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Weight management in young adults with type 1 diabetes: The advancing care for type 1 diabetes and obesity network sequential multiple assignment randomized trial pilot results.
Igudesman, D, Crandell, J, Corbin, KD, Zaharieva, DP, Addala, A, Thomas, JM, Casu, A, Kirkman, MS, Pokaprakarn, T, Riddell, MC, et al
Diabetes, obesity & metabolism. 2023;(3):688-699
Abstract
AIMS: Co-management of weight and glycaemia is critical yet challenging in type 1 diabetes (T1D). We evaluated the effect of a hypocaloric low carbohydrate, hypocaloric moderate low fat, and Mediterranean diet without calorie restriction on weight and glycaemia in young adults with T1D and overweight or obesity. MATERIALS AND METHODS We implemented a 9-month Sequential, Multiple Assignment, Randomized Trial pilot among adults aged 19-30 years with T1D for ≥1 year and body mass index 27-39.9 kg/m2 . Re-randomization occurred at 3 and 6 months if the assigned diet was not acceptable or not effective. We report results from the initial 3-month diet period and re-randomization statistics before shutdowns due to COVID-19 for primary [weight, haemoglobin A1c (HbA1c), percentage of time below range <70 mg/dl] and secondary outcomes [body fat percentage, percentage of time in range (70-180 mg/dl), and percentage of time below range <54 mg/dl]. Models adjusted for design, demographic and clinical covariates tested changes in outcomes and diet differences. RESULTS Adjusted weight and HbA1c (n = 38) changed by -2.7 kg (95% CI -3.8, -1.5, P < .0001) and -0.91 percentage points (95% CI -1.5, -0.30, P = .005), respectively, while adjusted body fat percentage remained stable, on average (P = .21). Hypoglycaemia indices remained unchanged following adjustment (n = 28, P > .05). Variability in all outcomes, including weight change, was considerable (57.9% were re-randomized primarily due to loss of <2% body weight). No outcomes varied by diet. CONCLUSIONS Three months of a diet, irrespective of macronutrient distribution or caloric restriction, resulted in weight loss while improving or maintaining HbA1c levels without increasing hypoglycaemia in adults with T1D.
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Associations of Dietary Intake with the Intestinal Microbiota and Short-Chain Fatty Acids Among Young Adults with Type 1 Diabetes and Overweight or Obesity.
Igudesman, D, Crandell, JL, Corbin, KD, Hooper, J, Thomas, JM, Bulik, CM, Pence, BW, Pratley, RE, Kosorok, MR, Maahs, DM, et al
The Journal of nutrition. 2023;(4):1178-1188
Abstract
BACKGROUND Diet, a key component of type 1 diabetes (T1D) management, modulates the intestinal microbiota and its metabolically active byproducts-including SCFA-through fermentation of dietary carbohydrates such as fiber. However, the diet-microbiome relationship remains largely unexplored in longstanding T1D. OBJECTIVES We evaluated whether increased carbohydrate intake, including fiber, is associated with increased SCFA-producing gut microbes, SCFA, and intestinal microbial diversity among young adults with longstanding T1D and overweight or obesity. METHODS Young adult men and women with T1D for ≥1 y, aged 19-30 y, and BMI of 27.0-39.9 kg/m2 at baseline provided stool samples at baseline and 3, 6, and 9 mo of a randomized dietary weight loss trial. Diet was assessed by 1-2 24-h recalls. The abundance of SCFA-producing microbes was measured using 16S rRNA gene sequencing. GC-MS measured fecal SCFA (acetate, butyrate, propionate, and total) concentrations. Adjusted and Bonferroni-corrected generalized estimating equations modeled associations of dietary fiber (total, soluble, and pectins) and carbohydrate (available carbohydrate, and fructose) with microbiome-related outcomes. Primary analyses were restricted to data collected before COVID-19 interruptions. RESULTS Fiber (total and soluble) and carbohydrates (available and fructose) were positively associated with total SCFA and acetate concentrations (n = 40 participants, 52 visits). Each 10 g/d of total and soluble fiber intake was associated with an additional 8.8 μmol/g (95% CI: 4.5, 12.8 μmol/g; P = 0.006) and 24.0 μmol/g (95% CI: 12.9, 35.1 μmol/g; P = 0.003) of fecal acetate, respectively. Available carbohydrate intake was positively associated with SCFA producers Roseburia and Ruminococcus gnavus. All diet variables except pectin were inversely associated with normalized abundance of Bacteroides and Alistipes. Fructose was inversely associated with Akkermansia abundance. CONCLUSIONS In young adults with longstanding T1D, fiber and carbohydrate intake were associated positively with fecal SCFA but had variable associations with SCFA-producing gut microbes. Controlled feeding studies should determine whether gut microbes and SCFA can be directly manipulated in T1D.
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Design of the Advancing Care for Type 1 Diabetes and Obesity Network energy metabolism and sequential multiple assignment randomized trial nutrition pilot studies: An integrated approach to develop weight management solutions for individuals with type 1 diabetes.
Corbin, KD, Igudesman, D, Addala, A, Casu, A, Crandell, J, Kosorok, MR, Maahs, DM, Pokaprakarn, T, Pratley, RE, Souris, KJ, et al
Contemporary clinical trials. 2022;:106765
Abstract
Young adults with type 1 diabetes (T1D) often have difficulty co-managing weight and glycemia. The prevalence of overweight and obesity among individuals with T1D now parallels that of the general population and contributes to dyslipidemia, insulin resistance, and risk for cardiovascular disease. There is a compelling need to develop a program of research designed to optimize two key outcomes-weight management and glycemia-and to address the underlying metabolic processes and behavioral challenges unique to people with T1D. For an intervention addressing these dual outcomes to be effective, it must be appropriate to the unique metabolic phenotype of T1D, and to biological and behavioral responses to glycemia (including hypoglycemia) that relate to weight management. The intervention must also be safe, feasible, and accepted by young adults with T1D. In 2015, we established a consortium called ACT1ON: Advancing Care for Type 1 Diabetes and Obesity Network, a transdisciplinary team of scientists at multiple institutions. The ACT1ON consortium designed a multi-phase study which, in parallel, evaluated the mechanistic aspects of the unique metabolism and energy requirements of individuals with T1D, alongside a rigorous adaptive behavioral intervention to simultaneously facilitate weight management while optimizing glycemia. This manuscript describes the design of our integrative study-comprised of an inpatient mechanistic phase and an outpatient behavioral phase-to generate metabolic, behavioral, feasibility, and acceptability data to support a future, fully powered sequential, multiple assignment, randomized trial to evaluate the best approaches to prevent and treat obesity while co-managing glycemia in people with T1D. Clinicaltrials.gov identifiers: NCT03651622 and NCT03379792. The present study references can be found here: https://clinicaltrials.gov/ct2/show/NCT03651622 https://clinicaltrials.gov/ct2/show/NCT03379792?term=NCT03379792&draw=2&rank=1 Submission Category: "Study Design, Statistical Design, Study Protocols".
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Precision Medicine Approach to Develop and Internally Validate Optimal Exercise and Weight-Loss Treatments for Overweight and Obese Adults With Knee Osteoarthritis: Data From a Single-Center Randomized Trial.
Jiang, X, Nelson, AE, Cleveland, RJ, Beavers, DP, Schwartz, TA, Arbeeva, L, Alvarez, C, Callahan, LF, Messier, S, Loeser, R, et al
Arthritis care & research. 2021;(5):693-701
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OBJECTIVE To apply a precision medicine approach to determine the optimal treatment regime for participants in an exercise (E), dietary weight loss (D), and D + E trial for knee osteoarthritis that would maximize their expected outcomes. METHODS Using data from 343 participants of the Intensive Diet and Exercise for Arthritis (IDEA) trial, we applied 24 machine-learning models to develop individualized treatment rules on 7 outcomes: Short Form 36 physical component score, weight loss, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain/function/stiffness scores, compressive force, and interleukin-6 level. The optimal model was selected based on jackknife value function estimates that indicate improvement in the outcomes if future participants follow the estimated decision rule compared to the optimal single, fixed treatment model. RESULTS Multiple outcome random forest was the optimal model for the WOMAC outcomes. For the other outcomes, list-based models were optimal. For example, the estimated optimal decision rule for weight loss indicated assigning the D + E intervention to participants with baseline weight not exceeding 109.35 kg and waist circumference above 90.25 cm, and assigning D to all other participants except those with a history of a heart attack. If applied to future participants, the optimal rule for weight loss is estimated to increase average weight loss to 11.2 kg at 18 months, contrasted with 9.8 kg if all participants received D + E (P = 0.01). CONCLUSION The precision medicine models supported the overall findings from IDEA that the D + E intervention was optimal for most participants, but there was evidence that a subgroup of participants would likely benefit more from diet alone for 2 outcomes.
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Dietary intake on days with and without hypoglycemia in youth with type 1 diabetes: The Flexible Lifestyle Empowering Change trial.
Igudesman, D, Crandell, J, Zhong, VW, Cristello Sarteau, A, Kahkoska, AR, Corbin, K, Pratley, R, Kosorok, MR, Maahs, DM, Mayer-Davis, EJ
Pediatric diabetes. 2020;(8):1475-1484
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OBJECTIVE To address a common perception that hypoglycemia is associated with increased dietary intake, we examined calorie and carbohydrate consumption on days with and without hypoglycemia among adolescents with type 1 diabetes (T1D). METHODS Days (N = 274) with 24-hour dietary recalls and continuous glucose monitoring were available for 122 adolescents with T1D in the Flexible Lifestyle Empowering Change trial (age 13-16 years, diabetes duration >1 year, hemoglobin A1c 8%-13%). Days with no hypoglycemia, clinical hypoglycemia (54-69 mg/dL) or clinically serious hypoglycemia (<54 mg/dL) were further split into night (12-5:59 am) and day (6 am-11:59 pm). Mixed models tested whether intake of calories or carbohydrates was greater on days with than without hypoglycemia. RESULTS Fifty-nine percent, 23% and 18% of days had no hypoglycemia, clinical hypoglycemia and clinically serious hypoglycemia, respectively. Intake of calories and carbohydrates was not statistically significantly different on days with clinical hypoglycemia (57.2 kcal [95% CI -126.7, 241.5]; 12.6 g carbohydrate [95% CI -12.7, 38.0]) or clinically serious hypoglycemia (-74.0 kcal [95% CI -285.9, 137.9]; (-7.8 g carbohydrate [95% CI -36.8, 21.1]), compared to days without hypoglycemia. Differences by day and night were not statistically significant. CONCLUSIONS Among adolescents with T1D, daily intake of calories and carbohydrates did not differ on days with and without hypoglycemia. It is possible that hypoglycemic episodes caused by undereating relative to insulin dosing, followed by overeating, leading to a net neutral difference. Given the post-hoc nature of these analyses, larger studies should be designed to prospectively test the hypoglycemia-diet relationship.
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Identification of clinically relevant dysglycemia phenotypes based on continuous glucose monitoring data from youth with type 1 diabetes and elevated hemoglobin A1c.
Kahkoska, AR, Adair, LA, Aiello, AE, Burger, KS, Buse, JB, Crandell, J, Maahs, DM, Nguyen, CT, Kosorok, MR, Mayer-Davis, EJ
Pediatric diabetes. 2019;(5):556-566
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BACKGROUND/OBJECTIVE To identify and characterize subgroups of adolescents with type 1 diabetes (T1D) and elevated hemoglobin A1c (HbA1c) who share patterns in their continuous glucose monitoring (CGM) data as "dysglycemia phenotypes." METHODS Data were analyzed from the Flexible Lifestyles Empowering Change randomized trial. Adolescents with T1D (13-16 years, duration >1 year) and HbA1c 8% to 13% (64-119 mmol/mol) wore blinded CGM at baseline for 7 days. Participants were clustered based on eight CGM metrics measuring hypoglycemia, hyperglycemia, and glycemic variability. Clusters were characterized by their baseline features and 18 months changes in HbA1c using adjusted mixed effects models. For comparison, participants were stratified by baseline HbA1c (≤/>9.0% [75 mmol/mol]). RESULTS The study sample included 234 adolescents (49.8% female, baseline age 14.8 ± 1.1 years, baseline T1D duration 6.4 ± 3.7 years, baseline HbA1c 9.6% ± 1.2%, [81 ± 13 mmol/mol]). Three Dysglycemia Clusters were identified with significant differences across all CGM metrics (P < .001). Dysglycemia Cluster 3 (n = 40, 17.1%) showed severe hypoglycemia and glycemic variability with moderate hyperglycemia and had a lower baseline HbA1c than Clusters 1 and 2 (P < .001). This cluster showed increases in HbA1c over 18 months (p-for-interaction = 0.006). No other baseline characteristics were associated with Dysglycemia Clusters. High HbA1c was associated with lower pump use, greater insulin doses, more frequent blood glucose monitoring, lower motivation, and lower adherence to diabetes self-management (all P < .05). CONCLUSIONS There are subgroups of adolescents with T1D for which glycemic control is challenged by different aspects of dysglycemia. Enhanced understanding of demographic, behavioral, and clinical characteristics that contribute to CGM-derived dysglycemia phenotypes may reveal strategies to improve treatment.
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Assessment of a Precision Medicine Analysis of a Behavioral Counseling Strategy to Improve Adherence to Diabetes Self-management Among Youth: A Post Hoc Analysis of the FLEX Trial.
Kahkoska, AR, Lawson, MT, Crandell, J, Driscoll, KA, Kichler, JC, Seid, M, Maahs, DM, Kosorok, MR, Mayer-Davis, EJ
JAMA network open. 2019;(5):e195137
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IMPORTANCE The Flexible Lifestyles Empowering Change (FLEX) trial, an 18-month randomized clinical trial testing an adaptive behavioral intervention in adolescents with type 1 diabetes, showed no overall treatment effect for its primary outcome, change in hemoglobin A1c (HbA1c) percentage of total hemoglobin, but demonstrated benefit for quality of life (QoL) as a prespecified secondary outcome. OBJECTIVE To apply a novel statistical method for post hoc analysis that derives an individualized treatment rule (ITR) to identify FLEX participants who may benefit from intervention based on changes in HbA1c percentage (primary outcome), QoL, and body mass index z score (BMIz) (secondary outcomes) during 18 months. DESIGN, SETTING, AND PARTICIPANTS This multisite clinical trial enrolled 258 adolescents aged 13 to 16 years with type 1 diabetes for 1 or more years, who had literacy in English, HbA1c percentage of total hemoglobin from 8.0% to 13.0%, a participating caregiver, and no other serious medical conditions. From January 5, 2014, to April 4, 2016, 258 adolescents were recruited. The post hoc analysis excluded adolescents missing outcome measures at 18 months (2 participants [0.8%]) or continuous glucose monitoring data at baseline (40 participants [15.5%]). Data were analyzed from April to December 2018. INTERVENTIONS The FLEX intervention included a behavioral counseling strategy that integrated motivational interviewing and problem-solving skills training to increase adherence to diabetes self-management. The control condition entailed usual diabetes care. MAIN OUTCOMES AND MEASURES Subgroups of FLEX participants were derived from an ITR estimating which participants would benefit from intervention, which would benefit from control conditions, and which would be indifferent. Multiple imputation by chained equations and reinforcement learning trees were used to estimate the ITR. Subgroups based on ITR pertaining to changes during 18 months in 3 univariate outcomes (ie, HbA1c percentage, QoL, and BMIz) and a composite outcome were compared by baseline demographic, clinical, and psychosocial characteristics. RESULTS Data from 216 adolescents in the FLEX trial were reanalyzed (166 [76.9%] non-Hispanic white; 108 teenaged girls [50.0%]; mean [SD] age, 14.9 [1.1] years; mean [SD] diabetes duration, 6.3 [3.7] years). For the univariate outcomes, a large proportion of FLEX participants had equivalent predicted outcomes under intervention vs usual care settings, regardless of randomization, and were assigned to the muted group (HbA1c: 105 participants [48.6%]; QoL: 63 participants [29.2%]; BMIz: 136 participants [63.0%]). Regarding the BMIz univariate outcome, mean baseline BMIz of participants assigned to the muted group was lower than that of those assigned to the intervention and control groups (muted vs intervention: mean difference, 0.48; 95% CI, 0.21 to 0.75; P = .002; muted vs control: mean difference, 0.86; 95% CI, 0.61 to 1.11; P < .001); this group also had a higher proportion of individuals with underweight or normal weight using weight status cutoffs (95 [69.9%] in muted group vs 24 [54.6%] in intervention group and 11 [30.6%] in control group; χ24 = 24.67; P < .001). The approach identified subgroups estimated to benefit based on HbA1c percentage (54 participants [25.0%]), QoL (89 participants [41.2%]), and BMIz (44 participants [20.4%]). Regarding the HbA1c percentage outcome, participants expected to benefit from the intervention did not have significantly higher baseline HbA1c percentages than those expected to benefit from usual care (9.4% vs 9.2%; difference, 0.2%; 95% CI, -0.16% to 0.56%; P = .44). However, participants in the muted group had higher mean HbA1c percentages at baseline than those assigned to the intervention or control groups (muted vs intervention: 9.9% vs 9.4%; difference, 0.5%; 95% CI, 0.13% to 0.89%; P = .02; muted vs control; 9.9% vs 9.2%; difference, 0.7%; 95% CI, 0.34% to 1.08%; P = .001). No significant differences were found between subgroups estimated to benefit in terms of the composite outcome from the FLEX intervention (91 participants [42.1%]) vs usual care (125 participants [57.9%]). CONCLUSIONS AND RELEVANCE The precision medicine approach represents a conceptually and analytically novel approach to post hoc subgroup identification. More work is needed to understand markers of positive response to the FLEX intervention. TRIAL REGISTRATION ClinicalTrial.gov identifier: NCT01286350.
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Longitudinal Phenotypes of Type 1 Diabetes in Youth Based on Weight and Glycemia and Their Association With Complications.
Kahkoska, AR, Nguyen, CT, Adair, LA, Aiello, AE, Burger, KS, Buse, JB, Dabelea, D, Dolan, LM, Malik, FS, Mottl, AK, et al
The Journal of clinical endocrinology and metabolism. 2019;(12):6003-6016
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CONTEXT Subclinical and clinical complications emerge early in type 1 diabetes (T1D) and may be associated with obesity and hyperglycemia. OBJECTIVE Test how longitudinal "weight-glycemia" phenotypes increase susceptibility to different patterns of early/subclinical complications among youth with T1D. DESIGN SEARCH for Diabetes in Youth observational study. SETTING Population-based cohort. PARTICIPANTS Youth with T1D (n = 570) diagnosed 2002 to 2006 or 2008. MAIN OUTCOME MEASURES Participants were clustered based on longitudinal body mass index z score and HbA1c from a baseline visit and 5+ year follow-up visit (mean diabetes duration: 1.4 ± 0.4 years and 8.2 ± 1.9 years, respectively). Logistic regression modeling tested cluster associations with seven early/subclinical diabetes complications at follow-up, adjusting for sex, race/ethnicity, age, and duration. RESULTS Four longitudinal weight-glycemia clusters were identified: The Referent Cluster (n = 195, 34.3%), the Hyperglycemia Only Cluster (n = 53, 9.3%), the Elevated Weight Only Cluster (n = 206, 36.1%), and the Elevated Weight With Increasing Hyperglycemia (EWH) Cluster (n = 115, 20.2%). Compared with the Referent Cluster, the Hyperglycemia Only Cluster had elevated odds of dyslipidemia [adjusted odds ratio (aOR) 2.22, 95% CI: 1.15 to 4.29], retinopathy (aOR 9.98, 95% CI: 2.49 to 40.0), and diabetic kidney disease (DKD) (aOR 4.16, 95% CI: 1.37 to 12.62). The EWH Cluster had elevated odds of hypertension (aOR 2.18, 95% CI: 1.19 to 4.00), dyslipidemia (aOR 2.36, 95% CI: 1.41 to 3.95), arterial stiffness (aOR 2.46, 95% CI: 1.09 to 5.53), retinopathy (aOR 5.11, 95% CI: 1.34 to 19.46), and DKD (aOR 3.43, 95% CI: 1.29 to 9.11). CONCLUSIONS Weight-glycemia phenotypes show different patterns of complications, particularly markers of subclinical macrovascular disease, even in the first decade of T1D.
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A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns.
Gourley, GR, Li, Z, Kreamer, BL, Kosorok, MR
Pediatrics. 2005;(2):385-91
Abstract
OBJECTIVES Neonatal jaundice is a greater problem for infants fed breast milk, compared with formula. This study tested the hypotheses that feeding breastfed newborns beta-glucuronidase inhibitors during the first week after birth would increase fecal bilirubin excretion and would reduce jaundice without affecting breastfeeding deleteriously. METHODS Sixty-four breastfed newborns were randomized to 4 groups, ie, control or receiving 6 doses per day (5 mL per dose) of L-aspartic acid, enzymatically hydrolyzed casein (EHC), or whey/casein (W/C) for the first week. L-aspartic acid and EHC inhibit beta-glucuronidase. Transcutaneous bilirubin levels (primary outcome) were measured daily (Jaundice Meter [Minolta/Air Shields, Hatboro, PA] and Bilicheck [Respironics, Pittsburgh, PA]). All stools were collected, and fecal bile pigments, including bilirubin diglucuronide, bilirubin monoglucuronides, and bilirubin, were analyzed with high-performance liquid chromatography. Follow-up assessments included day 7 body weight, day 6/7 prebreastfeeding/postbreastfeeding weights, maternal ratings, and ages at formula introduction and breastfeeding cessation. RESULTS The groups were comparable at entry. Overall, the L-aspartic acid, EHC, and W/C groups had significantly lower transcutaneous bilirubin levels than did the control group (75.8%, 69.6%, and 69.2%, respectively, of the control mean, 8.53 mg/dL, at the bilirubin peak on day 4). The L-aspartic acid, EHC, and W/C groups had significantly lower transcutaneous bilirubin levels on days 3 to 7. Fecal bile pigment excretion was greatest in the L-aspartic acid group, significantly greater than control values. There were no significant differences in dosages, follow-up measurements, and maternal ratings. CONCLUSIONS Use of minimal aliquots of L-aspartic acid and EHC for beta-glucuronidase inhibition results in increased fecal bilirubin excretion and less jaundice, without disruption of the breastfeeding experience. Decreased jaundice in the W/C group, which lacked a beta-glucuronidase inhibitor, suggests a different mechanism.
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Evidence on improved outcomes with early diagnosis of cystic fibrosis through neonatal screening: enough is enough!
Farrell, PM, Lai, HJ, Li, Z, Kosorok, MR, Laxova, A, Green, CG, Collins, J, Hoffman, G, Laessig, R, Rock, MJ, et al
The Journal of pediatrics. 2005;(3 Suppl):S30-6
Abstract
OBJECTIVE To generate and examine evidence in support of diagnosing cystic fibrosis (CF) early through newborn screening (NBS). STUDY DESIGN Using a randomized controlled trial with unique unblinding/surveillance, we evaluated patients with CF receiving similar treatment after assignment to an early diagnosis (screened) group or to a control group. Outcomes studied at diagnosis and longitudinally included measures of nutritional status and lung disease. RESULTS Assessment of patients with CF without meconium ileus who had pancreatic insufficiency revealed marked differences in age and condition at diagnosis--screened patients had significantly better length/height, weight, and head circumference. Follow-up evaluation for 16 years showed that height and weight differences persisted long term. Although screened patients had better chest x-ray scores at diagnosis, our trial suggests that the effects of confounders such as Pseudomonas aeruginosa infections led to deterioration of their scores after 10 years, but there were no significant differences between the 2 CF/pancreatic insufficiency subgroups. CONCLUSIONS Early diagnosis of CF and aggressive nutritional management can prevent malnutrition and growth failure. Although CF NBS provides a potential opportunity for better pulmonary outcomes, it appears that other factors can predominate over time in pulmonary prognosis. Overall, the Wisconsin trial is positive and provides enough evidence for routine CF NBS.
