Journal Club Dr Sidharth Kumar Sethi MD, Fellowship [IPNA, ISN, ISPN] https://www.pediatric-nephrology.com
Background <ul><li>Idiopathic nephrotic syndrome  </li></ul><ul><ul><li>40 to 50% show frequent relapses </li></ul></ul><u...
Infections and Relapses <ul><li>Follow minor infections of the upper respiratory or gastrointestinal tracts  </li></ul><ul...
Short term daily steroids during infections <ul><li>Two previous studies </li></ul><ul><li>Both found an effect on relapse...
Research Question <ul><li>Whether the strategy of short-term administration of small daily doses of prednisolone during in...
Aim of the study <ul><li>To study the effect of  short term </li></ul><ul><li>administration of small daily doses of </li>...
Study Design <ul><li>Design:  Randomized controlled trial  </li></ul><ul><li>Period:  September 2006 to October 2009 (Enro...
Inclusion criteria <ul><li>Patients aged 1 to 16 yrs  </li></ul><ul><li>Recently diagnosed frequently relapsing nephrotic ...
Exclusion Criteria <ul><li>Impaired renal function (serum creatinine 1.2 mg/dl confirmed once over a period of 2 weeks) </...
Standard Treatment <ul><li>Alternate-day prednisolone </li></ul><ul><ul><li>1.5 mg/kg for 4 weeks, </li></ul></ul><ul><ul>...
Randomisation <ul><li>Allocation concealment </li></ul><ul><ul><li>opaque sealed envelopes opened at inclusion. </li></ul>...
Intervention <ul><li>The presence of an infection defined : </li></ul><ul><li>(1) fever: 38°C-2 measurements axillary temp...
Follow up <ul><li>Supplements of calcium carbonate  </li></ul><ul><ul><li>(250 mg/d <6 yrs; 500 mg/d >6 yrs) </li></ul></u...
Relapse definition and management <ul><li>Presence of 3 to 4 + proteinuria for 3 consecutive days after 7 days of the onse...
Follow up <ul><li>Visits  </li></ul><ul><ul><li>every 2 months for 1 year </li></ul></ul><ul><li>Blood levels of creatinin...
Serious Infections <ul><li>Lower respiratory tract infection, peritonitis, and cellulitis  </li></ul><ul><li>Hospitalized ...
Outcomes <ul><li>Primary outcome  </li></ul><ul><ul><li>comparing the rates of infection- associated relapses (relapses oc...
Premature termination  <ul><li>Treatment failure.  </li></ul><ul><ul><li>2 or more relapses in any 6-month period  </li></...
Sample Size <ul><li>Relapse rate of 4.6 + 1.4 relapses/yr in patients with frequent relapses </li></ul><ul><li>70%  presum...
Statistical Analysis <ul><li>Stata, version 9.1.  </li></ul><ul><li>Intention to treat.  </li></ul><ul><li>Incidence (rela...
Incidence Density Rates <ul><li>The  incidence rate  is the number of new cases per population in a given time period. </l...
Example of Relapse Rates <ul><li>Incidence proportion (28 per 1,000) is divided by the number of years (two) </li></ul><ul...
Statistical Analysis <ul><li>Stata, version 9.1.  </li></ul><ul><li>Intention to treat.  </li></ul><ul><li>Incidence (rela...
Rate Ratio <ul><li>Calculated to compare the ratio of events occurring at any given point in time. </li></ul><ul><li>Rate ...
Number needed to Treat <ul><li>The inverse of the absolute risk reduction or increase and the number of patients that need...
NNT Example Prophylaxis RF No RF Total Risk Yes 15 285 300 0.05 No 49 251 300 0.16 ARR 0.11 NNT 9
68 patients alternate-day prednisolone alone (strata 1) 32 received alternate-day prednisolone and levamisole (strata 2)
 
Relapse rates @ 12 months <ul><li>44 relapses (31 infection-associated) intervention group  </li></ul><ul><li>76 (56 infec...
 
Infections <ul><li>Number of infections </li></ul><ul><ul><li>226 Intervention group </li></ul></ul><ul><ul><li>161 Contro...
Infection Relapse Correlation
Adjusted Analysis & Number Needed to Treat <ul><li>Mean numbers of relapses per infection  </li></ul><ul><ul><li>Intervent...
Treatment failures and Add on therapy <ul><li>Treatment failures </li></ul><ul><li>2 intervention group (at 6- and 10-mont...
Sub-group Analysis
Discussion: Salient points of results <ul><li>With follow-up over 1 year, showed daily administration during intercurrent ...
Previous studies <ul><ul><li>Saudi Arabia, Mattoo et al  Nephron 85: 343–345, 2000 </li></ul></ul><ul><li>n=36  </li></ul>...
Previous studies <ul><li>Randomized, placebo-controlled trial from Sri Lanka </li></ul><ul><li>n=48 patients  </li></ul><u...
Infections <ul><li>Number of infections </li></ul><ul><ul><li>226 Intervention group </li></ul></ul><ul><ul><li>161 Contro...
More infections in intervention group! <ul><li>Precise reason unclear </li></ul><ul><li>Included four patients, each with ...
Critical Appraisal  <ul><li>Randomised controlled Trial </li></ul><ul><li>Well defined protocol </li></ul><ul><li>Case def...
Limitations <ul><li>Subjects with  mild courses of nephrotic syndrome.  </li></ul><ul><li>Difficult nephrotic syndrome wit...
Limitations <ul><li>Lack of a placebo arm  </li></ul><ul><ul><li>adequate allocation concealment before randomization </li...
Conclusions <ul><li>Long-term, alternate-day prednisolone with or without levamisole show reduced relapses  during infecti...
<ul><li>Thank You </li></ul>
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Daily Steroids during infections in frequently relapsing Nephrotic syndrome

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Daily Steroids during infections in frequently relapsing Nephrotic syndrome

  1. 1. Journal Club Dr Sidharth Kumar Sethi MD, Fellowship [IPNA, ISN, ISPN] https://www.pediatric-nephrology.com
  2. 2. Background <ul><li>Idiopathic nephrotic syndrome </li></ul><ul><ul><li>40 to 50% show frequent relapses </li></ul></ul><ul><ul><ul><li>ISKDC: J Am Soc Nephrol 8: 769–776, 1997 </li></ul></ul></ul><ul><ul><li>Prolonged course with risks of life threatening infections, thromboembolic complications </li></ul></ul><ul><ul><li>side effects of therapy </li></ul></ul><ul><li>Need to examine safe and effective treatment regimens for patients with frequently relapsing nephrotic syndrome. </li></ul><ul><ul><li>Pediatr Nephrol 20: 1523–1530, 2005 </li></ul></ul>
  3. 3. Infections and Relapses <ul><li>Follow minor infections of the upper respiratory or gastrointestinal tracts </li></ul><ul><ul><li>J Pediatr 108: 378–382, 1986 </li></ul></ul><ul><li>50 to 70% of relapses of nephrotic syndrome among children in developing countries follow URI </li></ul><ul><li>Mechanism not clear but immunosuppressive agents </li></ul><ul><ul><li>attenuate the upregulation of T cells </li></ul></ul><ul><ul><li>reduce the risk of infection associated relapses </li></ul></ul><ul><ul><li>Arun S, Bhatnagar S, Menon S, Saini S, Hari P, Bagga A: Efficacy of zinc supplements in reducing relapses in steroid-sensitive nephrotic syndrome. Pediatr Nephrol 24: 1583–1586, 2009 </li></ul></ul>
  4. 4. Short term daily steroids during infections <ul><li>Two previous studies </li></ul><ul><li>Both found an effect on relapse rates, BUT </li></ul><ul><ul><li>the first study- small number </li></ul></ul><ul><ul><li>the second study- did not examine its long-term benefit </li></ul></ul><ul><ul><li>Mattoo TK, Mahmoud MA: Increased maintenance corticosteroids </li></ul></ul><ul><ul><li>during upper respiratory infection decrease the </li></ul></ul><ul><ul><li>risk of relapse in nephrotic syndrome. </li></ul></ul><ul><ul><li>Nephron 85: 343–345, 2000 </li></ul></ul><ul><ul><li>Abeyagunawardena AS, Trompeter RS: Increasing the </li></ul></ul><ul><ul><li>dose of prednisolone during viral infections reduces the </li></ul></ul><ul><ul><li>risk of relapse in nephrotic syndrome: A randomized controlled </li></ul></ul><ul><ul><li>trial. Arch Intern Med 93: 226–228, 2008 </li></ul></ul>
  5. 5. Research Question <ul><li>Whether the strategy of short-term administration of small daily doses of prednisolone during infectious illnesses was effective in reducing annual relapse rates in patients with frequently relapsing nephrotic syndrome. </li></ul>
  6. 6. Aim of the study <ul><li>To study the effect of short term </li></ul><ul><li>administration of small daily doses of </li></ul><ul><li>prednisolone during infectious illnesses in </li></ul><ul><li>reducing annual relapse rates in patients with </li></ul><ul><li>frequently relapsing nephrotic syndrome. </li></ul>
  7. 7. Study Design <ul><li>Design: Randomized controlled trial </li></ul><ul><li>Period: September 2006 to October 2009 (Enrollment, 18 months) </li></ul><ul><li>Approval: Institutional Ethics Board, </li></ul><ul><li>Informed written consent from a parent before inclusion. </li></ul>
  8. 8. Inclusion criteria <ul><li>Patients aged 1 to 16 yrs </li></ul><ul><li>Recently diagnosed frequently relapsing nephrotic syndrome (at least two relapses in 6 months or more than three relapses in 12 months) </li></ul><ul><li>Eligible for therapy with long term, alternate-day prednisolone with or </li></ul><ul><li>without levamisole. </li></ul>
  9. 9. Exclusion Criteria <ul><li>Impaired renal function (serum creatinine 1.2 mg/dl confirmed once over a period of 2 weeks) </li></ul><ul><li>Intake of immunosuppressive medications other than oral prednisolone in the preceding 6 months, or </li></ul><ul><li>Steroid threshold exceeding 1 mg/kg on alternate days for maintaining remission and </li></ul><ul><ul><li>one or more features of steroid toxicity (body mass index, 95th percentile for age, cataract, or stage 2 hypertension </li></ul></ul>
  10. 10. Standard Treatment <ul><li>Alternate-day prednisolone </li></ul><ul><ul><li>1.5 mg/kg for 4 weeks, </li></ul></ul><ul><ul><li>followed by tapering by 0.25 mg/kg every 2 weeks until a dose of 0.5 to 0.75 mg/kg on alternate days was reached. </li></ul></ul><ul><li>Patients requiring prednisolone at a dose of 1 mg/kg on alternate days to maintain remission but without the above features of steroid toxicity </li></ul><ul><ul><li>combination of levamisole (2 mg/kg on alternate days) and alternate day prednisolone as above. </li></ul></ul><ul><li>Treatment with long-term, alternate-day prednisolone with or without levamisole was given for 1 year. </li></ul>
  11. 11. Randomisation <ul><li>Allocation concealment </li></ul><ul><ul><li>opaque sealed envelopes opened at inclusion. </li></ul></ul><ul><li>Randomisation </li></ul><ul><ul><li>stratified randomization on the basis of therapy with or without levamisole into intervention and control groups. </li></ul></ul>
  12. 12. Intervention <ul><li>The presence of an infection defined : </li></ul><ul><li>(1) fever: 38°C-2 measurements axillary temperature at least 1 hr apart </li></ul><ul><li>(2) rhinorrhea or cough for more than 1 day </li></ul><ul><li>(3) diarrhea (3 or more semiformed stools/d for 2 days). </li></ul><ul><li>Intervention group </li></ul><ul><li>Increase the frequency of prednisolone administration from alternate-day to daily treatment for 7 days, without changing the dose of prednisolone. </li></ul><ul><li>Control group </li></ul><ul><li>Same treatment with alternate-day prednisolone. </li></ul><ul><li>Dose not changed during allergies, insect bites, injuries, immunization, and any presumed noninfectious illness. </li></ul>
  13. 13. Follow up <ul><li>Supplements of calcium carbonate </li></ul><ul><ul><li>(250 mg/d <6 yrs; 500 mg/d >6 yrs) </li></ul></ul><ul><li>Parent daily examine the first morning urine specimen by dipstick </li></ul><ul><li>Written record </li></ul><ul><ul><li>Details of infections </li></ul></ul><ul><ul><li>treatment taken </li></ul></ul><ul><li>Written instructions </li></ul><ul><ul><li>therapy, including telephonic advice followed by a hospital visit within 1 week. </li></ul></ul>
  14. 14. Relapse definition and management <ul><li>Presence of 3 to 4 + proteinuria for 3 consecutive days after 7 days of the onset of an infectious illness. </li></ul><ul><li>Treatment: </li></ul><ul><ul><li>Prednisolone </li></ul></ul><ul><ul><li>2 mg/kg per d until remission (trace/negative protein for 3 consecutive days) </li></ul></ul><ul><ul><li>1.5 mg/kg; alternate days; 4 weeks </li></ul></ul><ul><ul><li>and tapered. </li></ul></ul>
  15. 15. Follow up <ul><li>Visits </li></ul><ul><ul><li>every 2 months for 1 year </li></ul></ul><ul><li>Blood levels of creatinine, albumin, and cholesterol </li></ul><ul><ul><li>at enrollment, 6 months, and 12 months. </li></ul></ul>
  16. 16. Serious Infections <ul><li>Lower respiratory tract infection, peritonitis, and cellulitis </li></ul><ul><li>Hospitalized </li></ul><ul><li>Both groups </li></ul><ul><ul><li>prednisolone (0.5 mg/kg per d orally) or an equivalent IV hydrocortisone during therapy </li></ul></ul>
  17. 17. Outcomes <ul><li>Primary outcome </li></ul><ul><ul><li>comparing the rates of infection- associated relapses (relapses occurring in the week after the 7-day intervention period) and expressed as episodes/patient per yr. </li></ul></ul><ul><li>Secondary outcomes </li></ul><ul><ul><li>frequency and type of infections </li></ul></ul><ul><ul><li>cumulative amount of prednisolone </li></ul></ul>
  18. 18. Premature termination <ul><li>Treatment failure. </li></ul><ul><ul><li>2 or more relapses in any 6-month period </li></ul></ul><ul><ul><li>Exit the study </li></ul></ul><ul><ul><li>alternative medications. </li></ul></ul>
  19. 19. Sample Size <ul><li>Relapse rate of 4.6 + 1.4 relapses/yr in patients with frequent relapses </li></ul><ul><li>70% presumed to follow infections </li></ul><ul><li>50 patients required in each group to show 50% reduction in frequency of infection-associated relapses </li></ul><ul><li>power of 80%, alpha error of 5%, and dropout rate of 10%. </li></ul>
  20. 20. Statistical Analysis <ul><li>Stata, version 9.1. </li></ul><ul><li>Intention to treat. </li></ul><ul><li>Incidence (relapse) density rates and rate differences calculated. </li></ul><ul><li>Poisson regression: compare relapse rates </li></ul><ul><li>One-way ANOVA: assess the association between the number of relapses and infections. </li></ul><ul><li>On the basis of the rate ratio , the number needed to be treat to reduce the frequency of relapses to less than three per year </li></ul>
  21. 21. Incidence Density Rates <ul><li>The incidence rate is the number of new cases per population in a given time period. </li></ul><ul><li>When the denominator is the sum of the person-time of the at risk population, it is also known as the incidence density rate or person-time incidence rate . </li></ul>
  22. 22. Example of Relapse Rates <ul><li>Incidence proportion (28 per 1,000) is divided by the number of years (two) </li></ul><ul><li>The Relapse rate is 14 cases per 1000 person-years </li></ul><ul><ul><li>14 relapses would be expected for 1000 children observed for 1 year </li></ul></ul>
  23. 23. Statistical Analysis <ul><li>Stata, version 9.1. </li></ul><ul><li>Intention to treat. </li></ul><ul><li>Incidence (relapse) density rates and rate differences calculated. </li></ul><ul><li>Poisson regression: compare relapse rates </li></ul><ul><li>One-way ANOVA: assess the association between the number of relapses and infections. </li></ul><ul><li>On the basis of the rate ratio , the number needed to be treat to reduce the frequency of relapses to less than three per year </li></ul>
  24. 24. Rate Ratio <ul><li>Calculated to compare the ratio of events occurring at any given point in time. </li></ul><ul><li>Rate Ratio = </li></ul><ul><li>Incidence Rate 1/Incidence Rate 2 </li></ul>
  25. 25. Number needed to Treat <ul><li>The inverse of the absolute risk reduction or increase and the number of patients that need to be treated for one to benefit compared with a control. </li></ul><ul><li>The ideal NNT is 1, where everyone has improved with treatment and no-one has with control. </li></ul><ul><li>The higher the NNT, the less effective is the treatment. </li></ul>
  26. 26. NNT Example Prophylaxis RF No RF Total Risk Yes 15 285 300 0.05 No 49 251 300 0.16 ARR 0.11 NNT 9
  27. 27. 68 patients alternate-day prednisolone alone (strata 1) 32 received alternate-day prednisolone and levamisole (strata 2)
  28. 29. Relapse rates @ 12 months <ul><li>44 relapses (31 infection-associated) intervention group </li></ul><ul><li>76 (56 infection-associated) in the controls. </li></ul>
  29. 31. Infections <ul><li>Number of infections </li></ul><ul><ul><li>226 Intervention group </li></ul></ul><ul><ul><li>161 Control Group (P<0.04). </li></ul></ul><ul><ul><li>92% URI </li></ul></ul><ul><ul><li>6% gastroenteritis </li></ul></ul><ul><ul><li>2% fever without any localizing signs </li></ul></ul>
  30. 32. Infection Relapse Correlation
  31. 33. Adjusted Analysis & Number Needed to Treat <ul><li>Mean numbers of relapses per infection </li></ul><ul><ul><li>Intervention 0.13 + 0.1 </li></ul></ul><ul><ul><li>Control groups 0.35 + 0.2 </li></ul></ul><ul><ul><li>Mean difference 0.22 (95% CI 0.16, 0.28) (P=0.04). </li></ul></ul><ul><li>Poisson regression, adjusted for occurrence of infections, daily administration of prednisolone during infections independently resulted in a 59% reduction in the rate of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). </li></ul><ul><ul><li>Reduces frequency of relapses to less than 3 per yr </li></ul></ul><ul><ul><li>For every one out of six patients with frequent relapses </li></ul></ul>
  32. 34. Treatment failures and Add on therapy <ul><li>Treatment failures </li></ul><ul><li>2 intervention group (at 6- and 10-month follow-ups) </li></ul><ul><li>four control group (1 at 6-months & 3 at 9-month follow-up) </li></ul><ul><li>Treated </li></ul><ul><ul><li>cyclophosphamide (n=2) or calcineurin inhibitors (n=4) </li></ul></ul><ul><li>Enalapril for stage 1 hypertension. </li></ul><ul><ul><li>0.2 mg/kg/d </li></ul></ul><ul><ul><li>1 patient intervention group </li></ul></ul><ul><ul><li>2 patients control group </li></ul></ul>
  33. 35. Sub-group Analysis
  34. 36. Discussion: Salient points of results <ul><li>With follow-up over 1 year, showed daily administration during intercurrent infections </li></ul><ul><ul><li>reduced relapse rates by almost one-half </li></ul></ul><ul><ul><li>higher proportion of patients with sustained remission. </li></ul></ul><ul><li>1 of every 6 patients receiving intervention showed infrequent relapses, </li></ul><ul><li>Reduction in relapse rates chiefly due to a reduced number of infection-associated relapses. </li></ul><ul><li>Seventy percent relapses intervention group and 74% controls preceded by infections, chiefly URI </li></ul>
  35. 37. Previous studies <ul><ul><li>Saudi Arabia, Mattoo et al Nephron 85: 343–345, 2000 </li></ul></ul><ul><li>n=36 </li></ul><ul><ul><li>patients with steroid-dependent nephrotic syndrome </li></ul></ul><ul><ul><li>prednisone maintenance dose of 0.5 mg/kg on alternate days </li></ul></ul><ul><li>Alternate patients allocated to either </li></ul><ul><ul><li>receive daily prednisone for 5 days during URI or </li></ul></ul><ul><ul><li>continue on alternate-day prednisone. </li></ul></ul><ul><li>At a 2-year follow-up, </li></ul><ul><ul><li>significant reduction in relapse rates in the former. </li></ul></ul><ul><li>Limitations </li></ul><ul><ul><li>small number </li></ul></ul><ul><ul><li>not randomized </li></ul></ul><ul><ul><li>did not provide estimates of infections and prednisone dosage in the two groups. </li></ul></ul>
  36. 38. Previous studies <ul><li>Randomized, placebo-controlled trial from Sri Lanka </li></ul><ul><li>n=48 patients </li></ul><ul><ul><li>steroid-dependent nephrotic syndrome receiving long-term treatment with low-dose (<0.6 mg/kg), alternate-day prednisolone </li></ul></ul><ul><li>Allocated to </li></ul><ul><ul><li>receive prednisolone or placebo daily, in the same dose as that prescribed on alternate days during remission, for 7 days at the first sign of an upper respiratory tract infection. </li></ul></ul><ul><ul><li>Therapy switched during the second infectious illness. </li></ul></ul><ul><li>Forty (83.3%) completed the study </li></ul><ul><li>Significantly lower relapse rates when receiving daily therapy </li></ul><ul><li>Limitations </li></ul><ul><ul><li>Patients observed for two consecutive infections </li></ul></ul><ul><ul><li>the effect of the intervention on the long-term unclear. </li></ul></ul><ul><ul><li>Arch Intern Med 93: 226–228, 2008 </li></ul></ul>
  37. 39. Infections <ul><li>Number of infections </li></ul><ul><ul><li>226 Intervention group </li></ul></ul><ul><ul><li>161 Control Group (P<0.04). </li></ul></ul><ul><ul><li>92% URI </li></ul></ul><ul><ul><li>6% gastroenteritis </li></ul></ul><ul><ul><li>2% fever without any localizing signs </li></ul></ul>
  38. 40. More infections in intervention group! <ul><li>Precise reason unclear </li></ul><ul><li>Included four patients, each with 12 to 14 URI episodes </li></ul><ul><li>Mild and self-limiting </li></ul><ul><li>Did not require antibiotic therapy. </li></ul><ul><li>Did not appear to be related to steroids </li></ul><ul><ul><li>Trend toward lower cumulative steroid dose in the intervention group. </li></ul></ul><ul><li>The risk of serious infections that required hospitalization & corticosteroid side effects similar </li></ul>
  39. 41. Critical Appraisal <ul><li>Randomised controlled Trial </li></ul><ul><li>Well defined protocol </li></ul><ul><li>Case definitions: Infection </li></ul><ul><li>Treatment uniform </li></ul><ul><li>Sample size calculation </li></ul><ul><li>Randomisation </li></ul><ul><ul><li>Allocation concealment </li></ul></ul><ul><ul><li>Allocation </li></ul></ul><ul><li>Intervention </li></ul><ul><li>Consort statement </li></ul>
  40. 42. Limitations <ul><li>Subjects with mild courses of nephrotic syndrome. </li></ul><ul><li>Difficult nephrotic syndrome with a prolonged duration of disease or high steroid threshold or those showing steroid </li></ul><ul><li>toxicity excluded. </li></ul><ul><li>Steroid threshold in this study was 0.5 to 0.75 mg/kg every other day, </li></ul><ul><ul><li>Unclear whether this intervention useful in patients with a lower steroid threshold </li></ul></ul><ul><ul><li>Similar benefits in patients cotreated with other immunosuppressive agents, e.g., MMF or CNI </li></ul></ul><ul><li>The effect in patients from developed countries and in populations where infections dont constitute a major cause for relapses of nephrotic syndrome unclear </li></ul>
  41. 43. Limitations <ul><li>Lack of a placebo arm </li></ul><ul><ul><li>adequate allocation concealment before randomization </li></ul></ul><ul><ul><li>subsequently aware of the allocation </li></ul></ul><ul><ul><li>potential for bias. </li></ul></ul><ul><li>Diagnosis of infection was clinical </li></ul><ul><ul><li>no efforts for virological or bacteriological confirmation </li></ul></ul><ul><li>Judgment of excluding allergies on the basis of clinical presentation, past patient history, and family history. </li></ul>
  42. 44. Conclusions <ul><li>Long-term, alternate-day prednisolone with or without levamisole show reduced relapses during infectious illnesses. </li></ul><ul><li>Recommend consider intervention for reducing infection-associated relapses in selected patients with frequently relapsing nephrotic syndrome. </li></ul>
  43. 45. <ul><li>Thank You </li></ul>

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