Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction A Systematic Review and Meta-analysis

Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in v...

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Published in:JAMA network open Vol. 4; no. 2; p. e2036337
Main Authors: Mykoniatis, Ioannis, Pyrgidis, Nikolaos, Sokolakis, Ioannis, Ouranidis, Andreas, Sountoulides, Petros, Haidich, Anna-Bettina, van Renterghem, Koenraad, Hatzichristodoulou, Georgios, Hatzichristou, Dimitrios
Format: Journal Article
Language:English
Published: United States American Medical Association 18.02.2021
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ISSN:2574-3805, 2574-3805
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Abstract Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.
AbstractList Importance Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. Objective To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Data Sources Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Study Selection Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data Extraction and Synthesis Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. Results A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24;I2 = 77%; 95% PI, −0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, −0.06 to 1.65;I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23;I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40;I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83;I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85;I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. Conclusions and Relevance This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.
Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.
This systematic review and meta-analysis compares the outcomes of monotherapy and combination treatments according to self-reports of erectile function by men with erectile dysfunction.
Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes.ImportanceCombining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes.To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED.ObjectiveTo assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED.Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020.Data SourcesStudies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020.Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included.Study SelectionRandomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included.Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Data Extraction and SynthesisData extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients.Main Outcomes and MeasuresA meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients.A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high.ResultsA total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high.This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.Conclusions and RelevanceThis study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.
Author Hatzichristou, Dimitrios
Sokolakis, Ioannis
Pyrgidis, Nikolaos
Haidich, Anna-Bettina
Ouranidis, Andreas
Sountoulides, Petros
Mykoniatis, Ioannis
van Renterghem, Koenraad
Hatzichristodoulou, Georgios
AuthorAffiliation 1 Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece
6 Department of Urology, Jessa Hospital, Hasselt University, Hasselt, Belgium
5 Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Aristotle University of Thessaloniki Medical School, University Campus, Thessaloniki, Greece
4 Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece
2 Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany
7 Department of Urology, University Hospitals Leuven, Leuven, Belgium
3 Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, Thessaloniki, Greece
AuthorAffiliation_xml – name: 7 Department of Urology, University Hospitals Leuven, Leuven, Belgium
– name: 4 Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece
– name: 2 Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany
– name: 3 Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, Thessaloniki, Greece
– name: 1 Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece
– name: 5 Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Aristotle University of Thessaloniki Medical School, University Campus, Thessaloniki, Greece
– name: 6 Department of Urology, Jessa Hospital, Hasselt University, Hasselt, Belgium
Author_xml – sequence: 1
  givenname: Ioannis
  surname: Mykoniatis
  fullname: Mykoniatis, Ioannis
  organization: Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece
– sequence: 2
  givenname: Nikolaos
  surname: Pyrgidis
  fullname: Pyrgidis, Nikolaos
  organization: Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece, Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany
– sequence: 3
  givenname: Ioannis
  surname: Sokolakis
  fullname: Sokolakis, Ioannis
  organization: Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany
– sequence: 4
  givenname: Andreas
  surname: Ouranidis
  fullname: Ouranidis, Andreas
  organization: Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, Thessaloniki, Greece, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece
– sequence: 5
  givenname: Petros
  surname: Sountoulides
  fullname: Sountoulides, Petros
  organization: Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece
– sequence: 6
  givenname: Anna-Bettina
  surname: Haidich
  fullname: Haidich, Anna-Bettina
  organization: Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Aristotle University of Thessaloniki Medical School, University Campus, Thessaloniki, Greece
– sequence: 7
  givenname: Koenraad
  surname: van Renterghem
  fullname: van Renterghem, Koenraad
  organization: Department of Urology, Jessa Hospital, Hasselt University, Hasselt, Belgium, Department of Urology, University Hospitals Leuven, Leuven, Belgium
– sequence: 8
  givenname: Georgios
  surname: Hatzichristodoulou
  fullname: Hatzichristodoulou, Georgios
  organization: Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany
– sequence: 9
  givenname: Dimitrios
  surname: Hatzichristou
  fullname: Hatzichristou, Dimitrios
  organization: Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33599772$$D View this record in MEDLINE/PubMed
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– reference: 33599768 - JAMA Netw Open. 2021 Feb 1;4(2):e2037292
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SecondaryResourceType review_article
Snippet Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial...
Importance Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce...
This systematic review and meta-analysis compares the outcomes of monotherapy and combination treatments according to self-reports of erectile function by men...
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StartPage e2036337
SubjectTerms Adrenergic alpha-Antagonists - therapeutic use
Angiotensin-Converting Enzyme Inhibitors - therapeutic use
Antioxidants - therapeutic use
Clinical trials
Combined Modality Therapy
Drug Therapy, Combination
Enzymes
Equipment and Supplies
Erectile dysfunction
Erectile Dysfunction - therapy
Extracorporeal Shockwave Therapy
Folic Acid - therapeutic use
Humans
Hypoglycemic Agents - therapeutic use
Male
Meta-analysis
Metformin - therapeutic use
Online Only
Original Investigation
Phosphodiesterase 5 Inhibitors - therapeutic use
Sildenafil Citrate - therapeutic use
Tadalafil - therapeutic use
Treatment Outcome
Urological surgery
Urology
Vitamin B Complex - therapeutic use
Subtitle A Systematic Review and Meta-analysis
Title Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction
URI https://www.ncbi.nlm.nih.gov/pubmed/33599772
https://www.proquest.com/docview/2667859314
https://www.proquest.com/docview/2491079781
https://pubmed.ncbi.nlm.nih.gov/PMC7893498
Volume 4
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