Sex differences in cardiovascular risk may be related to sex differences in diet patterns: a narrative review.

CONTEXT: Cardiovascular disease (CVD) is the leading cause of death in the United States and globally. The social and biological differences in diet patterns among men and women may play a role in their differential cardiovascular risk. OBJECTIVE: To describe the dietary patterns associated with CVD risk and investigate the differences in diet patterns between men and women, if these differences affect cardiovascular risk, and to explore potential mechanisms of action. METHODS: Diet patterns associated with CVD risk were described based on epidemiological and experimental trials. Observational and experimental studies together with systematic and non-systematic reviews were synthesised to examine sex differences in diet and cardiovascular risk factors. RESULTS: Differences in vasculature and body composition between sexes may be mediated by dissimilarities in adherence to diet patterns and nutrient metabolism. Salt sensitivity and breakdown and storage of lipids may account for some differences in CVD risk between men and women. Sex differences in social norms, cognitive processing, and odour perception may be affected by biological differences and contribute to differences in cardiovascular risk and dietary patterns. CONCLUSION: The relation between diet patterns and cardiovascular risk is well-established and sex differences in diet patterns likely differentially affect CVD risk between men and women.

Effect of high-dose cholecalciferol (vitamin D3) on bone and body composition in children and young adults with HIV infection: a randomized, double-blind, placebo-controlled trial.

It is unknown whether vitamin D supplementation positively impacts body composition and bone outcomes in children and young adults with HIV. This RCT found that despite increasing 25(OH)D concentrations, high dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection. INTRODUCTION: The objective of this paper was to determine the impact of high-dose daily cholecalciferol (vitamin D3) supplementation on body composition and bone density, structure, and strength in children and young adults with perinatally acquired (PHIV) or behaviorally acquired (BHIV) HIV infection. METHODS: Participants were randomized to receive vitamin D3 supplementation (7000 IU/day) or placebo for 12 months. Serum 25-hydroxyvitamin D [25(OH)D] concentrations, dual energy X-ray absorptiometry (DXA) of the whole body and lumbar spine, and peripheral quantitative computed tomography (pQCT) of tibia sites were acquired at 0, 6, and 12 months. DXA and pQCT outcomes were expressed as sex- and population-ancestry specific Z-scores relative to age and adjusted for height or tibia length, as appropriate. RESULTS: Fifty-eight participants (5.0 to 24.9 years) received vitamin D3 supplements (n = 30) or placebo (n = 28). At enrollment, groups were similar in age, sex, population ancestry, growth status, serum 25(OH)D concentrations, body composition, and size-adjusted bone measures. Median 25(OH)D concentrations were similar (17.3 ng/mL in the vitamin D3 supplementation group vs 15.6 ng/mL in the placebo group), and both groups had mild bone deficits. At 12 months, 25(OH)D rose significantly in the vitamin D supplementation group but not in the placebo group (26.4 vs 14.8 ng/mL, respectively, p < 0.008). After adjusting for population ancestry, sex, antiretroviral therapy use, and season, there were no significant treatment group differences in bone or body composition outcomes. CONCLUSIONS: Despite increasing 25(OH)D concentrations, 12 months of high-dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection.

The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial.

OBJECTIVES: We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength. METHODS: This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency. Power was quantified using peak jump power, and energy was quantified using peak jump height. Muscular force was quantified using isometric ankle plantar- and dorsiflexion, isokinetic knee flexion and extension. Muscular strength was quantified using isometric handgrip strength. RESULTS: After 12-months, serum 25-hydroxyvitamin D [25(OH)D] was higher with supplementation versus placebo (ß=12.1 ng/mL; P<0.001). In intention-to-treat analyses, supplementation improved neuromuscular motor skills versus placebo (ß=1.14; P=0.041). We observed no effect of supplementation on jump power, jump energy, muscular force, or muscular strength outcomes versus placebo. CONCLUSIONS: Among HIV-infected children and young adults supplementation with daily high-dose vitD3 increased concentration of serum 25(OH)D and improved neuromuscular motor skills versus placebo.

Total Energy Expenditure of Infants with Congenital Heart Disease Who Have Undergone Surgical Intervention.

Growth failure is often observed in infants with congenital heart disease (CHD); it is unclear, however, whether growth failure is due to increased total energy expenditure (TEE). An observational study of infants with CHD and surgical intervention within the first 30 days of life and healthy infants of similar age was undertaken. TEE was measured using the doubly labeled water method in 3-month-old infants (n = 15 CHD, 12 healthy) and 12-month-old infants (n = 11 CHD, 12 healthy). Multiple linear regression models were fit to examine the association between health status (CHD vs. healthy) and TEE. The accuracy of equations for calculating TEE was also determined. TEE for CHD infants was not significantly different from healthy infants at 3 and 12 months; TEE in CHD infants was 36.4 kcal/day higher (95 % CI -46.3, 119.2; p = 0.37) and 31.7 kcal/day higher, (95 % CI -71.5, 134.8; p = 0.53) at 3 and 12 months, respectively, compared to healthy infants. The 2002 Dietary Reference Intake (DRI) equation and the 1989 Recommended Dietary Allowance equation over-estimated measured TEE to a lesser extent than CHD specific equations; the 2002 DRI yielded the smallest mean difference between calculated versus measured TEE (difference 79 kcal/day). During the first year of life, TEE of infants with CHD and interventional surgery within the first month of life was not different than age-matched healthy infants. When calculating TEE of ≤12-month-old infants with CHD who have undergone surgical intervention, the 2002 DRI equation may be used as a starting point for estimating initial clinical energy intake goals.

Early rapid weight gain among formula-fed infants: Impact of formula type and maternal feeding styles.

BACKGROUND: What and how infants are fed are considered important determinants for the risk factor of early rapid gain weight. OBJECTIVES: We conducted secondary analyses on data from a randomized clinical trial, wherein infants randomized to feed cow milk formula had double the incidence of early rapid weight gain than those fed extensively hydrolyzed protein formula, to determine whether maternal feeding styles had independent effects or interactive effects with infant formula type on early rapid weight gain. METHODS: Anthropometry and feeding patterning (number of daily formula feeds) were measured monthly, and maternal feeding styles were measured at 0.5, 3.5, and 4.5 months. Longitudinal models were fitted using generalized estimating equations and separate logistic models conducted. RESULTS: The treatment groups did not differ in formula feeding patterning or in maternal feeding styles, which were stable across the first 4.5 months. Feeding styles had no significant effects on early rapid weight gain and did not interact with formula group. However, type of infant formula had a direct and independent impact on early rapid weight gain (P = 0.003). CONCLUSIONS: The type of infant formula had a differential impact on early rapid weight gain independent of maternal feeding style, highlighting the self-regulatory capabilities of infants.

Building better bones in childhood: a randomized controlled study to test the efficacy of a dietary intervention program to increase calcium intake.

BACKGROUND/OBJECTIVES: Many children do not consume the recommended daily allowance of calcium. Inadequate calcium intake in childhood may limit bone accrual. The objective of this study was to determine if a behavioral modification and nutritional education (BM-NE) intervention improved dietary calcium intake and bone accrual in children. SUBJECTS/METHODS: 139 (86 female) healthy children, 7-10 years of age, were enrolled in this randomized controlled trial conducted over 36 months. Participants randomized to the BM-NE intervention attended five sessions over a 6-week period designed to increase calcium intake to 1500 mg/day. Participants randomized to the usual care (UC) group received a single nutritional counseling session. The Calcium Counts Food Frequency Questionnaire was used to assess calcium intake; dual energy X-ray absorptiometry was used to assess areal bone mineral density (aBMD) and bone mineral content (BMC). Longitudinal mixed effects models were used to assess for an effect of the intervention on calcium intake, BMC and aBMD. RESULTS: BM-NE participants had greater increases in calcium intake that persisted for 12 months following the intervention compared with UC. The intervention had no effect on BMC or aBMD accrual. Secondary analyses found a negative association between calcium intake and adiposity such that greater calcium intake was associated with lesser gains in body mass index and fat mass index. CONCLUSIONS: A family-centered BM-NE intervention program in healthy children was successful in increasing calcium intake for up to 12 months but had no effect on bone accrual. A beneficial relationship between calcium intake and adiposity was observed and warrants future study.

High energy expenditure is not protective against increased adiposity in children.

BACKGROUND: Low levels of energy expenditure (TEE) may contribute to excess weight during childhood, but limited longitudinal data exist. OBJECTIVES: This is to test whether low TEE during the first 6 years of life could predict excess weight status at 8 years. METHODS: Total energy expenditure from doubly labelled water, weight, stature, waist circumference and fat mass and fat-free mass (FFM) in children at 0.25, 2, 4 and 6 years of age. This cohort includes individuals at high (n = 27) and low risk (n = 26) for childhood obesity, based upon whether pre-pregnant maternal obesity. A linear mixed effects model was fit to TEE. Individual variation was accounted for as a random effect. Residual TEE was calculated for age and individually averaged across time. RESULTS: Fat-free mass (kg) was highly correlated (R2 = 0.91) with TEE (kcal/day), and waist circumference and sex were also significant predictors of TEE. TEE residual tracked within individuals. TEE residuals did not correlate with either BMI or %fat at age 8 years. CONCLUSION: Using the residual TEE approach to identify high and low TEE during the first 6 years of life did not explain excess weight at 8 years of life in this cohort of children at high and low risk of obesity based upon maternal obesity status.

Evaluation of low density spine software for the assessment of bone mineral density in children.

Pediatric dual-energy X-ray absorptiometry spine scans often cannot be analyzed with standard software due to a failure to identify the bone edges of low density vertebrae. Low density spine (LDS) software improves bone detection compared with standard software. The objective of this study was to compare bone mineral density (BMD) measurements obtained with the standard and LDS software in 27 healthy nonobese, 32 obese, and 41 chronically ill children, ages 2-18 years. Lumbar spine (L1-L4) BMD, measured by standard analysis, ranged from 0.531-1.244 gm/cm2. Reanalysis with the LDS software resulted in a systematic increase (mean +/- SD) in estimated bone area of 17.0+/-5.0%, an increase in bone mineral content of 6.1+/-6.3%, and a mean decrease in BMD of 8.7+/-1.7% (all p < 0.001). This resulted in a mean decrease in BMD Z score of 0.7+/-0.2. Linear regression models, predicting standard BMD from LDS BMD, were fit for the three subject groups (R2 = 0.993-0.995). Small differences in slopes were detected across groups (p = 0.07); LDS BMD predicted higher standard BMD in obese subjects. In conclusion, LDS analysis resulted in a clinically significant decrease in measured BMD. The association between analysis methods was exceptionally high (R2 > 0.99), indicating that LDS BMD accurately predicts standard BMD. Although LDS BMD in obese subjects predicts higher standard BMD results than in nonobese subjects, the small difference is of questionable clinical significance. LDS software is a useful tool for the assessment of BMD in children.

The effects of naltrexone, an oral beta-endorphin antagonist, in children with the Prader-Willi syndrome.

Children with the Prader-Willi syndrome have severe and often intractable hyperphagia unresponsive to medical or surgical treatment. Although the effect of opioid antagonists on suppressing appetite in humans has been inconsistent, we evaluated the effectiveness of a new opioid antagonist, naltrexone, in suppressing appetite in four obese adolescents with the Prader-Willi syndrome. Data were collected during the double blind oral administration of the drug and placebo for two 7-day periods. No clinical or biochemical toxicity was apparent during the naltrexone period, and measures of attention span, alertness, and mood did not change. Nutrient intake remained excessive during both the drug and placebo periods. Thus, naltrexone was ineffective in suppressing appetite, at least during the short term.

Survey of clinical nutrition training programs for physicians.

Clinical nutrition training programs for physicians were surveyed to determine their number, demographic characteristics, primary teaching focuses, number of available trainee positions, funding bases, trainee numbers, backgrounds, and career positions taken. Twenty-two active programs were identified, compared with 38 programs in 1993. Thirteen of the programs were primarily focused on adult nutrition and 7 were focused on pediatric nutrition. Twelve programs appeared to have nutrition as their sole subspecialty focus, 8 were housed within gastroenterology fellowships, and 2 were within endocrinology fellowships. Most programs included training in research, which is conducted during a second or third year, or both. The decrease in numbers of programs appears to have resulted not only from relocation, retirement of key faculty members, and loss of training grants, but also because of the clearer definition of clinical nutrition training programs in this survey. The changes also reflect a national trend toward decreasing subspecialization. Within this climate, it is apparent that a new model for the training and career activities of physician nutrition specialists is needed that will attract more physicians into the discipline of nutrition. Intersociety efforts are underway to address this need and to develop a unified voice that can guide clinical nutrition training for physicians into the 21st century.

Potassium, magnesium, and calcium balance in obese adolescents on a protein-sparing modified fast.

Ten obese adolescents consumed the protein-sparing modified fast (PSMF), a high-protein, low-carbohydrate diet, for 92 +/- 19 d and lost 14.7 +/- 5.3 kg. The effect of weight loss using the PSMF on potassium, magnesium, and calcium was evaluated using balance method at days 2-4 and 12-20, RBC-Mg, RBC-K and total body K (TBK). The vitamin- and mineral-supplemented PSMF allowed positive Ca and K balance and improved Mg balance (p less than 0.005). TBK decreased significantly, 118.7 +/- 13.7 to 97.4 +/- 1.0 g (3.04 +/- 0.35 to 2.50 +/- 0.03 mol) from baseline to 90 d (p less than 0.001), with no change in the RBC-K concentration. An unexpected finding was a significant decrease in RBC-Mg, 3.2 +/- 1.1 to 1.8 +/- 0.3 mmol/L (p less than 0.001) after 60-90 d on the diet despite maintenance of normal serum Mg level.

Body composition of children with cystic fibrosis with mild clinical manifestations compared with normal children.

Because growth and anthropometric measurements are frequently below normal in patients with cystic fibrosis (CF), the body composition of 23 children (6-9 y of age) who had mild manifestations of CF was examined and compared with a control group of 24 subjects similar in age, sex, and weight. Skinfold measurements, total body water (TBW) by deuterium oxide dilution, and total body electroconductivity (TOBEC) were measured. Skinfold and TBW measurements demonstrated that fat mass and fat-free mass did not differ significantly between the two groups. No significant difference in percent body fat was found by using the skinfold equations of Slaughter et al (13.8% vs 15.3%), although percent body fat (TBW method) differed between the groups (P < 0.05). TOBEC measurements (CF, n = 14) were not used in the group comparison. The majority of the methods demonstrated that the CF group achieved normal growth and body composition, with a possible trend of fat depletion.

One-year follow-up of weight, total body potassium, and total body nitrogen in obese adolescents treated with the protein-sparing modified fast.

Seventeen obese adolescents were treated with the protein-sparing modified fast (PSMF), a high-protein, low-carbohydrate, low-calorie diet, for approximately 3 mo and then followed for a total of 12 mo. The diet provided a mean of 880 kcal.kg-1. d-1 and 2.5 g protein. kg IBW-1. d-1. Body composition was determined using four skinfold measurements, total body potassium (TBK), and total body nitrogen (TBN) at baseline, 3 mo, and 12 mo. Twelve subjects returned for follow-up at 1 y (71%) and 48% had sustained weight loss with the percentage ideal body weight for height decreased from 154 to 125 over the year. Six subjects had TBK and TBN measured and TBK decreased 13.0% and TBN decreased 14.3% over the year. This reflected a change toward normalization of the predicted TBK from 121 to 102% and TBN from 119 to 102%.

Energy expenditure of children and adolescents with severe disabilities: a cerebral palsy model.

Spastic quadriplegic cerebral palsy (SQCP) is a severe disability that is associated with abnormal physical activity, body composition, and food intake and with frequent malnutrition. This study examined the pattern of dietary intake, anthropometry, and energy expenditure in a group of subjects with SQCP aged 2-18 y and a normal control group. The energy expenditure pattern was determined from resting energy expenditure (REE, n = 61 SQCP; n = 37 control group) by using indirect calorimetry and from total energy expenditure (TEE, n = 32 SQCP; n = 32 control group) by using the doubly labeled water method. Physical activity, including the chronic spasticity of SQCP, was estimated from the ratio of TEE to REE. Abnormal growth and body composition were common and dietary intake was markedly overreported in the children with SQCP. Children with SQCP were divided according to body fat stores determined by triceps-skinfold-thickness measurements. The children with low fat stores had a lower REE adjusted for fat-free mass compared with the SQCP and control groups with adequate fat stores. TEE was significantly lower for the SQCP group than for the control group. The ratio of TEE to REE, indicating energy for nonbasal needs, was significantly lower in the SQCP children than in the control group, with the adequately nourished SQCP children having lower ratios than the more poorly nourished SQCP group. The nonbasal energy expenditure, such as for physical activity and spasticity, of children with SQCP was low. The nutrition-related growth failure and abnormal pattern of REE are likely related to inadequate energy intake.

Energy intake, not energy output, is a determinant of body size in infants.

BACKGROUND: It has been proposed that the primary determinants of body weight at 1 y of age are genetic background, as represented by parental obesity, and low total energy expenditure. OBJECTIVE: The objective was to determine the relative contributions of genetic background and energy intake and expenditure as determinants of body weight at 1 y of age. DESIGN: Forty infants of obese and 38 infants of lean mothers, half boys and half girls, were assessed at 3 mo of age for 10 risk factors for obesity: sex, risk group (obese or nonobese mothers), maternal and paternal body mass index, body weight, feeding mode (breast, bottle, or both), 3-d energy intake, nutritive sucking behavior during a test meal, total energy expenditure, sleeping energy expenditure, and interactions among them. RESULTS: The only difference between risk groups at baseline was that the high-risk group sucked more vigorously during the test meal. Four measures accounted for 62% of the variability in weight at 12 mo: 3-mo weight (41%, P = 0.0001), nutritive sucking behavior (9%, P = 0.0002), 3-d food intake (8%, P = 0.0002), and male sex (3%, P = 0.05). Food intake and sucking behavior at 3 mo accounted for similar amounts of variability in weight-for-length, body fat, fat-free mass, and skinfold thickness at 12 mo. Contrary to expectations, neither total nor sleeping energy expenditure at 3 mo nor maternal obesity contributed to measures of body size at 12 mo. CONCLUSIONS: Energy intake contributes significantly to measures of body weight and composition at 1 y of age; parental obesity and energy expenditure do not.

Effect of chemotherapy on the energy and protein metabolism of children near the end of treatment for acute lymphoblastic leukemia.

Eight children in the final 3 mo of chemotherapy for acute lymphoblastic leukemia were studied while on oral 6-mercaptopurine (6MP) maintenance therapy and then again 4-9 mo after chemotherapy had been completed. Six of the eight were also studied a second time while on 6MP in the 24-h period after receiving intravenous methotrexate (MTX). 6MP reduced protein oxidation after a test meal and reduced fasting urinary urea excretion by enhancing the reutilization of endogenous amino acids for protein synthesis. MTX had no detectable effects on protein metabolism but reduced overnight carbohydrate utilization by enhancing fat utilization. A similar enhancement of fat utilization was evident after a test meal. The two drugs in combination resulted in effects on protein and energy metabolism that were the sum of the individual effects plus an increase in the rate of whole-body protein turnover and synthesis.

Early risk factors for increased adiposity: a cohort study of African American subjects followed from birth to young adulthood.

BACKGROUND: Obesity is an increasing concern in the United States. Effective prevention of obesity requires the risk factors to be well defined. African Americans have a high risk of obesity. OBJECTIVE: The objective of this study was to identify risk factors, present at birth, for increased adiposity in adulthood in an African American population. DESIGN: In this retrospective analysis of a prospective cohort study, anthropometric and socioeconomic variables were collected at birth. A representative sample of 447 African American subjects was followed up until young adulthood, when skinfold thickness was measured. Associations between the independent variables and increased adiposity (skinfold thickness above the 85th percentile) were explored by using unadjusted and adjusted analyses. RESULTS: Three variables measured at birth were independently associated with adiposity in young adulthood, explaining 12% of the variance. The odds ratios (with 95% CIs) of these variables for increased adiposity were 2.7 (1.2, 6.2) for female sex, 4.0 (1.4, 11. 2) for first-born status, and 1.15 (1.06, 1.25) for each unit increment in maternal prepregnancy body mass index (BMI; in kg/m(2)). After adjustment for these variables, birth weight for gestational age and socioeconomic variables were not associated with adiposity. CONCLUSIONS: This cohort study of African American subjects was the first to identify first-born status as an independent risk factor for increased adiposity in adulthood in a US population. The results of the study strengthen previous reports of the effect of female sex and maternal BMI on adulthood obesity. Identification of risk factors early in life may help target prevention toward high-risk children and allow healthy lifestyles to be established before the onset of obesity.

Prospective evaluation of growth, nutritional status, and body composition in children with cystic fibrosis.

BACKGROUND: Several cross-sectional studies have shown improvement in the growth of children with cystic fibrosis (CF) because of increased awareness of and more comprehensive care of their special nutritional needs. However, longitudinal data on the nutritional status of these children are rare. OBJECTIVE: The objective was to compare changes in growth, body composition, and nutritional status between children with and without CF. DESIGN: This was a prospective 3-y cohort study of 25 children aged 5-10 y with CF, mild pulmonary disease, and pancreatic insufficiency and of 26 healthy control children. Three methods were used to assess body composition: measurements of skinfold thickness, total body water by deuterium oxide, and total-body electrical conductivity. Growth and body-composition changes over time were analyzed by a longitudinal mixed-effects model. RESULTS: Over the 3 y of the study, the statural growth of the boys with CF was slower than that of the control subjects (P = 0.004). The same divergence over time between the boys with and without CF was observed for fat-free mass assessed by skinfold-thickness measurements and total body water (P = 0.008 and 0.02, respectively) and for fat mass assessed by skinfold-thickness measurements and total-body electrical conductivity (P = 0.009 and 0.001, respectively). The differences in the pattern of changes in growth and body composition were less striking for girls. CONCLUSIONS: Despite comprehensive care, the growth of boys with CF was impaired on the basis of height, fat-free mass, and fat mass, when observed longitudinally. Caution should be used when interpreting cross-sectional measurements because they often do not detect suboptimal growth.

Nutrition training in graduate medical (residency) education: a survey of selected training programs.

Because limited information exists about nutrition training of residents, we studied the teaching practices of nationally recognized nutrition programs. Two hundred thirty-eight nutrition educators and 787 residency-program directors identified 160 institutions with strong nutrition training. The 23 highest-ranked programs were surveyed and 7 were visited. The results showed that 1) clinically active physician-nutritionist role models are the key elements in teaching residents clinical nutrition; 2) multidisciplinary nutrition support teams are valuable learning resources unless they function primarily as technical support services; 3) nutrition elective rotations, although highly effective, are taken by a minority of residents; 4) the nutrition curriculum should include practical learning materials and conferences; and 5) a research environment is important to attract qualified physician-nutritionist role models. A major deficit is teaching nutritionally based approaches to disease prevention in the ambulatory setting. Finally, a shortage of nutrition-oriented physician role models is probably the major constraint in teaching nutrition to residents.

Dietary intake of healthy children with cystic fibrosis compared with normal control children.

Because a low calorie intake may result in growth failure and malnutrition in patients with cystic fibrosis (CF), the dietary and energy intakes of 22 children with CF who had mild lung disease and excellent Shwachman scores were examined and compared with those of 23 normal control subjects similar in age (5 to 10 years), gender, and weight. The children with CF consumed significantly more calories than the control subjects. Calorie intake was 111 +/- 19.9% (mean +/- SD) of estimated requirements (World Health Organization recommendations) for the CF group and 97 +/- 18.7% for the control group (P = .014). Calories consumed per kilogram of body weight were 117% of World Health Organization (CF) vs 97% (control) (P = .009). Calorie intake compared to the 1989 Recommended Dietary Allowance was 106 +/- 20.6% for the CF group vs 93 +/- 19.1% for the control group. Fat consumed as a percent of total calories was similar: 33.5% (CF) vs 32.2% (control). All children with CF had pancreatic insufficiency and, on average, consumed a large number of pancreatic enzyme supplements, resulting in dietary fat absorption of 86 +/- 12%. It is concluded that these children with CF were able to maintain normal growth and energy stores on a diet that was relatively high in calories compared to control subjects and moderate in percent fat, along with an aggressive pancreatic enzyme supplement regimen.