Optimizing clinical nutrition research: the role of adaptive and pragmatic trials.

Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally been the preferred method for determining the effects of nutritional interventions on health outcomes. Nevertheless, obtaining a holistic understanding of intervention efficacy and effectiveness in real-world settings is stymied by inherent constraints of efficacy RCTs. These limitations are further compounded by the complexity of nutritional interventions and the intricacies of the clinical context. Herein, we explore the advantages and limitations of alternative study designs (e.g., adaptive and pragmatic trials), which can be incorporated into RCTs to optimize the efficacy or effectiveness of interventions in clinical nutrition research. Efficacy RCTs often lack external validity due to their fixed design and restrictive eligibility criteria, leading to efficacy-effectiveness and evidence-practice gaps. Adaptive trials improve the evaluation of nutritional intervention efficacy through planned study modifications, such as recalculating sample sizes or discontinuing a study arm. Pragmatic trials are embedded within clinical practice or conducted in settings that resemble standard of care, enabling a more comprehensive assessment of intervention effectiveness. Pragmatic trials often rely on patient-oriented primary outcomes, acquire outcome data from electronic health records, and employ broader eligibility criteria. Consequently, adaptive and pragmatic trials facilitate the prompt implementation of evidence-based nutritional recommendations into clinical practice. Recognizing the limitations of efficacy RCTs and the potential advantages of alternative trial designs is essential for bridging efficacy-effectiveness and evidence-practice gaps. Ultimately, this awareness will lead to a greater number of patients benefiting from evidence-based nutritional recommendations.

The Feasibility of a Health Care Application in the Treatment of Patients Undergoing Radical Cystectomy.

PURPOSE: Patients who undergo radical cystectomy of bladder cancer are at high risk for complications and hospital readmissions. Studies indicate insufficient preoperative education and perioperative monitoring. The aim of this study was to demonstrate the feasibility of implementing a health care application to provide more patient education and more thorough monitoring perioperatively. MATERIALS AND METHODS: Participants with home Wi-Fi access who were undergoing radical cystectomy were recruited for this pilot trial. Each subject was provided a tablet preloaded with the m.Care (LifeScience Technologies, Leawood, Kansas) health care application, an accelerometer and vital sign equipment. Participants were asked to watch educational videos, use the provided accelerometer and perform vital sign monitoring. RESULTS: In 1 year 20 participants enrolled in the study and 15 completed it. The most frequently viewed videos were "Ileal Conduit versus Neobladder" and "Comprehensive Care Pathway." All participants used the accelerometer and 60% kept up with syncing the data regularly. The average step count preoperatively was 5,679 reflecting a sedentary population. Step counts decreased during the inpatient stay (1,351 steps) and trended toward baseline during the postoperative period (3,156 steps). Vital signs were recorded on 85% of assigned days and generated 33 triggers for intervention. While most triggers led to repeat assessment, education and encouragement, 4 participants underwent outpatient treatment, including cultures, intravenous fluids, antibiotics or dronabinol prescription, without the need for hospital readmission. CONCLUSIONS: Providing more education and monitoring perioperatively is feasible using a health care application. Testing is warranted to determine the extent to which implementation will improve patient triaging and reduce readmissions.

Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: Results of a Pilot Randomized Controlled Clinical Trial.

PURPOSE: Poor preoperative nutritional status is associated with a higher complication rate after radical cystectomy in patients with bladder cancer. Given the short interval between diagnosis and radical cystectomy, we compared the effect of short-term specialized immunonutrition to that of a standard oral nutritional supplement on the acute inflammatory response and arginine status in patients treated with radical cystectomy. MATERIALS AND METHODS: In this prospective, randomized study in 29 men 14 received specialized immunonutrition and 15 received oral nutritional supplement. Each group drank 3 cartons per day for 5 days before and 5 days after radical cystectomy. The Th1-Th2 balance, plasma interleukin-6 and plasma amino acids were measured at baseline, intraoperatively and on postoperative days 2, 14 and 30. Body composition was measured by dual energy x-ray absorptiometry at baseline and on postoperative days 14 and 30. Differences in outcomes were assessed using the generalized linear mixed model. RESULTS: In the specialized immunonutrition group there was a 54.3% average increase in the Th1-Th2 balance according to the tumor necrosis factor-α-to-interleukin-13 ratio from baseline to intraoperative day, representing a shift toward a Th1 response. In the oral nutritional supplement group the Th1-Th2 balance decreased 4.8%. The change in the Th1-Th2 balance between the specialized immunonutrition and oral nutritional supplement groups significantly differed (p <0.027). Plasma interleukin-6 was 42.8% lower in the specialized immunonutrition group compared to the oral nutritional supplement group on postoperative day 2 (p = 0.020). In the specialized immunonutrition group plasma arginine was maintained from baseline to postoperative day 2 and yet the oral nutritional supplement group showed a 26.3% reduction from baseline to postoperative day 2 (p = 0.0003). The change in appendicular muscle loss between the groups was not statistically significant. CONCLUSIONS: Th1-to-Th2 ratios, peak interleukin-6 levels and plasma arginine suggest that consuming specialized immunonutrition counteracts the disrupted T-helper balance, lowers the inflammatory response and prevents arginine depletion due to radical cystectomy.

Experiences and Perspectives of Polycystic Kidney Disease Patients following a Diet of Reduced Osmoles, Protein, and Acid Precursors Supplemented with Water: A Qualitative Study.

BACKGROUND: Salt, protein, acid precursors, and fluid intake have been identified as factors that influence cyst growth in ADPKD. Unfortunately, the feasibility of following these dietary restrictions/enhancements from a patient's point-of-view has yet to be studied. The purpose of this study is to understand better the experiences of patients following a relatively complex dietary prescription targeting these factors. METHODS: Twelve adults with ADPKD and kidney function >30ml/min/1.73m2 were recruited from the University of Kansas Medical Center Polycystic Kidney Disease clinic. In a qualitative design, semi-structured interviews of participants were conducted following a four week dietary intervention (experimental diet lower in sodium, protein, and acid precursors, and supplemented with water) either face-to-face or by telephone. All interviews were recorded, transcribed verbatim, and checked for accuracy. Transcripts were analyzed thematically for emerging themes. RESULTS: Participants reported that eating less meat and more fruits and vegetables were the easiest components of the diet, whereas reaching the daily goal amount of fruits and vegetables and tracking the diet constantly were the most difficult components. Participants had little difficulty with fluid intake and reported the prescribed fluid goal as achievable. The tracking system for fruits and vegetables and protein was reported to be both helpful and intuitive, but tracking their intake on paper was tedious. Eating out was the most significant barrier to following the diet with some individuals avoiding restaurants in order to comply with the dietary prescription. CONCLUSION: Participants on the experimental diet heightened their awareness of the consumption of dietary salt, protein, acid precursors, and fluid intake. Additionally, most participants believed adherence to the prescribed diet was feasible. However, participants wanted less cumbersome ways to track and monitor the diet, especially given that the prescribed diet is designed for lifelong adherence. Future studies should focus on targeting these specific dietary factors in larger groups of more ethnically and culturally diverse populations to help inform clinicians and how best to help diverse populations adhere to the dietary intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01810614.

Renal formulas pretreated with medications alters the nutrient profile.

BACKGROUND: Pretreating renal formulas with medications to lower the potassium and phosphorus content is common in clinical practice; however, the effect of this treatment on other nutrients is relatively unstudied. We examine whether nutrient composition is affected by pretreating renal formulas with sodium polystyrene sulfonate (SPS) suspension and sevelamer carbonate. METHODS: Fixed medication doses and treatment times were utilized to determine changes in the nutrient composition of Suplena® and Similac® PM 60/40. The effect of simultaneously adding both medications (co-administration) to the formula on the nutrient composition of Suplena® was also evaluated. RESULTS: Pretreatment of Suplena® with SPS reduced the concentrations of calcium (11-38 %), copper (3-11 %), manganese (3-16 %), phosphorus (0-7 %), potassium (6-34 %), and zinc (5-20 %) and increased those of iron (9-34 %), sodium (89-260 %), and sulfur (19-45 %) and the pH (0.20-0.50 units). Pretreatment of Similac® PM 60/40 with SPS reduced the concentrations of calcium (8-29 %), copper (5-19 %), magnesium (3-26 %), and potassium (33-63 %) and increased those of iron (13-87 %) and sodium (86-247 %) and the pH (0.40-0.81 units). Pretreatment of both formulas with the SPS suspension led to significant increases in the aluminum concentration in both formulas (507-3957 %). No differences in potassium concentration were observed between treatment times. Unexpectedly, the levels of neither phosphorus nor potassium were effectively reduced in Suplena® pretreated with sevelamer carbonate alone or when co-administered with SPS. CONCLUSIONS: Pretreating formula with medications alters nutrients other than the intended target(s). Future studies should be aimed at predicting the loss of these nutrients or identifying alternative methods for managing serum potassium and phosphorus levels in formula-fed infants. The safety of pretreating formula with SPS suspension should also be examined.

Short-term soy isoflavone intervention in patients with localized prostate cancer: a randomized, double-blind, placebo-controlled trial.

PURPOSE: We describe the effects of soy isoflavone consumption on prostate specific antigen (PSA), hormone levels, total cholesterol, and apoptosis in men with localized prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a double-blinded, randomized, placebo-controlled trial to examine the effect of soy isoflavone capsules (80 mg/d of total isoflavones, 51 mg/d aglucon units) on serum and tissue biomarkers in patients with localized prostate cancer. Eighty-six men were randomized to treatment with isoflavones (n=42) or placebo (n=44) for up to six weeks prior to scheduled prostatectomy. We performed microarray analysis using a targeted cell cycle regulation and apoptosis gene chip (GEArrayTM). Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol were analyzed at baseline, mid-point, and at the time of radical prostatectomy. In this preliminary analysis, 12 genes involved in cell cycle control and 9 genes involved in apoptosis were down-regulated in the treatment tumor tissues versus the placebo control. Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared to men receiving placebo were not statistically significant. CONCLUSIONS/SIGNIFICANCE: These data suggest that short-term intake of soy isoflavones did not affect serum hormone levels, total cholesterol, or PSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00255125.

Drug-vitamin D interactions: a systematic review of the literature.

Extensive media coverage of the potential health benefits of vitamin D supplementation has translated into substantial increases in supplement sales over recent years. Yet, the potential for drug-vitamin D interactions is rarely considered. This systematic review of the literature was conducted to evaluate the extent to which drugs affect vitamin D status or supplementation alters drug effectiveness or toxicity in humans. Electronic databases were used to identify eligible peer-reviewed studies published through September 1, 2010. Study characteristics and findings were abstracted, and quality was assessed for each study. A total of 109 unique reports met the inclusion criteria. The majority of eligible studies were classified as class C (nonrandomized trials, case-control studies, or time series) or D (cross-sectional, trend, case report/series, or before-and-after studies). Only 2 class C and 3 class D studies were of positive quality. Insufficient evidence was available to determine whether lipase inhibitors, antimicrobial agents, antiepileptic drugs, highly active antiretroviral agents, or H2 receptor antagonists alter serum 25(OH)D concentrations. Atorvastatin appears to increase 25(OH)D concentrations, whereas concurrent vitamin D supplementation decreases concentrations of atorvastatin. Use of thiazide diuretics in combination with calcium and vitamin D supplements may cause hypercalcemia in the elderly or those with compromised renal function or hyperparathyroidism. Larger studies with stronger study designs are needed to clarify potential drug-vitamin D interactions, especially for drugs metabolized by cytochrome P450 3A4 (CYP3A4). Healthcare providers should be aware of the potential for drug-vitamin D interactions.

Soy protein isolate increases urinary estrogens and the ratio of 2:16alpha-hydroxyestrone in men at high risk of prostate cancer.

Specific estrogen metabolites may initiate and promote hormone-related cancers. In epidemiological studies, significantly lower excretion of urinary estradiol (E2) and lower ratio of urinary 2-hydroxy estrogens to 16alpha-hydroxyestrone (2:16 OH-E1) have been reported in prostate cancer cases compared to controls. Although soy supplementation has been shown to increase the ratio 2:16 OH-E1 in women, no studies to our knowledge have investigated the effects of soy supplementation on estrogen metabolism in men. The objective of this randomized controlled trial was to determine the effects of soy protein isolate consumption on estrogen metabolism in men at high risk for developing advanced prostate cancer. Fifty-eight men supplemented their habitual diets with 1 of 3 protein isolates: 1) isoflavone-rich soy protein isolate (SPI+) (107 mg isoflavones/d); 2) alcohol-washed soy protein isolate (SPI-) (<6 mg isoflavones/d); or 3) milk protein isolate (MPI), each providing 40 g protein/d. At 0, 3, and 6 mo of supplementation, the urinary estrogen metabolite profile was measured by GC-MS. Both soy groups had higher E2 excretion than the MPI group at 3 and 6 mo. After 6 mo of supplementation, the SPI+ group had a significantly higher urinary 2:16 OH-E1 ratio than the MPI group. Increased urinary E2 excretion and 2:16 OH-E1 ratio in men consuming soy protein isolate are consistent with studies in postmenopausal women and suggest that soy consumption may be beneficial in men at high risk of progressing to advanced prostate cancer as a result of effects on endogenous estrogen metabolism.

Consumption of Lactobacillus acidophilus and Bifidobacterium longum does not alter phytoestrogen metabolism and plasma hormones in men: a pilot study.

OBJECTIVE: The aim of this study was to determine whether equol excretion status and plasma hormone and leptin concentrations can be influenced by consumption of a probiotic supplement. A secondary focus was to investigate whether male equol excretors have a hormone profile consistent with reduced prostate cancer risk. DESIGN: The design was a randomized, single-blinded, placebo-controlled, parallel-arm trial. SUBJECTS: Thirty-one (31) of the initially enrolled 39 subjects, 18 to 37 years old, completed all study requirements. INTERVENTION: Subjects consumed either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules for 2 months. Fasting plasma concentrations of testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide (AAG), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), and leptin were measured on days 1 and 57. Urinary excretion of genistein, glycitein, daidzein, O-desmethylangolensin (O-Dma), and equol was measured on days 4 and 61 following a 4-day soy challenge. RESULTS: Probiotic consumption did not significantly alter equol excretor status, plasma hormone, or leptin concentrations in these subjects. At baseline, there were no differences in plasma hormone concentrations between equol excretors and nonexcretors; however, the low number of equol excretors included in this study limits the strength of this finding. CONCLUSIONS: The 2-month intervention with probiotic capsules did not significantly alter equol excretion, plasma hormone, or leptin concentrations in these subjects. A secondary finding was that male equol excretors in this study did not exhibit a hormone profile consistent with reduced prostate cancer risk, although this result should be interpreted with caution.