Cross-over studies underestimate energy compensation:The example of sucrose-versus sucralose-containing drinks

AbstractThe vast majority of preload-test-meal studies that have investigated the effects on energy intake of disguised nutrient or other food/drink ingredient manipulations have used a cross-over design. We argue that this design may underestimate the effect of the manipulation due to carry-over effects. To test this we conducted comparable cross-over (n = 69) and parallel-groups (n = 48) studies testing the effects of sucrose versus low-calorie sweetener (sucralose) in a drink preload on test-meal energy intake. The parallel-groups study included a baseline day in which only the test meal was consumed. Energy intake in that meal was used to control for individual differences in energy intake in the analysis of the effects of sucrose versus sucralose on energy intake on the test day. Consistent with our prediction, the effect of consuming sucrose on subsequent energy intake was greater when measured in the parallel-groups study than in the cross-over study (respectively 64% versus 36% compensation for the 162 kcal difference in energy content of the sucrose and sucralose drinks). We also included a water comparison group in the parallel-groups study (n = 24) and found that test-meal energy intake did not differ significantly between the water and sucralose conditions. Together, these results confirm that consumption of sucrose in a drink reduces subsequent energy intake, but by less than the energy content of the drink, whilst drink sweetness does not increase food energy intake. Crucially, though, the studies demonstrate that study design affects estimated energy compensation

The glycaemic effects of single doses of Panax ginseng in young healthy volunteers

The results of two acute placebo-controlled, double-blind cross-over studies assessing the effect of Panax ginseng (G115) on blood glucose levels are reported. In study 1, thirty participants received three treatments: placebo; 200 mg G115; 400 mg G115. In study 2, twenty-seven participants received four treatments: placebo (0 mg ginseng and 30 mg saccharin); ginseng (200 mg ginseng and 30 mg saccharin); placebo–glucose (0 mg ginseng and 25 g oral glucose); ginseng–glucose (200 mg ginseng and 25 g oral glucose). Blood glucose levels were measured at baseline (at 09.00 hours after an overnight fast) and then 60, 90 (study 1 only) and 120 min post-dose. Both studies demonstrated that G115 alone significantly lowers fasting blood glucose levels. Conversely, in study 2 there was a significant drink × ginseng interaction suggesting opposing glycaemic effects of ginseng under fasting and raised blood glucose conditions. These data have implications for the use of ginseng in individuals with poor gluco-regulation

Panax ginseng has no effect on indices of glucose regulation following acute or chronic ingestion in healthy volunteers

In the absence of effective pharmacotherapy for diabetes there has been an increase in the use of, and research into, alternative treatment strategies. These include exercise, dietary interventions and the use of supplements including extracts of ginseng. Two separate, placebo-controlled, double-blind, cross-over studies investigating the effects of chronic ingestion of Panax ginseng (study 1 used G115, study 2 used Cheong Kwan Jang) on glycated Hb (HbA1c; study 1, n 18; study 2, n 11), fasting plasma insulin (study 1, n 17; study 2, n 12), fasting plasma glucose and postprandial response (following breakfast) (study 1, n 23; study 2, n 14) in healthy volunteers are reported. In both studies it was found that Panax ginseng had no effect on any gluco-regulatory parameter investigated. These results are not consistent with those reported for a diabetic sample (albeit using slightly different outcomes). These results would suggest that chronic use of Panax ginseng by non-diabetic individuals will have little long-term effect on glucose regulation. The benefits to glucose regulation associated with long-term ginseng use may only be present in populations with compromised glucose control; however, further research is needed to confirm such a speculation

Some t-tests for N-of-1 trials with serial correlation

N-of-1 trials allow inference between two treatments given to a single individual. Most often, clinical investigators analyze an individual's N-of-1 trial data with usual t-tests or simple nonparametric methods. These simple methods do not account for serial correlation in repeated observations coming from the individual. Existing methods accounting for serial correlation require simulation, multiple N-of-1 trials, or both. Here, we develop t-tests that account for serial correlation in a single individual. The development includes effect size and precision calculations, both of which are useful for study planning. We then evaluate and compare their Type I and II errors and interval estimators to those of usual t-tests analogues via Monte Carlo simulation. The serial t-tests clearly outperform the usual t-tests commonly used in reporting N-of-1 results. Examples from N-of-1 clinical trials in fibromyalgia patients and from a behavioral health setting exhibit how accounting for serial correlation can change inferences. These t-tests are easily implemented and more appropriate than simple methods commonly used; however, caution is needed when analyzing only a few observations. Keywords: Autocorrelation; Cross-over studies; Repeated measures analysis; Single-case experimental design; Time-seriesComment: 23 pages, 6 figures, 6 table

Is Motorized Treadmill Running Biomechanically Comparable to Overground Running? A Systematic Review and Meta-Analysis of Cross-Over Studies

Background Treadmills are often used in research, clinical practice, and training. Biomechanical investigations comparing treadmill and overground running report inconsistent findings. Objective This study aimed at comparing biomechanical outcomes between motorized treadmill and overground running. Methods Four databases were searched until June 2019. Crossover design studies comparing lower limb biomechanics during non-inclined, non-cushioned, quasi-constant-velocity motorized treadmill running with overground running in healthy humans (18-65 years) and written in English were included. Meta-analyses and meta-regressions were performed where possible. Results 33 studies (n = 494 participants) were included. Most outcomes did not differ between running conditions. However, during treadmill running, sagittal foot-ground angle at footstrike (mean difference (MD) − 9.8° [95% confidence interval: − 13.1 to − 6.6]; low GRADE evidence), knee flexion range of motion from footstrike to peak during stance (MD 6.3° [4.5 to 8.2]; low), vertical displacement center of mass/pelvis (MD − 1.5 cm [− 2.7 to − 0.8]; low), and peak propulsive force (MD − 0.04 body weights [− 0.06 to − 0.02]; very low) were lower, while contact time (MD 5.0 ms [0.5 to 9.5]; low), knee flexion at footstrike (MD − 2.3° [− 3.6 to − 1.1]; low), and ankle sagittal plane internal joint moment (MD − 0.4 Nm/kg [− 0.7 to − 0.2]; low) were longer/higher, when pooled across overground surfaces. Conflicting findings were reported for amplitude of muscle activity. Conclusions Spatiotemporal, kinematic, kinetic, muscle activity, and muscle-tendon outcome measures are largely comparable between motorized treadmill and overground running. Considerations should, however, particularly be given to sagittal plane kinematic differences at footstrike when extrapolating treadmill running biomechanics to overground running

A maximum likelihood estimation procedure for binary data from cross-over studies

A maximum likelihood estimation procedure is presented for the expected frequencies when modelling binary data from two-period cross-over studies. This procedure provides a simple approach to parameter estimation in models for binary data from cross-over experiments, and in particular for a log-nonlinear model proposed by Becker and Balagtas (1993).http://www.sastat.org.za/journal.ht

Impact of in shoe and barefoot placed frontal wedges on plantar loading: A systematic review

Eleven papers were included in the final review. Four were cross-over studies, other four were quasi-experimental studies and three were RCTs. These eleven studies included 320 patients, with ages ranging from 20 to 60 years. Regarding the risk of bias, most of the observational studies and RCTs had a moderate level of quality. Conclusions: The results suggest that lateral wedges are more effective, producing a lateral shift of the centre of pressure and increasing the pressure. Regarding the impact on the peak impact force there seems to be less consensus among the published data.Funding for open access charge is provided by Universidad de Malaga/CBUA

Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Background. The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase 2 dose-finding study of rostafuroxin, a digitoxygenin deivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. Methods. OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24 h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). Results. Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P=0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P=0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P=0.03) for systolic office BP; 0.70 mm Hg (P=0.08) for diastolic office BP; 0.36 mm Hg (P=0.49) for 24-h systolic BP; and 0.05 mm Hg (P=0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤=0.028), but carry-over effects were not significant (P≥=0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. Conclusions. In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. Trial Registration: NCT00415038 http://www.clinicaltrials.gov)

Iron absorption from a novel iron-enriched fungal fortificant in young women

Iron deficiency is the most prevalent micronutrient deficiency, attributing to approximately 800 million individuals with anemia, worldwide. This nutrient deficiency is greatly attributed to consumption of high plant-based diets and foods that have low bioavailable iron. Challenges arise in iron fortification, as the most affordable and conventional iron compounds have low bioavailability, therefore efforts have been made towards finding an iron fortificant with high bioavailability. The objective of this research was to determine the iron absorption of an iron-enriched fungus, Aspergillus oryzae (ASP-p) and determine its effectiveness compared to current fortificants ferric pyrophosphate (FePP) and ferrous sulfate (FeSO4). Two, single-blinded cross-over studies were conducted using a dual-labelled isotope method in young female subjects. Results indicated a 2.3 fold higher absorption in ASP-p compare to FePP (P = 0.0001), whereas ASP-p reported significantly lower absorption (P = 0.0001) than FeSO4