions: The Ethics of Synthetic Biology and Emerging Technologies. President Barack Obama asked the Commission last May to assess the status of synthetic biology on the same day that the J Craig Venter Institute announced the creation of the first synthetic living cell. The Commission rightly concludes that a new life form was not created by Venter’s team, which inserted a synthetic (man-made) genome of a naturally existing bacterium into a related bacterial cell. The process, the group stated, only represents an alteration of an already existing life form. The report’s 18 recommendations were unanimously endorsed by the Commission. On the one hand, the group encourages the expansion of research within the emerging specialty of synthetic biology. On the other, the group emphasises that the field of synthetic biology is in its infancy and does not yet pose any immediate bio-terror (deliberate) or bio-error (inadvertent) threats in creating new organisms that might warrant formation

of new federal oversight bodies. Instead, crossgovernmental coordination, oversight, and monitoring of the specialty’s scientific progress are recommended. To aid transparency, the report advises that a biology equivalent of the political factcheck.org site is created, as a resource and forum for discussion. Artificially altered organisms tailored to deliver customised drugs or targeted vaccines are already being made. Early in 2012, more efficient full-scale production of the antimalarial drug (artemisinin) from engineered Escherichia coli is to begin. Production of influenza vaccine is another key area of research. The global market for synthetic biology is projected to exceed US$4·5 billion by 2015. Most of the relevant research is currently being pioneered in the USA. The rest of the world should reorganise its existing synthetic biology brain power and technological potential. What is also lacking within the promising emerging field of synthetic biology is international guidance and prioritisation. Synthetic biology must be a global endeavour. ■ The Lancet

World Health Organization

A breath of fresh indoor air

For WHO’s guidelines see http:// www.euro.who.int/__data/ assets/pdf_file/0009/128169/ e94535.pdf

2

Since they were first published in 1987, WHO’s guidelines for air quality have been fundamental for providing information to regulatory authorities in air pollution. On Dec 15, WHO, together with a multidisciplinary panel of experts, released new guidelines for indoorair quality, this time focusing on chemical indoor-air pollutants including carbon monoxide, formaldehyde, and nitrogen dioxide. Poor quality indoor air is a major cause of morbidity and mortality worldwide, accounting for 2·7% of the global disease burden and contributing to about 1·6 million deaths every year (mostly due to acute infections of the lower respiratory tract in children younger than 5 years in low-income countries). This effect on health is substantial and the burden of disease is much greater than that caused by outdoor-air pollutants; however, indoor-air pollution remains lower on public-health agendas than does outdoor-air pollution. The new guidelines emphasise the threat of harmful indoor chemicals and combustion products that are released from solid fuels, for example,

which are still used by more than 3 billion people worldwide for cooking and heating. Because implementation of such measures is beyond the capacity of the individual building user, the guidelines are directed not only at public-health officials, but also at specialists and authorities who have the power to implement the relevant regulatory measures to ensure access to clean indoor air. The guidelines do not instruct on how to take action; rather, they provide scientific bases and uniform recommendations that countries can adopt and develop into legal standards. However, WHO will support its member states in compiling evidence and developing and applying the relevant policies. Whether this assistance will be sufficient is uncertain—WHO should make a call to action to set the ball rolling. The importance of interventions to reduce exposure to indoor-air pollution is reflected in Millennium Development Goals 1, 3, 4, and 7. As 2011 looms, governments worldwide need to ensure that they provide access to clean indoor air for all. ■ The Lancet www.thelancet.com Vol 377 January 1, 2011

Comment

Will an aspirin a day help keep fatal cancer away?

www.thelancet.com Vol 377 January 1, 2011

Which fatal cancers, in addition to colorectal cancer, could aspirin help to prevent? On the basis of results from the current analysis and from previous studies, effects on oesophageal, stomach, and lung cancer mortality seem likely. The reduction in oesophageal and stomach cancer mortality is supported by consistent reductions in observational studies.7,8 Although results from observational studies of lung cancer have been varied,7,9,10 lung cancer mortality was significantly reduced in both Rothwell and colleagues’ analysis and in the Women’s Health Study.6 Results for prostate and pancreatic cancer mortality are suggestive, but should be interpreted more cautiously. The reduction in prostate cancer mortality was not statistically significant and, although slightly lower incidences of prostate cancer have been noted in some observational studies,11 few have examined prostate cancer mortality. Pancreatic cancer mortality was significantly lower (p=0·04) after the first 5 years in the intervention period analysis, but observational studies do not support an effect.12 Further research focusing on longterm daily use is needed to clarify whether aspirin can reduce mortality from prostate and pancreatic cancer. Can we assume that after 5 years on a regimen of daily aspirin, an individual will experience a 34% reduction in risk of fatal cancer, as suggested by the intervention period analysis? Assumptions about the exact magnitude of effects on cancer mortality should be made with caution because the confidence interval indicates the reduction in risk could plausibly be as low

See Articles page 31

Photolibrary

Observational studies and randomised trials indicate that long-term aspirin use can reduce incidence and mortality from colorectal cancer;1,2 however, evidence from randomised trials about other cancers is limited. Peter Rothwell and colleagues, in The Lancet,3 provide important new evidence that long-term daily aspirin lowers mortality from several cancers other than colorectal cancer, and could have a meaningful effect on overall cancer mortality. In a pooled analysis, including the intervention periods of eight randomised trials that lasted up to 9 years, cancer mortality was 21% lower in the aspirin group than in the control group, driven mainly by a 34% reduction in cancer mortality after the first 5 years of follow-up. In a longer-term analysis, including 20 years of follow-up from the intervention and post-intervention periods of three of the eight trials, cancer mortality was 22% lower in participants randomised to receive aspirin for 5–9 years than in those not randomised to aspirin. Rothwell and colleagues’ analyses are informative about the dose and duration of aspirin use that might be necessary to reduce cancer mortality. 75–100 mg per day seems to have been as effective as 300–1200 mg at reducing cancer mortality. However, even low doses of aspirin cannot be used without substantial risk of serious side-effects. Doses of 75–100 mg per day increase the risk of serious gastrointestinal bleeding, possibly as much as do doses of 300–325 mg.4,5 For duration of use, in the long-term analysis no reduction in cancer mortality was noted in participants who were randomised to receive aspirin for less than 5 years, indicating that daily use for at least 5 years will probably be needed to reduce cancer mortality significantly. Results from Rothwell and colleagues’ analysis, which included only trials of daily use, contrast with the null results for overall cancer mortality in the Women’s Health Study,6 a large 10-year randomised trial of 100 mg aspirin taken every other day. These different results suggest that aspirin might need to be used daily to reduce cancer mortality significantly; however, differences in study populations and chance could also have contributed to the contrast in results. Delayed effects of aspirin use could possibly be detected in the future during long-term post-intervention follow-up of the Women’s Health Study.

3

Comment

as 13%, and results for overall cancer mortality might not be completely generalisable to populations in which the proportion of deaths from specific types of cancer is different. In the long-term analysis, which provides the most precise results about specific cancers, about 39% of participants were current smokers and lung cancer was one of the major contributors to the overall reduction in cancer mortality. Most of the additional reduction in overall cancer mortality was due to fewer deaths from colorectal, oesophageal, and prostate cancer. In view of this pattern of results, the generalisability of results for overall cancer mortality to specific groups of patients should be considered. For example, whether a similarsized reduction in cancer mortality could be expected for a woman who has never smoked and has recently had a negative screening colonoscopy is unclear. Clinical guidelines for aspirin use from the US Preventive Services Task Force recommend not using aspirin specifically for colorectal cancer prevention,13 and do not consider cancer when balancing the risk of serious gastrointestinal bleeding against the benefit from prevention of cardiovascular disease.14 Future guideline committees should consider whether effects on cancer mortality might contribute to the overall balance of risks and benefits of daily aspirin use.

I declare that I have no conflicts of interest.

Eric J Jacobs

14

Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA [email protected]

1

2

3

4 5 6

7 8

9 10

11

12

13

Flossman E, Rothwell PM, for the British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369: 1603–13. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741–50. Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2010; published online Dec 7. DOI:10.1016/S0140-6736(10)62110-1. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321: 1183–87. Laine L. Review article: gastrointestinal bleeding with low-dose aspirin—what’s the risk? Aliment Pharmacol Ther 2006; 24: 897–908. Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005; 294: 47–55. Bosetti C, Gallus S, La Vecchia C. Aspirin and cancer risk: an updated quantitative review to 2005. Cancer Causes Control 2006; 17: 871–88. Abnet CC, Freedman ND, Kamangar F, Leitzmann MF, Hollenbeck AR, Schatzkin A. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis. Br J Cancer 2009; 100: 551–57. Hernández-Díaz S, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of lung cancer. Int J Cancer 2007; 120: 1565–72. Feskanich D, Bain C, Chan AT, Pandeya N, Speizer FE, Colditz GA. Aspirin and lung cancer risk in a cohort study of women: dosage, duration and latency. Br J Cancer 2007; 97: 1295–99. Mahmud SM, Franco EL, Aprikian AG. Use of nonsteroidal anti-inflammatory drugs and prostate cancer risk: a meta-analysis. Int J Cancer 2010; 127: 1680–91. Larsson SC, Giovannucci E, Bergkvist L, Wolk A. Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006; 15: 2561–64. US Preventive Services Task Force. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 2007; 146: 361–64. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 150: 396–404.

Rituximab maintenance in follicular lymphoma: PRIMA Published Online December 21, 2010 DOI:10.1016/S01406736(10)62272-6 See Articles page 42

4

Follicular non-Hodgkin lymphoma is the most common indolent lymphoma in Europe and the USA. This disease was thought to be incurable with standard therapeutic modalities, with major causes of death being disease progression, transformation to more aggressive lymphoma histology, and complications of therapy. Rituximab—an anti-B-cell monoclonal antibody, which targets the CD20 antigen—has had a profound impact on the treatment and outcome of follicular lymphoma in the past decade. Several cohorts of patients from network-based and population-based clinical trials have had improved survival since rituximab use became routine practice.1,2 Indeed, for patients with follicular

lymphoma, prospective trials have shown better benefits in overall survival with rituximab plus chemotherapy than with chemotherapy alone.3,4 The optimum dose and schedule of rituximab is still unknown.5 Extended schedules or maintenance approaches have been assessed in patients with follicular lymphoma after initial treatment with single-agent rituximab and after chemotherapy alone. These studies showed a substantial impact of rituximab on progression-free survival, with suggestions of benefit in overall survival.6,7 Additionally, no major safety concern arose; despite B-cell depletion being prolonged when extended schedules were used, numbers of infections were increased only slightly. www.thelancet.com Vol 377 January 1, 2011

Rituximab plus chemotherapy is now the most commonly used regimen in the initial treatment of follicular lymphoma,8 with median progression-free survival exceeding 3 years. Until now, the benefit of rituximab maintenance after rituximab plus chemotherapy was unknown. In The Lancet, Gilles Salles and colleagues9 report the initial outcome of the PRIMA trial, which enrolled 1217 patients, and randomised (1:1) 1019 of these to 2 years of rituximab maintenance therapy (single dose every 8 weeks) or to observation, both following remission after rituximab plus chemotherapy. This trial is the largest randomised study ever in follicular lymphoma and is a huge accomplishment by the GELA lymphoma group. The patients were a highrisk group, with almost 80% having intermediate-risk or high-risk scores on a validated follicular lymphoma international prognostic index (FLIPI). All had indications for therapy including bulk of disease, symptoms, or laboratory abnormalities. Although three different chemotherapy regimens were used as induction therapy, most patients (75%) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rendering the results especially relevant to current practice. Of the 1217 patients who received induction therapy, 16% did not proceed to randomisation. Only a third of these patients were lost because of disease progression; most of the remaining patients were withdrawn because of toxic effects during chemotherapy. The characteristics of the randomised group were very similar to the group of patients who were initially enrolled in the study. Patients receiving rituximab maintenance therapy had significantly better rates of 3-year progression-free survival than did those receiving observation (75% vs 58%). The benefit to maintenance was observed in all FLIPI groups. Time to next antilymphoma treatment was also longer in the maintenance group than in the observation group, although the next lymphoma therapy could have been single-agent rituximab in the observation group. Toxic effects were raised in the maintenance group, with most increased effects being infections. The toxic effects were mostly slight and self-limiting. A few patients had immunoglobulin concentrations followed up; there was no significant decrement in concentrations of IgG or IgM in this subset. Other experiences of prolonged maintenance suggest that concentrations of IgM often fall, with a few patients developing IgG deficiencies.6 www.thelancet.com Vol 377 January 1, 2011

Science Photo Library

Comment

Non-Hodgkin Lymphoma (green)

B-cell recovery has not been presented in the PRIMA study; in past studies, at least 6–12 months are needed for full B-cell recovery after rituximab.10 What are the implications of these impressive findings for clinical practice? Should all patients with follicular lymphoma receive rituximab maintenance after induction therapy? The scarcity of a benefit in overall survival after maintenance therapy should be emphasised. Moreover, of considerable interest, two quality-of-life questionnaires were administered, and there were no differences noted between the maintenance group and the observation group. Although Salles and colleagues interpreted this finding as no decrement in quality of life with maintenance therapy, an alternative and equally plausible explanation is that there is no benefit in quality of life to the patient in maintaining remission. The endpoint of progression-free survival in cancer is used as a surrogate of clinical benefit presuming improved quality of life maintaining remission. These findings suggest that this improvement might not be the case in this indolent (and often asymptomatic) disease. Longer follow-up of the PRIMA trial is needed to answer additional important questions. Does the observed safety profile persist in longer follow-up? Does rituximab resistance develop in the maintenance patients therefore precluding future therapies? Is a strategy of observation and rituximab therapy at time of disease progression equivalent or superior to scheduled maintenance in the long term (a key question also being addressed by 5

Comment

the RESORT trial11)? Do the PRIMA findings extend to the large group of follicular lymphoma patients with asymptomatic disease not requiring therapy? Finally, in an era of increased health-care costs, what benefit is necessary to justify the cost of this maintenance strategy, which at my institution would cost Medicare more than US$60 000 per patient? An analysis of cost-effectiveness would be very helpful in addressing this issue. Until these questions are answered, to state that maintenance is needed for all patients with follicular lymphoma who are initially treated with rituximab plus chemotherapy seems premature. However, maintenance is an option and the PRIMA investigators are to be congratulated for this important contribution, and are strongly encouraged to continue follow-up of these patients to answer the questions that remain.

2

3

4

5

6

7

8

9

Jonathan W Friedberg Division of Hematology and Oncology, James P Wilmot Cancer Center, University of Rochester, NY 14642, USA [email protected] I am a Scholar of Clinical Research of the Leukemia & Lymphoma Society. 1

Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 2005; 23: 8447–52.

10

11

Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 2005; 23: 5019–26. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–23. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–32. Friedberg JW. Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy. Hematol Am Soc Hematol Educ Program 2005; 1: 329–34. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28: 4480–84. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 2009; 27: 1607–14. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol 2009; 27: 1202–08. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2010; published online Dec 21. DOI:10.1016/S0140-6736(10)62175-7. Anolik JH, Friedberg JW, Zheng B, et al. B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny. Clin Immunol 2007; 122: 139–45. Kahl BS. Eastern Cooperative Oncology Group 4402: Rituximab Extended Schedule or Retreatment Trial (RESORT). Clin Lymphoma Myeloma 2006; 6: 423–26.

Wormy mothers, healthy babies: case closed or conundrum? Published Online December 21, 2010 DOI:10.1016/S01406736(10)62271-4 See Articles page 52

6

Vaccines seem to be less effective in poor communities of low-income countries than in the high-income countries where they were developed. Responses to oral vaccines for polio, cholera, or rotaviruses,1 and to parenterally administered vaccines for BCG, measles, or typhoid, are lower in African and Asian populations2 than in wealthy countries. Whether modulation of immune responses by exogenous factors contributes to these outcomes remains unresolved; therefore, parasitic infections in developing countries are especially interesting. Three decades ago, Williams and Greenwood3 found that children infected with malaria parasites respond poorly to meningococcal vaccination, and, in cross-sectional or non-randomised longitudinal studies, parasitic helminths have been shown to be associated with poor vaccine-induced responses.4 Because vaccination is the most cost-effective way of reducing child mortality, any measure that improves vaccine effectiveness in developing countries should be seriously considered.

In The Lancet, Emily Webb and colleagues5 test the hypothesis that helminth infections during pregnancy attenuate responses of infants to vaccination. In more than 2300 mothers and newborn babies, the investigators found that single-dose anthelmintic treatment of Ugandan mothers during pregnancy affected neither the cytokine nor the antibody responses of their infants to vaccine antigens. The similarity in the immunological responses of infants to vaccines, irrespective of maternal treatment, was paralleled by similar birth outcomes and incidence of disease episodes in the first year of life. In a subanalysis of the effect of albendazole on mothers who were hookworm-positive, some effects were seen in responses of interferon-γ to mycobacterial antigens, and in T-helper-2 cytokines in response to tetanus toxoid;5 however, these responses were not of clinical relevance. Thus, this trial resolves speculation about whether helminth infections in the second and third trimester of pregnancy could affect www.thelancet.com Vol 377 January 1, 2011

immune responses of newborn babies to vaccines, and are thereby associated with detrimental health indicators. This finding has serious implications for policy makers who advocate the use of anthelmintic treatment during pregnancy. Webb and colleagues’ trial raises several issues. First, the conclusions can only be applied to maternal hookworm infection, because neither Trichuris trichiura nor filaria are affected by albendazole or praziquantel treatment; ascariasis was rare, and whether the study was well powered enough to accurately ascertain the effects of schistosomiasis is unclear. Importantly, the investigators had previously shown that hookworm infection affected immunological responses of mothers and infants,6 which raised the question of whether those effects were due to the infection itself or to confounders, and justified the reported trial. However, Webb and colleagues do not indicate whether they observed an effect of hookworms on immune responses by comparing the hookworm-infected and uninfected subgroups within the placebo group. Second, whether or not exposure to infection was interrupted is unclear; the study was randomised at the individual level and other members of the pregnant mothers’ household would act as reservoirs of infection. Could household or village randomisation be a more powerful approach? A related issue is the low intensity of helminth infection observed in this adult Ugandan population, which might benefit from the use of new, more sensitive PCR-based methods of detection to more accurately establish the treatment effect.7,8 In Europe, exposure during pregnancy to farming environments that are rich in microorganisms, and possibly helminth antigens, results in a change in immune responsiveness of cord blood and reduced susceptibility to allergic diseases in childhood.9 Regulatory T cells are upregulated in mononuclear cells of cord blood in infants with in-utero exposure to farm environments.10 Two issues arise from these studies: (1) allergic outcomes in infancy—as previously studied in Uganda by the Elliott group11—could be a useful control in the current study by Webb and colleagues, because an effect of maternal anthelmintic treatment in that context would emphasise that certain immune responses can be modified by helminths, but not, importantly, immune responses to early-life vaccines; and (2) exposures at conception (Sangare L, Walson JA, www.thelancet.com Vol 377 January 1, 2011

Abbie Trayler-Smith/Panos

Comment

personal communication) or in the first trimester of pregnancy, might hold the key to profound effects. Finally, the duration of postnatal follow-up might be an issue, because at least two published studies have reported that the effects of in-utero sensitisation due to pregnancy-related infection with Plasmodium falciparum become apparent in only the second year of life.12,13 Helminths are thought to affect immune responses to coinfection (such as P falciparum) and responses to vaccination in childhood; however, Webb and colleagues’ study did not determine the status of helminth infection in the infants aged 12 months. Therefore, the results of placebo-controlled albendazole treatment to determine the effect of intestinal helminths on vaccine-induced responses in childhood are eagerly awaited. The study’s elegant design and its effectiveness in a challenging setting, where frequent data collection must have been daunting, are noteworthy and should ensure that it is a template for future trials that aim to expand our knowledge of the complex, but extremely important, infections that might leave clinically relevant immunological imprints in early life. *Maria Yazdanbakhsh, Adrian J F Luty Department of Parasitology, Leiden University Medical Center, Leiden 2300, Netherlands [email protected] We declare that we have no conflicts of interest. 1

Serazin AC, Shackelton LA, Wilson C, Bhan MK. Improving the performance of enteric vaccines in the developing world. Nat Immunol 2010; 11: 769–73.

7

Comment

2 3 4

5

6

7

Labeaud AD, Malhotra I, King MJ, King CL, King CH. Do antenatal parasite infections devalue childhood vaccination? PLoS Negl Trop Dis 2009; 3: e442. Williamson WA, Greenwood BM. Impairment of the immune response to vaccination after acute malaria. Lancet 1978; 1: 1328–29. van Riet E, Hartgers FC, Yazdanbakhsh M. Chronic helminth infections induce immunomodulation: consequences and mechanisms. Immunobiology 2007; 212: 475–90. Webb EL, Mawa PA, Ndibazza J, et al. Effect of single-dose anthelmintic treatment during pregnancy on an infant’s response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial. Lancet 2010; published online Dec 21. DOI:10.1016/S0140-6736(10)61457-2. Elliott AM, Namujju PB, Mawa PA, et al, for the Mother and Baby study team. A randomised controlled trial of the effects of albendazole in pregnancy on maternal responses to mycobacterial antigens and infant responses to Bacille Calmette-Guérin (BCG) immunisation [ISRCTN32849447]. BMC Infect Dis 2005; 5: 115. Supali T, Verweij JJ, Wiria AE, et al. Polyparasitism and its impact on the immune system. Int J Parasitol 2010; 40: 1171–76.

8

9

10 11

12

13

Verweij JJ, Brienen EA, Ziem J, Yelifari L, Polderman AM, Van Lieshout L. Simultaneous detection and quantification of Ancylostoma duodenale, Necator americanus, and Oesophagostomum bifurcum in fecal samples using multiplex real-time PCR. Am J Trop Med Hyg 2007; 77: 685–90. Schaub B, Liu J, Höppler S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 2009; 123: 774–82. von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 2010; 10: 861–68. Elliott AM, Mpairwe H, Quigley MA, et al. Helminth infection during pregnancy and development of infantile eczema. JAMA 2005; 294: 2032–34. Schwarz NG, Adegnika AA, Breitling LP, et al. Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis 2008; 47: 1017–25. Malhotra I, Dent A, Mungai P, et al. Can prenatal malaria exposure produce an immune tolerant phenotype? A prospective birth cohort study in Kenya. PLoS Med 2009; 6: e1000116.

Pathogenic C difficile is here (and everywhere) to stay Published Online November 16, 2010 DOI:10.1016/S01406736(10)61885-5 See Articles page 63

Kudos to Martijn Bauer and colleagues1 for surveying in The Lancet the Clostridium difficile landscape across Europe. In the USA, Canada, and Europe, the recent epidemic BI/NAP1/027 strain of the toxinotype III infection has placed C difficile infection in the limelight,

Panel: Pathogenetically and epidemiologically important information about C difficile isolates Molecular typing Toxinotyping3 • A+ B+ CDT+ (IIIa-c, IV, V, VI, VII, IX, XIV, XV, XXII, XXIII, XXIV, XXV, XXVIII). • A+ B+ CDT- (0, I, II, XII, XIII, XVIII, XIX, XX, XXI, XXVI, XXVII, XXIX). • B+ A- CDT+ (X, V-like, XVI, XVII, XXX, XXXI) • B+ A- CDT- (VIII). • CDT+ A-B- (XIa, XIb). Restriction endonuclease analysis (eg, BI). PCR ribotyping (eg, 018, 027, 056, 078). Pulse-field gel electrophoresis (eg, NAP1). Multilocus variable-number tandem-repeat analysis or others. Antimicrobial susceptibility pattern Clindamycin, broad spectrum penicillins, cephalosporins, fluoroquinolones, and others (eg, macrolides or carbapenems). Other Geographical location, hospital acquired versus community acquired, outbreak-related or not, severity of disease association, degree of sporulation. A+B+ refers to production of TcdA (toxin A) and TcdB (toxin B). CDT=C difficile binary toxin. CDT+ refers to presence of complete cdt locus (gene encoding for binary toxin). Toxinotype is defined by changes in PaLoc (19·6 kb region of chromosome encoding TcdA and TcdB) and cdt locus.

8

with striking increases in infection rates, in the need for colectomy and intensive care, and in mortality during the past decade.2 Key traits of C difficile isolates are listed in the panel. Increases in rates and severity of disease were attributed to the BI/NAP1/027 type III strain, which has a deletion in tcdC (a negative-regulatory gene) resulting in increased production of toxins A and B, production of binary toxin, fluoroquinolone resistance, and increased numbers of spores.4,5 However, reports have not yet found the 027 strain to be associated with severe disease, especially in non-epidemic settings.6 Just as others have reported, Bauer and colleagues1 have shown a diversity of PCR ribotypes causing C difficile infection, with more non-027 (018 and 056) strains associated with deaths. Some studies have shown no association of C difficile strain type with disease severity.7 In our experience, the “BI-ness” of an isolate is not what determines the degree of intestinal inflammation, but rather, its resistance to fluoroquinolones.8 What then is driving the continued increases in C difficile infections and their severity? C difficile infection has been repeatedly referred to as an emerging infection; however, the disease might have been around for as long as we have been exposed to antibiotics, or even before. Although pseudomembranous colitis after gastrointestinal surgery was described by John Finney in 1893, it was not until the 1950s that pseudomembranous colitis became associated with antibiotic use. Since toxigenic C difficile was recognised as the cause of www.thelancet.com Vol 377 January 1, 2011

Comment

antibiotic-associated colitis and pseudomembranous colitis in the late 1970s,9 many outbreaks and cases have been documented. Antibiotic use has been implicated as a key risk factor for the development of C difficile infection. Although almost all antibiotics have been associated with C difficile infection, the most prominent ones have been clindamycin (1970s), cephalosporins and penicillins (1980s–90s), and fluoroquinolones (2000s). Our data and others’ have linked fluoroquinolone use to the recent increases in C difficile infections.10,11 Selective pressure from antimicrobial agents has long been known to drive the emergence of resistant pathogens, including meticillin-resistant Staphyloccocus aureus, penicillinresistant Streptococcus pneumoniae, extendedspectrum β-lactamase-producing Escherichia coli, and carbapenem-resistant enterobacteriacae. Severe or even fatal disease develops in the often already debilitated hosts. However, none of the leading resistant pathogens that cause severe infections has been as closely associated with the disruption of the host’s normal flora as has C difficile. The rich and diverse intestinal microbiome inhibits C difficile growth.12 This protection is compromised in the presence of broadspectrum antibiotics, especially those to which the pathogen is resistant. With the development of more potent and broad-spectrum antibiotics for other resistant pathogens, we can only expect the problem of C difficile infection to continue. Thus, although it is important to know where C difficile lurk and what types of bacteria these are (whether or not they are directly related to virulence or severity of disease), we also need to know the antibiotic susceptibilities of these isolates. Knowledge of the susceptibilities might not be relevant to treatment of the infection itself, but will probably identify the predisposing and prevailing antibiotic pressure to which we are subjecting our crucial microbiome. Bauer and colleagues’1 data give a snapshot of the relative distribution of the different types of clinically relevant C difficile isolates in Europe. An important follow through would be the genotypic and phenotypic resistance patterns of these isolates. These are the isolates that will probably spill over into the community, the food supply, and animal husbandry— which can also be another source of antibiotic pressure and potential reservoirs for C difficile—and cause www.thelancet.com Vol 377 January 1, 2011

C difficile infection in those who otherwise have no risk factors.13–15 To stay ahead of these costly and deadly outbreaks, we need to know what is out there and to identify and ameliorate what is driving their increasing frequency and severity. One thing is certain: antibiotic-resistant C difficile and other resistant pathogens are here to stay, as long as antibiotics are around. Cirle A Warren, *Richard L Guerrant Center for International Health (CAW) and Center for Global Health (RLG); Division of Infectious Diseases, University of Virginia, Charlottesville, VA 22908, USA [email protected] We are partly supported by NIH grants (grant number U01 AI075526). RLG is on a scientific advisory board for Probiotics and is a cofounder of AlGlutamine, LLC. CAW declares that she has no conflicts of interest. 1

2

3 4

5 6

7

8

9

10

11

12 13

14

15

Bauer MP, Notermans DW, van Benthem BHB, et al, for the ECDIS Study Group. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2010; published online Nov 16. DOI:10.1016/S01406736(10)61266-4. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009; 7: 526–36. Rupnik M. Clostridium difficile toxinotypes. August, 2010. http://www.mf.uni-mb.si/mikro/tox (accessed Sept 13, 2010). Akerlund T, Persson I, Unemo M, et al. Increased sporulation rate of epidemic Clostridium difficile type 027/NAP1. J Clin Microbiol 2008; 46: 1530–33. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin genevariant strain of Clostridium difficile. N Engl J Med 2005; 353: 2433–41. Cloud J, Noddin L, Pressman A, Hu M, Kelly C. Clostridium difficile strain NAP-1 is not associated with severe disease in a nonepidemic setting. Clin Gastroenterol Hepatol 2009; 7: 868–73. Wilson V, Cheek L, Satta G, et al. Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom. Clin Infect Dis 2010; 50: e77–81. Pawlowski SW, Archbald-Pannone L, Carman RJ, et al. Elevated levels of intestinal inflammation in Clostridium difficile infection associated with fluoroquinolone-resistant C difficile. J Hosp Infect 2009; 73: 185–87. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978; 298: 531–34. Archbald-Pannone L, Alcantara-Warren C, Lyman J, Guerrant RL. Fluoroquinolone use and increased incidence of C difficile associated diarrhea. UVA J Med 2009; 6: 45–48. Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005; 26: 273–80. Borriello SP. The influence of the normal flora on Clostridium difficile colonisation of the gut. Ann Med 1990; 22: 61–67. Centers for Disease Control and Prevention (CDC). Surveillance for community-associated Clostridium difficile—Connecticut, 2006. MMWR Morb Mortal Wkly Rep 2008; 57: 340–43. Bakker D, Corver J, Harmanus C, et al. Relatedness of human and animal Clostridium difficile PCR ribotype 078 isolates based on multilocus variable-number tandem-repeat analysis and tetracycline resistance. J Clin Microbiol 2010; 48: 3744–49. Jhung MA, Thompson AD, Killgore GE, et al. Toxinotype V Clostridium difficile in humans and food animals. Emerg Infect Dis 2008; 14: 1039–45.

9

Comment

The white plague returns to London—with a vengeance In 1660, John Bunyan (1628–88), an English Christian writer and preacher, described tuberculosis as “The Captain among these men of death” when tuberculosis case rates in London had reached a phenomenal 1000 per 100 000 population per year,1 far more than current rates of 340 per 100 000 in sub-Saharan African countries.2 During the 19th century, the white plague, as tuberculosis was named in Victorian Britain (due to the loss of skin colour seen in London tuberculosis patients), continued to ravage Britain, and up to 25% of deaths in Europe were caused by this disease. The death toll from tuberculosis began to fall in London at the start of the 20th century, as living standards (better housing, nutrition, and economic status) improved; subsequent tuberculosis control was achieved by the introduction in the early 1960s of antituberculosis drugs, improved health services, and BCG vaccination. By the early 1980s, tuberculosis was considered to be conquered in the UK and National Health Service (NHS) tuberculosis services were scaled down considerably. Presently, 1·7 million people die of tuberculosis globally each year and the disease is out of control in 22 high-burden countries worldwide.2 Easy travel and migration, and poor socio-economic and living conditions in certain groups, have allowed the disease to re-surface as a public health problem in all European countries. The incidence in the UK has gradually increased over the past 15 years. In 2009, over 9000 cases were reported, a rate

The Bridgeman Art Library

Published Online December 17, 2010 DOI:10.1016/S01406736(10)62176-9

Poor housing conditions in Victorian London

10

of 14·6 per 100 000 population.3,4 This pattern is striking when compared with the general decline in other western European countries; the UK is the only European country where tuberculosis incidence rates continue to rise.3 Tuberculosis has returned to London in force with an increase in the number of cases by nearly 50% since 1999, from 2309 in 1999 to 3450 in 2009,3 accounting for almost 40% of all tuberculosis cases in the UK.3,4 Because the current gold standard for diagnosis (sputum microscopy and culture) only detects up to 70% of active cases, and London general practitioners require education and heightened awareness to improve diagnosis,5 the number of cases reported is underestimated. Drug-resistant tuberculosis is also becoming an important problem in London. During the past 10 years, an ongoing outbreak of isoniazid-resistant tuberculosis in hard-to-reach groups is spreading, with 172 isoniazid-resistant cases reported in London in 2009.6 Ominously, there were a further 58 cases of multidrug-resistant tuberculosis in 2009.7 The increase in the number of tuberculosis cases in the UK has largely been in non-UK born groups; in 2009, these were black African (28%), Indian (27%), and white (10%).3 Interestingly many of these cases were not in new migrants; 85% of individuals born overseas had lived in the UK for 2 or more years, and tuberculosis was common in London boroughs that are relatively deprived.3 Poor housing, inadequate ventilation, and overcrowding—conditions prevalent in Victorian Britain—are causes of the higher tuberculosis incidence rates in certain London boroughs. In all European countries, the disease is mainly concentrated in high-risk groups, such as migrants, refugees, homeless people, drug users, prisoners, and HIV-infected groups.6,8 Prisons provide ideal breeding grounds for tuberculosis and development of drug resistance. The spread of tuberculosis in prisons to prisoners and staff, and resultant spillover into the community when inmates are released or when they need to be transferred for specialist hospital care, are emerging problems in London. A retrospective 4-year (2004–07) study9 of 205 prisoners with newly diagnosed tuberculosis showed that prisoners were more likely to be UK born (47% vs 25%), to be white (33% vs 22%), and to have pulmonary tuberculosis (75% vs 56%) compared www.thelancet.com Vol 377 January 1, 2011

Comment

with all other patients in the UK during that period (29 340 cases aged 16 years or older). Over one-third of culture-confirmed cases (48/139) in prisoners were resistant to isoniazid. Importantly, only 48% of prisoners diagnosed with active disease completed treatment and 20% were lost to follow-up. The ominous tuberculosis situation in London is reminiscent of the unexpected outbreaks of multidrug-resistant tuberculosis in New York and Californian prisons in the early 1990s,10 which arose as a result of complacency of the respective states’ tuberculosis surveillance and control programmes. A large financial investment, with political and legal support, was required to re-establish effective tuberculosis control. An extensive standardised manual of clinical polices and protocols, with a wide outreach service,11 has maintained control to date. Lessons need to be learnt from that situation to reverse the increasing tuberculosis trends in London. A recent London tuberculosis service review assessment has important recommendations,12 which will, if implemented by the UK’s NHS, allow standardisation of tuberculosis clinical policy and practice and improve responsiveness of London’s tuberculosis services’ needs. An immediate and serious long-term political and financial commitment is needed from the UK Government through the NHS if the tide is to be turned against the return of the white plague in London, and if tuberculosis is to be controlled. Such measures will erase London’s reputation as the tuberculosis capital of Europe.

Alimuddin Zumla Department of Infection, University College London Medical School, Windeyer Institute of Medical Sciences, London W1T 4JF, UK [email protected] I declare that I have no conflicts of interest. 1

2

3

4 5

6

7

8

9

10 11

12

Daniel TM. The history of tuberculosis: past, present and challenges for the future. In: Schaaf S, Zumla A, eds. Tuberculosis–a comprehensive clinical reference London: Saunders Elsevier, 2009: 1–7. WHO. Global tuberculosis control—epidemiology, strategy, financing. http:// www.who.int/tb/publications/global_report/2009/en/index.html (accessed Nov 6, 2010). Health Protection Agency (UK). Tuberculosis in the UK: annual report on tuberculosis surveillance in the UK 2009. http://www.hpa.org.uk/ Publications/InfectiousDiseases/Tuberculosis/0912TuberculosisintheUK/ (accessed Nov 6, 2010). Crofts JP, Gelb D, Andrews N, Delpech V, Watson JM, Abubakar I. Investigating tuberculosis trends in England. Public Health 2008; 122: 1302–10. Griffiths C, Sturdy P, Brewin P, et al. Educational outreach to promote screening for tuberculosis in primary care: a cluster randomised controlled trial. Lancet 2007; 369: 1528–34. Mitchell SL, Seoudi N, Hutchison DC, Drobniewski FA. Multidrug-resistant tuberculosis: resistance rates to first and reserve antituberculosis drugs in the UK in 2008/9 and the role of rapid molecular tests for drug resistance. Thorax 2010; published online Sept 29. DOI:10.1136/thx.2010.148866. Gilbert RL, Antoine D, French CE, Abubakar I, Watson JM, Jones JA. The impact of immigration on tuberculosis rates in the United Kingdom compared with other European countries. Int J Tuberc Lung Dis 2009; 13: 645–51. Hollo V, Amato-Gauci A, Kodmon C, Manissero D. Tuberculosis in the EU and EEA/EFTA countries: what is the latest data telling us? Euro Surveill 2009; 14: Pii=19151. Anderson C, Story A, Brown T, Drobniewsky F, Abubakar I. Tuberculosis in UK prisoners: a challenge for control. J Epidemiol Community Health 2010: 64: 373–76. Drobniewski, F. Tuberculosis in prisons—forgotten plague. Lancet 1995; 346: 948–49. New York City Department of Health and Mental Hygiene, NY Health Department. Clinical policies and protocols, 4th edn. March, 2008. http:// www.nyc.gov/html/doh/downloads/pdf/tb/tb-protocol.pdf (accessed Nov 6, 2010). Hayward JA, Murray D, Iny I, et al. London TB service review and needs assessment. 2010. http://www.brit-thoracic.org.uk/Portals/0/Clinical%20 Information/Tuberculosis/P263%20PHAST%20London%20TB%20 Project%20Final%20report%20I.pdf (accessed Nov 6, 2010).

Health and philanthropy—the tobacco connection On June 14, the world’s two richest men, Mexico’s Carlos Slim Helú and the USA’s Bill Gates, jointly announced that they would each contribute US$50 million to the Latam health project to increase vaccinations and improve child nutrition and natal health in central America.1 Slim already contributes reputedly $2·5 billion annually to his Instituto Carlos Slim de la Salud, which runs a large variety of health programmes in Latin America.2 The latest announcement will naturally attract widespread acclaim as an outstanding example of philanthropy. But it also invites important questions about consistency and competing interests. Any assessment of Slim’s net contribution to public health must balance the impact of his philanthropic www.thelancet.com Vol 377 January 1, 2011

contributions as well as the indirect health consequences that flow from his wealth generation with a less appreciated source of his wealth. Descriptions of Slim’s vast fortune generally concentrate on his telecommunications empire.3 Relatively little is mentioned about his long-standing majority ownership of the Mexican tobacco company Cigatam,3 which has since 2007 been 80% owned by Philip Morris.4 Slim’s website acknowledges that Cigatam “turned out to be the first and most important because of its cash flow, providing the Group with sufficient liquidity to capitalize on available opportunities and thereby increase its acquisitions of big companies”.5 Nor is it

Published Online August 25, 2010 DOI:10.1016/S01406736(10)61036-7

11

Bloomberg via Getty Images

Comment

Carlos Slim and Bill Gates

as widely publicised that he has a continuing role as a non-executive director6 of the world’s largest tobacco company, Philip Morris International (PMI). The company’s shareholders doubtless expect him—like all directors—to make a major contribution to maximise investment returns and the company’s bottom line. PMI’s website6 notes that Slim serves on its finance, product innovation, and regulatory affairs committees. The purposes of these committees include to “monitor the financial condition of the Company, oversee the sources and use of cash flow, capital structure and resulting financial needs”,7 to “monitor and review the development of new product strategies, key legislative, regulatory and public policy issues and trends affecting the Company”, and to “anticipate, respond to, and challenge where appropriate, regulatory and fiscal proposals”.8 This must include responding to international efforts at tobacco control. It is inconceivable that Slim would not have known of the action Philip Morris is currently taking against Uruguay in the International Centre for the Settlement of Industrial Disputes objecting (among other things) to that nation’s new requirement for large graphic healthwarnings on cigarette packs.9 The tobacco industry has long suffered ethical bottom-feeder status with both the public and the corporate world. The Reputation Institute’s 2010 report,10 which involved over 80 000 respondents in 12

32 countries, saw the tobacco industry ranked a distant last of 25 industries on “reputation”. Why? This is an industry whose products kill over 5·5 million people each year, on average 15 years earlier than normal life expectancy.11 It is an industry which has engineered the chemistry and design of its products to, as one infamous 1984 Philip Morris internal memorandum put it, “make it harder for existing smokers to leave the product”.12 It is an industry whose product is responsible for the inexorable rise of lung cancer, the world’s leading cause of cancer death and a disease that was very uncommon before the mass production and marketing of cigarettes.13 Slim’s massive contributions to Latin American health undoubtedly do much good. But the consequences of his continuing history of high-level regional and global involvement in the tobacco industry are hardly trivial in any assessment of his public health footprint. Gates’ philanthropy is unmatched this century. His commitment to reducing some of the world’s worst infectious diseases has poured unprecedented capital into health projects in many of the world’s poorest and unhealthiest nations. His contributions will have already saved uncounted lives. Gates has recently begun to fund tobacco-control projects in low-income and middle-income nations, joining New York’s mayor Michael Bloomberg in injecting an estimated $500 million to try and curb tobacco use in the world’s poorest nations.14 In April this year,15 the Bill & Melinda Gates Foundation withdrew a grant of $5·2 million to Canada’s International Development Research Centre (IDRC), after it emerged that the IDRC’s chair, Barbara McDougall, was a very recent board member of Imperial Tobacco Canada.16 The Gates Foundation statement17 said: “The foundation was recently informed that the chair of the board of our partner, the International Development Research Centre (IDRC), has until recently also been a Director of Imperial Tobacco Canada, Ltd. We are deeply disappointed by this revelation and feel this conflict is unacceptable as we work to support meaningful tobacco control programs in Africa. Therefore, we are terminating our tobacco control grant to IDRC, effective immediately. We remain committed to tobacco control work and look forward to continuing to partner with the anti-tobacco community to reduce tobacco use in Africa.” www.thelancet.com Vol 377 January 1, 2011

Comment

Gates’ decision just 2 months later to partner with Slim is plainly inconsistent. He apparently did not know of McDougall’s appointment when he funded the IDRC. He might well not have known about Slim’s tobacco connections when he joined with him in the Latam project. He must know now. His subsequent actions with IDRC were an outstanding example of principled philanthropy. Let us hope he makes the same call again.

7

Simon Chapman

11

School of Public Health, University of Sydney, Sydney, NSW 2006, Australia [email protected] I declare that I have no conflicts of interest. 1

2 3 4

5 6

Anon. World’s richest want better health for Latam poors. Reuters June 14, 2010. http://www.reuters.com/article/idUSN1415624220100614 (accessed June 22, 2010). Chapman S. International tobacco control should repudiate Jekyll and Hyde health philanthropy. Tob Control 2008; 17: 1. Anon. Carlos Slim Helú: business activity. http://www.carlosslim.com/act_ empresarial_ing.html (accessed June 22, 2010). Philip Morris International. Philip Morris International announces agreement in principle to acquire additional 30% stake in Mexican tobacco business from Grupo Carso. July 18, 2007. http://www.pmi.com/eng/media_center/press_ releases/Pages/200707180000.aspx (accessed June 22, 2010). Anon. Carlos Slim Helú: biography. http://www.carlosslim.com/biografia_ ing.html (accessed June 22, 2010). Philip Morris International. Board of Directors. http://www.pmi.com/eng/ about_us/corporate_governance/pages/board_of_directors.aspx (accessed June 22, 2010).

www.thelancet.com Vol 377 January 1, 2011

8

9

10

12 13 14

15

16

17

Philip Morris International. Finance Committee Charter http://www.pmi.com/ eng/documents/finance_committee_charter.pdf (accessed June 23, 2010). Philip Morris International. Product Innovation and Regulatory Affairs Committee Charter. http://www.pmi.com/eng/documents/product_ innovation_and_regulatory_affairs_committee_charter.pdf (accessed June 23, 2010). Dias FC. Philip Morris initiates arbitration against Uruguay over new labeling requirements, taxes. May 11, 2010. http://www. investmenttreatynews.org/cms/news/archive/2010/05/11/philip-morrisinitiates-arbitration-against-uruguay-over-new-labeling-requirementstaxes.aspx (accessed June 22, 2010). Reputation Institute. Global reputation PulseTM reports. http://www. reputationinstitute.com/knowledge-center/global-pulse (accessed June 22, 2010). Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3: e442. Webb WH. Status of Marlboro Development Programme. July 12, 1984. http://legacy.library.ucsf.edu/tid/gmr98e00 (accessed June 22, 2010). Oschner A. Bronchogenic carcinoma: a largely preventable lesion assuming epidemic proportions. Chest 1971; 59: 358–59. Goldman H. Bloomberg, Gates set $500 million anti-tobacco fight (update1) 23 July 2008. http://www.bloomberg.com/apps/news?pid=news archive&sid=atfHVx2DGsqE (accessed June 22, 2010). Anon. Gates Foundation pulls funding from IDRC due to ties to Big Tobacco. April 12, 2010. http://www.marketwire.com/press-release/ Gates-Foundation-pulls-funding-from-IDRC-due-to-ties-to-BigTobacco-1146077.htm (accessed June 22, 2010). Todkill A. Tobacco control and the collateral damage of conflict of interest. Open Med 2010; 4: http://www.openmedicine.ca/article/view/411/325 (accessed June 22, 2010). Bill & Melinda Gates Foundation. Statement regarding IDRC tobacco control grant. April 12, 2010. http://www.gatesfoundation.org/ press-releases/Pages/statement-on-idrc-grant-100412.aspx (accessed June 23, 2010).

13

Comment

Offline: Revising our expectations

Photolibrary

The Bridgeman Art Library

What will 2011 bring us? In the western world, thanks to ruthless political ideology and cruel opportunism, we will see the biggest roll back of the welfare state since its creation. Millions of people will be plunged into poverty. Their health, and the health of their children, will suffer— and not only in the short term, but for a generation to come. It is fashionable today to hate the state. But we forget the contribution the state has made to our overall wellbeing. Material deprivation and mortality are closely linked. The idea that a classe dangereuse threatens our polity—an undeserving poor that needs to be kicked and harassed into work—is a myth that has gained currency in every era, fuelled by fear and mistrust among an insecure middle-class and fanned by governments desperate to maintain their tenuous grip on power. But the state has been critical to human survival. The connection between the notion of human welfare and state responsibility brought peace, competent administration, compulsory schooling, good housing, a public health system, nutrition, hygiene laws, investment in science, reliable health statistics, safe water, sanitation, and a new compassion that fostered solidarity and social protection. State and society are interdependent. Doctors should energetically reject the arguments of those who ignore this history. We must be the vanguard of popular resistance to check this brutal philistinism. *

Photolibrary

Corbis

Not only will the state become quantitatively smaller, it will also change qualitatively. Look at our universities. No longer will universities be places for independent critical inquiry. Most have secured a decent settlement in science from government in exchange for throwing humanities departments to the wolves and for accepting a new role as handmaidens to the economy. In the UK, some of our best scientific leaders have been co-opted into this collusive betrayal. They say: the science community must justify itself to the political class by delivering economic growth. But if we define impact in this one-dimensional way, we will strip any remaining moral purpose from the mission of our universities. Perhaps this is the goal—to weaken, once and for all, one of the few remaining sources of socially progressive analysis and thought. *

14

Global health will undergo a period of reassessment, even retrenchment. During 2010, there was much optimism that enormously successful vertical approaches to disease—the Global Fund and GAVI, for example—would evolve into broader alliances. The Global Fund might expand its mandate to include maternal, newborn, and child health. GAVI might develop a larger healthsystems window to go beyond simply funding vaccine programmes. These hopes, under huge financial pressure, have died in a fire of recrimination. GAVI deposed its leadership, unhappy that the core mission was being tampered with. Interviews for the new Executive Director of GAVI will take place next month. And the Board of the Global Fund last month rejected attempts to make it more than an organisation dedicated to HIV, tuberculosis, and malaria. Silos will be back in fashion for 2011. * Except, perhaps, for one: UNAIDS. Those who have suggested the time is right to close UNAIDS have usually been squashed by the ardent advocacy of the AIDS movement. But there are voices inviting more mature reflection about the future of this UN initiative. When one visits UNAIDS in Geneva, one finds an elegant new building sitting opposite WHO’s ageing headquarters. It is tempting to think that UNAIDS is like WHO—an intergovernmental body, constituted to exist forever. Not so. UNAIDS is a programme—a very successful programme—but not an agency. On June 25–27, 2001, nations came together in a Special Session at the UN General Assembly. There, they made an unprecedented Declaration of Commitment on HIV/AIDS. This coming June will be the tenth anniversary of that commitment. What should UNAIDS do? It should certainly seek to reaffirm that declaration. But it should also invite the wider global community to consider an incremental shutdown of UNAIDS over the next decade, reallocating responsibilities to organisations that may be better equipped to deal with the next phase of the epidemic. The success of UNAIDS—eg, on access to antiretrovirals and human rights—puts it in a strong position to call on its co-sponsors to step up to the future challenges the AIDS epidemic presents. Such would be a fitting sign off. Richard Horton [email protected]

www.thelancet.com Vol 377 January 1, 2011

World Report

Myths and realities about drug addiction in Mexico As the death toll from Mexico’s war on drugs continues to soar, a spate of attacks on recovering addicts has focused attention on the country’s domestic drug consumption. Mary Cuddehe reports. One Sunday in early December, gunmen burst into two drugrehabilitation centres in Ciudad Juarez, Mexico, killing four patients and wounding five. It was the latest of a series of attacks against drugtreatment facilities in the north of the country that began in the summer of 2008. In October, 13 people were killed in this way in Tijuana. And in a single grim episode in July, 19 were marched out of a clinic, lined up against a wall, and slaughtered. The massacres, cruel and perplexing, have shocked Mexicans, who fail to see the logic of assassinating powerless drug addicts. And while authorities have developed theories about the attacks—they now claim that criminals use the centres as recruiting grounds—the violence has also reminded the nation of the issue of addiction itself. It is an interesting issue. For a while now, Mexico’s explosive addiction rate has been a feature of political speeches and media reports—part of the larger rationale for the government’s battle against drug organisations that has plunged the country into chaos and resulted in 30 000 deaths. The notion links back to the 2008 release of a national household drug-use survey that showed 51% more Mexicans self-reporting as addicts than did in the previous study from 2002. “It is clear to everyone that our nation has stopped being a transit country for drugs going to the United States and become an important market as well”, Eduardo Medina Mora, then the attorney general, noted. “Mexico confronting a drug addiction epidemic”, read a Houston Chronicle headline. “Mexico struggles with soaring drug addiction rate”, read another, in the Toronto Globe and Mail. Even the USA has acknowledged the problem by pledging funding for treatment and www.thelancet.com Vol 377 January 1, 2011

prevention programmes through the Merida Initiative. In fact, the widely reported data that fuelled the panic—460 000 addicts and 4·5 million citizens who have tried illicit drugs at least once—actually represent a trend that is closer to “slow and steady” than “soaring”. In all, the percentage of the population that has experimented

“...Mexico’s explosive addiction rate has been a feature of political speeches and media reports—part of the larger rationale for the government’s battle against drug organisations...” with illegal drugs rose from 4·6 to 5·2. For a country with 110 million people, and arguably more narcotics passing through it at any given time than anywhere in the world, this hardly makes for an epidemic. By contrast, a study assessing WHO data that was published the same year as Mexico’s showed that 42% of Americans had smoked marijuana and 16% had used cocaine. “Mexico doesn’t compare with other countries”, says Luis Solis, director of the National Council Against Addictions (CONADIC), an arm of the Health Ministry. “The problem isn’t as serious as in other countries”, echoes Victor Marquez, the director of treatment at the Youth Integration Center, a non-profit drug-rehabilitation group. No one is discounting the seriousness of addiction as a threat to public health— or that the Mexican rate is indeed on the rise. But viewed in the context of the cartel war that is currently unravelling the social fabric of Mexico, a curious fact is the relatively small effect on domestic consumption. Up until the 1990s, South American cocaine found its way to the USA

primarily via Caribbean maritime paths. When US agencies shut down those routes, they effectively diverted the transitory trade to overland corridors in Mexico. As Medina Mora himself has said: “Drugs are like water. They always find their course.” More than 90% of cocaine that enters the USA now travels through its southern neighbour, according to US State Department estimates. This figure has been reported at somewhere between 300 and 500 tons per year. Additionally, thousands of pounds of marijuana are grown inside the country, largely in the northwestern region known as the Golden Triangle, where the states of Sinaloa, Durango, and Chihuahua, meet and where the poppy that is the base for opium and heroin is also cultivated. Targeting the traffickers who run these operations has done little to change the numbers. On the contrary, according to the UN Office on Drug and Crime’s 2010 World Drug Report, opiate production increased 120% in 2008, ranking Mexico as the world’s third largest producing country (although it is still insignificant measured against Afghanistan, which accounts for 90% of the global supply). In 2009, cannabis cultivation spiked 35% to 12 000 hectares—the highest since 1992. Methamphetamine manufacturing, an important source of income for the cartels, has also increased. In August, 2009, authorities raided a crystal-meth laboratory so enormous and complex it took a reporter for a national newspaper 6 hours to cross. The factory, which the press nicknamed “Crystal City”, was said to turn out about 100 kg of methamphetamine a day. Given the staggering quantities, and the unchecked power that the drug gangs exert in certain regions— 15

AFP/Getty Images

World Report

Mexican soldiers guard 4·5 tons of marijuana seized in November last year

residents of a small town in the border state of Tamaulipas recently abandoned their homes en masse, taking shelter as refugees in a neighbouring city, after criminals took over—it would not be unreasonable to expect the cartels to force their product on the local population. But while reported estimates have put the yearly domestic drug sales figure as high as $5 billion, this is small change compared with the $30 billion market in the USA. There are various theories about why, statistically speaking, Mexicans are justnot that into drugs. One has to do with the government’s substanceabuse prevention programmes. Treatment as a method for drug addiction was written into the 1917 Constitution, but it was not until the 1970s that Mexico’s demandreduction efforts truly began to take shape. In 1969, the governmentfunded non-profit Youth Integration Centers opened. The country’s most established organisation, it operates 110 clinics nationwide and gets about 80% of its financing—about $5 million a year—from the Health Ministry. A few years later, the Health Ministry created its own Center for Drug-Dependence Studies (now the National Institute of Psychiatry). By the 1980s, the private rehabilitation industry was expanding as well. The era, it turns out, was pivotal for drugs in Mexico in more ways than one. 16

Today there are thousands of private and public institutions dealing with all forms of substance abuse, mostly alcohol, according to Solis. Costs and quality range widely. Public outpatient programmes, which have been expanded under President Felipe Calderon, can be as inexpensive as $5 a week—the highest-priced private options cost as much as $10 000 a month. Since Calderon took office in 2006, the new Centers for New Life programme has opened more than 300 treatment centres for at-risk communities. Also, in April, 2009, the law the president had proposed to decriminalise possession of illicit substances was passed. Designed to combat what the government considers to be the rapidly expanding street trade, known as narcomenudeo, the law established personal-use limits. Anyone caught with up to a 0·5 g of cocaine, 50 mg of heroin, or 40 mg of methamphetamine is encouraged to seek treatment, and third-time offenders are required to do so. To many critics, the law was largely pointless because police officers, who are poorly paid and prone to bribes, rarely make small-possession arrests. But it also required the development of a national strategy for prevention and treatment programmes, and the Health Ministry has since taken steps to train and certify drug counsellors. Calderon “has done much

more than previous administrations”, says Marquez. The importance of the Mexican family, the country’s social conservatism, and its deep Catholic roots also help explain the traditionally low incidence of substance abuse. Marcela Lopez, a health researcher with Mexico’s Autonomous University, says “Mexico has more factors of protection than risk”, and this is especially so when compared with the USA. Also important is the fact that fewer Mexicans have the time or financial freedom for the sort of recreational use that fuels much of the drug trade in western Europe and the USA. Roughly half the population lives in poverty. Ultimately, though, it all comes down to the bottom line—the fact that a pound of marijuana can fetch a higher price in San Francisco than in San Luis Potosi. The Mexican attorney general’s office recently reported that $10·9 billion worth of drugs had been confiscated since the beginning of the war in 2006, and government spokespeople on both sides of the border point out how their bi-national interdiction efforts have made smuggling more difficult for the cartels. But the ever-increasing drugproduction efforts and the endless raids on vast, air-conditioned border tunnels, specially designed semisubmersibles, and even shipments of frozen sharks stuffed with cocaine tell a different story. No matter how many seizures are made, the lucrative US market is worth the risk. Mexico’s cartels operate a wildly profitable, tax-free business. But the fact that most of their customers live in another country is some scant consolation for Mexican public health officials. If the domestic market were anywhere near as enticing, they would surely focus on their home turf instead of the USA. In which case, the government really might have to face an epidemic.

Mary Cuddehe www.thelancet.com Vol 377 January 1, 2011

World Report

Pulse oximeters breathe life into surgery in poorer nations Anaesthetists worldwide have joined forces with safer-surgery advocate Atul Gawande to enable low-income nations to buy vital pulse oximeters. Tony Kirby reports. With worldwide demand for surgery reaching an all time high, so attention has focused on outcomes of surgical procedures. Among the many things taken for granted in the operating theatre in high-income countries is the availability of good quality pulse oximeters—devices that monitor the level of oxygenation in a patient’s blood and alert the physician if oxygen concentrations drop below safe levels, allowing rapid intervention. The devices are essential in any setting in which a patient’s blood oxygenation is unstable, including routine operations, emergency and intensive care, and also hospital wards. Unsurprisingly, lowincome and middle-income countries have little or no access to such devices, and poor or non-existent training for the often low-quality devices they do have. Pulse oximeters use a finger probe to measure the oxygen saturation of haemoglobin in the peripheral circulation. The technology in its current form became available in the early 1980s, and by the early 1990s pulse oximeters were adopted as a standard of care in international anaesthesia. Today, 58 countries have established anaesthesia-monitoring standards, and all include pulse oximetry as a minimum requirement. The World Federation of Societies of Anaesthesiologists (WFSA) includes pulse oximeters as a minimum standard of care in all hospitals where surgery is undertaken. Introduction of these devices into developed countries such as the UK reduced death rates by 20 times, from one in 10 000 operations to one in 185 000. In stark contrast, anaesthesia mortality in low-income countries today has been reported to be as high as one in 133. A study published in 2010 by Gawande and colleagues in The Lancet www.thelancet.com Vol 377 January 1, 2011

showed that across sub-Saharan Africa, between 60% and 70% of operating theatres have no pulse oximeter, compared with a global average of 20%. Almost 100% of highincome country operating theatres possess these vital devices. This followed a 2009 study that showed

“Introduction of pulse oximetry is one of the most urgent improvements that could be made to anaesthesia safety.” substantial gaps in pulse oximetry availability and training in pilot sites in Uganda, Vietnam, India, and the Philippines. But the introduction of oximetry led to a sustained change in anaesthesia practice in these settings; with early detection of hypoxia that was managed appropriately, and, vitally, the characteristics of the ideal oximeter for low-resource settings were defined. Stephen Ttendo, President of the Uganda Society of Anaesthetists, says that the reality faced at present by many anaesthetists in resourcepoor operating theatres is that they can only monitor patients by feeling their radial artery or watching for their blood going dark. “Use of pulse oximeters will fundamentally improve the way we look after our patients in developing countries”, he says. “Helping these countries to reach a critical mass of trained anaesthetists is essential. If these numbers are in place, advocacy and sustainability of essential health services will become a reality because the voices of these professionals will be so loud that they cannot be ignored by policy makers.” The Association of Anaesthetists for Great Britain and Ireland (AAGBI), WFSA, Harvard University, and other partners are helping Uganda to

increase its numbers of anaesthetists from the current 20 to 40 by 2013, with hopes of more than 100 by 2020. About 7 million people die or have major complications from surgery worldwide every year. The introduction of WHO’s Safe Surgery Checklist—created by surgeon Atul Gawande (Brigham and Women’s Hospital, Boston, MA, USA)—in 2008 has been changing the landscape of surgery in many settings, including the UK. The checklist enables medical teams to eliminate errors that can lead to increased morbidity and mortality. The strength of the checklist comes through its simplicity and nearuniversal applicability in all countries, irrespective of income. But one item on the checklist prevents its complete rollout in poor countries: the requirement for a pulse oximeter. Anaesthetists, including Ian Wilson, President of AAGBI, raised concerns during the checklist drafting that without the introduction of pulse oximeters, mortality and complications would remain unacceptably high. Wilson and WFSA colleagues then worked with Gawande and partners to develop the Lifebox project—to bring cheap, good quality pulse oximeters to low-income countries. The result is that early this year, the Lifebox oximeter devices (Lifeboxes) will be available for US$250 through the Lifebox website, with vital replacement probes (needed on average every 6 months) available for just $25. In the USA, pulse oximeters can cost $1000. Gawande has seen first-hand the dire need for pulse oximeters during a trip to India. “The man had been seen in the emergency ward for a tubercular empyema and left to wait in the emergency ward more than an hour for an operating room”, he recalls. “Even in the operating room

For more on Lifebox see http://www.lifebox.org

See Articles Lancet 2006; 376: 1055–61

17

Isabeau Walker

World Report

An oximeter in use during anaesthesia at Kayunga Hospital in Uganda

it was not recognised that he needed immediate drainage until he had a cardiac arrest and in the time it took to act he died. If this ward had had pulse oximeters, the doctors would have been able to tell immediately that despite his relatively good appearance compared with other patients, this man was one of the sickest on the ward”, says Gawande. “Introduction of pulse oximetry is one of the most urgent improvements that could be made to anaesthesia safety”, Wilson told The Lancet. “Many of our members have worked in developing countries where there continues to be extremely high anaesthesia related mortality.” As part of the Lifebox initiative, the pulse oximeter design was put out to tender, drawing on the earlier work by Wilson and colleagues. Their message was simple: the oximeter had to meet International Organization for Standardization requirements and be suitable for use in low-resource settings—robust, resistant to damage, with probes that were durable and reusable. Furthermore, the oximeter had to be suitable for all ages. And of course, most importantly, be cheap. WHO and WFSA endorsed these specifications. From eight competing manufacturers, Acare Technology, Taiwan, won the tender. Their oximeter costs $199 ($250 including delivery), with replacement probes available for $25. 18

Concerns have been raised that these low-cost devices could be bought or sold on to more wealthy nations. “The contract between the project and the manufacturer stipulates that the Lifebox oximeters will only be available to not-forprofit hospitals in low-income, or lower middle-income countries”, says Wilson. “The project will monitor purchasers who have to agree not to re-sell the oximeters. Clearly there is some risk that oximeters will end up in the wrong places, but we hope strict monitoring will prevent this.” A key part of the project is that each oximeter is supplied with educational materials including videos, tutorials, and a manual—all available free on a CD. Part of the project is to run training workshops, so that the technology is accompanied by the knowledge of how to use and look after the oximeters to make them last longer and sustain improved standards of operative care. Gawande and Wilson hope that donors will step in to bulk-buy the oximeters for distribution to those countries most in need. Such efforts will, says Gawande, save vital time in getting the devices rolled out. “A donor taking on the purchase and distributing free devices to countries could happen much more quickly than lengthy negotiations with health ministries of low-income countries such as many found in Africa. Such negotiations could take a year or more”, he says. Ongoing WHO pilot projects in Moldova and Zambia are testing the effects of pulse oximeters on outcomes of surgery in low-income nations, as well as the other aspects of the Safe Surgery Checklist. Developing effective procurement systems for hospitals in low-income and middle-income countries will make a major contribution to the quality and safety of anaesthesia and surgical care. Wilson and Gawande agree that there is potential to increase access to devices such as

combined anaesthesia monitors (non-invasive blood pressure, capnography, and electrocardiogram) and essential items of disposable equipment such as spinal needles, sutures, and sterile gloves. Currently, items as basic as alcohol gel rub for hand-washing can cost nine times as much in Africa as in developed countries. The Lifebox project has now, with the help of the global children’s charity Smile Train, ordered 2000 Lifeboxes for delivery in spring 2011 to various countries. But the Lifebox team are now appealing for extra help to get past the finishing line for this initial phase. “We are seeking other partners and funds, and those will be crucial to our success”, says Gawande. “This is a gamble and an experiment in providing market power for poor hospitals and using it to drive the checklist into place as well. The two go hand in hand. The oximeters are an essential component of dramatically improving the safety of surgical care. The surgery checklist is another. And local training and monitoring to drive a culture of increasing safety is important as well. This together is the Lifebox mission.” Before this large-scale roll out, 200 oximeters are being shipped out to test and refine the best strategies for ensuring reliable delivery, learning, and governance. The ultimate aim is to update the more than 70 000 operating theatres worldwide without the monitors, with an expected order of more than 10 000 monitors in the first 2 years. Like Wilson, Gawande is excited about the precedent that Lifebox could be setting: “If this works, imagine being able to further build the market power of low-income hospitals to lower the price barrier for all kinds of essential technologies for safety and basic health-care services, while also helping us bring quality and safety practices.”

Tony Kirby www.thelancet.com Vol 377 January 1, 2011

Perspectives

Book Eyewitness accounts from surgeons in Gaza Was it a necessary invasion undertaken as humanely as possible to eradicate a potent source of terrorism? Or a brutal attack on a civilian population designed to create fear? These two narratives are replayed in relation to the Israel–Gaza conflict of 2008–09. Israeli doctors remind me about the reality of the attacks by rockets on Israeli cities, the fears induced by suicide bombings, and the threats of outside invasion— together with the absolute necessity of a national home for the Jewish people who are still under threat of harassment in many countries. At the same time, Palestinians speak to me of their history of dispossession and discrimination, continuing violence against property and land, and their right to resist occupation and oppression. Both these perspectives must be understood, and acts of violence condemned wherever they originate. And yet is there not an issue of justice at stake? These matters are explored in Eyes in Gaza, a disturbing description of the conflict in Gaza by two experienced Norwegian surgeons, Mads Gilbert and Erik Fosse, who were among the very few westerners allowed into Gaza after the start of the war. The book is a day by day account of the incredible work performed by these two dedicated surgeons, side by side with their Palestinian colleagues, during 16 days at the height of the conflict. It is a hugely moving work. Much of it is about children—according to Gilbert and Fosse “The attack hit the children of Gaza particularly hard: more than 300 children killed and over 1600 injured.“ The two surgeons write alternate chapters, describe their cases, and evoke the atmosphere in the hospital as child after child was admitted with life-threatening injuries. They wonder at the superb emergency www.thelancet.com Vol 377 January 1, 2011

action taken by their Palestinian colleagues in the challenging working conditions of a packed intensive care unit with erratic electricity supplies and the continual stress of possible injury to their own families. Reading the book, one gets to know these fine colleagues, and their patients.

“It is now accepted that doctors who do not speak out against torture are complicit. Should we not apply the same argument in respect of any war that devastates civilians?“ 12-year-old Ahmed, the nephew of a Palestinian surgeon, who died after both legs and much of his genitals were blown off. Mahmoud, aged 11 years, who was sent by his parents to play on the roof since they thought it would be safer than playing on the street, and returned with 20–30 small dotted holes in his chest wall, and died shortly after, hit by an accurately targeted drone rocket. 9-month-old Jumana, whose hand was amputated after the house in which her family were sheltering was bombed, killing 11 family members. In total during 2 weeks Gilbert and Fosse performed 270 operations, which included 53 amputations, 36 brain operations, and 43 fracture treatments. When the time came to leave, the horrors did not end. As part of a convoy of 16 ambulances taking seriously ill and ventilated patients for transfer to Egypt, Gilbert and Fosse describe how they were stopped before reaching the border and subjected to warning tank fire, forcing their return to Al-Shifa hospital. It was another 3 days before they could finally leave, again subject to bombings as they passed into Egypt. Eyes in Gaza is also a political book that made me reflect on the wider context of these events. As

the conflict progressed, there was increasing unease in certain segments of the Israeli population, particularly among medical professionals active in Physicians for Human Rights, and many assisted with relief efforts. However, this did not turn into mass political opposition, and indeed I received a letter from the President of the Israeli Medical Association as follows: “Regarding your request that we call on the government to stop further bombardment, I am sure you are aware that we are not a political organization.” So, it becomes political to call for a halt to a humanitarian disaster. The same motivation was perhaps behind what I regard as the failure of UK medical royal colleges and the British Medical Association to make statements beyond bland words about this humanitarian disaster. For me, this is a sad reflection on a failure to understand the social determinants of health. The two Norwegian surgeons were, therefore, vitally important as reporters when no western or Israeli reporters were allowed into Gaza. Their message did get out. In a special edition of The Lancet in January, 2009, Gilbert and Fosse gave a graphic account of the hospital conditions that could leave no one unaware of the tragedy unfolding in Gaza. An accompanying Editorial stated “We are disappointed by the silence of national medical associations and professional bodies worldwide. Their leaders, through their inaction, are complicit in a preventable tragedy…” It is now widely accepted that doctors who do not speak out against torture are complicit. Should we not apply the same argument in respect of any war that devastates civilians?

Eyes in Gaza Mads Gilbert, Erik Fosse. Quartet Books Ltd, 2010. Pp 332. £20·00. ISBN 070437191X.

Tony Waterston [email protected]

19

Perspectives

Exhibition Journey through the afterlife

The Trustees of the British Museum

A dead man’s heart is weighed in a balance against a feather that represents truth, while he affirms that, in life, he had not committed any one of 42 sins, which include murder, theft, blasphemy, or stealing the gods’ food from the temples. His innocence, as judged by the gods, will mean that the deceased either attains eternal life or his body will be eaten by the Devourer. This judgment was one of the important stages in the ancient Egyptians’ journey from death to eternal life and is one of the scenes depicted in the British Museum’s major exhibition Ancient Egyptian Book of the Dead. The visitor is taken on a unique journey, through a series of thematic sections that encompass the Egyptians’ preparation and burial of the mummy, through dangers encountered in passing from this world, to the ultimate joys experienced in the land of eternity. An essential possession for this journey was the Book of the Dead—a set of spells, often accompanied by exquisite illustrations, and customarily inscribed on papyrus or coffins and linen wrappings.

Ancient Egyptian Book of the Dead The British Museum, London, UK, until March 6, 2011. http://www. britishmuseum.org/whats_on/ all_current_exhibitions/book_of_ the_dead.aspx

The Trustees of the British Museum

See Online for webvideo

The Book of the Dead was essentially a powerful tool of Egyptian magic, and the specific positioning of spells on one coffin on display was clearly intended to provide magical protection for the relevant body parts of the mummy inside. A mummy shroud provides an intriguing glimpse into practices in an embalmer’s workshop: clearly an item of “undertaker’s stock”, it has been decorated with the relevant magical spells, but the text contains spaces for the names of a future purchaser and his wife to be inserted later. Various physical and magical procedures were deemed necessary for a safe passage to the next world. The “Day of Burial” part of this exhibition looks at mummification and “Opening of the Mouth”, when the priest used magical tools to touch the mummy, coffin, and other tomb goods to enable them to “function” for their owner in the next world. Ancestral statues and a letter to a deceased relative asking her to take action to cure the writer’s illness, illustrate poignant attempts to retain a link between the dead and the living.

Rosalie David Weighing of the heart, detail from the Book of the Dead of Ani

20

Among the many spells in the Book of the Dead are those to activate magical power in protective jewellery (amulets) placed on the mummy, while others provide a kind of “travel guide”, detailing the various features that the deceased would encounter on the journey to the afterlife. Other spells empower the dead to repel or avoid threats posed by snakes, crocodiles, insects, slaughter, and a diet of excrement and urine encountered in the afterlife. I found the exhibits relating to the role of scribes, their equipment, and the production methods and evolution of the Book of the Dead especially interesting. It also demonstrates how ongoing research by Egyptologists and conservators can shed light on possible regional traditions, previously unsuspected links between fragments held in different museums, and how infrared techniques have been used to identify the hitherto unknown name of one papyrus owner. The final display contains the unravelled Greenfield Papyrus, the greatest in length of any known copy of the Book of the Dead, which belonged to Nesitanebisheru, daughter of the High Priest Pinudjem II, who virtually usurped the king’s role throughout southern Egypt in about 930 BC. This papyrus provides a dramatic and fitting conclusion to an exhibition that effectively explores Egyptian mythical and spiritual ideas of life and death. The wide range of objects on display, several short films, and an excellent multimedia guide featuring curators’ and conservators’ comments about the exhibits and their personal involvement in the project all help to reveal something about the aspirations, fears, and moral dilemmas present in one of the world’s oldest civilisations.

[email protected]

www.thelancet.com Vol 377 January 1, 2011

Perspectives

Clare Gerada is the first female chair of the UK’s Royal College of General Practitioners (RCGP) for more than half a century, and enters the role at one of the most challenging times in the history of the profession. The UK Government’s plans to hand over commissioning of services and accompanying large budgets to GPs have been denounced by some, and cautiously welcomed by others. As RCGP chair, Gerada will be at the forefront of the profession’s responses to these major challenges. Gerada was absorbed into the profession from her earliest years, thanks to her father’s role as a family doctor for a large Italian community in the UK town of Peterborough. The young Gerada would peer over the balcony of her home—that doubled as the surgery—and also accompany her dad on his home visits. She completed her medical degree at University College Hospital in London. Among the areas that fascinated her most during her training were emergency medicine and mental health, and she completed a rotation at the Maudsley Hospital in London to hone her psychiatric interests. In the late 1980s, Gerada made some pioneering steps in the field of drug addiction and helped set up a “barefoot” style clinic for drug addicts in London who found themselves isolated from the conventional general practice model of care. “It was a big relief for these patients to talk to a doctor about regular health matters separate to their addiction problems. Such basic things as diet and blood pressure advice. I even detected several cases of diabetes”, Gerada told The Lancet. Part of the clinic’s remit was to improve access of drug users to primary care. Gerada was able to maintain the clinic through her GP training and her first years in practice. She then had to manage an addiction of her own—the desire to combat health inequalities at the coal face. Gerada decided to combine the best of both worlds, by becoming a GP at a multidisciplinary practice at the Hurley Clinic in the Lambeth Borough of London, where she remains a partner today. In this practice, care of families, ministers, and civil servants takes place alongside that of drug addicts and people with severe mental health disorders. Gerada’s first night on call saw her visit a Member of Parliament and a patient living in a squat in successive home visits. Those early years as a GP also saw her set up a specialist service for pregnant drug users and an inter-practice liaison service for mental health issues. “I think we changed the way substance misuse was managed in this country”, says Gerada. Mark Ashworth, a partner at the Hurley Clinic, describes Gerada as an innovator who is now a household name in the world of primary care substance abuse. As an example of one of Gerada’s many innovative projects for the practice, Ashworth explains that www.thelancet.com Vol 377 January 1, 2011

“We now employ six teachers in a project called the Health Education Links Team. This team goes into local schools with a health education message, a project that started from Clare’s observation of how little professional exchange there was between local teachers and GPs.” Since becoming a GP in 1990, Gerada has hailed the job as “everything I had ever wanted it to be and much more”. She started just after a controversial new contract for GPs in the UK. Out-of-hours care was then the responsibility of GPs, but this meant that many doctors would need to work through the night and into the next day, leaving some of them exhausted. The new contract in 2004 saw local primary care trusts take over responsibility for this service using co-operative models with certain practices on call, but although some areas had enough doctors many others were underserved. Gerada hopes that new health reforms proposed by UK Health Secretary Andrew Lansley “will return responsibility for commissioning out-of-hours care back to GPs but in a sustainable way”. As for the other reforms, Gerada is positive about GPs commissioning local services and increased involvement of patients in decision making. She also favours reduced bureaucracy, and hails the advent of the paperless GP surgery earlier this century as a real watershed moment in the profession. But introducing a direct performance-related incentive—for example, to keep patients out of hospital— would immediately, Gerada believes, introduce a conflict of interest into patient consultations. She also thinks that “too much will be changing too fast, whatever the merits of the individual changes”, and that GP training should be extended from 3 years to 5 years to help cover all the skills required. “If we really want to make a difference to the communities we serve, we need to build in time to go out into the community and find the problems before they find us.” She gives the examples of targeting high hypertension rates among Afro-Caribbean men and high diabetes rates in Asian populations, as well as breakfast clubs, parenting classes, and school clinics to keep people healthy, all this as the demands of an ageing population also mount on general practice. “The future cannot just be about quicker access to tests”, says Gerada. “A mother being given parenting and cookery classes to prevent obesity in her family could be just as important.” She hopes the forthcoming Health Bill from the UK Government will allow the seeds for these issues to be sown. “Ultimately, these new GP commissioners, when appointed, will need to be brave and look beyond the surgery for the future of general practice”, says Gerada.

RCGP

Profile Clare Gerada: Chair of UK’s Royal College of General Practitioners

See Online for webvideo

Tony Kirby [email protected]

21

Perspectives

The art of medicine Of wandering doctors, cities, and humane hospitals

Marek H Dominiczak

Legend has it that on the island of Kos in Greece, Hippocrates taught his pupils under a plane tree. There is something symbolic in the simplicity of such a depiction. It reminds one that doctors have often been wanderers, not bound to particular locations or buildings. They went out to see the sick in their own surroundings. Of course, the sick have always needed shelter and respite space. However, as more complex medical procedures developed, specific space was also required to perform them. Thus the respite and treatment strands converged on an architectural platform and, with time, led to the development of modern hospitals. The contemporary debate about what constitutes an optimum healing space to a large extent relates to the balance between the shelter-respite and the active treatment-related functions. This essay attempts to trace key historical developments of healing spaces. While early doctors were wanderers, spiritual healers often were not. A temple had been the dominant architectural form in human communities long before Hippocratic medicine, and indeed before the rise of European culture. In ancient Greece, healing was linked to worship: the centres of healing were the temples of the god of health Asklepios, known as Asklepeions. The largest of these were in Epidauros on the Greek mainland, and on the Hippocratic island of Kos. The monumental three-level temple on Kos stood on a hill facing the distant sea. Visitors were admitted at the lower level. They were subsequently taken to the higher terrace with open views, where they were to spend the night and be visited by Asklepios. The Kos Asklepeion very well illustrates the role

Paimio Hospital, Finland, where Alvar Aalto’s concept of total design included interiors, furniture, and utensils

22

of architecture as a framework for a healing ritual, and shows how spectacular blending with surrounding nature enhanced its impact on the “treated”. In the Middle Ages, Christianity, very much in the GraecoRoman tradition, associated worship with monumental architecture. Caring for the sick and the destitute was part of the Christian message of charity. The early “hospitals” sheltered the poor, the pilgrims, and the abandoned children. For the sick, they were places of terminal care rather than of active treatment. They were appended to churches, and particularly to monasteries. The St John Hospital in Bruges founded in 1188 (probably by the city rather than the Church) was such a church-like building: by the 15th century it had three halls containing “patient” cubicles and the church space, which was an integral part of the hospital. The main altar painted by Hans Memling was visible from the wards. Prayer was a dominant part of the healing process. Subsequently, the ownership of more institutions became secular. In the Catholic city states, a city often owned hospitals jointly with the Church. In England, dissolution of the monasteries during the Reformation of 1536–41 forced a change of ownership. In London, St Bartholomew’s Hospital (founded in 1123) and three others were granted by King Henry VIII to the City of London in 1546. City hospitals were often prominent public buildings. In Siena, the Santa Maria della Scala Hospital faces the cathedral across the main square. In Florence, the Foundling Hospital designed by Filippo Brunelleschi in 1419 is an outstanding example of renaissance architecture. The next major change in thinking about hospitals took place in the 18th century. It followed the Enlightenment emphasis on rationality, science, and nature. Later, during a reform of hospitals in France, their improvement amounted largely to the architectural redesign, particularly the introduction of pavilion structure, first in the Hôpital Lariboisiere, opened in Paris in 1854. This created a more open space that improved ventilation and access. Interestingly, the pavilion design later provided a framework for separate housing of emerging medical specialties. A true revolution in the concept of the hospital was caused by the accelerating progress of medical science in the late 18th and the 19th century. Hospital-based care maximised the medical experience by bringing together patients with similar conditions, facilitating statistical assessment, and—importantly—making clinical teaching possible. Thus, scholars entered hospitals, which became major sites of medical research on a trajectory rising until the late 20th century. A parallel, and complementary contribution to hospital design in the 19th century was the work of Florence Nightingale (1820–1910) and her nursing colleagues who www.thelancet.com Vol 377 January 1, 2011

Perspectives

reorganised hospital wards by applying the concepts of cleanliness and antisepsis, after spectacular results achieved at a field hospital in Scutari in 1854, during the Crimean War. The new science needed specialised spaces: laboratories gradually became part of hospitals, and the main dwelling places of scientists. This had a major influence on the architectural shape of hospitals—they became buildings with wards at the core, surrounded by increasingly complex support structures. In the early modernist period architecture gained increasing importance as a tool for social change. Architects such as Charles Edouard Jeanneret (1887–1965), better known as Le Corbusier, developed comprehensive plans for cities with new “division-of-function” layouts. Le Corbusier was fascinated by industrial buildings, processes, and mass production. He famously named his Unité d’Habitation (housing unit) in Marseille built in 1947–52 a “machine for living”. In addition, the “organic” architecture of Charles Rennie Mackintosh (1868–1928), Frank Lloyd Wright (1867-1959), and Antoni Gaudi (1852–1926) achieved new sophistication in manipulating textures and materials, and fusion of architecture with the natural environment. The emphasis on access to natural light and to surrounding nature became the hallmark of modernism— neutralising to an extent the effects of stern functionality. Within health care, this was particularly applicable to tuberculosis sanatoria built in the early 20th century, to allow patients ample access to fresh air, which was at that time regarded as a therapeutic measure. An extraordinary healing space implementing these principles was designed by a Finnish architect Alvar Aalto (1898–1976), in Paimio near Turku. His building was integrated with the surrounding forest but in addition Aalto applied the concept of total design that included the building, the interiors, and even small utensils. The hospital still functions as a health-care unit; it recently became a UNESCO World Heritage Site. In contrast to the sanatoria, the architecture of urban hospitals became increasingly determined by limited space and rising maintenance costs. The minimalist skyscraper, which turned out to be the most economical form of a building, was eventually widely used in hospital architecture. A “tower and podium” hospital evolved, with a ward tower and the podium containing support services. In these technically complex structures, the therapeutic functions, in a continuation of modernist zeal, had had unqualified priority, while the respite function withered. Architecturally, the undiluted functionality often created rather sinister structures, which the architect Markus Schaefer has said “neglected basic human needs”. Schaefer has suggested that “the hospital building stripped the patient of her privacy and individuality, the healing machine of her body”. Hospital space became increasingly perceived by patients and visitors as overwhelming, incomprehensible, and even threatening. Retrospectively, it was an astonishing lack of cultural balance. One could argue that the neglect of humane aspects www.thelancet.com Vol 377 January 1, 2011

of hospitals had roots in the rather insensitive nature of modernist science. One also wonders whether the postFlexnerian, strongly focused view of medical science that became a mantra of medical education in the 20th century had an effect here. Or was it the disengagement of the arts and humanities from the medical landscape? The end of the 20th century saw some change, with increasing emphasis on individual rights and the contextualisation of medicine. These ideas influenced the design of a new generation of hospital spaces—all in the context of consumer culture and aesthetics. Also at that time, an application of scientific method to hospital architecture emerged in the form of evidence-based design. A seminal paper by R S Ulrich, published in Science in 1984, showed that access to natural light improves patients’ recovery after surgery. There is now a substantial body of evidence that relates aspects of design to outcomes such as patient safety, infections, medical errors, falls, pain, sleep, depression, and length of hospital stay. Thus, in the context of individual rights, privacy, openness, and also aesthetics sparked by consumerism, architecture returns again to a prominent role: it becomes an advocate of cultural trends, which require an adjustment of architectural spaces beyond their functionality. Openness and clarity of structure become paramount for a hospital, not only from a functional but also from a cultural point of view. The challenge is to achieve this in a sustainable way while also allowing for future morphing of hospital spaces in response to medical science-driven requirements. There is a serious cultural role for a health-care facility in the contemporary world. A modern hospital can potentially enhance inclusiveness and social cohesion. The Philips Index: America’s Health and Well-Being Report 2010 has shown that inhabitants rank the access to local hospitals as the most important factor related to wellbeing after safety and crime rate. The quality of health care was also a factor in the recent international Livable Cities survey—therefore it has an impact on the global “status” of cities, their attractiveness, and consequent investment prospects. What about the medical world? Since hospital spaces have both a functional and cultural meaning, they deserve more mention in medical education. At the University of Glasgow Medical School we have recently introduced an interdisciplinary teaching module on hospital spaces as part of the medical humanities teaching programme. Doctors started as wanderers—however, today, many wander no more. And they need to be aware of their dwellings. This essay is based on the Presidential Address I gave to the Royal Medico-Chirurgical Society of Glasgow in October, 2010.

Marek H Dominiczak College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK [email protected]

Further reading Cox M, Irby DM. American Medical Education 100 years after the Flexner Report. N Engl J Med 2006; 355: 1339–44. Dominiczak MH. Medicine, architecture and the arts. Opportunities for dialogue. In: Law A, ed. Space to heal. Edinburgh: Sleeper Publications, 2009, 5–21. Schaefer M. Building hospitals— hospital buildings. Rotterdam: The Berlage Institute, 2005. Ulrich RS. View through a window may influence recovery from surgery. Science 1984; 224: 420–21. Ulrich RS, Zimring VC, Zhu X. A review of the research literature on evidence-based healthcare design. Healthcare Leadership White Paper Series. Atlanta GA: Georgia Institute of Technology, 2008. Philips Index: America’s Health and Well-being Report 2010. http://www.newscenter.philips. com/pwc_nc/main/standard/ resources/corporate/press/2010/ Philips_index/The_Philips_ Index_Americas_Health_and_ Well-being_report.pdf (accessed Dec 14, 2010).

23

Corbis

Obituary

Frank John Fenner Australian virologist who had a leading role in the global eradication of smallpox and the use of myxomatosis to control rabbits in Australia. Born on Dec 21, 1914, in Ballarat, Australia, he died on Nov 22, 2010, aged 95 years. It was the summer of 1951, and the Australian media were in an uproar. Myxoma virus, which scientists hoped would control the country’s rabbit plague, had escaped into the wild. Within weeks, millions of rabbits had died across the Murray-Darling Basin. This was good news. The trouble was that an outbreak of human encephalitis had sprung up in the same region at the same time. Was the same virus infecting human beings and rabbits? Scientists working under Sir Frank Macfarlane Burnet, the head of Melbourne’s Walter and Eliza Hall Institute, quickly established that the two diseases weren’t connected, but the message didn’t seem to be getting through to the public. The chairman of a local hospital challenged Burnet to test the harmlessness of the virus on himself, so he turned to an expert in poxviruses who had previously worked at the Hall Institute, Frank Fenner. “Burnet consulted me and we decided that it was absolutely safe”, Fenner wrote in an autobiography. “I prepared a suspension and injected Burnet subcutaneously with one, 10 and 100 rabbit-infectious doses; Burnet inoculated me…none of us showed lesions or an antibody response…and the public was reassured.” This straightforward retelling of a dramatic national moment is classic Fenner. As a major figure in 20th-century Australian science and a prolific writer, he was a man whose style focused more on facts than personal drama. “Frank was a 24

fascinating character”, says Ian Gust, a medical virologist who was the research and development director for the medicinal products manufacturer, CSL Limited. “He was not only a great historian of virology, but he was also the history.” After time as a medical resident at Adelaide Hospital and completing a diploma of tropical medicine, Fenner enlisted in the Royal Australian Army Medical Corps in 1940. During the war, he served in New Guinea as a malariologist and was made a Member of the Order of the British Empire for his important role in controlling the disease among troops. Immediately after the war, he accepted a position at the Walter and Eliza Hall Institute, where he took up Burnet’s suggestion and began studying mousepox. “Frank was a great basic scientist in the field of virology”, says Sir Gustav Nossal, who became the head of the Hall Institute in 1965 when Burnet retired. “His landmark studies were on mousepox. He investigated everything to do with how the mousepox virus behaves in the body of the mouse, the totality of the epidemiology, clinical features, the spread, the way it multiplies. Those were really landmark studies.” After a fellowship at the Rockefeller Institute in New York, Fenner was invited by Nobel laureate Howard Florey to head the department of microbiology at the Australian National University’s newly established John Curtin School of Medical Research. He would work there until 1967, during which time myxomatosis was his main research subject. “What Frank did was to study in meticulous detail the myxomatosis epidemic that ran through Australia and in particular chart the changes in both virus and host—the virus mutating and the rabbits being so decimated by the disease”, said Nossal. In 1967, he was appointed director of the John Curtin School, a post he held until 1973 when he put medical research aside to set up a new Centre for Resource and Environmental Studies. “The thing about Frank was that he was extremely organised, and that’s why he was so effective at setting things up”, said Professor Peter Doherty, who won a Nobel Prize for research conducted at the John Curtin School. “In science, good institutions are very important, and he was important in setting up good institutions.” Fenner’s organisational skills also played a vital part in ending smallpox as a human problem. He served as chairman of the Global Commission for the Certification of Smallpox Eradication, a body set up to confirm the work of WHO’s mammoth eradication programme. In May, 1980, he presented a report to the World Health Assembly stating that the effort had been successful. “He was the prince of Australian virologists”, said Nossal. “He was a modest and self-effacing person, steady and steadfast, and just absolutely focused and systematic.” Fenner is survived by his daughter, Marilyn, two grandchildren, and a great-grandchild.

Stephen Pincock [email protected]

www.thelancet.com Vol 377 January 1, 2011

Correspondence

that sucrose has long-term negative effects.5 We agree with Slater and colleagues that every effort should be made to minimise nociceptive pathway activation in infants.

Rebeccah Slater and colleagues (Oct 9, p 1225)1 question the benefit of sucrose for alleviating procedural pain in infants. We believe that they might have overstated their conclusions and suggest a more cautious interpretation of the study findings. In agreement with other studies,2 Slater and colleagues report a significant reduction in observed pain scores in infants given sucrose compared with placebo. An intriguing observation was the absence of any difference in nociceptive pathway activity in infants who received sucrose or placebo. On this basis, Slater and colleagues conclude that oral sucrose is ineffective for pain relief in infants, and discourage its routine use in infants. We disagree that the documented cortical measures are a reliable surrogate of perceived pain in infants. The WHO definition of pain refers to the subjective and emotional experience being of primary importance. Our access to infants’ emotions is through their behaviour. The fact that “pain pathway nerves” are active during procedures in infants who are calm after sucrose is not unexpected. We disagree that a reduction in clinical observation scores should not be interpreted as pain relief. Limitations of the study include the small sample size and that electrophysiological monitoring was limited in spatial and temporal domains. The effect of sucrose on neural pathways of the brain relevant to emotional responses to pain was not investigated. Whether a blunting of the behavioural response to pain reduces the adverse effects of nociceptive pathway activation remains to be determined.3 Substantial media interest has been generated, questioning the safety of sucrose administration on the developing brain.4 There is no evidence

We declare that we have no conflicts of interest.

www.thelancet.com Vol 377 January 1, 2011

D Steed, L Port, *T G Connell, J Standish, J Munro, L Takacs, I McKenzie [email protected] Department of General Medicine (DS, LP, TGC, JS, JM) and Comfort Kids Program, Department of Anaesthesia and Pain Management (LT, IM), Royal Children’s Hopital Melbourne, Parkville, Melbourne, VIC 3052, Australia 1

2

3

4

5

Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376: 1225–32. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2010; 1: CD001069. Hohmeister J, Kroll A, Wollgarten-Hadamek I, et al. Cerebral processing of pain in school-aged children with neonatal nociceptive input: an exploratory fMRI study. Pain 2010; 150: 257–67. Campbell D. Newborn babies should not be given sugar as pain relief, says study. The Guardian Sept 2, 2010. Stevens B, Yamada J, Beyene J, et al. Consistent management of repeated procedural pain with sucrose in preterm neonates: is it effective and safe for repeated use over time? Clin J Pain 2005; 21: 543–48.

Practitioners should disregard the advice of Rebeccah Slater and colleagues1 that sucrose “should not be used routinely for procedural pain in infants”. Such a change in practice would be a retrograde step in the struggle to provide optimum care for newborn infants, and is not supported by the study itself nor the references they quote. Slater and colleagues state that there is “absence of evidence for an analgesic action of sucrose in this study”. Analgesia is defined as “absence of pain in response to stimulation which would normally be painful”. Seven of 20 “facial non-responders” in the sucrose group seem to have had an analgesic action, particularly given that none of the 24 participants in the sterile water group exhibited this effect. Slater and colleagues speculate that this effect of sucrose could occur

at the midbrain owing to its ability to “inhibit facial motor activity”. “Absence of evidence of effect in this study”, does not mean evidence of absence of true effect. The study was designed with a power of 80%, meaning that the probability of missing a true effect is 20%. Slater and colleagues define a drop of 30% amplitude during a 450–750 ms section of their EEG data as clinically significant, yet do not explain why. Furthermore Slater and colleagues do not explain adequately why they analysed only a 300 ms section of their data; there does seem to be a visible difference in the trace with sucrose compared with water at 750–950 ms. This might support the notion that there is indeed a nociceptive response with sucrose. The question remains: does EEG nociceptive-specific brain activity at a particular locus during a specific time in the presence of oral sucrose mean that the child had pain but could not express it; or has the child received the signal from the heel but not perceived it as pain and therefore not expressed pain behaviour? A further important question: is it the nociception or the subsequent cortical pain response that leads to long-term sequelae, and how might sucrose modify this response?

Science Photo Library

Oral sucrose for procedural pain in infants

We declare that we have no conflicts of interest.

Paul A Heaton, *Andrew M Fernando, David Herd [email protected] Yeovil District Hospital, Higher Kingston, Yeovil BA21 4AT, UK (PAH, AMF); and Mater Children’s Hospital, Raymond Terrace, South Brisbane, QLD, Australia (DH) 1

Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376: 1225–32.

Rebeccah Slater and colleagues1 report that oral sucrose did not diminish localised brain activity (electroencephalography [EEG]) and a spinal nociceptive reflex (electromyography [EMG]) after heel lance. Conversely, sucrose significantly reduced behavioural expressions, consistent with a Cochrane review.2 We consider the

Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/

25

Correspondence

conclusion, “sucrose should not be used routinely for procedural pain in infants without further investigation”1 unjustified. The selected indices did not recognise pain as engaging widely distributed, serial and parallel, dynamic activation in multiple areas of the brain.3,4 EEG activity was reported for only one of 32 recording electrodes, and thus did not address multiple brain regions that might have been activated.5 The suggestion of dissociation between brain activity and the experience and expression of pain is reminiscent of Descartes’ dualism. The intervention clearly affected behaviour, with the neural measures not identifying the biological substrate. Other methodological issues could account for differences between the neural and behavioural measures. The single control procedure was not randomly ordered. Only 44 of 59 infants were included in the analysis of EEG and premature infant pain profile (34 of 59 in the EMG analysis). These 25% and 42% attrition rates, respectively, might have eliminated infants with vigorous facial displays contributing to dissociation between measures. Although infant pain assessment is imperfect and imprecise, caution should prevail concerning conclusions on well supported pain-relieving strategies. Because one selected measure of neural activity was not responsive to sucrose does not preclude other measures from being responsive. Researchers and clinicians have an ethical responsibility to consider oral sucrose for painful procedures, while doing further effectiveness research using validated cognitive and behavioural assessment measures. We declare that we have no conflicts of interest.

*Bonnie Stevens, Kenneth Craig, Celeste Johnston, Denise Harrison, Arne Ohlsson [email protected] Centre for Nursing, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (BS); University of British Columbia, Vancouver, BC, Canada (KC);

26

McGill University, Montreal, QC, Canada (CJ); Royal Children’s Hospital, Melbourne, VIC, Australia (DH); and University of Toronto, Toronto, ON, Canada (BS, AO) 1

2

3

4 5

Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376: 1225–32. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2010; 1: CD001069. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000; 288: 1769–72. Tracey I. Imaging pain. Br J Anaesth 2008; 101: 32–39. Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical representation of the sensory dimension of pain. J Neurophysiol 2001; 86: 402–11.

in the context of conclusions were premature infant pain profile and facial expressions, both of which were affected by sucrose, as shown in many earlier studies.5 Development of objective physiological tools for assessment of neonatal pain is a major endeavour, which calls for careful and solid reasoning. Advanced-looking tools might bring a high-impact audience to old discoveries. However, use of unfounded tools will readily bring unsound conclusions, which might sooner or later become counterproductive to the field itself. I declare that I have no conflicts of interest.

Rebeccah Slater and colleagues1 studied the effect of sucrose in treating neonatal pain, and they conclude that “oral sucrose does not significantly affect activity in neonatal brain or spinal cord nociceptive circuits, and therefore might not be an effective analgesic drug”. The neurophysiological data considered by Slater and colleagues as the primary outcome measure do not really provide a physiologically sensible bridge to their conclusions. Slater and colleagues call their electroencephalography (EEG) response a “specific nociceptive brain activity”, because they earlier showed it to come after heel lance but not after a tactile touch. It is obvious that a heel lance also results in arousal,2 causing a comparable scalp response, which can even be seen after an auditory stimulus.3 Hence, the EEG response seen by Slater and colleagues is not proven to be specific to the noxiousness of the stimulus. Slater and colleagues also measured spinal reflexes as the other index of pain response. As every neurologist would expect, spinal reflexes to noxa are not affected by sucrose, which naturally works at supraspinal level. The immaturity of descending inhibition4 makes this approach particularily poor in neonates, and useless with respect to Slater and colleagues’ conclusions. The sound measures

Sampsa Vanhatalo sampsa.vanhatalo@helsinki.fi Department of Children’s Clinical Neurophysiology, PO Box 280 (Lastenlinnantie 2), 00029 Helsinki, Finland 1

2

3

4 5

Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376: 1225–32. Norman E, Rosén I, Vanhatalo S, et al. Electroencephalographic response to procedural pain in healthy term newborn infants. Pediatr Res 2008; 64: 429–34. Hrbek A, Hrbkova M, Lenard H-G. Somato-sensory, auditory and visual evoked responses in newborn infants during sleep and wakefulness. Electroencephalogr Clin Neurophysiol 1969; 26: 597–603. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci 2005; 6: 507–20. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2010; 1: CD001069.

Rebeccah Slater and colleagues1 conclude that “oral sucrose does not significantly affect activity in neonatal brain or spinal cord nociceptive circuits, and therefore might not be an effective analgesic drug”. In the Summary, they state that “59 newborn infants…were randomly assigned to receive 0·5 mL 24% sucrose solution or 0·5 mL sterile water 2 min before undergoing a clinically required heel lance.” In two previous systematic reviews about sucrose,2,3 the single dose commonly used was 2 mL in full-term and preterm infants and 0·5 mL per kg for www.thelancet.com Vol 377 January 1, 2011

Correspondence

We declare that we have no conflicts of interest.

*Maria Beatriz Martins Linhares, Cláudia Maria Gaspardo, Francisco Eulógio Martinez [email protected] Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14024250, Brazil 1

2

3

4

Slater R, Cornelissen L, Fabrizi L, et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 2010; 376: 1225–32. Gaspardo CM, Linhares MBM, Martinez FE. The efficacy of sucrose for the relief of pain in neonates: a systematic review of the literature. J Pediatr (Rio J) 2005; 81: 435–42. Stevens B, Yamada J,Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2010; 1: CD001069. Gaspardo CM, Miyase CI, Chimello JT, Martinez FE, Linhares MBM. Is pain relief equally efficacious and free of side effects with repeated doses of oral sucrose in preterm neonates? Pain 2008; 137: 16–25.

Authors’ reply Given the importance of pain and pain relief in clinical practice, the area is extraordinarily poorly understood— nowhere more so than in the infant population. Noxious procedures are repeatedly performed on infants in hospital, and the short-term and long-term consequences of this are of increasing concern.1 Current clinical assessment of infant pain, such as the premature infant pain profile (PIPP), makes use of indirect www.thelancet.com Vol 377 January 1, 2011

methods that have not been validated against other objective independent measures. Despite this lack of validation, these measures are widely used as a measure of “infant pain” and, on the basis of these measures, application of a sweet solution to the infant’s mouth is thought sufficient to alleviate procedural pain. D Steed and colleagues’ claim that “access to infants’ emotions is through their behaviour” is not supported by mechanistic data or hypothesis. The acceptance of such claims will deflect attention from the profound activity-dependent changes in brain development that noxious stimulation can evoke and from asking how this can be prevented. In our study, we showed that activity in the brain after a noxious procedure is not affected by sucrose, despite the well documented effects of sucrose on facial expression. It is fact, not speculation as Paul Heaton and colleagues claim, that sucrose can reduce pain-related behaviour through brainstem mechanisms.2 We therefore challenge the community to question whether infants who receive sucrose really are adequately relieved of their pain and, more importantly, adequately protected from the potential adverse effects that pain might cause to the developing nervous system. Our electroencephalography (EEG) recordings were not used (as suggested by Bonnie Stevens and colleagues) to localise brain activity but to detect real-time nociceptive-specific activity in the brain. We recorded from 32 electrodes and, because the nociceptive-specific potential is maximal at the midline,3 we used the signal at a single central electrode as an outcome measure. Furthermore, we disagree with Heaton and colleagues that our decision to focus on the EEG activity in the time-window from 450 to 750 ms after stimulation is not justified: this study, as well as our previous publications, show that nociceptive-specific brain activity is present during this time frame.3

The nociceptive-specific potential cannot be compared to the “arousal” responses referred to by Sampsa Vanhatalo: they are not statedependent and have different amplitude, latency, and morphology. They cannot easily be seen by use of frequency analysis of non-timelocked EEG, which, in the study by Norman and colleagues,4 revealed only muscle activity. Thus by use of careful and rigorous (albeit novel) experimental analysis, we have identified a nociceptive potential that can be used to explore analgesic regimens and improve the experience of infants in hospital. Our paper did not show that sucrose was positively harmful and we have no evidence that this is the case (as was erroneously suggested in the press). One might question the wisdom of giving the equivalent of a “half can of Coke Classic per day”5 to infants in the name of analgesia when activation of the brain goes on unabated. There is also a distinct possibility that the routine use of sucrose has led to other potentially effective analgesic strategies (for example “kangaroo care” or pharmacological approaches) being neglected. What our study did show is that we cannot afford to make assumptions about analgesia simply because of an unfounded belief that the PIPP score taps into the infant “pain experience” when direct measurements from the infant brain are telling another story.

Science Photo Library

repeated doses in preterm infants. In our study,4 we tested the efficacy of oral sucrose 2 min before puncture for blood collection in preterm infants using the 0·5 mL/kg dose. Considering that participants in Slater and colleagues’ study were full-term infants with a mean birthweight of 3449 g (SD 453), the question is whether the single dose of 0·5 mL used was sufficient to obtain analgesia. We suggest that this methodological question should be addressed in future studies before concluding that “the ability of sucrose to reduce clinical observational scores after noxious events in newborn infants should not be interpreted as pain relief”.1

We declare that we have no conflicts of interest.

*Rebeccah Slater, Stewart Boyd, Judith Meek, Maria Fitzgerald [email protected] Nuffield Department of Anaesthetics, University of Oxford, Oxford, UK (RS); Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK (RS, MF); Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children, London, UK (SB); and Elizabeth Garrett Anderson Obstetric Wing, University College Hospital, London, UK (JM) 1

Anand KJ, Aranda JV, Berde CB, et al. Summary proceedings from the neonatal pain-control group. Pediatrics 2006; 117 (3 Pt 2): S9–22.

27

Correspondence

2

3

4

5

Anseloni VC, Ren K, Dubner R, Ennis M. A brainstem substrate for analgesia elicited by intraoral sucrose. Neuroscience 2005; 133: 231–43. Slater R, Worley A, Fabrizi L, et al. Evoked potentials generated by noxious stimulation in the human infant brain. Eur J Pain 2010; 14: 321–26. Norman E, Rosén I, Vanhatalo S, et al. Electroencephalographic response to procedural pain in healthy term newborn infants. Pediatr Res 2008; 64: 429–34. Holsti L, Grunau RE. Considerations for using sucrose to reduce procedural pain in preterm infants. Pediatrics 2010; 125: 1042–47.

Corbis

International response to Niger’s hunger crisis

For The Lancet’s Series on maternal and child undernutrition see http://www.thelancet.com/ series/maternal-and-childundernutrition

28

Samuel Loewenberg’s World Report entitled “Niger’s hunger crisis: a legacy of lessons unlearned” (Aug 21, p 579)1 paints an unfair picture of the international community’s response to last year’s food crisis in Niger. It is regretful that Loewenberg was not able to reflect more accurately the extensive international and European mobilisation to mitigate the effect of this crisis. The risk of a food crisis in the Sahel was identified as early as September, 2009, once it was clear that the erratic rains in July and August, 2009, would negatively affect the size of the harvest. The European Commission started working with the local authorities and with international non-governmental organisations, the Red Cross, and UN partners to raise awareness and mobilise support. It made available in late 2009 a first allocation of €10 million to assist partners in mitigation and preparedness action. Our financial support was stepped up as the food crisis worsened and continued high food prices pushed many households over the edge into crisis. In total, the Commission allocated €108·9 million in humanitarian assistance to address the situation and was instrumental in mobilising further international support through a “Friends of the Sahel” network.

Our funding helped to ensure the large-scale availability and distribution of special ready-to-use therapeutic foods, such as PlumpyNut (which had proven to be so effective in 2005), and supported blanket feeding operations to reach as many children at risk as possible. We actively encouraged the large-scale use of direct cash transfers to the most vulnerable, which was instrumental in ensuring that food remained available in local markets, albeit at a high price. We also sought to facilitate food purchases in the countries of the region, where possible, which provided an incentive to local production. In doing so, we have put into practice the lessons learned from the 2005 Niger food crisis—which were also reflected in The Lancet Series on undernutrition, published in 2008. There can be no doubt that many tens of thousands of lives were saved as a result. These actions were additional to the Commission’s existing long-term strategy to promote nutritional security in the Sahel. The Commission had adopted in 2007 a Sahel strategy based on the three pillars of improving the knowledge base; providing support for pilot, innovative, and replicable action to reduce undernutrition; and advocacy to raise awareness in government and development partners on nutrition issues. The effect of this strategy is starting to show in the increased importance given to food and nutrition security by government and development partners in the region and by the speed in which partners responded to the risks caused by last year’s crisis. This is not to say that everything has been perfect, but we have striven to learn from the past and to apply more modern and efficient methods. And this deserves some acknowledgment. I am the European Union’s Commissioner for International Cooperation, Humanitarian Aid and Crisis Response.

Kristalina Georgieva [email protected] European Commission, 1049 Brussels, Belgium 1

Loewenberg S. Niger’s hunger crisis: a legacy of lessons unlearned. Lancet 2010; 376: 579–81.

The Greek economic crisis: a primary health-care perspective The Greek economic crisis has caused global concern owing to its sideeffects and risks involved for both the eurozone and the global economic community. Analysis of the problem shows that the major sources of inadequacy are the severe structural weaknesses in Greek public administration, economy, and society, which lead to bureaucracy, corruption, low quality of services, and high costs. Greek health care is a typical example of a bleeding economic sector. Although the total health-care expenditure rose from 5·3% of gross domestic product in 1991 to 9·7% in 2008, Greece has actually got worse in terms of global health outcomes.1 Why is that? Administrative barriers affect every aspect of the Greek healthcare system, with perhaps the largest insufficiencies located in primary care.2 In general, Greek primary care is highly fragmented, since there are several different public and private providers involved, with no coordination between them and no gatekeeping system.3 Some of the main reasons for the high primary health-care costs are the repetition of tests and prescriptions due to poor information transfer between providers and the vast induced demand for health-care services. The latter is perhaps the most important factor and can be explained by the large number of specialists—the highest among countries of the Organisation for Economic Cooperation and Development—and the www.thelancet.com Vol 377 January 1, 2011

Correspondence

ineffectiveness of the existing control mechanisms of health insurance funds who incur the costs.4 We strongly believe that the above problems could be addressed by ensuring adequate political will and social consensus. The integration of all primary-care providers, the establishment of the multidisciplinary primary-care team, and the enactment of the family doctor institution are necessary to obtain comprehensive, continuous, and efficient health care.5 The introduction and implementation of diagnostic and treatment guidelines in daily clinical practice could result in a better quality of care and a rationalisation of health-care expenditure. The induced demand for medical services seems an intractable problem, but might be controlled by a reduction in the production of new physicians. Greece is struggling to manage its fiscal problems, overcome recession, and maintain a social welfare state. To achieve these goals and get out of the crisis, it is time for Greece to capitalise on moral, economic, political, and scientific support from international bodies and advanced nations by making drastic organisational reforms in all aspects of the public sector, including health care. We declare that we have no conflicts of interest.

*Nikolaos Oikonomou, Yannis Tountas [email protected] Centre for Health Services Research, Medical School, University of Athens, 115 27 Athens, Greece 1 2

3

4

5

OECD. OECD health data 2010. Paris: OECD, 2010. Tountas Y, Karnaki P. The ‘‘unexpected’’ growth of the private health sector in Greece. Health Policy 2005; 74: 167–80. Mossialos E, Allin S, Davaki K. Analysing the Greek health system: a tale of fragmentation and inertia. Health Econ 2005; 14 (suppl 1): S151–68. Oikonomou N, Mariolis A. Three trends that undermine the Greek health system: is there a way out? Eur J Gen Pract 2009; 15: 67–68. Lionis C, Symvoulakis EK, Markaki A, et al. Integrated primary health care in Greece, a missing issue in the current health policy agenda: a systematic review. Int J Integr Care 2009; 9: e88.

www.thelancet.com Vol 377 January 1, 2011

When will the sun shine on Cyprus’s National Health Service? It has been 9 years since an official parliamentary law was passed in Cyprus to implement a primarycare-driven health-care coverage system for the entire population. Since then, the Health Insurance Organisation has been set up as the single payer, which, in collaboration with McKinsey consultants, has brought forth a detailed design for the long-awaited Cyprus National Health Service (NHS). However, despite the project reaching its final stages, a cloud of doubt remains over whether the government will take the plunge and implement what it has so carefully planned. Little has changed since a World Report in The Lancet stated in 2005 that “there has not been sufficient pressure on the government to adopt a universal health plan”.1 Cypriot health care is still divided, with 50% of the population using public healthcare services and 50% private health care. Primary care is underdeveloped, with general practitioners (GPs) comprising only 9·8% of all physicians, and with a decreasing trend.2 This proportion compares with an average of 25·5% for the European Union3 and about 50% for the UK. Patients have often not heard of a “GP”, and certainly not registered with one. Thus, there is commonly no continuity or co-ordination of care. Quality-improvement strategies are lacking.4 The isolation between private and public health care leads to duplication of tests, and of resource use.5 Specifically, the public-sector cost is growing at a double-digit rate, thereby reaching a level in the near future at which the government budget will not be able to sustain it. Furthermore, direct access to specialists often leads to the patient

not having a unified health record; additionally, holistic preventive care often slips through the net. By contrast with other EU countries, Cypriots pay 52% of healthcare cost out-of-pocket (43% of the population pay for private prescriptions). The new NHS proposed for Cyprus aims at equity in finance, universal coverage, shifting of service provision from secondary to primary care, efficiency, high quality standards, and containment of cost through a global budget. Every person will be registered with a personal primarycare physician of their choice. The free choice of specialist physician (public or private) after referral as well as hospital (public or private) will also lie with the patient. We urge the government to take concrete steps towards implementing the health-care reform— ie, finalise the NHS information technology system and GPs’ training tender—thus moving Cyprus’s health care forward while helping to control health expenditure growth. We declare that we have no conflicts of interest.

*George Samoutis, Constantinos Paschalides [email protected] Messinis 3, 2301 Nicosia, Cyprus (GS); and Tiptree Medical Centre, Tiptree, UK (CP) 1

2

3

4

5

Antoniadou M. Can Cyprus overcome its health-care challenges? Lancet 2005; 365: 1017–20. Cyprus Medical Association. Registry of medical specialties in Cyprus. http://www. cyma.org.cy/ (accessed Dec 14, 2010). WHO Regional Office for Europe. European health for all database. http://www.euro. who.int/en/what-we-do/data-andevidence/databases/european-healthfor-all-database-hfa-db2 (accessed Dec 14, 2010). Samoutis GA, Soteriades ES, Stoffers HE, Philalithis A, Delicha EM, Lionis C. A pilot quality improvement intervention in patients with diabetes and hypertension in primary care settings of Cyprus. Fam Pract 2010; 27: 263–70. Andreou M, Pashardes P, Pashourtidou N. Cost and value of health care in Cyprus. Policy paper. Nicosia: University of Cyprus, 2010. http://www.ucy.ac.cy/data/ ecorece/DOP02-10.pdf (accessed Dec 14, 2010).

29

Correspondence

Reporting on the modes of data collection

Science Photo Library

To gather more insight into the methods of data collection currently used in medical research, we analysed research studies published in four high-impact general medical journals and three epidemiological journals in 2008–09.1 Two epidemiologists independently assessed the modes of data collection reported in each research paper. Surprisingly, the proportion of inconsistencies between the two reviewers was high, especially for papers published in general medical journals (about 30%). Further examination revealed that these inconsistencies were mainly due to unclear reporting of the methods used, with phrases such as “Information was collected on [list of variables]”, “Race/ethnicity was assessed by the investigator or study coordinator”, and “Sociodemographic, clinical, treatment (…), and laboratory data are collected” without any specification. Did they use questionnaires or interviews, were any measurements taken, or was it all hearsay? The choice of the method of data collection for a particular study depends on several factors, including, but not limited to, the type of study, sensitivity of the topic of interest, and costs of the measurements.2 Valid measurement of exposures, outcomes, and potential confounders is essential in medical research to prevent biased results.3 Since different methods of data collection yield various amounts of measurement error, detailed reporting on the methods used is of great importance to assess the quality of the study by both readers and reviewers or editors. Additionally, an adequate description of the methods of data collection used enables other research groups to replicate the original study. In our view, researchers should improve the description of the modes of data collection used in their studies. 30

In addition, we encourage medical journals to pay more attention to the way in which the methods are reported to improve the possibilities of critical appraisal. We declare that we have no conflicts of interest.

The Lancet has rightly emphasised that authors of papers must make a substantial contribution.3 It is also important that all major contributors are recognised, either as an author or with an acknowledgment.

*Marleen M H J van Gelder, Reini W Bretveld, Nel Roeleveld

I have received payment for lectures or speakers’ bureaux from Dako, Ipsogen, Hammersmith Hospital, and Netherlands Cancer Institute.

[email protected] Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands 1

2

3

Van Gelder MMHJ, Bretveld RW, Roeleveld N. Web-based questionnaires: the future in epidemiology? Am J Epidemiol 2010; 172: 1292–98. Armstrong BK, White E, Saracci R. Principles of exposure measurement in epidemiology. New York: Oxford University Press, 1992. Rothman KJ, Greenland S, Lash TL. Validity in epidemiologic studies. In: Rothman KJ, Greenland S, Lash TL. Modern epidemiology, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2008: 137–46.

Andrew H S Lee [email protected] Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK 1 2

3

Kang S. Anecdotes in medicine—15 years of Lancet case reports. Lancet 2010; 376: 1448–49. Wilson R, Liston J, Cooke J, et al. Clinical guidelines for breast cancer screening assessment. Sheffield: NHS Cancer Screening Programmes, 2005. The Lancet. The role and responsibilities of coauthors. Lancet 2008; 372: 778.

All important contributions to papers should be recognised In her Comment (Oct 30, p 1448),1 Seema Kang discusses Case Reports in The Lancet according to specialty interest and mentions that “more than one specialty might be involved in managing a case”. She comments on the absence of contributions from general practice, but makes no comment on the contribution of other specialities such as radiology and pathology. Many patients require multidisciplinary investigation or management. For example, in the diagnosis of breast disease, the triple approach of clinical examination, radiology, and pathology is recommended.2 Over the past 2 years (November, 2008, to October, 2010) histopathology had an important role in the diagnosis in 36 Case Reports in The Lancet. A histopathologist was an author in 20. In the other 16 there was no apparent recognition of histopathology in terms of authorship or acknowledgment, although it had an essential role in ten and was contributory in six.

Department of Error Tatem AJ, Smith DL, Gething PW, Kabaria CW, Snow RW, Hay SI. Ranking of elimination feasibility between malaria-endemic countries. Lancet 2010; 376: 1579–91—In this Series paper (Nov 6), the fourth sentence under the heading “Estimation of intensity of endemic P falciparum transmission” should have read: “R0 is a measure of maximum potential transmission, and if R0 is 1 or greater, then endemic malaria transmission can be sustained”. Additionally, the title for figure 1 should have read “Categorical map of Plasmodium falciparum reproductive number, PfRc, indicating the extent to which transmission needs to be reduced for elimination”. These corrections have been made to the online version as of Dec 31, 2010. The InFACT Global H1N1 Collaboration. InFACT: a global critical care research response to H1N1. Lancet 2010; 375: 11–13—In this Comment (Jan 2), the name of the third member of the InFACT Global H1N1 Collaboration was misspelled. The correct spelling is “Neill K J Adhikari”. This correction has been made to the online version as of Dec 31, 2010.

www.thelancet.com Vol 377 January 1, 2011

Articles

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials Peter M Rothwell, F Gerald R Fowkes, Jill F F Belch, Hisao Ogawa, Charles P Warlow, Tom W Meade

Summary Background Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events.

Lancet 2011; 377: 31–41

Methods We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries.

See Comment page 3

Results In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68–0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0·66, 0·50–0·87; gastrointestinal cancers, 0·46, 0·27–0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72–0·88, p