Maternal consumption of a docosahexaenoic acid– containing functional food during pregnancy: benefit for infant performance on problem-solving
but not on recognition memory tasks at age 9 mo1–3
Michelle P Judge, Ofer Harel, and Carol J Lammi-Keefe
ABSTRACT Background: There are few studies reporting on docosahexaenoic acid (DHA, 22:6n 3) supplementation during pregnancy and infant cognitive function. DHA supplementation in pregnancy and infant problem solving in the first year have not been investigated. Objective: We tested the hypothesis that infants born to women who consumed a DHA-containing functional food during pregnancy would demonstrate better problem-solving abilities and recognition memory than would infants born to women who consumed the placebo during pregnancy. Design: In a double-blind, placebo-controlled, randomized trial, pregnant women consumed a DHA-containing functional food or a placebo from gestation week 24 until delivery. Study groups received DHA-containing cereal-based bars (300 mg DHA/92-kcal bar; average consumption: 5 bars/wk; n 14) or cereal-based placebo bars (n 15). The Infant Planning Test and Fagan Test of Infant Intelligence were administered to infants at age 9 mo. The problemsolving trial included a support step and a search step. The procedure was scored on the basis of the infant’s performance on each step and on the entire problem (intention score and total intentional solutions). Scores were generated on the basis of the cumulative performance of the infant on 5 trials. Results: Treatment had significant effects on the performance of problem-solving tasks: total intention score (P 0.017), total intentional solutions (P 0.011), and number of intentional solutions on both cloth (P 0.008) and cover (P 0.004) steps. There were no significant differences between groups in any measure of Fagan Test of Infant Intelligence. Conclusion: These data point to a benefit for problem solving but not for recognition memory at age 9 mo in infants of mothers who consumed a DHA-containing functional food during pregnancy. Am J Clin Nutr 2007;85:1572–7. KEY WORDS Docosahexaenoic acid, DHA, pregnancy, infants, cognition, problem solving, recognition memory, functional food
According to animal studies, specific regions of the brain, including the cerebral cortex, synapses, and retinal rod photoreceptors, have particularly high concentrations of DHA (2– 4). Adequate DHA intake is especially important during pregnancy, because it accumulates in fetal tissue at a particularly high rate during the third trimester (5). Studies conducted in animals provided evidence of disturbances in the brain development of offspring that related to DHA deficiency induced during gestation (6 –10). Farquharson et al (11) showed, on autopsy, that human infants who had received breast milk, which is known to contain DHA, had significantly higher concentrations of DHA in the cerebral cortex than did infants who were fed formula containing no DHA. In the United States and Canada, maternal DHA intake during pregnancy is far below the currently recommended amount of 300 mg/d (12–16), which raises concerns about the neurologic development of infants. The fetal conversion of -linolenic acid (ALA; 18:3n 3) to DHA is extremely limited (17), which compounds this concern. The placenta compensates in part for this limited conversion with a greater preference for the fatty acid– binding protein located in the basal placental membrane for DHA than for other long-chain polyunsaturated fatty acids or their precursors (18 –21). From investigations in humans, we have an appreciation for the importance of supplemental DHA during the postnatal period in improving the problem-solving abilities of term infants (21, 22). We reasoned that maternal DHA intake during gestation likely plays a more critical role than does infant dietary DHA
1 From the Department of Nutritional Sciences, University of Connecticut, Storrs, CT (MPJ); the Pennington Biomedical Research Center and Human Nutrition and Food, School of Human Ecology, Louisiana State University, Baton Rouge, LA (CJL-K); and the Department of Statistics, University of Connecticut, Storrs, CT (OH). 2 Supported by the US Department of Agriculture Initiative for Future Agriculture and Food Systems; Nestec, Ltd, Switzerland; the US Department of Agriculture Agricultural Research Service; the University of Connecticut Research Foundation; the National Fisheries Institute; and the American Dietetic Association Foundation. 3 Address reprint requests to CJ Lammi-Keefe, Human Nutrition and Food, 298 B Knapp Hall, School of Human Ecology, Louisiana State University, Baton Rouge, LA 70803. E-mail: firstname.lastname@example.org. Received October 4, 2006. Accepted for publication January 29, 2007.
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Docosahexaenoic acid (DHA; 22:6n 3) has a central role in regulating the biophysical properties of neural membranes (1).
Am J Clin Nutr 2007;85:1572–7. Printed in USA. © 2007 American Society for Nutrition
DIETARY DHA BENEFITS INFANT PROBLEM SOLVING
TABLE 1 Nutrient content of cereal-based bars consumed by the intervention and placebo groups Nutrient Carbohydrate (g) Dietary fiber (g) Fat (g) Protein (g) Energy (kcal)
TABLE 2 Scoring criteria used for the 2-step problem-solving trial1 Step Cloth step Cloth behavior Fixation No intention (score 0) Play; cover not within reach Fixate away from cover Ignore cover Play; cover not removed Fixate away from toy Ignore toy Possible intention (score 1) Hesitant pulling Fixate briefly away from cover Attempt to grasp Hesitant removal Fixate briefly away from toy Attempt to grasp toy Clear intention (score 2) Pull cloth Fixation cover continuously Pick up cover Remove cover Fixate on toy continuously Pick up toy
Amounts per 23-g bar 18 0.3 1.71 1.3 92
Intervention: 1.7 g fish oil containing 300 mg docosahexaenoic acid; placebo: 1.7 g corn oil.
Cover behavior Cover step Cover behavior Fixation Toy retrieval
intake after birth because the process of cellular differentiation occurs during the fetal period and has been largely completed by birth (23). To our knowledge, only Helland et al (24) and Colombo et al (25) have investigated infant cognitive function (recognition memory and habituation, respectively) related to maternal DHA supplementation. Helland et al (24) investigated recognition memory at 6 and 9 mo of age and reported no advantages for cod liver oil supplementation over placebo. In a subset of that same cohort, however, Helland et al (26) showed a higher intelligence quotient at age 4 y in those children whose mothers consumed the cod liver oil during pregnancy and lactation than in the children whose mothers did not consume cod liver oil. Colombo et al (25) provided evidence of better infant performance on habituation and free-play attention tasks during the first year and less distractibility during the second year in infants whose mothers consumed a DHA-containing food during pregnancy than in infants whose mothers did not. These findings (25, 26) point to the notion that DHA may be particularly beneficial to speed of information processing and attention control but not to memory processes during the first 2 y of life. The aim of the current study was to assess problem-solving and recognition memory abilities of infants at age 9 mo as a function of maternal consumption of a DHA-containing functional food during pregnancy.
SUBJECTS AND METHODS
Adapted from Willatts et al, 1998 (22).
trained researcher interviewed the women for 24-h dietary recalls. Infant medical histories and dietary intake records at ages 4, 6, and 9 mo were obtained from the mother or primary caretaker. Developmental assessments were conducted only on healthy infants, and primary caretakers were instructed to call to reschedule their developmental appointments if infants became ill before a scheduled assessment. Care was also taken to schedule appointments during the time of day when the infant was most alert or active. Subject recruitment was approved and conducted in accordance with ethical standards for human experimentation as outlined by the Office of Research Compliance at both Hartford Hospital and the University of Connecticut. Women with a history of drug or alcohol addiction, hypertension, smoking, hyperlipidemia, renal disease, liver disease, diabetes, or psychiatric disorder were excluded from study participation. Problem solving A 2-step problem-solving test was presented to each infant in the home setting at age 9 mo to evaluate the infant’s ability to execute a series of steps to retrieve a toy (21, 22, 28 –32). Completion of the 2-step problem was scored by assessing the infant’s ability to pull a toy within reach (support step) and to uncover the toy (search step). Video recordings of each problem-solving trial were collected for later scoring. Infants were first presented separately with the support and search steps to provide a period of familiarization before presentation of the 2 collective steps. Once the infant was familiarized, the 2-step problem was presented to each infant 5 times, and performances on all 5 presentations were recorded for later scoring. The 2 main variables used for analyses were total intention score and intentional solutions. The total intention score was generated from the mean score of the 5 individual trials (Table 2). This score was based on cumulative performance on the 2 individual steps; the total potential score was 12. Total intentional solutions represented the number of times the infant was able to complete each of the 5 trials and successfully retrieve the toy. Intentional solutions for each individual step of the 2-step problem were also considered. Video recordings were scored on the basis of the infant’s performance on each step according to a procedure standardized
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Subjects In a double-blind, placebo-controlled trial, 29 pregnant women aged 18 –35 y who were at 20 wk of gestation were recruited. Study groups received the DHA-containing cerealbased bars [1.7 g total fat, 300 mg DHA as low-eicosapentaenoic oil (EPA) fish oil; EPA:DHA 1:8 per bar; n 14] or the cerealbased placebo bars (1.7 g total fat as corn oil; n 15). The amount of DHA in the bars is generally accepted as safe during pregnancy and was set according to current recommendations (27). Women from both study groups were assigned to consume 3, 5, or 7 bars/wk from gestation week 24 until delivery. Overall, women consumed an average of 5 bars/wk (average DHA consumption: 214 mg/d). The cereal-based bars did not differ in energy, carbohydrate, protein, or total fat content (Table 1). Women were instructed to consume bars beginning at gestation week 24 and to continue until delivery. Bars were delivered to women once a month. Women were given logs in which to record bar intake, and these logs were collected monthly. Four times during the trial period (gestation week 22 to delivery), a
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TABLE 3 Group characteristics of the women and infants in the docosahexaenoic acid (DHA) and placebo groups DHA group (n 14)1 Maternal age (y) Maternal education (y) Parity WIC participation (n) Single (n) Married (n) Prepregnancy BMI (kg/m2) Total pregnancy weight gain (kg) Gestational age (wk) Sex Birth weight (g) Infant head circumference (cm) Infant length (cm) APGAR score 1 min 5 min
by Willatts et al (30). Problem-solving trials were administered and scored by a single tester who was blinded to test groups. One-third of the videos were scored by a second rater. Scores between raters were highly correlated (r 0.88 – 0.99, P 0.007) for main outcome and intermediate variables. Recognition memory Recognition memory was assessed with the Fagan Test of Infant Intelligence (FTII) at infant age 9 mo by a single person trained in the procedure (33). In brief, cards with pictures were presented. In this procedure, infants are given time to become familiar with one picture before being presented with a second, novel picture. The time spent looking at each familiar and novel picture was then recorded by using FAGAN TEST for WINDOWS software [version 2.0; InfanTest Corporation, Cleveland, OH (33)]. A computer-generated report detailing the scaled novelty score, risk status, time spent looking, and the number of looks was used for data analyses. Assessments were conducted primarily in the infants’ home environments, and instructions were given to parents before test initiation to minimize potential disturbances, such as sound and light. Statistical analysis All statistical analyses were conducted with SAS software (version 9.1; SAS Institute, Cary, NC) (34). Comparisons between groups for all outcome variables and intermediate steps were conducted by using PROC GLM. Most variables were normally distributed; however, the intentional score for the cover step was skewed and therefore log transformed before analyses. Analyses of baseline characteristics included the Student’s t test for numeric variables and the chi-square test for categorical variables.
Placebo group (n 15) 24 4.1 12 1.7 2.0 0.9 14 11 4 29 7.65 14.2 7.36 39.0 1.0 10 M, 5 F 3222 363 34.4 1.26 50.0 3.3 8.0 8.6 1.85 1.15
P 0.7263 0.3933 0.3093 0.2494 0.4114 0.4114 0.1313 0.2283 0.0193 0.0964 0.1013 0.7023 0.0633 0.5863 0.1533 Downloaded from www.ajcn.org by guest on March 6, 2011
23.5 3.42 12.6 2.2 1.6 0.9 11 12 2 25 4.7 18.0 8.4 39.9 0.8 5 M, 9 F 3465 406 34.2 0.8 52.1 2.3 8.3 9.0 0.6 0
Total number of subjects included in analyses unless otherwise noted. x SD (all such values). 3 Student’s t test. 4 Chi-square test. 5 n 14. 6 n 13.
in the placebo group). The mean maternal dietary DHA intake did not differ significantly between groups: it was 99 mg DHA/d for the entire cohort. Mothers in the intervention group consumed a combined mean DHA intake of 313 mg/d from diet and the DHA-containing functional food. Problem solving A zero score was assigned for the cover behavior in the first step and all subsequent behaviors (ie, cover, fixation, or toy) in the second step if the infant pulled the cloth too far, which made the cover and the toy fall off the table. There were no significant group differences in the number of times that infants pulled the cloth off the table. In the trial, a “tip” occurs when the infant is able to maneuver the cloth to knock the toy onto the table without removing the cover. The act of tipping is an acceptable yet unusual means of retrieving the toy (P Willatts, unpublished observations, 2002). There were no significant group differences in the number of times the toy was tipped onto the table. The raw mean scores by group for all problem-solving variables before adjustment via regression analyses are outlined in Table 4. In addition, we present the P values of the regression analyses after adjustment for confounding variables. Independent and potentially confounding variables included gestational age, maternal hematocrit, prepregnancy body mass index (BMI), maternal education, and infant feeding type. Of these independent variables, only gestational age and baseline maternal hematocrit were significant (P 0.05) within the regression model. Neither maternal hemoglobin nor hematocrit status in the third trimester were significant within the regression model, and, therefore, they were not included. Type I (ie, sequential) sum of squares was chosen on the basis of a low level
There were no significant differences between groups for most of the baseline characteristics, which indicated that the randomization effort was successful (Table 3). The women in the DHA group had a significantly (P 0.019) longer gestational period than did the women in the placebo group, and infant length trended toward being significantly greater in the DHA group (P 0.063). Information regarding the risk of maternal depression was collected via medical record review, and there were no differences between groups when analyzed by using a Student’s t test. The incidence of venereal disease during pregnancy was low in both groups, and there were no significant differences between groups. The modes of infant feeding were categorized as formula with DHA (n 1 and 1 from the intervention and 1 placebo group, respectively); formula containing no DHA (n 5 and 8); breast milk only (n 0 and 2); combination of breast milk and formula containing no DHA (n 3 and 2); breastfed 1–2 mo and then changed to formula containing no DHA (n 3 and 0); and breastfed 2– 4 mo and then changed to formula containing no DHA (n 2 and 2). There were no significant differences between study groups with respect to infant feeding type. There were no group differences in infant age at the time of administration of the FTII (x SD: 279.8 8.9 d in the DHA group and 282.1 10.8 d in the placebo group) or of the problemsolving test (278.3 9.1d in the DHA group and 277.7 6.6 d
DIETARY DHA BENEFITS INFANT PROBLEM SOLVING
TABLE 4 Presentation of raw mean scores by group and results of regression analyses for infant performance on the 2-step problem at 9 mo of age1 DHA group (n 14) Intention score Cloth average Cover average Total average Intentional solutions Cloth Cover Total 4.9 3.1 8.0 3.4 2.5 2.5 0.83 1.8 2.3 1.3 1.3 1.3 Placebo group (n 15) 4.28 2.4 6.7 2.3 1.7 1.7 1.2 1.9 3.0 1.7 1.6 1.5 P2 NS NS 0.017 0.008 0.004 0.011
1 Means outlined are raw scores and do not reflect covariate adjustments. 2 Regression model was adjusted for gestational age, maternal hematocrit, prepregnancy BMI, maternal education, and infant feeding type. 3 x SD (all such values).
of correlation between covariates, which supported the assumption of variable independence. In the regression analyses, significant differences were noted in both total average score and total intentional solutions on the 2-step problem-solving test (Table 4). There were significant group differences for 2 collective steps and intermediate steps of the 2-step problem, including intentional solutions of both the cloth and cover steps (Table 4). Recognition memory Recognition memory was also assessed by using regression analyses. Independent and potentially confounding variables of recognition memory included the maternal educational level, prepregnancy BMI, maternal hematocrit, and infant feeding type. Type I sum of squares was chosen on the basis of a low level of correlation between covariates, which supports the assumption of variable independence. There were no significant differences between groups in the scaled novelty score, risk score, total time needed to complete the test, the total number of looks during the test, or the average amount of time spent looking (Table 5).
Our results show better problem-solving but not recognition memory abilities at age 9 mo in infants whose mothers consumed the DHA-containing functional food during pregnancy than in infants whose mothers did not consume DHA-containing functional food during pregnancy. This is the first study to report on
TABLE 5 Comparison of Fagan Test of Infant Intelligence outcome variables by group at age 9 mo1 DHA group (n 15) Scaled novelty score Risk score Total time No. of looks Time spent looking (s)2 54.8 0.5 322.5 101.7 3.2 6.9 0.8 208.7 18.5 1.8 Placebo group (n 15) 57.7 0.1 317.4 106.3 3.1 5.1 0.5 166.2 21.8 1.6
1 All values are x SD. DHA, docosahexaenoic acid. No significant differences were found between groups by regression analysis.
problem-solving abilities during the first year of life in relation to maternal dietary DHA intake. Our finding of no differences in recognition memory corroborate the findings of Helland et al, who supplemented with fish oil during pregnancy and the first 3 mo of breastfeeding (24). In contrast to the historical understanding, more recent studies of human toddlers (35) and nonhuman primates (36) point to a discontinuity in the development of infant looking and searching tasks. Young infants who understood the location of hidden objects, as shown by their use of a looking task, did not perform as well when asked to search and retrieve an object (35). In a different study, an accelerated decline in look duration was reported during the first year (25), which suggests that visual attention declines in late infancy, making way for more complex integrated attention (37, 38). This decline in looking has been suggested as showing improved processing efficiency and a greater ability to disengage (37, 39). Our finding of no differences between groups in visual attention using the FTII is not surprising, given that the infants were 9 mo old. The work by Colombo et al (25) suggests that the FTII may have been more sensitive at ages 4 and 6 mo. Our finding provides further evidence for the idea that visual attention declines in late infancy; however, the FTII was interesting to consider in parallel with problem solving because problem solving requires the ability to disengage attention from the first step and to proceed to the subsequent steps. Our finding of better problem solving in the DHA group supports the idea that DHA plays a particularly important role in the development of endogenous attention that is required for infants’ goal-directed behavior (38). In the present study, the number of times that infants pulled the cloth off the table during the problem-solving task was the same for both of the study groups, which suggests that our findings are related to mental processing and not to motor control (21). Problem solving requires that an infant both remember that a toy is hidden and be able to pay sufficient attention to execute a series of steps to achieve a goal. In the same study that showed an accelerated decline in look duration, Colombo et al (25) reported that toddlers whose mothers received DHA during pregnancy had less distractibility in the second year than did control subjects. In another study, Dunstan et al (40) reported better hand-eye coordination in toddlers whose mothers received high doses of DHA during pregnancy than in control subjects. Our findings corroborate those of others that infant and toddler endogenous attention in late infancy is affected by maternal DHA supplementation during pregnancy (25, 40). Infant problem-solving or search behavior strategies related to the development of the object concept were first developed in 1953 by the developmental psychologist Piaget (41). The findings from the present study are important from the standpoint of the relation between problem solving in infancy and intelligence quotient in early childhood (42). It has been suggested that problem-solving abilities in infancy are more indicative of infant cognition than are the more standardized tests (28, 42). An important study showing a beneficial effect of DHA on intelligence quotient later in childhood was conducted by using the Kaufman Asessment Battery for Children (mental processing component) at age 4 y in children whose mothers were given cod liver oil supplementation during gestation and during the first few months of breastfeeding (26). Our finding of benefit to problem-solving abilities at age 9 mo complements the report of improved mental processing at 4 y (26) and supports the notion that the endogenous attention that develops during the first year (38) continues
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throughout childhood and is affected by maternal DHA supplementation during pregnancy. The problem-solving mean intentional solutions reported here for the DHA group are slightly higher than those reported for the population studied by Willatts et al (22), which received additional DHA only during the postnatal period. It is interesting that the number of intentional solutions in our placebo group was comparable to the scores that are typically reported (22). These results may point to DHA supplementation during gestation as being particularly beneficial to infant cognitive development. Future studies with the goal of comparing DHA supplementation during the prenatal and postnatal periods with respect to problem solving may help identify the most critical period for DHA supplementation. In addition to better problem solving, infants of the DHA group had a significantly longer period of gestation, which corroborates the findings of Olsen et al (43). From the cognitive standpoint, a longer period of gestation affords the developing fetus more time for central nervous system development. Iron is known to be important to fatty acid synthesis and infant cognitive development and therefore was included as a covariate in our regression model. Generally, fatty acid synthesis has been shown to be dependent on iron-dependent enzymes integral to the metabolic pathway (44). From a cognitive standpoint, iron deficiency is known to have profoundly negative effects on the dopaminergic system, affecting the function of the basal ganglia involved in procedural memory and motor function (45– 47). Procedural memory and motor function are integral to performance on problem-solving tasks. Within our regression model, maternal hemoglobin and hematocrit during the third trimester were not significant, and maternal baseline hematocrit status was the most significant measure of iron status. Although further work is necessary to elucidate the mechanisms underlying observations of better cognitive development related to maternal DHA intake in human infants (25, 26, 40), investigations conducted in animal models have provided some important histologic and cellular information that brings us closer to an answer. The frontal cortex is very important for planning abilities involved in problem solving and is the locale for deep-brain structures, including the basal ganglia. The frontal cortex is particularly vulnerable to DHA insufficiency in piglets and nonhuman primates (48, 49). Autopsies conducted on human infants found significantly greater DHA accumulation in the frontal cortex in infants with 40 wk gestation than in those with 24 wk gestation (50), which supports this possibility. A recent report by Diau et al (51) showed in the nonhuman primate that the basal ganglia, which are important to psychomotor behavior (52), have the highest DHA accumulation of any structure of the brain. Collectively, these results from animal and human studies point to the frontal cortex as being particularly vulnerable to DHA deficits during early development. Our finding of improved infant problem-solving abilities related to maternal DHA intake during pregnancy is underscored by studies conducted on a cellular level in the animal model that link DHA supplementation with functional outcome. These examinations of DHA and central nervous system development have focused primarily on nerve axon growth facilitated by the growth cone, synaptic signaling, and alterations in neurotransmitter production. In a hippocampal cell culture, Calderon et al (53) showed that DHA significantly increased the population of
neurons with longer neurite length per neuron and a higher number of branches than were seen in other fatty acids. The growth cone of the developing neuron appears to be particularly abundant in DHA, and deficiency decreases neuronal growth cone DHA concentrations, which results in an impairment of axonal growth (6, 7). Membranes involved in synaptic communication had significantly lower concentrations of DHA in deficient rats than in control rats. Furthermore, DHA deficiency during gestation modified catecholamine biosynthesis in the brain, induced behavioral disturbances, and decreased learning ability in offspring (54). DHA deficiency induced interruptions in the dopaminergic pathway and there were subsequent functional deficits in the neonatal piglet model (48). These findings are of particular interest because they link DHA deficiency, subsequent altered brain development, and impaired functional status (48, 54). Results from animal models are compelling, and they provide some mechanistic possibilities for our observations in humans. This work highlights the benefits of DHA consumption during pregnancy in a relatively small cohort of women who were mostly unmarried, and future investigations using a larger more heterogeneous population may provide further evidence for the applicability to the general population. An examination of doseeffect relations would be prudent in the future. There is a need for efforts focused on the promotion of safe intake of DHA-rich foods during pregnancy. The developmental advantages reported by us and others (24 –26, 40) contribute to our current understanding of the role of DHA in infant development and should be considered in the development of community education programs related to nutrient needs for pregnant women and women of child-bearing age.
We are grateful to so many who were instrumental in making this project a success. We thank the staff at Hartford Hospital (Women’s Ambulatory Health Services), especially Brunella Ibarrola, Griselle Corcino, Lynn Deasy, and John Greene, who appreciated the importance of this work and supported us in establishing subject recruitment and follow-up procedures; Peter Willatts of the Department of Psychology at the University of Dundee provided us with the technical information and background necessary to implement the problem-solving procedure and interpret the results; James Green and Ann Ferris served as doctoral advisors and participated in project planning; and Stephanie Wei enthusiastically scored the problem-solving videos used to establish reliability for our scoring procedure. University of Connecticut graduate students Amber Courville, Charlotte DeMare, Melissa Keplinger, and Elizabeth McArthur worked collaboratively in recruitment and follow-up activities. We especially thank the families from the Greater Hartford Area who took time from their busy lives to commit to participation in this longitudinal project. The authors’ responsibilities were as follows—MPJ: design, execution, analysis, and manuscript writing; OH: analysis and manuscript writing; and CJL-K: design, analysis, and manuscript writing. None of the authors had a personal or financial conflict of interest.
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