EE: Going Beyond Nutrition to UnderstandChild Growth and DevelopmentLaura SmithRebecca Stoltzfus,Francis Ngure, BrieReid, ...
(Victora et al. 2010)The “Window of Opportunity” for Improving Nutrition isvery small… Pre-pregnancy until 18-24 months of...
What is causing all this stunting?
Cause #1: MalnourishedMother• Malnourished mothers give birth to babies that are smallerand shorter than normal• 50% of Gu...
Cause #2: Poor Diet• Systematic review of the efficacy and effectiveness ofcomplementary feeding interventions in developi...
Cause #3: Diarrhea• Between 6-18 months of age, children in developing countrieshave around 9 episodes of diarrhea.• Many ...
However:Evidence exists that the effect of WASHinterventions on linear growth isindependent of its effect on diarrhea.In s...
Peru:(Checkley, et al)• Children assessed for diarrhea and growth from birthto 2 years• Household sanitation and water ass...
Rural Ethiopia: HH Hygiene Index was thevariable most strongly associated with stuntingAlive and Thrive baseline data; F N...
Cause #4:The EnvironmentalEnteropathy Hypothesis• A subclinical condition of the small intestine, calledenvironmental ente...
Microbial translocationMicrobial products crossinto blood streamThe lining of the gutis only one cell thickIf the gut is i...
EE is a major cause of post-natal stunting,anemia and immune competenceEE can be prevented or reduced bypreventing infants...
Chronic immune activation↑ pro-inflammatorycytokinesImmunosenescence(premature aging) of adaptivecell-mediated immune syst...
HAZ changes over first 18 months in stunted and non-stunted infantsBirth 6wks 3mo 6mo 12mo 15mo9mo 18mo
IGF-1 and IGFBP3 were lower in stuntedinfants, beginning at 6 wk0 3 6 9 12 15 18020406080Age (months)MedianIGF-1(ng/mL)0 3...
Development of the WASH Intervention(Efficacy = “Proof of concept”)WASH Goal:All infants never ingest any faeces between b...
Conventional WASH formative research(2008-2009)Sanitation HIGHLYvalued don’t have alatrine because lackmoney; a Blair VIP ...
• 6 hour observation of 20 babies, recorded what and howoften went in the mouth and if visibly dirty• Returned and collect...
FindingsMost frequent:38 time in 6 hours75% visiby dirtyDirtiestSoil (3 ate avg 11 bites)chicken faeces, stones
If allowed, toddlers consumepoultry fecesPeruvian shantytown families:– Households who owned free-range poultry:• Average ...
% HH with Ecoli + sampleE coil/Per gramAverage E ColiPer DayInfant Food 0% 0 0Drinking Water54% 2 800Soil inlaundry area60...
24Babies are fed on*Ground in the yard(60-80% E coli+) or*Kitchen floor(81% E coli+)
Source: World Bank, accessed 6.23.11http://web.worldbank.org/WBSITE/EXTERNAL/TOPICS/EXTWAT/EXTTOPSANHYG/
LaundryWaterNappy HandlingProtective Play Spacefor babies!
A new way of thinking about WASH in the first 1000 days• Protective play space, to protect developing child fromcontaminat...
ControlInfant Feeding:Education +NutributterWASH:Integrated Water,Hygiene & SanitationWASH+Infant Feeding2x2 Factorial Des...
ObjectiveTo measure the independent and combined effects ofWASH and infant nutrition on stunting and anemiaamong children ...
Protective play spaceGoal: Culturally-acceptable, economical product that could belocally fabricated, which protects babie...
EarlyChildhoodDevelopmentNutritionStimulationSocialProtectionHygieneProgrammatic approaches for nutrition,stimulation and ...
SHINE Investigators:MoHCWGoldberg Mangwadu – Director of Environmental Health, MoHCW (Co-PI)Cynthia Chasokela – Director o...
Zimbabwe SHINESZimbabwe Sanitation Hygiene Infant NutritionEfficacy StudyObservation: babies with healthier guts and less ...
Community-basedTwo entire rural districtstotal popn: 180,000K
Standard Care1. Revived VHW network2. Strengthened PMTCT care3. EBF Promotion4. Latrine at end of studyInfant Nutrition1. ...
Implementation• Enroll 4,800 pregnant women at 10-12weeks gestation and follow them until theirbabies are 18 months old.• ...
Outcomes• Among all 4800 infants assess growth,anemia, intervention uptake, relevantbehaviors• Among 1600 infants, assess ...
The context: IOstudyLaundry areaBare soil andanimal waste
Micro team
Results: IO phase summary• Barely no HW for infants:21 times (in 13/23 HH) in 130 hoursHWWS 6/21: all as part of a bath.• ...
Results: Micro phase summaryA one year old ingesting chicken feces, soil and400 ml of contaminated water:On average 10 m...
Key messages• Chicken feces and soil ingestion arepredominant pathways• Exploratory soil ingestion and geophagia couldbe m...
Key messages• Caregiver’s HWWS after fecal contact is notcommon.• WASH interventions need to focus more onprotecting infan...
IYCF InterventionPromote optimal use of locally available foods,responsive feeding, nutrient density, feeding duringillnes...
Prior to Trial Launch
Village Health Worker RevitalizationFull complement recruited, trained (8 months) Providetools (bike, kit, uniforms)
Campaign to promote Exclusivebreastfeeding for all to 6 months1. Health workertraining2. Social marketing
Implement WHO 2010 Prevention of Mother to ChildTransmission of HIV and Infant Feeding Guidance
EE is caused by environmental exposure• Fetuses and newborns do not have it• People acquire it moving into developing coun...
• EE is a major cause of child stunting• EE can be prevented or reduced bypreventing infants and young children fromingest...
Fecal contaminationEnvironmentAltered bacterial load, compositionand/or timing of colonisationIntestinal inflammation and ...
IGF-1• 70 amino acid polypeptide• Mostly produced by liver• Mediates the effects of growth hormone• Important in fetal and...
Inflammatory markers were higher in stunted infantsP values for all time points 6 w to 12 mo,p<0.0010 3 6 9 12 15 185.05.5...
Stunted Non stunted0100200300400500MaternalIGF-1(ng/mL)Mean 95.9 Mean 114.3P=0.020 1000 2000 3000 4000 500005101520InfantI...
Intestinal Fatty Acid Binding Protein (I-FABP)• Very small (15kD) cytoplasmic protein• Found in enterocytes• Involved in i...
High I-FABP levels in stunted and non-stunted Zimbabwean infantsNon stunted Stunted02000400060008000I-FABP(pg/mL)Non stunt...
I-FABP was higher in stunted infants0 3 6 9 12 15 1801×10062×1006MonthsI-FABPstuntedP value frommultivariate modelthat inc...
Summary• Growth hormone axis is perturbed very early in life inapparently healthy Zimbabwean infants with poorlinear growt...
Zimbabwe SHINESZimbabwe Sanitation Hygiene Infant NutritionEfficacy StudyObservation: babies with healthier guts and less ...
Going Beyond Nutrition to Understand Child Growth and Development_Laura Smith_4.25.13
Going Beyond Nutrition to Understand Child Growth and Development_Laura Smith_4.25.13
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  • 8 items in index: mother’s hands, child’s hands, compound cleanliness, yard swept, garbage observed, indoor cleanliness, floor swept, dirty clothes. Kronbach’sα = 0.77.Regression on HAZ adjusted for WHO IYCF indicators, SES, sanitation, water, child age &amp; sex, size at birth, morbidity, food security, maternal height &amp; age, region.
  • Cases and controls were selected based on anthropometric indices at 18 mo of age. Eligible infants were born to mothers who tested HIV-negative throughout follow-up, for whom anthropometric data and archived plasma of sufficient volume (&gt;0.2 mL) at &gt;3 time-points were available. Of 14110 enrolled women, 9209 tested HIV-negative at baseline and remained uninfected throughout follow-up. From the 9209 infants born to these women, xxx  stunted and 101 non-stunted infants fulfilled our selection criteria at 18 mo. To maximize our sample size, we used all 101 controls, and randomly selected 101 cases from the stunted group. Plasma samples were available for all children at 18 mo, and for x%, x%, x%, x% and x% at birth, 6 w and 3, 6, 12 mo, respectively.  Bernard/Robert, could you add data in green highlighted sections?
  • 1 year old baby estimates
  • Wet areas within reach of a crawling baby and most HH with rubbish pits at the edge of the kitchen yard.
  • A child ingesting 1 g of chicken feces, I g of laundry area soil and 400 ml of contaminated water
  • Going Beyond Nutrition to Understand Child Growth and Development_Laura Smith_4.25.13

    1. 1. EE: Going Beyond Nutrition to UnderstandChild Growth and DevelopmentLaura SmithRebecca Stoltzfus,Francis Ngure, BrieReid, Gretel Pelto, Mduduzi Mbuya,Andrew Prendergast, Jean HumphreyDivision of Nutritional Sciences
    2. 2. (Victora et al. 2010)The “Window of Opportunity” for Improving Nutrition isvery small… Pre-pregnancy until 18-24 months of age
    3. 3. What is causing all this stunting?
    4. 4. Cause #1: MalnourishedMother• Malnourished mothers give birth to babies that are smallerand shorter than normal• 50% of Guatemalan babies are born stunted (Ruel 2001)– Prevalence of stunting at birth not well documented– Good length data on newborns is very hard to get!Estimates of 30-50% of stunting is due to intra-uterine factors.Effective macronutrient interventions for pregnant women are notwell established.
    5. 5. Cause #2: Poor Diet• Systematic review of the efficacy and effectiveness ofcomplementary feeding interventions in developing countries– Dewey & Adu-Afarwuah, 2008– 42 studies/programs, most published 1996-2006• Children who received interventions gained:– 0.0 – 0.76 Z scores weight-for-age– 0.0 – 0.64 Z scores length-for-ageThe best studies caused a 0.7 Z score improvement. BUT:the average growth deficit of African and Asian children is -2.0 ZAt best, diet solved 1/3 of the problem.
    6. 6. Cause #3: Diarrhea• Between 6-18 months of age, children in developing countrieshave around 9 episodes of diarrhea.• Many authors reported that diarrhea accounts for 10-80% ofgrowth faltering• But others contend that children grow at “catch-up rates”between episodes, and thus recover these deficitsThe Lancet Nutrition Series (2008) concluded that byimplementing sanitation and hygiene interventions with 99%coverage, child malnutrition would be reduced by only 2.4%
    7. 7. However:Evidence exists that the effect of WASHinterventions on linear growth isindependent of its effect on diarrhea.In several studies, WASH had a bigger effecton growth than it did on diarrhea
    8. 8. Peru:(Checkley, et al)• Children assessed for diarrhea and growth from birthto 2 years• Household sanitation and water assessed• What predicted height deficit at 2 years?16% explained by how much diarrhea thechild had experienced40% explained by the level of sanitation andwater in child’s household
    9. 9. Rural Ethiopia: HH Hygiene Index was thevariable most strongly associated with stuntingAlive and Thrive baseline data; F Ngure (2013, in prep)
    10. 10. Cause #4:The EnvironmentalEnteropathy Hypothesis• A subclinical condition of the small intestine, calledenvironmental enteropathy (EE)• Characterized by:– Flattening of the villi of the gut, reducing its surface area– Thickening of the surface through which nutrients must be absorbed– Increased permeability to large molecules and cells (microbes)• Likely causes:– Too many microbes in the gut– Effects of toxins on the gutDecreased nutrient absorption + Infiltration of microbes
    11. 11. Microbial translocationMicrobial products crossinto blood streamThe lining of the gutis only one cell thickIf the gut is injured andbecomes permeable, gapsopen up between cellsChronic immuneactivationDiverts nutrients fromgrowth to infection-fighting
    12. 12. EE is a major cause of post-natal stunting,anemia and immune competenceEE can be prevented or reduced bypreventing infants and young children fromingesting human and animal feces through apackage of interventions that improvesanitation and hygiene.Environmental Enteropathy andStunting Hypothesis:
    13. 13. Chronic immune activation↑ pro-inflammatorycytokinesImmunosenescence(premature aging) of adaptivecell-mediated immune system↑Hepcidin ↓Growth Factor(IGF-1)Anemia StuntingImpaired response tovaccines and infections
    14. 14. HAZ changes over first 18 months in stunted and non-stunted infantsBirth 6wks 3mo 6mo 12mo 15mo9mo 18mo
    15. 15. IGF-1 and IGFBP3 were lower in stuntedinfants, beginning at 6 wk0 3 6 9 12 15 18020406080Age (months)MedianIGF-1(ng/mL)0 3 6 9 12 15 18050010001500IGFBP3MonthsP values for all time points 6 w to 12 mo,p<0.001Values for healthy European children rangefrom 54-170 ng/mLP values for all time points 6 w to 18 mo,p<0.001stunted stunted
    16. 16. Development of the WASH Intervention(Efficacy = “Proof of concept”)WASH Goal:All infants never ingest any faeces between birthto 18 months
    17. 17. Conventional WASH formative research(2008-2009)Sanitation HIGHLYvalued don’t have alatrine because lackmoney; a Blair VIP is asource of status• Infant stools less offensive than adults’• Handwashing is seldom with soap• Frequently feed cold leftover food
    18. 18. • 6 hour observation of 20 babies, recorded what and howoften went in the mouth and if visibly dirty• Returned and collected samples of most frequent anddirtiest things mouthed for micro analysisBaby Observation Study (2011)
    19. 19. FindingsMost frequent:38 time in 6 hours75% visiby dirtyDirtiestSoil (3 ate avg 11 bites)chicken faeces, stones
    20. 20. If allowed, toddlers consumepoultry fecesPeruvian shantytown families:– Households who owned free-range poultry:• Average ingestion of poultry feces by toddlers per12-hour observation period was 3.9 times– Marquis GM et al., Am J Public Health 1990Rural Zimbabwe:– Not selected for poultry ownership:• 3 of 7 toddlers directly ate chicken feces during a6-hour observation period.– Ngure F et al., submitted, 2012
    21. 21. % HH with Ecoli + sampleE coil/Per gramAverage E ColiPer DayInfant Food 0% 0 0Drinking Water54% 2 800Soil inlaundry area60-80% 70 1,400Chicken feces100% 10,000,000 10,000,000Clearly, kids must stop eating dirt and chicken poop!
    22. 22. 24Babies are fed on*Ground in the yard(60-80% E coli+) or*Kitchen floor(81% E coli+)
    23. 23. Source: World Bank, accessed 6.23.11http://web.worldbank.org/WBSITE/EXTERNAL/TOPICS/EXTWAT/EXTTOPSANHYG/
    24. 24. LaundryWaterNappy HandlingProtective Play Spacefor babies!
    25. 25. A new way of thinking about WASH in the first 1000 days• Protective play space, to protect developing child fromcontaminated soil and animal feces (especially chickens)• Infant handwashing with soap, when outside of protectiveplay space.• Caregiver handwashing with soap after fecal contact andbefore preparing/serving food• Safe disposal of feces—especially of children• Water treatment• Avoid feeding leftovers, or reheat
    26. 26. ControlInfant Feeding:Education +NutributterWASH:Integrated Water,Hygiene & SanitationWASH+Infant Feeding2x2 Factorial Design
    27. 27. ObjectiveTo measure the independent and combined effects ofWASH and infant nutrition on stunting and anemiaamong children from birth to 18 months of ageAnd, on a sample of 1600 infants, measure thehypothesized “causal pathway” of EE1000 HIV- mothers600 HIV+ mothers
    28. 28. Protective play spaceGoal: Culturally-acceptable, economical product that could belocally fabricated, which protects babies and toddlers fromingesting soil while allowing physical and cognitivedevelopmentEngaged a marketing expert (Malinda Sanna, Spark) forconsumer researchDesign process led by team from Cornell’s Department ofDesign and Environmental Analysis and Human Development
    29. 29. EarlyChildhoodDevelopmentNutritionStimulationSocialProtectionHygieneProgrammatic approaches for nutrition,stimulation and social protection arewell developed.UNICEF 2006 Programming Experiences in EarlyChildhood DevelopmentLancet 2011 Child Development SeriesHygiene for babies(Baby WASH)needs to be furtherdeveloped and testedEnvironmental Protection?
    30. 30. SHINE Investigators:MoHCWGoldberg Mangwadu – Director of Environmental Health, MoHCW (Co-PI)Cynthia Chasokela – Director of NursingZvitamboJean Humphrey (Co-PI) Mduduzi Mbuya,Naume Tavengwa, Kuda Mutasa, Robert NtoziniJohns Hopkins Bloomberg School of Public HealthLarry Moulton, Jim Tielsch (J Humphrey)CornellRebecca StoltzfusUniversity of LondonAndrew PrendergastUniversity of British ColumbiaAmee MangesFundingGates, DFID, CIDA,NIH,Wellcome Trust,UNICEF
    31. 31. Zimbabwe SHINESZimbabwe Sanitation Hygiene Infant NutritionEfficacy StudyObservation: babies with healthier guts and less inflammation grow better.Biological hypothesis: babies who are protected from fecal ingestion willgrow better.Randomized trial hypotheses: babies whose households receive acomprehensive Water Sanitation & Hygiene (WASH) intervention will growbetter.WASHInterventionReducedfecalingestionBetterGrowthSan & HygBehaviorsHealthier Gut& LessInflammationWASH + Nutrition will have more benefit than either alone.
    32. 32. Community-basedTwo entire rural districtstotal popn: 180,000K
    33. 33. Standard Care1. Revived VHW network2. Strengthened PMTCT care3. EBF Promotion4. Latrine at end of studyInfant Nutrition1. Standard care2. Promote optimal use of local foodsfor complementary feeding3. 20 g Nutributter daily provided forinfants (6-18 mo)Sanitation/Hygiene1. Standard care2. VIP latrine3. 2 Tippy Taps and soap4. Water Guard5. Protected play area6. Promote safe feces disposal handwashing, water Rx, hygienic infantfeedingInfant Nutrition &Sanitation/Hygiene1. Standard care2. All Nutrition interventions3. All Sanitation/Hygiene interventions
    34. 34. Implementation• Enroll 4,800 pregnant women at 10-12weeks gestation and follow them until theirbabies are 18 months old.• Interventions delivered by 360 VillageHealth Workers on bicycle and Oxfam• Outcomes measured by 34 ResearchNurses on motorbike
    35. 35. Outcomes• Among all 4800 infants assess growth,anemia, intervention uptake, relevantbehaviors• Among 1600 infants, assess causalpathway (indicators of EE) at 3, 6, 12,18 months
    36. 36. The context: IOstudyLaundry areaBare soil andanimal waste
    37. 37. Micro team
    38. 38. Results: IO phase summary• Barely no HW for infants:21 times (in 13/23 HH) in 130 hoursHWWS 6/21: all as part of a bath.• Adult caregivers’ HWWS after contact with stool-7.5 % (4 HWWS/53 opportunities)• 9/23 (39 %) infants took:3 infants- active soil ingestion2 took chicken feces4 took stones from the dirt
    39. 39. Results: Micro phase summaryA one year old ingesting chicken feces, soil and400 ml of contaminated water:On average 10 million E. coli counts/g ofChicken fecesFrequency of E. coli: 22/22 HH (100 %)69 E. coli counts/g of wet shaded area soil:Frequency: 18/22 HH (82 %)800 E. coli counts from water.Frequency: 12/ 22 HH (55 %) Other bacteria population
    40. 40. Key messages• Chicken feces and soil ingestion arepredominant pathways• Exploratory soil ingestion and geophagia couldbe more prevalent in rural Zimbabwe thanobserved for 23 HH - 2 FGDs indicated this.• Water contamination is significant.• Infants HW barely practiced.
    41. 41. Key messages• Caregiver’s HWWS after fecal contact is notcommon.• WASH interventions need to focus more onprotecting infants from eating earth and chickenfeces• The idea of a washable mat or playing pen asa WASH intervention input
    42. 42. IYCF InterventionPromote optimal use of locally available foods,responsive feeding, nutrient density, feeding duringillnessProvide 20 g/d Nutributter 6-18 mo
    43. 43. Prior to Trial Launch
    44. 44. Village Health Worker RevitalizationFull complement recruited, trained (8 months) Providetools (bike, kit, uniforms)
    45. 45. Campaign to promote Exclusivebreastfeeding for all to 6 months1. Health workertraining2. Social marketing
    46. 46. Implement WHO 2010 Prevention of Mother to ChildTransmission of HIV and Infant Feeding Guidance
    47. 47. EE is caused by environmental exposure• Fetuses and newborns do not have it• People acquire it moving into developing countryand lose it moving out• Widely believed:Result of high exposure to fecal contamination inan environment of poor sanitation and hygiene
    48. 48. • EE is a major cause of child stunting• EE can be prevented or reduced bypreventing infants and young children fromingesting human and animal feces through apackage of interventions that improvesanitation and hygiene.Environmental Enteropathy andStunting Hypothesis:
    49. 49. Fecal contaminationEnvironmentAltered bacterial load, compositionand/or timing of colonisationIntestinal inflammation and reducedsurface areaIncreased intestinal permeabilityMicrobial translocationMicrobiomeIntestinalpathologyMicrobial translocationStuntingAnemiaActivates innateimmune system proinflammatorycytokinesImmuneactivationActivates adaptiveimmune systemImmunosenescenceImpaired responsesto vaccinations andinfections IGF-1 Hepcidin Erythropoiesis Iron absorption andmobilization
    50. 50. IGF-1• 70 amino acid polypeptide• Mostly produced by liver• Mediates the effects of growth hormone• Important in fetal and postnatal growth• Endocrine function (paracrine, autocrine)• Highly protein bound– 6 binding proteins– Mostly IGFBP3– Acid labile subunit
    51. 51. Inflammatory markers were higher in stunted infantsP values for all time points 6 w to 12 mo,p<0.0010 3 6 9 12 15 185.05.56.06.57.07.58.0LnCRPMonths0 3 6 9 12 15 1805101520AgeIL-60 3 6 9 12 15 181112131415MonthsLnAGP0 3 6 9 12 15 1801×10062×1006MonthssCD14P values frommultivariate modelsthat includedmaternal education,MUAC, sex, birthweight, and mixedfeeding.P=0.007 P=0.064NSP=0.023stunted
    52. 52. Stunted Non stunted0100200300400500MaternalIGF-1(ng/mL)Mean 95.9 Mean 114.3P=0.020 1000 2000 3000 4000 500005101520InfantIGF-1atbirth(ng/mL)Birth weight (grams)R=0.50P<0.0010 200000 400000 600000 80000001020304050InfantIGF-1atbirth(ng/mL)Infant AGP (MU/L)R=-0.39P<0.001105 106104105106Maternal AGP (MU/L)InfantAGP(MU/L)R=0.52P<0.001Maternal and infant values were correlated at birth
    53. 53. Intestinal Fatty Acid Binding Protein (I-FABP)• Very small (15kD) cytoplasmic protein• Found in enterocytes• Involved in intracellular transport of LCFA• Rapidly released into blood after cellular damage• Predominantly expressed in cells at tips of villi insmall intestine• Elevated in celiac disease compared to healthycontolsDerikx JP, J Clin Gastroenterol 2009
    54. 54. High I-FABP levels in stunted and non-stunted Zimbabwean infantsNon stunted Stunted02000400060008000I-FABP(pg/mL)Non stunted Stunted02000400060008000I-FABP(pg/mL)6 months 12 monthsMedian 859 Median 978 Median 1148Median 1070Healthy controls 172.7 pg/mL (±20.2) – mean age 22 yrs (range 1-61 yrs)Coeliac disease Median 784.7 pg/ml (±145.5)Advanced HIV (adults) 174.4 pg/mLP=0.36 P=0.13
    55. 55. I-FABP was higher in stunted infants0 3 6 9 12 15 1801×10062×1006MonthsI-FABPstuntedP value frommultivariate modelthat includedmaternal education,MUAC, sex, birthweight, and mixedfeeding.P=0.030
    56. 56. Summary• Growth hormone axis is perturbed very early in life inapparently healthy Zimbabwean infants with poorlinear growth.• Small intestinal damage and low-grade inflammationare evident post-natally and associated with stuntingby 18 mo of age• Diarrhea (measured by clinic visits) was notassociated with stunting.• Circulating levels of pro-inflammatory mediators andIGF-1 in mother-infant dyad at birth are associatedwith in utero growth.
    57. 57. Zimbabwe SHINESZimbabwe Sanitation Hygiene Infant NutritionEfficacy StudyObservation: babies with healthier guts and less inflammation grow better.Biological hypothesis: babies who are protected from fecal ingestion willgrow better.Randomized trial hypothesis: babies whose households receive acomprehensive Water Sanitation & Hygiene (WASH) intervention will growbetter.WASHInterventionReducedfecalingestionBetterGrowthSan & HygBehaviorsHealthier Gut& LessInflammation

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