Cystic fibrosis (CF) is an autosomal recessive genetic disorder that occurs approximately in one of every 2500 live births in the United States. Cystic fibrosis is characterized by multiorgan system involvement primarily affecting the lungs and the digestive tract. Pancreatic insufficiency (PI), which occurs in 85% to 90% of subjects with CF (1), is associated with inadequate digestion and absorption of dietary fat and other nutrients and is a major cause of the malnutrition, delayed growth and development seen in CF. In 2004, 90% of the patients with CF in the United States reported using pancreatic enzyme replacement therapy (PERT) as part of their dietary regimen (1).
Several studies have shown that better growth and nutritional status is strongly associated with better pulmonary function and survival in children with CF (2–8). Clinical nutrition and PERT management are the critical aspects of care to meet the nutritional needs of children with CF and PI to achieve optimal growth and nutritional status. However, despite these efforts, children with CF and PI have not achieved normal growth status with 24% falling below the 10th percentile for weight-for-age (1,9). Studies have found that the energy intake of children with CF was similar to their healthy peers. However, they failed to meet the CF dietary recommendations of greater than 120% for energy needed by healthy children and greater than 40% of calories from fat (10). Only 11% to 34% of children with CF met the goal of greater than 120% energy intake (11–17). Furthermore, adherence to treatment regimens in children and adults with CF has been found to be moderate to good for medications, including PERT, and poor to moderate for airway clearance (ie, chest physiotherapy) and dietary recommendations (11,14,18–21). Behavioral interventions have been successful in boosting overall energy intake and weight status in children aged 4 to 12 years (22,23). Less is known regarding strategies for improving meal- or snack-specific fat intake and PERT adherence in this age group. National data show that growth status begins to decline in children with CF after the age of 4 years, and pulmonary function declines through adolescence (1). Gaining a better understanding of adherence to PERT and dietary patterns during the preadolescent period may potentially help to prevent these declines.
The purpose of this study was to describe adherence to CF PERT and dietary recommendations, to investigate meal- and snack-specific fat composition and PERT adherence and to explore the relationship of PERT adherence to growth and pulmonary status in a sample of preadolescent school-age children with CF and PI.
PATIENTS AND METHODS
Subjects and Protocol
At enrollment, subjects ages 6.0 to 8.9 years from 13 CF centers in the United States were participating in a 24-month prospective study of nutritional status and lung disease. The diagnosis of CF and PI was established by the home CF center using clinical signs and duplicate sweat sodium and chloride measurements of greater than 60 mmol/L. Pancreatic insufficiency was determined from analysis of a 72-hour fecal fat sample with less than 93% absorption and/or an abnormal stool trypsin value of less than 80 μg/g. Exclusion criteria included the following: forced expiratory volume in 1 second (FEV1) of less than 40% predicted, significant liver disease, insulin dependent diabetes mellitus and Burkholderia cepacia sputum colonization. The data for this report were from the 24-month visit, when subjects were ages 8 to 11 years. The most complete and reliable information for meal and enzyme use patterns was available for this visit.
Children were evaluated in their usual state of health during an overnight visit at the General Clinical Research Center at the Children's Hospital of Philadelphia. Evaluations included 7-day weighed food record, use of pancreatic enzymes, percent estimated energy requirement (% EER), fat intake as percent Kcal, coefficient of fat absorption from a 72-hour stool collection, anthropometry, physical examination and pulmonary function test. The study protocol was approved by the Committee for the Protection of Human Subjects of the institutional review board at the Children's Hospital of Philadelphia and the subject's home institution. Informed consent was obtained from the parent and assent from each child.
Dietary Assessment and Enzyme Supplementation
Parent/caregiver and subjects were trained to collect accurate 7-day food records. They were given detailed verbal and written instructions for completing the 7-day dietary food record, which included all food and drink consumed in addition to reporting enzyme use at each meal and snack during each day for the course of the week. Measuring cups, spoons and an electronic digital food scale were provided, and the General Clinical Research Center research dietitians analyzed diet records. Maintaining usual food patterns and accuracy of reporting was encouraged. Families were encouraged to phone in for assistance while filling in these records accurately, and when the 7-day dietary recalls were sent in, follow-up phone calls were made to help families achieve greater accuracy in reporting. The Nutrition Data System (Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN) was used to obtain total energy intake and percent calories from protein, carbohydrate and fat per eating event per day.
The prescribed dose of enzyme number, brand and lipase units (LU) for meals and snacks were obtained from parental/caregiver report. As part of the 7-day food records, parents/caretaker recorded the number of enzyme capsules (number, brand and LU) actually taken with each eating event. Also, as part of this detailed record, enzyme use was documented as to whether the capsules were taken before, during or after the eating event or as a split dose. Expected intake included 3 meals (breakfast, lunch and dinner) and 3 snacks per day (morning, afternoon and evening), and missed eating events were noted.
Energy Intake and Loss
Energy intake was assessed using the Dietary Reference Intakes (24), which adjusts for height, weight and physical activity level. In a previous study of preadolescent children with CF (25), the ratio of total energy expenditure to resting energy expenditure was 1.68, which corresponds to the Dietary Reference Intakes' active level of physical activity (24). Therefore, energy intake was expressed as % EER for active children. The CF guidelines recommend that individuals with CF consume 120% EER or greater with 40% or greater energy from fat (10,26), equivalent to 3 meals and 3 snacks per day (27,28). After each annual protocol visit, a 72-hour stool collection was obtained; total fat content was determined (29) (Mayo Medical Laboratories, Rochester, MN), and coefficient of fat absorption was calculated from dietary fat intake and fat loss in the stool (30).
Adherence to PERT and Meal Pattern Recommendations
Adherence to PERT was assessed in 4 ways. First, a PERT adherence ratio (LU taken/LU prescribed) was calculated for all 7 days and averaged for each eating event and each day. For the purposes of this study, subjects were categorized into 3 groups based upon their PERT adherence ratio: 80% or greater was defined as good adherence; 60% to 79% as moderate adherence; and less than 60% as poor adherence to enzyme use. In this study, the levels of adherence were chosen to be generally compatible with those found for medication in other studies of subjects with CF (18–20). Second, using CF PERT safety and efficacy recommendations, subjects were classified as below, within or above enzyme guidelines. The 2 types of recommendations of 500 to 4000 LU/g of fat intake per day and 500 to 2500 LU/kg of body weight per meal were used (10,27,28,31). Snacks PERT recommendation were half of the enzyme dose amount used for meals, 250 to 1250 LU/kg of body weight per snack. Third, subjects were categorized according to timing of enzyme consumption around the eating events. The recommended timing for enzyme ingestion is either before or during the meal (32). The number of meals and snacks missed by each eating event (breakfast, lunch, evening snack, etc) was assessed, and the percent of total meals/snacks missed for the week was determined using the 3 meals and 3 snacks for possible meals (27). Finally, the percent of meals/snacks when enzymes were missed was calculated using the total number of meals eaten by each individual for 7 days as the denominator.
Anthropometric and Pulmonary Measures
Weight was measured using a digital scale (Scaletronix, White Plains, NY), and height was obtained with a Holtain (Crymych, United Kingdom) stadiometer. Body mass index was calculated as weight (kg)/height (m)2, and weight, height and body mass index values were compared with National Center for Health Statistics standards and z scores determined (9). Biological parental height was measured or reported, if unavailable, and used to calculate midparental height. The parental height method (33) was used to evaluate the subject height for genetic potential, and the parent-adjusted height was used to determine an adjusted height-for-age z score (9). Evaluation included incentive spirometry and lung volume measurements after administration of albuterol and chest physiotherapy. Percent predicted FEV1 was compared with reference values derived from Knudsen equations (34,35) and also from Wang equations (36). Genotype was obtained from medical records, or when unknown, a blood sample was submitted for determination (Genzyme Genetics, Pittsburgh, PA). Subjects were categorized as having DF508 homozygous genotype or having other genotypes including DF508 heterozygous or a combination of other mutations.
Data were analyzed using both descriptive and inferential statistical techniques. Measures of central tendency and variability were calculated for each outcome. Descriptive statistics are presented as mean ± standard deviation (SD) or median (range), depending upon skewness. Comparisons of continuous variables (ie, energy and fat intake, weight z score, FEV1, LU prescribed and taken per day, percent of meals missed per week, or percent meals when enzymes were not taken per week) by the 3 PERT adherence ratio groups or by the PERT adherence to guidelines groups (LU per gram of fat per day or LU per body weight per meal) were performed using analysis of variance. Post hoc Student t tests were used to determine the significance of the differences between specific groups. Sex differences were determined using Student t tests, and the χ2 test was used for categorical variables. Pearson correlation coefficients were used to explore associations between PERT adherence ratio and other measures of adherence (ie, percent meals missed per week), energy and fat intake, growth and pulmonary function status.
Ninety-one subjects were enrolled and 86 subjects completed the 24-month study. One subject was lost to follow-up and 4 declined to continue participation. For this analysis, 75 subjects had complete 7-day diet and enzyme records. There were no significant differences in age, sex, growth and nutritional or pulmonary status between the 11 subjects with incomplete data and the 75 with complete data.
Based upon the PERT adherence ratio of LU taken/LU prescribed per day, 29% of the subjects had good (≥80%) PERT adherence; 61% had moderate (60%–79%) and 9% had poor (<60%) PERT adherence. The PERT adherence ratio for the entire sample was 75 ± 14% (mean ± SD). Characteristics of the sample as a whole and of the subjects by PERT adherence ratio groups are presented in Table 1. In the entire sample, growth status was suboptimal (adjusted height-for-age z score, −0.7 ± 1.1; weight-for-age z score, −0.4 ± 1.2); percent predicted FEV1 was 91 ± 14 using Knudsen equations (34,35) and 95 ± 16 using Wang equations (36), and the coefficient of stool fat absorption was 85 ± 13% (not shown). Fifty-seven percent of the children were homozygous for DF508. Median energy intake was 2219 calories per day or 115% EER, and fat intake was 92 g of fat per day with 37% calories from fat. Sixty-one percent did not meet the CF recommendations of 120% or greater EER, and 72% did not achieve the recommended 40% calories from fat. Subjects missed 24% of meal or snack events per week, and these events were mostly snacks. Subjects missed a median of 0 meals and 1.3 snacks per day; enzymes were missed at 4% of meal/snack events that occurred per week.
There were no significant differences between PERT adherence ratio groups in LU per day of enzymes prescribed. As expected, children with good adherence to PERT took significantly more LU per day of enzymes than children with moderate or poor PERT adherence (P < 0.001). They also missed significantly fewer snacks per day and meals or snacks per week. In addition to taking lower doses of enzymes than prescribed at eating events, children with poor PERT adherence missed taking enzymes more frequently than children with moderate or good adherence to PERT. Children with poor PERT adherence also tended toward lower energy and fat intakes and better growth status, although this did not reach significance. When used as a continuous variable, however, the PERT adherence ratio was significantly negatively correlated with the percent of meals or snacks missed per week (r = −0.62, P < 0.001) and adjusted height-for-age z score (r = −0.28, P < 0.01) and positively correlated with energy intake as % EER (r = 0.28, P < 0.01). No significant differences were found between PERT adherence ratio groups and pulmonary function or genotype.
Sex differences were also explored. Despite being similar to girls in age, weight, height and dietary fat intake, boys were prescribed significantly more enzymes than girls (mean ± SD: 259,346 ± 85,882 vs 216,542 ± 84,330; P = 0.03), and boys tended to take more enzymes (192,330 ± 68,517 vs 162,343 ± 70,868; P = 0.07). There were no sex differences in PERT adherence or meals missed, pulmonary function or genotype.
The prescribed and actual PERT by each meal and snack during the 7-day period using LU per kilogram body weight per event are presented in Table 2. Fat intake was assessed for each eating event, with the greatest intake at the dinner meal and least for the morning snack. The average LU per kilogram body weight per meal fell within the guidelines of 500 to 2500 LU/kg per meal for both enzymes prescribed and enzymes taken. Average LU per kilogram per snack also fell within the guidelines (250–1250 LU/kg per snack). Similarly, overall LU per gram of fat per day were 2987 for prescribed and 2201 for actually taken enzymes and these fell within the recommended 500 to 4000 LU/g of fat per day (not shown). Subjects had better adherence to PERT at meals than snacks. Only 4% to 16% of the subjects had PERT adherence ratio of less than 80% at meals, whereas from 30% to 51% had less than 80% adherence for snacks: 15% to 43% had poor (<60%) adherence to snacks. Adherence was best for the dinner meal and the worst for the morning snack. Few meals were missed during the 7-day period (1% to 4%), although many snacks were missed (38% to 56%). The PERT adherence ratio was significantly correlated with the fat content of breakfast (r = 0.29, P = 0.01) but not lunch or dinner and was significantly correlated with the fat content of all snacks (r = 0.28–0.44, P < 0.02).
Adherence to the PERT recommendation of 500 to 4000 LU/g of fat per day and associations with weight status, total daily fat intake and the PERT adherence ratio are shown in Table 3. Most (88%) of the children fell within this guideline, whereas 4% took less and 8% took more than what is recommended. Children falling below the recommended guideline had better weight status and tended to have lower PERT adherence ratio, whereas children above the guideline had lower fat content in their meals or snacks.
Adherence to the PERT recommendations for LU per kilogram per eating event and associations with weight status, fat content of each eating event and the PERT adherence ratio are shown in Table 4, using 500 to 2500 LU/kg per meal and 250 to 1250 LU/kg per snack as the recommended levels. For meals, 85% to 89% of the children fell within the guidelines, whereas 5% to 7% were below the recommended doses, and 4% to 8% were above the recommended doses. Weight status was significantly and inversely associated (P < 0.05) with adherence to the guidelines because those children who fell below the recommended doses had higher weight status, and those above had lower weight status. For snacks, 58% to 68% fell within the guidelines, whereas 8% to 24% were below, and 18% to 23% were above the recommended doses. For both the morning and the afternoon snacks, the fat content was significantly and positively associated with adherence to the PERT guidelines. The PERT adherence ratio, the more general measure of overall adherence to PERT, was more strongly associated with adherence to the guidelines of LU per kilogram of body weight for snacks than for meals. Percent predicted FEV1 was not associated with adherence to the guidelines of either the LU per gram of fat per day or the LU per kilogram body weight per meal (not shown).
Most of the children (61%) took PERT before an eating event or split the dose before and during (13%) or before and after the event (8%). Eleven percent took PERT after eating events, either all of the time (8%) or some of the time (3%).
The management of PI with food intake and PERT is essential to supporting optimal growth and nutritional status in children with CF. In this study, we described overall adherence to PERT and dietary recommendations and also elucidated meal- and snack-specific patterns of PERT use and fat intake in preadolescent school-aged children with CF and PI. Most of the children did not meet CF dietary recommendation for greater than 120% energy requirement (61%) or greater than 40% calories as fat (72%) recommendations (10,26). Based upon PERT adherence ratio of LU taken/LU prescribed, 29% of the children had good (ratio, ≥80%) adherence to PERT; 61% had moderate (ratio, 60% to 79%) and 9% had poor adherence (ratio, <60%) to PERT. This level of adherence to PERT was comparable to that in other studies of children and adolescents with CF, where overall PERT adherence (actual use to prescribed use) was good to moderate, ranging from 70% to 85% (11,16,18–20). Few studies, however, described PERT adherence in association with specific eating events or have specifically examined adherence to PERT clinical care guidelines. The CF consensus report on nutrition (10) provides 2 approaches for PERT use: 500 to 4000 LU/g of fat per day and 500 to 2500 LU/kg per body weight per meal and 250 to 1250 LU/kg per body weight per snack. Using the method of LU per gram of fat per day, 88% of the children in our sample fell within the guidelines. Using the method of LU per kilogram per body weight per meal, adherence was good for meals (85% to 89% within the guidelines) and moderate for snacks (58% to 68%). Adherence to PERT was negatively associated with growth status, that is, children with poorer growth status were more adherent to PERT use; conversely, children with better growth status were less adherent. The PERT adherence was better in children who ate snacks more frequently and whose snacks had higher fat content. Pulmonary function was not associated with PERT adherence. The timing of enzyme ingestion around eating events was inappropriate in 11% of the children, who routinely took enzymes after the completion of the meal or snack.
Despite the fact that clinical nutrition and PERT management are both integral parts of CF care, children with CF and PI have not achieved normal growth status (1). Better growth and nutritional status has been associated with both survival (3–5) and pulmonary function (2,6–8) in CF. Understanding the adherence to PERT and dietary patterns may be particularly important for the preadolescent age group because growth status declines during this period. From the 2004 CF Foundation Patient Registry data, the median weight status peaks for children with CF at the 40th percentile at the age of 3 to 4 years and then steadily declines to the 22nd percentile at the age of 12 years (1,9). Pulmonary function begins to decline through adolescence (1), and older children with CF are less adherent to treatment, with adherence problems particularly increasing around the age of 10 years (21). Therefore, the preadolescent period may be a critical one for targeting efforts to improve dietary and PERT adherence in an effort to help prevent these declines in growth and pulmonary status.
Studies have shown that most children with CF failed to meet the CF dietary recommendations of greater than 120% energy requirement for their age and sex or greater than 40% calories as fat intake (11–13,16,37). From other studies, only 11% to 34% of infants, toddlers and school-age children consumed greater than 120% of their energy requirement (11,13,16,37). In our sample of 8- to 11-year-olds, 39% achieved greater than 120% energy requirement.
Rates of poor adherence vary depending on the health condition, severity, duration, regimen requirement and developmental stage of the child (38,39). In pediatric patients, in general, poor adherence to treatment regimens was common: approximately 50% adherence for medications and lower for more demanding treatments, such as dietary modifications, glucose monitoring and physical therapy (39–41). Similarly, in subjects with CF, there was greater adherence to prescribed medications, vitamin supplementation and PERT than to chest physiotherapy and dietary recommendations (11,14,18–21). In 1981, Passero et al. (20), in a study of 58 children and adults, found excellent adherence (∼90%) to medications and vitamins, moderate adherence (40%) to chest physiotherapy and poor adherence to dietary alterations (20%). A decade later, Gudas et al. (19) interviewed 100 subjects with CF, ages 5 to 20 years, and their parents and physicians and found high rates of adherence (85%) for medications which included enzymes but only moderate adherence to airway clearance and diet (65%). In 1996, with their first study on PERT adherence under current standards of CF care, Conway et al. (18) examined adherence including PERT in 80 adolescents and adults (ages 14 to 40 years) in a regional CF center in the United Kingdom. Adherence to PERT was better for meals than for snacks; 85% of the subjects reported good, and 12% reported moderate PERT adherence with meals; whereas 38% reported good, 36% reported moderate and 20% reported poor PERT adherence with snacks. Our results in preadolescent children were similar, with 84% to 96% of the subjects having 80% or better adherence to PERT for meals but only 50% to 70% for snacks. In 1999, Ievers et al. (42) also reported moderate adherence to PERT in a study of child and maternal knowledge of physician treatment recommendations. In summary, our finding of an overall PERT adherence ratio of 75% was comparable to the rates found for a broader age range of patients in other studies.
Other CF studies have explored the timing of enzyme administration with meals. In a 1998 study of CF PERT administration in 47 families and subjects (1–26 years), Rusakow et al. (43) found that 19% of the subjects took enzymes exclusively after meals, a practice that is considered least effective and inappropriate. In the present study, 11% of the children were taking enzymes after meals and snacks.
In our sample, children with the poorest weight status had the best PERT adherence. Other studies have confirmed a relationship between greater disease severity and greater adherence. In a study of adherence to airway clearance and aerosolized medications in 96 children, aged 9 to 16 years, and their parents, DeLambo et al. (44) found that more severely ill children were more likely to adhere to treatment than those with milder disease. Conway et al. (18) also found a significant association between overall adherence scores and disease severity in 14- to 40-year-old patients with CF. Children with more severe illness may experience more immediate benefits from PERT, and they and their caregivers may be more motivated to adhere to PERT.
There are many barriers to adherence to both dietary and PERT recommendations for patients of all ages with CF, and many have been specifically identified for school-aged children. Dietary guidelines stressing increased energy and fat intake are in opposition to the low-fat diet promoted for Americans. Many children receive similar messages regarding the composition of a healthy diet at home, at school and from the public media (16). Savage and Callery (45) found that parents of early adolescent children with CF who gained weight expressed concerns regarding their children eating “fatty foods.” In contrast, parents of those children who were losing weight or had poor growth status stress the importance of their children's increasing fat and energy intake. Even with appropriate enzyme use, some children experience stomachaches and diarrhea associated with increased fat intake and may develop taste aversions to fatty foods. Ineffective parent-child interactions at mealtimes have been shown to adversely affect adherence to dietary recommendations (37,46). Family communication problems and high levels of stress resulted in poorer adherence to treatments (21,47). Educational and behavioral interventions directed at facilitating better family interactions at mealtimes improved adherence to dietary recommendations and have proved successful in young school-aged children in boosting energy intake and promoting weight gain (22,23,48). The complexity and time requirement of the treatment regimens in CF are additional barriers to adherence, as is the lack of specific knowledge of caregivers and children regarding prescribed regimens (21,42,47). The work of Quittner et al. (21) suggested that providing detailed information about specifically prescribed treatments leads to greater adherence. Although specific barriers to PERT and dietary adherence were not explored in our study, results suggest certain target areas for interventions for PERT use with specific meals and snacks, snack fat content and timing of enzyme consumption. Our results also suggest that more attention to children with better growth status is required to ensure that they improve adherence to PERT and dietary recommendations and prevent the future declines in growth and pulmonary status often observed in this age group.
One unexpected finding was that boys were prescribed and tended to take more enzymes than girls, although there were no sex differences in age, body weight, dietary fat intake or PERT adherence. These findings may reflect caregiver bias on the part of the medical team and/or the family. Also, there may be more parental or caregiver sensitivity to the small size of male subjects, as has been suggested for children with growth delay and short stature (49).
There are a number of limitations to this study. First, parental recall of prescribed PERT was an indirect measure of prescribed PERT. It reflects the parents' knowledge and understanding of PERT recommendation and may differ from prescribed PERT. In the study by Ievers et al. (42), examining child (aged 6 to 12 years) and maternal knowledge of physician recommendations and adherence for PERT, maternal report of prescribed enzymes was very similar to prescriptions documented in the medical charts (r = 0.98 for meals and r = 0.84 for snacks; P < 0.001). A second limitation of the study was that the sample was restricted to families who completed the 7-day weighed food records. Adherence to PERT and dietary recommendations may have been overestimated in this sample because it may have included the most adherent families. Third, overreporting of dietary intake and PERT adherence may occur among parents of children with CF because they may place more importance on their child's health and nutrition than they would on healthy siblings (37). Finally, it may be more difficult to get accurate reporting of meal patterns and PERT adherence among school-aged children than among infants and toddlers because some meals and snacks occur away from home and are not as easy to capture. Strengths of the study include a large sample of children within a particular developmental stage and age range recruited from multiple CF centers, which enhances the generalizability of the study. Also, the examination of dietary and PERT patterns for each meal and snack provides new information for targeted research and care interventions.
In summary, most of these preadolescent children with CF and PI failed to meet the CF recommendations for energy and fat intake. Future educational, behavioral and general interventions should focus on the improvement in meal and snack composition, timing of enzyme ingestion and teaching the skills of adjustment of enzymes for specific meal or snack fat intake. Improvement in these food and medication behaviors may significantly improve the growth failure in some patients with CF and PI.
The authors sincerely thank all of the children and their families for participating in the study and the General Clinical Research Center and Nutrition Center at The Children's Hospital of Philadelphia for providing excellent research support. They also sincerely thank the Center Directors and staff at the 13 Cystic Fibrosis Centers from which the children were recruited: the Albany Medical Center (Albany, NY); Emory University (Atlanta, GA); Children's Hospital of Buffalo (Buffalo, NY); Children's Hospital of Philadelphia (Philadelphia, PA); Children's Medical Center (Dayton, OH); Children's National Medical Center (Washington, DC); Hershey Medical Center (Hershey, PA); Johns Hopkins Children's Center (Baltimore, MD); Long Island College Hospital (Brooklyn, NY); St. Christopher's Hospital for Children (Philadelphia, PA); Schneider Children's Hospital of Long Island (New Hyde Park, NY); State University New York at Stony Brook (Stony Brook, NY) and University of Florida (Gainesville, FL).
The authors participated in the following ways in creating this manuscript: the conception and design of this study (J.I.S. and V.A.S.), the acquisition of the data (V.A.S. and J.I.S.), the interpretation of the data (J.I.S., T.B. and V.A.S.) and the writing and revision of the manuscript for intellectual content (J.I.S., T.B. and V.A.S.). All authors have read and approved the final version of the manuscript to be submitted for publication. The authors have no conflicts of interest.
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