Safety assessment of L-Arg oral intake in healthy subjects: a systematic review of randomized control trials.

L-Arg is a nonessential amino acid but has many physiological roles. Accordingly, L-Arg has been used in various fields, but there is only limited information available about its safety upon overdose. Generally, the no-observed adverse effect level (NOAEL) is used when setting the upper amount for chemical substances. Recently, systematic reviews have been used to assess the safety as well as the effectiveness and usefulness of them. Therefore, we conducted an assessment of the safety of the oral intake of L-Arg in healthy subjects using gastrointestinal symptoms as an index. We limited the study design to only double-blind randomized controlled trials and searched PubMed, Cochrane Library, EBSCOhost, and Ichushi-Web from inception until May 2021. Assessment of the quality of studies was conducted using the Cochrane Collaboration tool and Jadad score, and the random effects model was used for data analysis. Ultimately, 34 studies were selected for inclusion in this work. The dosage of L-Arg used in the studies ranged from 2000 to 30,000 mg/day (or/one-time dose), and the treatment duration was 1-84 days. The increased risk of gastrointestinal symptoms associated with L-Arg intake from 23 studies (647 participants in total) in which such symptoms were reported was 0.01 (95% confidence interval: - 0.02-0.04), which was not significant difference. NOAEL was estimated as 7531 mg/ one-time dose using a weighted change-point regression model (UMIN000046133).Registration and protocol: Umin.ac.jp as UMIN000046133.

A change-point regression approach for estimating no observed adverse effect level from systematic review.

Systematic reviews can be used not only to evaluate the efficacy and usefulness of a drug or food ingredient, but also as a safety assessment method. One of the aims of safety assessment is to estimate the no observed adverse effect level and the lowest observed adverse effect level. However, no methodology to statistically estimate the no observed adverse effect level from systematic review results has yet been reported. Estimation of the no observed adverse effect level involves a search for the dose above which adverse events occur is even exploration of the thresholds in dose response. To search for the dose above which adverse events occur, we examined an estimation method using the weighted change-point regression model, which includes the weights of each study used for systematic reviews in the model. This model could be applied to safety data of an omega-3 study in the form of a systematic review. We demonstrated that the dose response to omega-3 intake regarding adverse events had a threshold value and that the no observed adverse effect level could be estimated using the developed model.

Estimation of inter-individual variability of protein requirement by indicator amino acid oxidation method.

The indicator amino acid oxidation (IAAO) method is a recently developed method to determine the protein requirement and is particularly useful for analyzing human subjects because of its minimal invasiveness. IAAO study is performed using two-phase regression analysis, with the break-point between these phases being the estimated average requirement. However, this method requires that the break-point lie within a certain range in advance, which is in practice difficult. Recently, the change-point regression model (CPRM) has been proposed to be more effective for two-phase regression analysis. There is also a need to re-evaluate the value corresponding to the recommended dietary allowance. Calculation of the recommended dietary allowance requires data on the average requirement and the inter-individual variability of this requirement. However, no inter-individual variability values have been reported in the IAAO method. The aim of this study was thus to estimate the inter-individual variation in protein requirement using CPRM. From seven IAAO studies, the inter-individual variability was estimated as a coefficient of variation of about 20%. The coefficient of variation of the protein requirement determined by IAAO study was wider than the ordinary coefficient of variation obtained from the nitrogen balance test.

A 100-m Sprint Time Is Associated With Deep Trunk Muscle Thickness in Collegiate Male Sprinters.

Introduction: One reason athletes train their trunk muscles is that the body's trunk stability has been shown to prevent injury. However, the relationship between body trunk muscle thickness, particularly that of deep muscles, and athletic performance remains to be clarified. Purpose: We aimed to explore the relationship between 100-m sprint performance and the sizes of the trunk stabilizing muscles, the psoas major muscle (PM), transversus abdominis (TA), and multifidus muscle (MM), in collegiate sprinters. Methods: Fourteen male sprinters belonging to a university athletics club participated in this study. The thicknesses of the TA and MM were measured using an ultrasonic diagnostic apparatus (ProSound C3; Aloka, Tokyo, Japan). The cross-sectional area of the PM was assessed by a magnetic resonance imaging apparatus (Vantage Elan; Toshiba Medical Systems, Tokyo, Japan). The relationship between these anthropometric parameters and the 100-m sprint time was analyzed by Spearman's correlation coefficient, multi- regression analysis, and the change-point regression model. Results: The sizes (mean ± SD) of the muscles were: PM, 43.074 ± 7.35 cm2; TA, 4.36 ± 0.72 mm; and MM, 3.99 ± 0.48 cm. The mean 100-m sprint time was 11.00 ± 0.48 s. Spearman's correlation analysis revealed that the 100-m sprint time had a significant moderate negative correlation with TA (ρ = -0.691, p < 0.01) and a low negative but not significant correlation with MM (ρ = -0.327, p = 0.28), whereas PM did not show a significant or in-negligible correlation. The change-point regression model found the change-points in the 100-m sprint time and the thickness of the TA and MM at 4.70 mm (95% CI: 4.00-5.43 mm) and 3.84 cm (95% CI: 3.28-4.31 cm), respectively. The sprint time decreased with an increase in the thickness of the muscles up to the change-points, whereas it did not change even if the muscles became thicker than the change-points. The change-points were consistently observed when the thickness of the muscles was normalized by body mass. Conclusion: Sprint performance for 100-m was found to be associated with TA and MM thickness in a biphasic manner. As muscle thickness increased, the sprint time decreased, followed by a plateau phase.

Determining amino acid requirements from repeated observations on indicator amino acid oxidation method by mixed-effect change-point regression models.

In nutrition studies, it is often of primary interest to determine the critical threshold value of some biological quantities. To determine the amino acid requirement, the tracer approach including the indicator amino acid oxidation method is useful for the investigation of human subjects. In this approach, measurements of amino acids other than the test amino acid are often repeatedly carried out with various intakes of the test amino acid. Change-point regression models have often been applied to determine the amino acid requirement. However, within-subject dependence due to repeated measurements has not been sufficiently taken into account. In this paper, we propose a mixed-effect change-point model to estimate the amino acid requirements when utilizing the tracer approach. Inference based on Akaike Information Criteria is introduced to include selection of the optimal model and construction of a confidence interval. Our method can easily be applied with a standard software package, and we found that appropriate accounting for within-subject dependence may lead to a much narrower confidence interval. We recommend application of a mixed-effect change-point regression model to determine the amino acid requirements in studies utilizing the tracer approach.