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PPI-based triple therapy in the eradication of H. pylori infection
746 CORRESPONDENCE
GASTROENTEROLOGY Vol. 117, No. 3
2. Simpson EJ, Chapman MAS, Dawson J, et al. In vivo metabolism of colonically administered 1-13C-butyrate in quiescent human ulcerative colitis. Gut 1998;42:A42.
PPI-Based Triple Therapy in the Eradication of H. pylori Infection Dear Sir: We read with great interest the editorial by Kuipers and Klinkenberg-Knol,1 who elegantly commented on the results of the MACH2 study.2 They attribute the excellent eradication rates obtained with two 1-week omeprazole-based triple regimens to the profound acid suppression induced by the proton pump inhibitor (PPI). The most plausible mechanisms they put forward are the direct antibacterial effect of omeprazole and, more likely, the achievement of high intragastric pH, which potentiates the effects of acid-labile antibiotics, such as amoxicillin and clarithromycin. However, both mechanisms are highly questionable. The former requires the action of the active sulfonamide form of omeprazole, which is formed in the canaliculus of the parietal cell and is not secreted into the gastric lumen,3 where it might inhibit the growth of Helicobacter pylori. The latter is counteracted by the fact that eradication rates similar to those of PPI-based triple therapies have also been observed when ranitidine is combined with 2 antibiotics for 7 days.4–7 The equivalent results obtained with omeprazole- and ranitidine-based triple regimens strongly reduce the role of profound acid suppression because it is well known that the antisecretory effect of H2-receptor antagonists is much less than that of PPIs.8 Kuipers and Klinkenberg-Knol correctly highlight that antibiotic resistance seriously hampered the success of PPI-based triple therapies in the MACH2 study. In particular, the effectiveness of omeprazole combined with metronidazole and clarithromycin (OMC) was reduced from 95% to 76% in the presence of primary metronidazole resistance, and the overall eradication rates obtained with both OMC and omeprazole plus amoxicillin and clarithromycin (OAC) were diminished from 93% to 75% when primary clarithromycin resistance was present. However, despite this negative impact of antibiotic resistance, a success rate of 75% can be still considered satisfactory. In fact, data from other studies9–14 clearly show that clarithromycin resistance is a major predictor of treatment failure when PPI-based triple regimens are used. Figure 1 shows the results of these studies. The median eradication rate was as low as 25% (confidence interval, 2%–43%) in patients with resistant strains and, in contrast, as high as 87% in patients with sensitive strains (confidence interval, 79%–96%). It is evident that the 25% rate deriving from 6 clinical studies is much lower than the 75% obtained by Lind et al. in a single trial.2 Therefore, the good results of this study achieved with both OMC and OAC in patients with resistant strains should be extrapolated with extreme caution to populations of other geographical areas. We believe that the low prevalences of primary metronidazole and clarithromycin resistance (27% and 3%, respectively) have greatly affected the favorable outcome of PPI-based triple therapies in the MACH2 study. It is well known that clarithromycin resistance is higher than 3% in several countries in Europe15 and in the United States16 and, more importantly, has progressively increased through the last years.17 This phenomenon is likely the major factor preventing the achievement of consistent results by 1-week PPI-based triple therapies in the various regions where they are adopted. Kuipers and Klinkenberg-Knol also stressed in their editorial that only 27% of patients with a preexistent clarithromycin-resistant strain achieved eradication in 3 large U.S. studies using OAC for 10 days.18 Furthermore, clarithromycin resistance seems to reduce the success
Figure 1. Eradication rates obtained with PPI-based triple therapy in relation to clarithromycin-sensitive (CLA-S) or clarithromycin-resistant (CLA-R) strains of H. pylori.
of OAC more than OCM regimens. OAC has not always provided the same excellent results observed in the MACH2 study, and lower than expected eradication rates have been found with this triple regimen by many investigators.19 For instance, in a recent large multicenter trial20 conducted in France, where primary clarithromycin resistance is as high as ⬃10%,15 eradication rates obtained with various 7-day OAC regimens have been disappointing (ranging from 60% to 75% on intention-to-treat analysis). The above considerations lead us to predict a low success of both OCM and OAC in populations with a high prevalence of background clarithromycin resistance; therefore, the good results globally observed in the MACH2 study do not seem to be easily reproducible worldwide. VINCENZO SAVARINO, M.D. Dipartimento di Medicina Interna e Specialita` Mediche Universita` di Genova MATTEO NERI, M.D. Dipartmento di Medicina e Scienze dell’Invecchiamento Universita` di Chieti SERGIO VIGNERI, M.D. Universita` di Chieti Istituto di Medicina Interna e Geriatria Universita` di Palermo, Italy 1. Kuipers EJ, Klinkenberg-Knol EC. Helicobacter pylori, acid, and omeprazole revisited: bacterial eradication and rebound hypersecretion (editorial). Gastroenterology 1999;116:479–483. 2. Lind T, Me´graud F, Unge P, et al. The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999;116:248–253. 3. Hirschowitz BI, Keeling D, Lewin M, et al. Pharmacological aspects of acid secretion. Dig Dis Sci 1995;40:3S–23S. 4. Adamek RJ, Opferkuch W, Wegener M. Modified short-term triple therapy—ranitidine, clarithromycin, and metronidazole—for cure of Helicobacter pylori infection. Am J Gastroenterol 1995;90:168– 169. 5. Spadaccini A, De Fanis C, Sciampa G, et al. Omeprazole versus ranitidine: short-term triple therapy in patients with Helicobacter pylori–positive duodenal ulcers. Aliment Pharmacol Ther 1996;10: 829–831. 6. Kihira K, Satoh K, Saikufu K, et al. Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11:511–514.
September 1999
7. Savarino V, Zentilin P, Bisso G, et al. Head-to-head comparison of 1-week triple regimens combining ranitidine or omeprazole with two antibiotics to eradicate Helicobacter pylori. Aliment Pharmacol Ther (in press). 8. Savarino V, Mela GS, Vigneri S, et al. Anti-Helicobacter regimens. Lancet 1996;347:1194. 9. Lamouliatte H, Cayala R, Zerbib F, et al. Triple therapy using proton pump inhibitor amoxicillin and clarithromycin for Helicobacter pylori eradication. Gut 1995;37:A362. 10. Cayala R, Zerbib F, Talbi P, Me´graud F, Lamouliatte H. Pre- and post-treatment clarithromycin resistance of Helicobacter pylori strains: a key factor of treatment failure. Gut 1995;37:A217. 11. Xia HX, Buckley M, Hyde D, et al. Effects of antibiotic-resistance on clarithromycin-combined triple therapy for Helicobacter pylori infection. Gut 1995;37:A218. 12. Yousfy MM, El Zimaity HMT, Al Assi MT. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9:209–212. 13. Moayyedy P, Sahay P, Tompkins DS, et al. Efficacy and optimum dose of omeprazole in a new one week triple therapy regimen to eradicate Helicobacter pylori. Eur J Gastroenterol Hepatol 1995; 7:835–840. 14. Miyaji H, Ito S, Azuma T, et al. The prevalence of the drug resistance in Helicobacter pylori and the effects of the resistance on the eradication therapy in Japan (abstr). Gastroenterology 1997;112:A222. 15. Me´graud F. Resistance of Helicobacter pylori to antibiotics. Aliment Pharmacol Ther 1997;11(suppl 1):43–53. 16. Vakil N, McSorley D, Hahn B, et al. Clarithromycin-resistant Helicobacter pylori in the United States (abstr). Gastroenterology 1997;112:A1057. 17. Morton D, Bardhan KD. A six-year assessment of tinidazole, metronidazole, clarithromycin, tetracyclin and amoxicillin resistance in Helicobacter pylori clinical isolates: a rising tide of antibiotic resistance (abstr)? Gastroenterology 1998;114:A960. 18. Laine L, Suchover L, Frantz J, et al. Twice-daily, 10-day triple therapy with omeprazole, amoxicillin, and clarithromycin for Helicobacter pylori eradication in duodenal ulcer disease: results of three multicenter, double-blind, United States trials. Am J Gastroenterol 1998;93:2106–2112. 19. Pipkin GA, Williamson R, Wood JR. Review article: one-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori. Aliment Pharmacol Ther 1998;12:823–837. 20. Bigard MA, Delchier JC, Riachi G, et al. One-week triple therapy using omeprazole, amoxicillin and clarithromycin for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia: influence of dosage of omeprazole and clarithromycin. Aliment Pharmacol Ther 1998;12:383–388.
Colonoscopic Screening of First-Degree Relatives of Patients With Colorectal Cancer Dear Sir: We read with great interest the article by Pariente et al.1 on colonoscopic screening of first-degree relatives of patients with sporadic colorectal cancer. They reported that the estimated risk for adenomas associated with a simple family history of colorectal cancer (i.e., only 1 affected first-degree relative) was 1.5, and 2.6 for high-risk adenomas. We agree that selection of the control population is probably the most difficult methodological problem in studies on familial screening of colorectal cancer; however, we are convinced that the solution proposed by Pariente et al. is not the most ideal. We suggest that the ‘‘case-control’’ terminology should be reserved for more specific study designs. Briefly, Pariente et al. identified all first-degree relatives of a group of 195 patients with colorectal cancer, and each relative who
CORRESPONDENCE 747
agreed to participate was matched with 2 ‘‘controls’’ for age, sex, and possible symptoms. Only 39% of the relatives identified (185/476) agreed to be examined. Control subjects were defined as patients referred for colonoscopy during the same period for symptoms such as hematochezia, transit abnormalities, abdominal pain, and functional bowel disorders. Undoubtedly, the comparability of these two series is quite low. We are convinced that, in a correct study design, first-degree relatives of patients with colon cancer should have been compared with relatives of patients with negative findings on colonoscopy, both identified in the same endoscopic series. Practically, this means offering an examination to all relatives (those with an index case and the others with an index subject with a negative result). Such a design may seem difficult because of practical problems and reduced compliance; total colonoscopy, however, can now be offered to nonselected asymptomatic subjects for screening,2 and acceptance may be expected to be high, particularly in a specific age group (45–65 years). Overall, the results of Pariente are difficult to interpret because of the comparison of a possibly highly selected group of relatives with a series of patients referred for other reasons. In addition, it is not clear if the 25 relatives of cancer patients who reported a previous colonoscopy in the last 3 years before the study (with several polyps identified) were included in the analysis. Prior colonic examinations were not checked for in the control population; previous colonoscopies performed in other centers could have yielded several polyps, and patients with such a personal history should have been excluded from the control series, according to Pariente’s design. We have previously reported results of a study in the September 1995 issue of GASTROENTEROLOGY3; we found that the estimated risk for polyps associated with such a family history was 1.9. We also found a significantly higher frequency of severely dysplastic lesions in this group of subjects. Our study, however, was designed to estimate the association between the presence of polyps and the reporting of a simple family history of colorectal cancer, i.e., the presence of 1 first-degree relative affected, in a consecutive series of asymptomatic patients with a complete colonoscopy. In our view, this type of comparison is more appropriate and less prone to selection bias, and also quite efficient. With more resources available, a more complex design as that discussed above (examination of 2 series of relatives) could provide more reliable results. Intermediate solutions are more costly and may provide results that are difficult to interpret. DOMENICO PALLI Epidemiology Unit, CSPO Careggi Hospital Florence, Italy STEFANIA FOSSI, M.D. FRANCO BAZZOLI, M.D. Department of Internal Medicine and Gastroenterology University of Bologna Policlinico S. Orsola Bologna, Italy 1. Pariente A, Milan C, Lafon J, et al. Colonoscopic screening in first-degree relatives of patients with ‘sporadic’ colorectal cancer: a case-control study. Gastroenterology 1998;115:7–12. 2. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112: 594–642. 3. Bazzoli F, Fossi S, Sottili S, et al. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788.
GASTROENTEROLOGY Vol. 117, No. 3
2. Simpson EJ, Chapman MAS, Dawson J, et al. In vivo metabolism of colonically administered 1-13C-butyrate in quiescent human ulcerative colitis. Gut 1998;42:A42.
PPI-Based Triple Therapy in the Eradication of H. pylori Infection Dear Sir: We read with great interest the editorial by Kuipers and Klinkenberg-Knol,1 who elegantly commented on the results of the MACH2 study.2 They attribute the excellent eradication rates obtained with two 1-week omeprazole-based triple regimens to the profound acid suppression induced by the proton pump inhibitor (PPI). The most plausible mechanisms they put forward are the direct antibacterial effect of omeprazole and, more likely, the achievement of high intragastric pH, which potentiates the effects of acid-labile antibiotics, such as amoxicillin and clarithromycin. However, both mechanisms are highly questionable. The former requires the action of the active sulfonamide form of omeprazole, which is formed in the canaliculus of the parietal cell and is not secreted into the gastric lumen,3 where it might inhibit the growth of Helicobacter pylori. The latter is counteracted by the fact that eradication rates similar to those of PPI-based triple therapies have also been observed when ranitidine is combined with 2 antibiotics for 7 days.4–7 The equivalent results obtained with omeprazole- and ranitidine-based triple regimens strongly reduce the role of profound acid suppression because it is well known that the antisecretory effect of H2-receptor antagonists is much less than that of PPIs.8 Kuipers and Klinkenberg-Knol correctly highlight that antibiotic resistance seriously hampered the success of PPI-based triple therapies in the MACH2 study. In particular, the effectiveness of omeprazole combined with metronidazole and clarithromycin (OMC) was reduced from 95% to 76% in the presence of primary metronidazole resistance, and the overall eradication rates obtained with both OMC and omeprazole plus amoxicillin and clarithromycin (OAC) were diminished from 93% to 75% when primary clarithromycin resistance was present. However, despite this negative impact of antibiotic resistance, a success rate of 75% can be still considered satisfactory. In fact, data from other studies9–14 clearly show that clarithromycin resistance is a major predictor of treatment failure when PPI-based triple regimens are used. Figure 1 shows the results of these studies. The median eradication rate was as low as 25% (confidence interval, 2%–43%) in patients with resistant strains and, in contrast, as high as 87% in patients with sensitive strains (confidence interval, 79%–96%). It is evident that the 25% rate deriving from 6 clinical studies is much lower than the 75% obtained by Lind et al. in a single trial.2 Therefore, the good results of this study achieved with both OMC and OAC in patients with resistant strains should be extrapolated with extreme caution to populations of other geographical areas. We believe that the low prevalences of primary metronidazole and clarithromycin resistance (27% and 3%, respectively) have greatly affected the favorable outcome of PPI-based triple therapies in the MACH2 study. It is well known that clarithromycin resistance is higher than 3% in several countries in Europe15 and in the United States16 and, more importantly, has progressively increased through the last years.17 This phenomenon is likely the major factor preventing the achievement of consistent results by 1-week PPI-based triple therapies in the various regions where they are adopted. Kuipers and Klinkenberg-Knol also stressed in their editorial that only 27% of patients with a preexistent clarithromycin-resistant strain achieved eradication in 3 large U.S. studies using OAC for 10 days.18 Furthermore, clarithromycin resistance seems to reduce the success
Figure 1. Eradication rates obtained with PPI-based triple therapy in relation to clarithromycin-sensitive (CLA-S) or clarithromycin-resistant (CLA-R) strains of H. pylori.
of OAC more than OCM regimens. OAC has not always provided the same excellent results observed in the MACH2 study, and lower than expected eradication rates have been found with this triple regimen by many investigators.19 For instance, in a recent large multicenter trial20 conducted in France, where primary clarithromycin resistance is as high as ⬃10%,15 eradication rates obtained with various 7-day OAC regimens have been disappointing (ranging from 60% to 75% on intention-to-treat analysis). The above considerations lead us to predict a low success of both OCM and OAC in populations with a high prevalence of background clarithromycin resistance; therefore, the good results globally observed in the MACH2 study do not seem to be easily reproducible worldwide. VINCENZO SAVARINO, M.D. Dipartimento di Medicina Interna e Specialita` Mediche Universita` di Genova MATTEO NERI, M.D. Dipartmento di Medicina e Scienze dell’Invecchiamento Universita` di Chieti SERGIO VIGNERI, M.D. Universita` di Chieti Istituto di Medicina Interna e Geriatria Universita` di Palermo, Italy 1. Kuipers EJ, Klinkenberg-Knol EC. Helicobacter pylori, acid, and omeprazole revisited: bacterial eradication and rebound hypersecretion (editorial). Gastroenterology 1999;116:479–483. 2. Lind T, Me´graud F, Unge P, et al. The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999;116:248–253. 3. Hirschowitz BI, Keeling D, Lewin M, et al. Pharmacological aspects of acid secretion. Dig Dis Sci 1995;40:3S–23S. 4. Adamek RJ, Opferkuch W, Wegener M. Modified short-term triple therapy—ranitidine, clarithromycin, and metronidazole—for cure of Helicobacter pylori infection. Am J Gastroenterol 1995;90:168– 169. 5. Spadaccini A, De Fanis C, Sciampa G, et al. Omeprazole versus ranitidine: short-term triple therapy in patients with Helicobacter pylori–positive duodenal ulcers. Aliment Pharmacol Ther 1996;10: 829–831. 6. Kihira K, Satoh K, Saikufu K, et al. Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11:511–514.
September 1999
7. Savarino V, Zentilin P, Bisso G, et al. Head-to-head comparison of 1-week triple regimens combining ranitidine or omeprazole with two antibiotics to eradicate Helicobacter pylori. Aliment Pharmacol Ther (in press). 8. Savarino V, Mela GS, Vigneri S, et al. Anti-Helicobacter regimens. Lancet 1996;347:1194. 9. Lamouliatte H, Cayala R, Zerbib F, et al. Triple therapy using proton pump inhibitor amoxicillin and clarithromycin for Helicobacter pylori eradication. Gut 1995;37:A362. 10. Cayala R, Zerbib F, Talbi P, Me´graud F, Lamouliatte H. Pre- and post-treatment clarithromycin resistance of Helicobacter pylori strains: a key factor of treatment failure. Gut 1995;37:A217. 11. Xia HX, Buckley M, Hyde D, et al. Effects of antibiotic-resistance on clarithromycin-combined triple therapy for Helicobacter pylori infection. Gut 1995;37:A218. 12. Yousfy MM, El Zimaity HMT, Al Assi MT. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9:209–212. 13. Moayyedy P, Sahay P, Tompkins DS, et al. Efficacy and optimum dose of omeprazole in a new one week triple therapy regimen to eradicate Helicobacter pylori. Eur J Gastroenterol Hepatol 1995; 7:835–840. 14. Miyaji H, Ito S, Azuma T, et al. The prevalence of the drug resistance in Helicobacter pylori and the effects of the resistance on the eradication therapy in Japan (abstr). Gastroenterology 1997;112:A222. 15. Me´graud F. Resistance of Helicobacter pylori to antibiotics. Aliment Pharmacol Ther 1997;11(suppl 1):43–53. 16. Vakil N, McSorley D, Hahn B, et al. Clarithromycin-resistant Helicobacter pylori in the United States (abstr). Gastroenterology 1997;112:A1057. 17. Morton D, Bardhan KD. A six-year assessment of tinidazole, metronidazole, clarithromycin, tetracyclin and amoxicillin resistance in Helicobacter pylori clinical isolates: a rising tide of antibiotic resistance (abstr)? Gastroenterology 1998;114:A960. 18. Laine L, Suchover L, Frantz J, et al. Twice-daily, 10-day triple therapy with omeprazole, amoxicillin, and clarithromycin for Helicobacter pylori eradication in duodenal ulcer disease: results of three multicenter, double-blind, United States trials. Am J Gastroenterol 1998;93:2106–2112. 19. Pipkin GA, Williamson R, Wood JR. Review article: one-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori. Aliment Pharmacol Ther 1998;12:823–837. 20. Bigard MA, Delchier JC, Riachi G, et al. One-week triple therapy using omeprazole, amoxicillin and clarithromycin for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia: influence of dosage of omeprazole and clarithromycin. Aliment Pharmacol Ther 1998;12:383–388.
Colonoscopic Screening of First-Degree Relatives of Patients With Colorectal Cancer Dear Sir: We read with great interest the article by Pariente et al.1 on colonoscopic screening of first-degree relatives of patients with sporadic colorectal cancer. They reported that the estimated risk for adenomas associated with a simple family history of colorectal cancer (i.e., only 1 affected first-degree relative) was 1.5, and 2.6 for high-risk adenomas. We agree that selection of the control population is probably the most difficult methodological problem in studies on familial screening of colorectal cancer; however, we are convinced that the solution proposed by Pariente et al. is not the most ideal. We suggest that the ‘‘case-control’’ terminology should be reserved for more specific study designs. Briefly, Pariente et al. identified all first-degree relatives of a group of 195 patients with colorectal cancer, and each relative who
CORRESPONDENCE 747
agreed to participate was matched with 2 ‘‘controls’’ for age, sex, and possible symptoms. Only 39% of the relatives identified (185/476) agreed to be examined. Control subjects were defined as patients referred for colonoscopy during the same period for symptoms such as hematochezia, transit abnormalities, abdominal pain, and functional bowel disorders. Undoubtedly, the comparability of these two series is quite low. We are convinced that, in a correct study design, first-degree relatives of patients with colon cancer should have been compared with relatives of patients with negative findings on colonoscopy, both identified in the same endoscopic series. Practically, this means offering an examination to all relatives (those with an index case and the others with an index subject with a negative result). Such a design may seem difficult because of practical problems and reduced compliance; total colonoscopy, however, can now be offered to nonselected asymptomatic subjects for screening,2 and acceptance may be expected to be high, particularly in a specific age group (45–65 years). Overall, the results of Pariente are difficult to interpret because of the comparison of a possibly highly selected group of relatives with a series of patients referred for other reasons. In addition, it is not clear if the 25 relatives of cancer patients who reported a previous colonoscopy in the last 3 years before the study (with several polyps identified) were included in the analysis. Prior colonic examinations were not checked for in the control population; previous colonoscopies performed in other centers could have yielded several polyps, and patients with such a personal history should have been excluded from the control series, according to Pariente’s design. We have previously reported results of a study in the September 1995 issue of GASTROENTEROLOGY3; we found that the estimated risk for polyps associated with such a family history was 1.9. We also found a significantly higher frequency of severely dysplastic lesions in this group of subjects. Our study, however, was designed to estimate the association between the presence of polyps and the reporting of a simple family history of colorectal cancer, i.e., the presence of 1 first-degree relative affected, in a consecutive series of asymptomatic patients with a complete colonoscopy. In our view, this type of comparison is more appropriate and less prone to selection bias, and also quite efficient. With more resources available, a more complex design as that discussed above (examination of 2 series of relatives) could provide more reliable results. Intermediate solutions are more costly and may provide results that are difficult to interpret. DOMENICO PALLI Epidemiology Unit, CSPO Careggi Hospital Florence, Italy STEFANIA FOSSI, M.D. FRANCO BAZZOLI, M.D. Department of Internal Medicine and Gastroenterology University of Bologna Policlinico S. Orsola Bologna, Italy 1. Pariente A, Milan C, Lafon J, et al. Colonoscopic screening in first-degree relatives of patients with ‘sporadic’ colorectal cancer: a case-control study. Gastroenterology 1998;115:7–12. 2. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112: 594–642. 3. Bazzoli F, Fossi S, Sottili S, et al. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995;109:783–788.