700
every advertisement (though not, in the UK or Ireland, a part of the
product licence) I would hold that the use of a valid, independently conducted, cost-effectiveness study does have a role in the promotion of a product. There must be provisos-namely, that the study is a genuine cost-effective or cost-benefit analysis and that the treatments so compared are truly equivalent in terms of dosage, efficacy, complications, and so on. In this study, by REMIT Consultants, all these points are well met. Your editorial also questions the competence of UK government staff to assess claims of cost-effectiveness. This competence does exist and is developing. Some applications for product licences already include cost-effectiveness analyses, and medical advisers to family health service authorities are considering such data on a regular basis. The white-paper has cost-benefit and costeffectiveness as very central issues in all aspects of the new National Health Service. Brocades Pharma stands by the results of this cost-effectiveness study as presented at the press conference and in the journal insert. We believe the results to be both valid and relevant. Gist-Brocades, Byfleet KT14 6RA, UK
JANE BARRETT
West
Glutathione peroxidase deficiency and childhood seizures SIR,-Dr Weber and colleagues (June 15, p 1443) suggest that glutathione peroxidase deficiency may cause childhood seizures. Over the past 20 years many different disease states have been attributed to such deficiency. None of these has stood the test of time. For example, in the cases of chronic granulomatous disease’ that Weber et al cite, re-examination of the neutrophil glutathione peroxidase enzyme activity and mRNA revealed that the original observations were incorrect and that the patients had, in fact, a deficiency in the membrane cytochrome bss8 that is characteristic of about 60% of patients with this disease.2 When many of the putative relations between clinical disorders and glutathione peroxidase were first described, it was not recognised that two conditions can cause lowering of the glutathione peroxidase activity. One of these is a common benign polymorphism that lowers the glutathione peroxidase content of red cells to less than half the mean normal value.3 Thus, in one of us (E. B.) glutathione peroxidase content is lower than that in many of the disorders in which a cause-and-effect relation was assumed, including some of the patients Weber et al report. Selenium deficiency, too, can produce a profound lack of glutathione peroxidase without any of the clinical consequences that have been
ascribed to the enzyme deficiency.4 Thus, the variation in red cell enzyme activity in patient populations is much greater than is often realised. The figure shows 1410 measurements of glutathione peroxidase in red cells of patients with various disorders. The values ranged from 3-33 to 422-3 IU/g haemoglobin (Hb) and many were lower than those in Weber and colleagues’ patients and in other case-reports in which a cause-and-effect relation between enzyme deficiency and morbid state was assumed. No clinical pattern was evident in the patients with glutathione peroxidase activities in the lower portion of the distribution; none of the 20 patients with the lowest values had been reported to have seizure disorders.
Since Weber and colleagues’ contention that the neurological deficit in the children is due to glutathione peroxidase deficiency is not supported by the values they report, nor by previous demonstration of an effect of glutathione peroxidase deficiency on leucocyte function, the suggestion that such deficiency impairs tissue function at all would have to rest on the reported time course of the neutrophil oxygen burst after stimulation in one of their patients. However, these data are by no means convincing. There is considerable variability in the rates and duration of superoxide (0 -) production in normal neutrophils after stimulation with phorbol myristate acetate.s In Weber and colleagues’ data there is no indication of the variability of the measurements made on neutrophils from either healthy adults or infants. Thus, whether the decay in 0 -production reported for the one patient falls outside the normal range cannot be determined. Even if it does, the measurement of 0 - decay in neutrophils is an indirect and non-specific measure of glutathione peroxidase activity.
Accordingly, we conclude that there is no reason to believe that there is a relation between glutathione peroxidase deficiency and seizure disorders and that, for the present, such deficiency must remain relegated to the category of non-diseases .6 ERNEST BEUTLER
JOHN T. CURNUTTE
Scripps Research Institute, La Jolla, California 9203, UK
LINDA FORMAN
B, Park BH, Malawista SE, Quie PG, Nelson DLL, Good RA. Chronic granulomatous disease in females: a deficiency of leucocyte glutathione peroxidase. N Engl J Med 1970; 283: 217-21. 2. Cumutte JT, Dinauer MC, Gelbart T, et al. Rare variant forms of chronic granulomatous disease: neutrophil glutathione peroxidase deficiency revisited. Clin Res 1990; 38: 350a. 3. Beutler E, Matsumoto F. Ethnic variation in red cell glutathione peroxidase activity. 1. Holmes
Blood 1975; 46: 103-10. 4. Thomson CD, Rea HM, Doesberg VM, Robinson MF. Selenium concentrations and glutathione peroxidase activities in whole blood of New Zealand residents. Br J Nutr 1977; 37: 457-60. 5. Cumutte JT, Badwey JA, Robinson JM, Kamovsky MJ, Kamovsky ML. Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate. J Biol Chem 1984; 259: 11851-57. 6. Beutler E. Red cell enzyme defects as non-diseases and as diseases. Blood 1979; 54: 1-7.
Pyrimethamine/sulfadoxine for falciparum malaria SIR,-It has been recommended that pyrimethamine/ sulfadoxine (’Fansidar’) should not be used alone to treat severe malaria because it acts too slowly.l However, three studies from Africa suggest that this recommendation may be unwarranted. In East Africa, parasite clearance and relief of symptoms were as prompt with oral and intramuscular fansidar as with quinine,3,4 whereas in West Africa falciparum parasites were eradicated more quickly with fansidar than with chloroquine.s We investigated the reasons for the apparent discrepancy between African results and those from South-East Asia, where this compound’s reputation for slowness originated.’ We first reviewed two studies from Thailand that are frequently cited to support the claim that fansidar has belated antimalarial activity.6Both included patients in whom treatment failed and who were, presumably, infected with fansidar-resistant parasites. The mean parasitaemia in one study was unusually high (more than 60 000/jj.l)," and parasite clearance time is a function of initial parasitaemia.8
falciparum
Erythrocyte GSHPx (IU/g Hb) 1410 erythrocyte glutathione peroxidase assays in patients with various disorders. Mean value
was
34 56
report; activity in the 4 solid circles
IU/g Hb, close to that of 35Weber et al cases reported by them is shown by
701
We then
analysed studies
at our
institute. Charts of
patients
enrolled in controlled trials of mefloquine (n=70), fansidar and quinine (n=34, unpublished) on the ThaiCambodian border between 1978 and 1983 were reviewed. All patients were Thai males 18 years or older with uncomplicated falciparum malaria, 1000-100 000 parasitised red cells1 blood on admission, and had parasites that cleared and did not recrudesce during the 28-day follow-up. There were no significant differences in the mean initial parasite counts of patients treated with fansidar, quinine, and mefloquine (26 929, 19 007, and 24 200/pl, respectively). The parasite clearance time was significantly shorter with fansidar than with quinine (62 vs 84 h, p < 0001); it was also shorter with fansidar than with mefloquine but the difference was not significant (62 vs 70 h, p=0-12). The percentage of initial parasitaemia remaining 24 h and 36 h after beginning treatment was significantly less after fansidar than after either quinine or mefloquine (p 0-1).
(n=29),9,11
We conclude that patient selection and the rapid emergence of fansidar resistance during the late 1970s in South-East Asia contributed to the misconception that fansidar acts slowly. Our data from Thailand on patients cured by fansidar are consistent with African results and indicate that fansidar’s reputation for slowness is undeserved. We agree with the recommendation3that antifolate drug combinations such as fansidar be investigated for the treatment of severe falciparum malaria in regions where the parasite remains susceptible to these agents. Department of Medicine, AFRIMS, AP0 AP 96546, USA
G. WATT G. D. SHANKS
Organization Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 22. 2. Cook GC. Prevention and treatment of malaria. Lancet 1988; i: 32-37. 3. Nevill CG, Watkins WM. Efficacy of pyrimethamine/sulfadoxine in uncomplicated severe falciparum malaria in Kenya. Lancet 1990; 336: 185. 4. Simao F, Macome A, Pateguana F, Schapira A. Comparison of intramuscular sulfadoxine-pyrimethamine and intramuscular quinine for the treatment of falciparum malaria in children. Trans R Soc Trop Med Hyg 1991; 85: 341-44. 5. Salako LA, Adio RA, Sowunmi A, Walker O. Parenteral sulphadoxinepyrimethamine (FansidarR): an effective and safe but under-used method of anti-malarial treatment. Trans R Soc Trop Med Hyg 1990; 84: 641-43. 6. Doberstyn EB, Hall AP, Vetvutanpibul K, Sonkom P. Single-dose therapy of falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine. Am J Trop Med Hyg 1976; 25: 14-19. 7 Pinichpongse S, Doberstyn EB, Cullen JR, Yisunsri L, Thongsombun Y, Thimasarn K. An evaluation of five regimens for the outpatient therapy of falciparum malaria in Thailand 1980-81. Bull WHO 1982; 60: 907-12. 8. White NJ, Krishna S. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans R Soc Trop Med Hyg 1989; 83: 767-77. 9. Doberstyn EB, Phintuyothin P, Neoypatimanondh S, Teerakiarkamjorn C. Singledose therapy of falciparum malaria with mefloquine or pyrimethaminesulfadoxine. Bull WHO 1979; 57: 275-79. 10. Dixon KE, Williams RG, Pongsupat T, Pitaktong U, Phintuyothin P. A comparative trial of mefloquine and fansidar in the treatment of falciparum malaria: failure of fansidar. Trans R Soc Trop Med Hyg 1982; 76: 664-67. 1. World Health
Vitamin A supplementation SIR,-Dr West and colleagues (July 13, p 67) show a 30% reduction in mortality among preschool children in Nepal who were given vitamin A supplements, and add to the evidence in favour of widespread distribution of vitamin A. Of the four randomised community trials published so far (West et al and refs 1-3) only that by Vijayaraghaven et aP has failed to fmd a significant effect of vitamin A on mortality among preschool children. Sommer and colleagues’1 study has been frequently criticised because it was not blinded or placebo-controlled. We have examined quality of the field work, analysis, and reporting of these studies. We have compared the four published articles (table). In Vijayaraghaven and colleagues’ study losses to follow-up were two-thirds greater among the controls than among the treatment group. If only 10% of those children who were lost to follow-up died, the results of the study would have shown a statistically significant positive effect of vitamin A. Vijayaraghaven and colleagues’ accounting of patients was also questionable. For example, they state that only children "between the ages of 1 and 5 years" were included in the study. However, in their table i it is reported that 3558 children under age 1 were also entered in the trial (22-6% of the total). In their table ill, where mortality of the treatment and control groups are reported, there is no indication that the data for infants are included. Since infants would be expected to have a high mortality rate it would be critical to analyse and report what happened to them. Vijayaraghaven et al state that their study took place over two years from January, 1987, to January, 1989. Since high-dose vitamin A capsules are usually given 6 months apart and these workers attempted to give only two doses of vitamin A, some children might have been followed for as long as 1 years after their last dose of vitamin A. Because the effect of supplemental vitamin A would not be expected to last that long the results would be biased towards the null hypothesis. This may not have been so, but it is difficult to be certain because the timing of the intervention and the timing of the outcome assessment were not adequately described. Overall, Vijayaraghaven and colleagues’ study seemed to have the most serious flaws with respect to implementation, analysis, and reporting. This may explain why its results differ from those of the other three trials, which showed a striking decrease in mortality in children given vitamin A supplements. Management Sciences for Health, Child Survival Program, Department of Health,
BENJAMIN P. LOEVINSOHN
Manila, Philippines
STEVEN L. SOLTER
1. Sommer
A, Tarwotjo I, Djunaedi E, et al. Impact of vitamin A supplementation on a randomised controlled community trial. Lancet 1986; i:
childhood mortality: 1169-73. 2. Rahmathullah
L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35.
3.
Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990; 336: 1342-45.
Vijayaraghaven K,
SELECTED METHODOLOGICAL ASPECTS OF FOUR PUBLISHED TRIALS OF VITAMIN A SUPPLEMENTATION I
*West etal
(Lancet July 13, p67). tProbably no loss to follow-up. tStatlstlcally significant difference between treatment and control subjects. §vitamin A was given every week, 90% of study subjects received > 70% of all doses.
1
I
I
every advertisement (though not, in the UK or Ireland, a part of the
product licence) I would hold that the use of a valid, independently conducted, cost-effectiveness study does have a role in the promotion of a product. There must be provisos-namely, that the study is a genuine cost-effective or cost-benefit analysis and that the treatments so compared are truly equivalent in terms of dosage, efficacy, complications, and so on. In this study, by REMIT Consultants, all these points are well met. Your editorial also questions the competence of UK government staff to assess claims of cost-effectiveness. This competence does exist and is developing. Some applications for product licences already include cost-effectiveness analyses, and medical advisers to family health service authorities are considering such data on a regular basis. The white-paper has cost-benefit and costeffectiveness as very central issues in all aspects of the new National Health Service. Brocades Pharma stands by the results of this cost-effectiveness study as presented at the press conference and in the journal insert. We believe the results to be both valid and relevant. Gist-Brocades, Byfleet KT14 6RA, UK
JANE BARRETT
West
Glutathione peroxidase deficiency and childhood seizures SIR,-Dr Weber and colleagues (June 15, p 1443) suggest that glutathione peroxidase deficiency may cause childhood seizures. Over the past 20 years many different disease states have been attributed to such deficiency. None of these has stood the test of time. For example, in the cases of chronic granulomatous disease’ that Weber et al cite, re-examination of the neutrophil glutathione peroxidase enzyme activity and mRNA revealed that the original observations were incorrect and that the patients had, in fact, a deficiency in the membrane cytochrome bss8 that is characteristic of about 60% of patients with this disease.2 When many of the putative relations between clinical disorders and glutathione peroxidase were first described, it was not recognised that two conditions can cause lowering of the glutathione peroxidase activity. One of these is a common benign polymorphism that lowers the glutathione peroxidase content of red cells to less than half the mean normal value.3 Thus, in one of us (E. B.) glutathione peroxidase content is lower than that in many of the disorders in which a cause-and-effect relation was assumed, including some of the patients Weber et al report. Selenium deficiency, too, can produce a profound lack of glutathione peroxidase without any of the clinical consequences that have been
ascribed to the enzyme deficiency.4 Thus, the variation in red cell enzyme activity in patient populations is much greater than is often realised. The figure shows 1410 measurements of glutathione peroxidase in red cells of patients with various disorders. The values ranged from 3-33 to 422-3 IU/g haemoglobin (Hb) and many were lower than those in Weber and colleagues’ patients and in other case-reports in which a cause-and-effect relation between enzyme deficiency and morbid state was assumed. No clinical pattern was evident in the patients with glutathione peroxidase activities in the lower portion of the distribution; none of the 20 patients with the lowest values had been reported to have seizure disorders.
Since Weber and colleagues’ contention that the neurological deficit in the children is due to glutathione peroxidase deficiency is not supported by the values they report, nor by previous demonstration of an effect of glutathione peroxidase deficiency on leucocyte function, the suggestion that such deficiency impairs tissue function at all would have to rest on the reported time course of the neutrophil oxygen burst after stimulation in one of their patients. However, these data are by no means convincing. There is considerable variability in the rates and duration of superoxide (0 -) production in normal neutrophils after stimulation with phorbol myristate acetate.s In Weber and colleagues’ data there is no indication of the variability of the measurements made on neutrophils from either healthy adults or infants. Thus, whether the decay in 0 -production reported for the one patient falls outside the normal range cannot be determined. Even if it does, the measurement of 0 - decay in neutrophils is an indirect and non-specific measure of glutathione peroxidase activity.
Accordingly, we conclude that there is no reason to believe that there is a relation between glutathione peroxidase deficiency and seizure disorders and that, for the present, such deficiency must remain relegated to the category of non-diseases .6 ERNEST BEUTLER
JOHN T. CURNUTTE
Scripps Research Institute, La Jolla, California 9203, UK
LINDA FORMAN
B, Park BH, Malawista SE, Quie PG, Nelson DLL, Good RA. Chronic granulomatous disease in females: a deficiency of leucocyte glutathione peroxidase. N Engl J Med 1970; 283: 217-21. 2. Cumutte JT, Dinauer MC, Gelbart T, et al. Rare variant forms of chronic granulomatous disease: neutrophil glutathione peroxidase deficiency revisited. Clin Res 1990; 38: 350a. 3. Beutler E, Matsumoto F. Ethnic variation in red cell glutathione peroxidase activity. 1. Holmes
Blood 1975; 46: 103-10. 4. Thomson CD, Rea HM, Doesberg VM, Robinson MF. Selenium concentrations and glutathione peroxidase activities in whole blood of New Zealand residents. Br J Nutr 1977; 37: 457-60. 5. Cumutte JT, Badwey JA, Robinson JM, Kamovsky MJ, Kamovsky ML. Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate. J Biol Chem 1984; 259: 11851-57. 6. Beutler E. Red cell enzyme defects as non-diseases and as diseases. Blood 1979; 54: 1-7.
Pyrimethamine/sulfadoxine for falciparum malaria SIR,-It has been recommended that pyrimethamine/ sulfadoxine (’Fansidar’) should not be used alone to treat severe malaria because it acts too slowly.l However, three studies from Africa suggest that this recommendation may be unwarranted. In East Africa, parasite clearance and relief of symptoms were as prompt with oral and intramuscular fansidar as with quinine,3,4 whereas in West Africa falciparum parasites were eradicated more quickly with fansidar than with chloroquine.s We investigated the reasons for the apparent discrepancy between African results and those from South-East Asia, where this compound’s reputation for slowness originated.’ We first reviewed two studies from Thailand that are frequently cited to support the claim that fansidar has belated antimalarial activity.6Both included patients in whom treatment failed and who were, presumably, infected with fansidar-resistant parasites. The mean parasitaemia in one study was unusually high (more than 60 000/jj.l)," and parasite clearance time is a function of initial parasitaemia.8
falciparum
Erythrocyte GSHPx (IU/g Hb) 1410 erythrocyte glutathione peroxidase assays in patients with various disorders. Mean value
was
34 56
report; activity in the 4 solid circles
IU/g Hb, close to that of 35Weber et al cases reported by them is shown by
701
We then
analysed studies
at our
institute. Charts of
patients
enrolled in controlled trials of mefloquine (n=70), fansidar and quinine (n=34, unpublished) on the ThaiCambodian border between 1978 and 1983 were reviewed. All patients were Thai males 18 years or older with uncomplicated falciparum malaria, 1000-100 000 parasitised red cells1 blood on admission, and had parasites that cleared and did not recrudesce during the 28-day follow-up. There were no significant differences in the mean initial parasite counts of patients treated with fansidar, quinine, and mefloquine (26 929, 19 007, and 24 200/pl, respectively). The parasite clearance time was significantly shorter with fansidar than with quinine (62 vs 84 h, p < 0001); it was also shorter with fansidar than with mefloquine but the difference was not significant (62 vs 70 h, p=0-12). The percentage of initial parasitaemia remaining 24 h and 36 h after beginning treatment was significantly less after fansidar than after either quinine or mefloquine (p 0-1).
(n=29),9,11
We conclude that patient selection and the rapid emergence of fansidar resistance during the late 1970s in South-East Asia contributed to the misconception that fansidar acts slowly. Our data from Thailand on patients cured by fansidar are consistent with African results and indicate that fansidar’s reputation for slowness is undeserved. We agree with the recommendation3that antifolate drug combinations such as fansidar be investigated for the treatment of severe falciparum malaria in regions where the parasite remains susceptible to these agents. Department of Medicine, AFRIMS, AP0 AP 96546, USA
G. WATT G. D. SHANKS
Organization Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 22. 2. Cook GC. Prevention and treatment of malaria. Lancet 1988; i: 32-37. 3. Nevill CG, Watkins WM. Efficacy of pyrimethamine/sulfadoxine in uncomplicated severe falciparum malaria in Kenya. Lancet 1990; 336: 185. 4. Simao F, Macome A, Pateguana F, Schapira A. Comparison of intramuscular sulfadoxine-pyrimethamine and intramuscular quinine for the treatment of falciparum malaria in children. Trans R Soc Trop Med Hyg 1991; 85: 341-44. 5. Salako LA, Adio RA, Sowunmi A, Walker O. Parenteral sulphadoxinepyrimethamine (FansidarR): an effective and safe but under-used method of anti-malarial treatment. Trans R Soc Trop Med Hyg 1990; 84: 641-43. 6. Doberstyn EB, Hall AP, Vetvutanpibul K, Sonkom P. Single-dose therapy of falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine. Am J Trop Med Hyg 1976; 25: 14-19. 7 Pinichpongse S, Doberstyn EB, Cullen JR, Yisunsri L, Thongsombun Y, Thimasarn K. An evaluation of five regimens for the outpatient therapy of falciparum malaria in Thailand 1980-81. Bull WHO 1982; 60: 907-12. 8. White NJ, Krishna S. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans R Soc Trop Med Hyg 1989; 83: 767-77. 9. Doberstyn EB, Phintuyothin P, Neoypatimanondh S, Teerakiarkamjorn C. Singledose therapy of falciparum malaria with mefloquine or pyrimethaminesulfadoxine. Bull WHO 1979; 57: 275-79. 10. Dixon KE, Williams RG, Pongsupat T, Pitaktong U, Phintuyothin P. A comparative trial of mefloquine and fansidar in the treatment of falciparum malaria: failure of fansidar. Trans R Soc Trop Med Hyg 1982; 76: 664-67. 1. World Health
Vitamin A supplementation SIR,-Dr West and colleagues (July 13, p 67) show a 30% reduction in mortality among preschool children in Nepal who were given vitamin A supplements, and add to the evidence in favour of widespread distribution of vitamin A. Of the four randomised community trials published so far (West et al and refs 1-3) only that by Vijayaraghaven et aP has failed to fmd a significant effect of vitamin A on mortality among preschool children. Sommer and colleagues’1 study has been frequently criticised because it was not blinded or placebo-controlled. We have examined quality of the field work, analysis, and reporting of these studies. We have compared the four published articles (table). In Vijayaraghaven and colleagues’ study losses to follow-up were two-thirds greater among the controls than among the treatment group. If only 10% of those children who were lost to follow-up died, the results of the study would have shown a statistically significant positive effect of vitamin A. Vijayaraghaven and colleagues’ accounting of patients was also questionable. For example, they state that only children "between the ages of 1 and 5 years" were included in the study. However, in their table i it is reported that 3558 children under age 1 were also entered in the trial (22-6% of the total). In their table ill, where mortality of the treatment and control groups are reported, there is no indication that the data for infants are included. Since infants would be expected to have a high mortality rate it would be critical to analyse and report what happened to them. Vijayaraghaven et al state that their study took place over two years from January, 1987, to January, 1989. Since high-dose vitamin A capsules are usually given 6 months apart and these workers attempted to give only two doses of vitamin A, some children might have been followed for as long as 1 years after their last dose of vitamin A. Because the effect of supplemental vitamin A would not be expected to last that long the results would be biased towards the null hypothesis. This may not have been so, but it is difficult to be certain because the timing of the intervention and the timing of the outcome assessment were not adequately described. Overall, Vijayaraghaven and colleagues’ study seemed to have the most serious flaws with respect to implementation, analysis, and reporting. This may explain why its results differ from those of the other three trials, which showed a striking decrease in mortality in children given vitamin A supplements. Management Sciences for Health, Child Survival Program, Department of Health,
BENJAMIN P. LOEVINSOHN
Manila, Philippines
STEVEN L. SOLTER
1. Sommer
A, Tarwotjo I, Djunaedi E, et al. Impact of vitamin A supplementation on a randomised controlled community trial. Lancet 1986; i:
childhood mortality: 1169-73. 2. Rahmathullah
L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35.
3.
Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990; 336: 1342-45.
Vijayaraghaven K,
SELECTED METHODOLOGICAL ASPECTS OF FOUR PUBLISHED TRIALS OF VITAMIN A SUPPLEMENTATION I
*West etal
(Lancet July 13, p67). tProbably no loss to follow-up. tStatlstlcally significant difference between treatment and control subjects. §vitamin A was given every week, 90% of study subjects received > 70% of all doses.
1
I
I
