- Email: [email protected]
EUROCARE-2: relevance for assessment of quality of cancer services?
Reverse iontophoresis for glucose sensing Constant current source – Cathode
Anode + Hydrogel pad containing glucose oxidase
Sensor electrode Glucose Glucose
Skin
To increase the clinical value of these devices more knowledge is needed—for example, about variations in the temporal relation between blood and interstitial glucose concentrations. Peak glucose concentrations in interstitial fluid may follow 2–45 min after acute increases in blood glucose concentrations.5 However, interstitial glucose concentrations commonly fall before blood-glucose concentrations do,8,9 and offer opportunities for sensors to give early warning of impending hypoglycaemia. John Pickup Department of Chemical Pathology, Guy’s, King’s and St Thomas’ School of Medicine, Guy’s Hospital, London SE1 9RT, UK
Anions (eg, Cl–)
Cations (eg, Na+)
1
2
temperature change and cause the measuring cycle to be skipped if thresholds are exceeded. In the trials, the device was calibrated after a 3 h run-in period by one measurement of capillary blood glucose. Patients with type 1 or 2 diabetes then wore the GlucoWatch for 12 h. There was good tracking of capillary glucose concentrations but with about an 18 min delay between the GlucoWatch and the blood readings. Patients in the studies noted mild skin irritation, oedema, and erythema. FDA approval was granted subject to the provision that patients undergo an extensive educational programme and that the detection and frequency of hypoglycaemia and hyperglycaemia is subjected to postmarketing evaluation. Clearly, further testing and development is required—for example, in the published studies2,3 data from the GlucoWatch were downloaded to a computer for analysis rather than being displayed on the device for the patients to read. At the moment, the device is intended to be an adjunct to standard home blood-glucose monitoring techniques rather than a replacement, but the eventual goal for this and similar glucose sensors must be to provide the patient with real-time blood glucose concentrations and warn about extreme blood glucose values without needing to sample capillary blood. The application of technology to diabetes care seems to be accelerating. The FDA also recently approved (June, 1999) a minimally invasive, transcutaneous glucose sensor (MiniMed Continuous Glucose Monitoring System, Sylmar, CA, USA) to monitor trends in glucose values. This type of device,5,6 which uses an enzyme electrode implanted in subcutaneous tissue and connected to an external monitor, has been undergoing development and testing for many years. The principal difficulties that have prevented clinical application are poor correspondence of tissue glucose values, obtained with sensors calibrated in vitro, with actual plasma glucose concentrations, and unpredictable glucose values.7 This relative “bioincompatibility” is probably the result of several factors, such as coating of the probes with protein, cells, or both, interference from electroactive substances, and changes in the local environment at the site of newly implanted transcutaneous sensors (ie, wound-induced variations in blood flow, cellular and protein accumulation, and glucose and oxygen concentrations). The MiniMed sensor can be worn for up to 3 days. Readings are made every 10 s and averaged over 5 min. As with the GlucoWatch, the MiniMed sensor does not provide the patient with realtime glucose values. At present it is intended to supplement conventional blood-glucose measurement of finger-prick samples.
THE LANCET • Vol 355 • February 5, 2000
3
4
5
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7 8
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Pickup J, McCartney L, Rolinski O, Birch D. In vivo glucose sensing for diabetes management: progress towards non-invasive monitoring. BMJ 1999; 319: 1289. Garg SK, Potts RO, Ackerman NR, Fermi SJ, Tamada JA, Chase H. Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes. Diabetes Care 1999; 22: 1708–14. Tamada J, Garg S, Jovanovic L, Pitzer KR, Fermi S, Potts RO. Non-invasive glucose monitoring: comprehensive clinical results. JAMA 1999; 282: 1839–44. Tamada JA, Bohannon JV, Potts RO. Measurement of glucose in diabetic subjects using noninvasive transdermal extraction. Nat Med 1995; 11: 1198–201. Rebrin K, Steil GM, Van Antwerp WP, Mastrototaro JJ. Subcutaneous glucose predicts plasma glucose independent of insulin: implications for continuous monitoring. Am J Physiol 1999; 40: E561–71. Mastrototaro J, Levy R, Leon-Paul G, White N, Mestman J. Clinical results from a continuous glucose sensor multi-center study. Diabetes 1998; 47 (suppl 1): 61A. Pickup JC. In vivo glucose monitoring: sense and sensorbility. Diabetes Care 1993; 16: 535–39. Thome-Duret V, Reach G, Gangnerau MN, et al. Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observations in blood. Anal Chem 1996; 68: 3822–26. Sternberg F, Meyerhof C, Mennel FJ, Mayer H, Bischof F, Pfeiffer EF. Does fall in tissue glucose precede fall in blood glucose? Diabetologia 1996; 39: 609–12.
EUROCARE-2: relevance for assessment of quality of cancer services? EUROCARE-2 is a study on how 1-year and 5-year survivals from cancer vary between European countries and over time. The data, now available in a 572-page book with accompanying CD-ROM, are well presented graphically and in tables, which caters for users who vary in their depth of interest and reading style.There is no doubt that the data for EUROCARE-2 have been carefully assembled and represent “an unprecedented effort of gathering together, standardizing and analysing cancer registry survival data”.1 The compilers of this work are clearly aware of biases that may arise in the collection of such data, most notably that not all cancers may be reported to cancer registries and that follow-up to confirm survival may be incomplete.They have taken great pains to minimise bias in data collection and to report data on the extent to which their attempts have met with success. They conclude reasonably that any remaining bias is unlikely to explain large differences in cancer survival between European countries. The data will probably be used to judge—or “benchmark”—the quality of health care in the countries surveyed. It is impossible, though, as the researchers point out, to conclude whether differences in outcome are due to differences in quality of care given, in access to care, or in earlier detection. Ignoring these distinctions would enable a general interpretation about how well each of the countries in the study is providing effective health care. However, the interpretation will be based on the assumption that early 427
detection increases longevity, rather than simply adding “lead time”—ie, prolonging survival from the time of diagnosis by increasing the number of years of recognition of disease between screen detection and the usual time of clinical detection.2 The value of early detection is not known for some cancers for which screening has been introduced, such as prostate cancer. Early detection may pick up prostate cancers that are slow growing and “inconsequential”. Because such cancers are unlikely to progress sufficiently to cause death, early detection and treatment will increase survival from time of detection but will not extend life.2 The same may be true for other cancers, such as some breast cancers, although there is evidence that early detection prolongs life for breast cancers overall. The survival rate from prostate cancer is twice as high in some European countries as in others, a difference that could be due simply to the presence of more inconsequential screen-detected cancers in countries with the higher survival rates. Despite these biases, the possibility remains that the discrepancies in survival between European countries found by EUROCARE-2 may still be due to differences in health-care provision. So what should be the next step? Should it be further and more refined comparative analysis of survival data with, for example, inclusion of data on stage and characteristics of health care, to find out the reasons for the differences? There are some insurmountable problems with this approach. For example, stage distribution is not available in EUROCARE-2. Although a major deficiency, it points to the difficulty in collecting data on stage. However, even if stage distribution is included in future data collections, standardisation will be difficult. Even minor staging upward of cancers by advanced technology may increase apparent survival in both the stage from which the cancers are removed and the stage to which they are reallocated.3 Beyond leading to the suggestion that expending more resources on cancer care may improve cancer outcome, will further data collection and analysis be targeted enough to give health-care planners and clinicians the information they need to make decisions? Probably not. What is needed is knowledge now on whether costeffective interventions are being applied, not further comparative survival data in 5–10 years’ time, no matter how refined those data may be. For some cancers, there is a wealth of randomised trials—and systematic reviews based on them—to guide decisions about appropriate care. If the aim is to improve care, why not assess directly the proportion of people within a country who receive appropriate cancer services? For example, instead of more between-country studies of survival from breast cancer, it would be easier and quicker to monitor the proportion of patients who are getting appropriate care and the proportion of women in appropriate age-groups who are undergoing high-quality mammographic screening.4,5 These data will require only small samples and be available quickly. In the longer term, within-country monitoring of trends in breast-cancer mortality will help to show whether the desired effect is being achieved.6 Another example is colon cancer. Evidence of much variation in survival rates from colorectal cancers detected a decade ago and a hypothesis that this difference may have been due to differences in early detection1 are not necessary preludes to using information from existing trials and systematic reviews to decide on the likely size of the effect of screening7 and to consider whether screening should be implemented. Nor are they needed for the assessment of
428
need to increase access to and use of adjuvant therapies for resected, intermediate-stage colorectal cancers, since there is evidence that use of these agents can prolong life.8 Cancer registries can and do provide valuable information on cancer occurrence, causes, and outcome. Their contributions include, for example, the generation of hypotheses about the dietary causation of cancer,9 the supplying of the initial evidence that environmental aflatoxin causes cancer in human beings,10 and the provision of the first reasonably certain evidence that Papsmear screening reduces the incidence of cervical cancer.11 Cancer-registry data are also commonly the starting point for assembling cases for epidemiological studies.12 Survival data from individual registries provide valuable information for clinicians and patients about prognosis. Between-country comparison of cancer survival can raise awareness, commonly quite forcibly, that differences in quality of health care need to be explored and addressed, but such exploration can and should proceed without a wait for these data. Health-care questions should be pro-active and problem-driven—eg, “What are the most effective interventions to prevent or manage cancer and are those effective interventions being implemented?” Questions should not be only reactive and data-driven—eg, “What are the reasons for striking differences in cancer survival?” EUROCARE-2 raises issues of quality of care. They can be addressed now by direct, rapid, and fairly simple approaches focusing more on the processes than the outcomes of care.13 *Les Irwig, Bruce Armstrong Department of Public Health and Community Medicine, University of Sydney, NSW 2006, Australia; Cancer Research and Registers, New South Wales Cancer Council, Sydney 1
2
3
4
5
6
7
8
9
10
11
12 13
Berrino F, Capocaccia R, Esteve J, et al. Survival of cancer patients in Europe: the EUROCARE-2 Study. IARC scientific publications no 151. Lyon: International Agency for Research on Cancer, 1999. Barratt A, Irwig L, Glasziou P, et al. Users’ guides to the medical literature XV11. How to use guidelines and recommendations about screening. JAMA 1999; 281: 2029–34. Feinstein AR, Sosin DM,Wells CK.The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312: 1604–08. Hill D, Jamrozik K,White V, et al. Surgical management of breast cancer in Australia in 1995. Kings Cross, Sydney: NHMRC National Breast Cancer Centre, 1999. Breastscreen Victoria. 1997 Annual Statistical Report. Carlton South Melbourne: Breastscreen Victoria Inc, 1999. Also available on http://www.breastscreen.org.au/publications.htm Kricker A, Farac K, Smith D, Sweeny A, McCredie M, Armstrong BK. Breast cancer in New South Wales in 1972–95: tumor size and the impact of mammographic screening. Int J Cancer 1999; 81: 877–80. Towler B, Irwig L, Glasziou P, Kewenter J,Weller D, Silagy C. A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, Hemoccult. BMJ 1998; 317: 559–65. Clinical Oncological Society of Australia and Australian Cancer Network.The prevention, early detection and management of colorectal cancer. Canberra: National Health and Medical Research Council Clinical Practice Guidelines 1999: 129–33. Also available at: http://www.health.gov.au/nhmrc/publicat/pdf/cp62.pdf Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 1975; 15: 617–31. Peers F, Bosch X, Kaldor J, Linsell A, Pluijmen M. Aflatoxin exposure, hepatitis B virus infection and liver cancer in Swaziland. Int J Cancer 1987; 39: 545–53. Hakama M. Trends in the incidence of cervical cancer in the Nordic countries. In: Magnus M.Trends in cancer incidence: causes and practical implications.Washington: Hemisphere Publishing Corporation, 1982: 279–92. Armstrong BK. The role of the cancer registry in cancer control. Cancer Causes Control 1992; 3: 569–79. Irwig L, Zwarenstein M, Zwi A, Chalmers I. A flow diagram to facilitate selection of interventions and research for health care. Bull World Health Organ 1998; 76: 17–24.
THE LANCET • Vol 355 • February 5, 2000
Anode + Hydrogel pad containing glucose oxidase
Sensor electrode Glucose Glucose
Skin
To increase the clinical value of these devices more knowledge is needed—for example, about variations in the temporal relation between blood and interstitial glucose concentrations. Peak glucose concentrations in interstitial fluid may follow 2–45 min after acute increases in blood glucose concentrations.5 However, interstitial glucose concentrations commonly fall before blood-glucose concentrations do,8,9 and offer opportunities for sensors to give early warning of impending hypoglycaemia. John Pickup Department of Chemical Pathology, Guy’s, King’s and St Thomas’ School of Medicine, Guy’s Hospital, London SE1 9RT, UK
Anions (eg, Cl–)
Cations (eg, Na+)
1
2
temperature change and cause the measuring cycle to be skipped if thresholds are exceeded. In the trials, the device was calibrated after a 3 h run-in period by one measurement of capillary blood glucose. Patients with type 1 or 2 diabetes then wore the GlucoWatch for 12 h. There was good tracking of capillary glucose concentrations but with about an 18 min delay between the GlucoWatch and the blood readings. Patients in the studies noted mild skin irritation, oedema, and erythema. FDA approval was granted subject to the provision that patients undergo an extensive educational programme and that the detection and frequency of hypoglycaemia and hyperglycaemia is subjected to postmarketing evaluation. Clearly, further testing and development is required—for example, in the published studies2,3 data from the GlucoWatch were downloaded to a computer for analysis rather than being displayed on the device for the patients to read. At the moment, the device is intended to be an adjunct to standard home blood-glucose monitoring techniques rather than a replacement, but the eventual goal for this and similar glucose sensors must be to provide the patient with real-time blood glucose concentrations and warn about extreme blood glucose values without needing to sample capillary blood. The application of technology to diabetes care seems to be accelerating. The FDA also recently approved (June, 1999) a minimally invasive, transcutaneous glucose sensor (MiniMed Continuous Glucose Monitoring System, Sylmar, CA, USA) to monitor trends in glucose values. This type of device,5,6 which uses an enzyme electrode implanted in subcutaneous tissue and connected to an external monitor, has been undergoing development and testing for many years. The principal difficulties that have prevented clinical application are poor correspondence of tissue glucose values, obtained with sensors calibrated in vitro, with actual plasma glucose concentrations, and unpredictable glucose values.7 This relative “bioincompatibility” is probably the result of several factors, such as coating of the probes with protein, cells, or both, interference from electroactive substances, and changes in the local environment at the site of newly implanted transcutaneous sensors (ie, wound-induced variations in blood flow, cellular and protein accumulation, and glucose and oxygen concentrations). The MiniMed sensor can be worn for up to 3 days. Readings are made every 10 s and averaged over 5 min. As with the GlucoWatch, the MiniMed sensor does not provide the patient with realtime glucose values. At present it is intended to supplement conventional blood-glucose measurement of finger-prick samples.
THE LANCET • Vol 355 • February 5, 2000
3
4
5
6
7 8
9
Pickup J, McCartney L, Rolinski O, Birch D. In vivo glucose sensing for diabetes management: progress towards non-invasive monitoring. BMJ 1999; 319: 1289. Garg SK, Potts RO, Ackerman NR, Fermi SJ, Tamada JA, Chase H. Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes. Diabetes Care 1999; 22: 1708–14. Tamada J, Garg S, Jovanovic L, Pitzer KR, Fermi S, Potts RO. Non-invasive glucose monitoring: comprehensive clinical results. JAMA 1999; 282: 1839–44. Tamada JA, Bohannon JV, Potts RO. Measurement of glucose in diabetic subjects using noninvasive transdermal extraction. Nat Med 1995; 11: 1198–201. Rebrin K, Steil GM, Van Antwerp WP, Mastrototaro JJ. Subcutaneous glucose predicts plasma glucose independent of insulin: implications for continuous monitoring. Am J Physiol 1999; 40: E561–71. Mastrototaro J, Levy R, Leon-Paul G, White N, Mestman J. Clinical results from a continuous glucose sensor multi-center study. Diabetes 1998; 47 (suppl 1): 61A. Pickup JC. In vivo glucose monitoring: sense and sensorbility. Diabetes Care 1993; 16: 535–39. Thome-Duret V, Reach G, Gangnerau MN, et al. Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observations in blood. Anal Chem 1996; 68: 3822–26. Sternberg F, Meyerhof C, Mennel FJ, Mayer H, Bischof F, Pfeiffer EF. Does fall in tissue glucose precede fall in blood glucose? Diabetologia 1996; 39: 609–12.
EUROCARE-2: relevance for assessment of quality of cancer services? EUROCARE-2 is a study on how 1-year and 5-year survivals from cancer vary between European countries and over time. The data, now available in a 572-page book with accompanying CD-ROM, are well presented graphically and in tables, which caters for users who vary in their depth of interest and reading style.There is no doubt that the data for EUROCARE-2 have been carefully assembled and represent “an unprecedented effort of gathering together, standardizing and analysing cancer registry survival data”.1 The compilers of this work are clearly aware of biases that may arise in the collection of such data, most notably that not all cancers may be reported to cancer registries and that follow-up to confirm survival may be incomplete.They have taken great pains to minimise bias in data collection and to report data on the extent to which their attempts have met with success. They conclude reasonably that any remaining bias is unlikely to explain large differences in cancer survival between European countries. The data will probably be used to judge—or “benchmark”—the quality of health care in the countries surveyed. It is impossible, though, as the researchers point out, to conclude whether differences in outcome are due to differences in quality of care given, in access to care, or in earlier detection. Ignoring these distinctions would enable a general interpretation about how well each of the countries in the study is providing effective health care. However, the interpretation will be based on the assumption that early 427
detection increases longevity, rather than simply adding “lead time”—ie, prolonging survival from the time of diagnosis by increasing the number of years of recognition of disease between screen detection and the usual time of clinical detection.2 The value of early detection is not known for some cancers for which screening has been introduced, such as prostate cancer. Early detection may pick up prostate cancers that are slow growing and “inconsequential”. Because such cancers are unlikely to progress sufficiently to cause death, early detection and treatment will increase survival from time of detection but will not extend life.2 The same may be true for other cancers, such as some breast cancers, although there is evidence that early detection prolongs life for breast cancers overall. The survival rate from prostate cancer is twice as high in some European countries as in others, a difference that could be due simply to the presence of more inconsequential screen-detected cancers in countries with the higher survival rates. Despite these biases, the possibility remains that the discrepancies in survival between European countries found by EUROCARE-2 may still be due to differences in health-care provision. So what should be the next step? Should it be further and more refined comparative analysis of survival data with, for example, inclusion of data on stage and characteristics of health care, to find out the reasons for the differences? There are some insurmountable problems with this approach. For example, stage distribution is not available in EUROCARE-2. Although a major deficiency, it points to the difficulty in collecting data on stage. However, even if stage distribution is included in future data collections, standardisation will be difficult. Even minor staging upward of cancers by advanced technology may increase apparent survival in both the stage from which the cancers are removed and the stage to which they are reallocated.3 Beyond leading to the suggestion that expending more resources on cancer care may improve cancer outcome, will further data collection and analysis be targeted enough to give health-care planners and clinicians the information they need to make decisions? Probably not. What is needed is knowledge now on whether costeffective interventions are being applied, not further comparative survival data in 5–10 years’ time, no matter how refined those data may be. For some cancers, there is a wealth of randomised trials—and systematic reviews based on them—to guide decisions about appropriate care. If the aim is to improve care, why not assess directly the proportion of people within a country who receive appropriate cancer services? For example, instead of more between-country studies of survival from breast cancer, it would be easier and quicker to monitor the proportion of patients who are getting appropriate care and the proportion of women in appropriate age-groups who are undergoing high-quality mammographic screening.4,5 These data will require only small samples and be available quickly. In the longer term, within-country monitoring of trends in breast-cancer mortality will help to show whether the desired effect is being achieved.6 Another example is colon cancer. Evidence of much variation in survival rates from colorectal cancers detected a decade ago and a hypothesis that this difference may have been due to differences in early detection1 are not necessary preludes to using information from existing trials and systematic reviews to decide on the likely size of the effect of screening7 and to consider whether screening should be implemented. Nor are they needed for the assessment of
428
need to increase access to and use of adjuvant therapies for resected, intermediate-stage colorectal cancers, since there is evidence that use of these agents can prolong life.8 Cancer registries can and do provide valuable information on cancer occurrence, causes, and outcome. Their contributions include, for example, the generation of hypotheses about the dietary causation of cancer,9 the supplying of the initial evidence that environmental aflatoxin causes cancer in human beings,10 and the provision of the first reasonably certain evidence that Papsmear screening reduces the incidence of cervical cancer.11 Cancer-registry data are also commonly the starting point for assembling cases for epidemiological studies.12 Survival data from individual registries provide valuable information for clinicians and patients about prognosis. Between-country comparison of cancer survival can raise awareness, commonly quite forcibly, that differences in quality of health care need to be explored and addressed, but such exploration can and should proceed without a wait for these data. Health-care questions should be pro-active and problem-driven—eg, “What are the most effective interventions to prevent or manage cancer and are those effective interventions being implemented?” Questions should not be only reactive and data-driven—eg, “What are the reasons for striking differences in cancer survival?” EUROCARE-2 raises issues of quality of care. They can be addressed now by direct, rapid, and fairly simple approaches focusing more on the processes than the outcomes of care.13 *Les Irwig, Bruce Armstrong Department of Public Health and Community Medicine, University of Sydney, NSW 2006, Australia; Cancer Research and Registers, New South Wales Cancer Council, Sydney 1
2
3
4
5
6
7
8
9
10
11
12 13
Berrino F, Capocaccia R, Esteve J, et al. Survival of cancer patients in Europe: the EUROCARE-2 Study. IARC scientific publications no 151. Lyon: International Agency for Research on Cancer, 1999. Barratt A, Irwig L, Glasziou P, et al. Users’ guides to the medical literature XV11. How to use guidelines and recommendations about screening. JAMA 1999; 281: 2029–34. Feinstein AR, Sosin DM,Wells CK.The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312: 1604–08. Hill D, Jamrozik K,White V, et al. Surgical management of breast cancer in Australia in 1995. Kings Cross, Sydney: NHMRC National Breast Cancer Centre, 1999. Breastscreen Victoria. 1997 Annual Statistical Report. Carlton South Melbourne: Breastscreen Victoria Inc, 1999. Also available on http://www.breastscreen.org.au/publications.htm Kricker A, Farac K, Smith D, Sweeny A, McCredie M, Armstrong BK. Breast cancer in New South Wales in 1972–95: tumor size and the impact of mammographic screening. Int J Cancer 1999; 81: 877–80. Towler B, Irwig L, Glasziou P, Kewenter J,Weller D, Silagy C. A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, Hemoccult. BMJ 1998; 317: 559–65. Clinical Oncological Society of Australia and Australian Cancer Network.The prevention, early detection and management of colorectal cancer. Canberra: National Health and Medical Research Council Clinical Practice Guidelines 1999: 129–33. Also available at: http://www.health.gov.au/nhmrc/publicat/pdf/cp62.pdf Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 1975; 15: 617–31. Peers F, Bosch X, Kaldor J, Linsell A, Pluijmen M. Aflatoxin exposure, hepatitis B virus infection and liver cancer in Swaziland. Int J Cancer 1987; 39: 545–53. Hakama M. Trends in the incidence of cervical cancer in the Nordic countries. In: Magnus M.Trends in cancer incidence: causes and practical implications.Washington: Hemisphere Publishing Corporation, 1982: 279–92. Armstrong BK. The role of the cancer registry in cancer control. Cancer Causes Control 1992; 3: 569–79. Irwig L, Zwarenstein M, Zwi A, Chalmers I. A flow diagram to facilitate selection of interventions and research for health care. Bull World Health Organ 1998; 76: 17–24.
THE LANCET • Vol 355 • February 5, 2000