Pairwise fitting of piecewise mixed models for the joint modeling of multivariate longitudinal outcomes, in a randomized crossover trial.

Many statistical models have been proposed in the literature for the analysis of longitudinal data. One may propose to model two or more correlated longitudinal processes simultaneously, with a goal of understanding their association over time. Joint modeling is then required to carefully study the association structure among the outcomes as well as drawing joint inferences about the different outcomes. In this study, we sought to model the associations among six nutrition outcomes while circumventing the computational challenge posed by their clustered and high-dimensional nature. We analyzed data from a 2 × $\times$ 2 randomized crossover trial conducted in Kenya, to compare the effect of high-dose and low-dose iodine in household salt on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in women of reproductive age and their household matching pair of school-aged children. Two additional outcomes, namely, urinary iodine concentration (UIC) in women and children were measured repeatedly to monitor the amount of iodine excreted through urine. We extended the model proposed by Mwangi et al. (2021, Communications in Statistics: Case Studies, Data Analysis and Applications, 7(3), 413-431) allowing flexible piecewise joint models for six outcomes to depend on separate random effects, which are themselves correlated. This entailed fitting 15 bivariate general linear mixed models and deriving inference for the joint model using pseudo-likelihood theory. We analyzed the outcomes separately and jointly using piecewise linear mixed-effects (PLME) model and further validated the results using current state-of-the-art Jones and Kenward methodology (JKME model) used for analyzing randomized crossover trials. The results indicate that high-dose iodine in salt significantly reduced blood pressure (BP) compared to low-dose iodine in salt. Estimates for the random effects and residual error components showed that SBP and DBP had strong positive correlation, with effect of the random slope indicating that significantly related outcomes are strongly associated in their evolution. There was a moderately strong inverse relationship between evolutions of UIC and BP both in women and children. These findings confirmed the original hypothesis that high-dose iodine salt has significant lowering effect on BP. We further sought to evaluate the performance of our proposed PLME model against the widely used JKME model, within the multivariate joint modeling framework through a simulation study mimicking a 2 × 2 $2\times 2$ crossover design. From our findings, the multivariate joint PLME model performed exceptionally well both in estimation of random-effects matrix (G) and Hessian matrix (H), allowing satisfactory model convergence during estimation. It allowed a more complex fit to the data with both random intercepts and slopes effects compared to the multivariate joint JKME model that allowed for random intercepts only. When a hierarchical viewpoint is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive definite. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters. The key highlight in this evaluation shows that multivariate joint JKME model is a powerful tool especially while fitting mixed models with random intercepts only, in crossover design settings. Addition of random slopes may lead to model complexities in most cases, resulting in unsatisfactory model convergence during estimation. To circumvent convergence pitfalls, extention of JKME model to PLME model allows a more flexible fit to the data (generated from crossover design settings), especially in the multivariate joint modeling framework.

A crossover randomized controlled trial examining the effects of black seed (Nigella sativa) supplementation on IL-1ß, IL-6 and leptin, and insulin parameters in overweight and obese women.

BACKGROUND: Nigella sativa (NS) oil has been found to have advantageous benefits in the management of inflammation and obesity. This study investigated the effect of NS supplementation on blood mRNA expressions and serum levels of IL-1ß, IL-6, leptin, and insulin concentrations in overweight/obese women. METHODS: In a crossover design, participants were randomized to receive either NS supplements(2000 mg/day) or placebo for 2 durations(8 weeks). With between-subject and within-subject components and interactions, a repeated-measure ANOVA model was used considering the treatment, time, and the carryover effects. Cohen's d(d) was used to measure the magnitude of the effects. RESULTS: Forty-six eligible participants were included. NS supplementation significantly reduced the mRNA expressions(d=-0.68, P = 0.03) and serum levels of IL-1ß with medium-high effect sizes(d=-1.6, P < 0.001). Significant reductions with large effect sizes were observed in the gene expression and serum levels of IL-6(d=-1.8, d=-0.78, respectively; P < 0.01) and Leptin(d=-1.9, d=-0.89, respectively; P < 0.01, serum leptin P carryover < 0.001). Despite the meaningful carryover effect for serum leptin, results remained significant following the first intervention period analysis(P < 0.001). A significant but low effect size decrease in serum insulin was observed(d=-0.3, P = 0.02). CONCLUSIONS: The clinical significance of present findings regarding improvements in obesity-related pro-inflammatory markers must be interpreted with caution due to some observed medium-low effect sizes. TRIAL REGISTRATION: IRCT20180430039475N1 (Date:25/6/2018).

Crossover shortage in potato is caused by StMSH4 mutant alleles and leads to either highly uniform unreduced pollen or sterility.

The balanced segregation of homologous chromosomes during meiosis is essential for fertility and is mediated by crossovers (COs). A strong reduction of CO number leads to the unpairing of homologous chromosomes after the withdrawal of the synaptonemal complex. This results in the random segregation of univalents during meiosis I and ultimately to the production of unbalanced and sterile gametes. However, if CO shortage is combined with another meiotic alteration that restitutes the first meiotic division, then uniform and balanced unreduced male gametes, essentially composed of nonrecombinant homologs, are produced. This mitosis-like division is of interest to breeders because it transmits most of the parental heterozygosity to the gametes. In potato, CO shortage, a recessive trait previously referred to as desynapsis, was tentatively mapped to chromosome 8. In this article, we have fine-mapped the position of the CO shortage locus and identified StMSH4, an essential component of the class I CO pathway, as the most likely candidate gene. A 7 base-pair insertion in the second exon of StMSH4 was found to be associated with CO shortage in our mapping population. We also identified a second allele with a 3,820 base-pair insertion and confirmed that both alleles cannot complement each other. Such nonfunctional alleles appear to be common in potato cultivars. More than half of the varieties we tested are carriers of mutational load at the StMSH4 locus. With this new information, breeders can choose to remove alleles associated with CO shortage from their germplasm to improve fertility or to use them to produce highly uniform unreduced male gametes in alternative breeding schemes.

Evaluation of a flexible piecewise linear mixed-effects model in the analysis of randomized cross-over trials.

Cross-over designs are commonly used in randomized clinical trials to estimate efficacy of a new treatment. They have received a lot of attention, particularly in connection with regulatory requirements for new drugs. The main advantage of using cross-over designs over conventional parallel designs is increased precision, thanks to within-subject comparisons. In the statistical literature, more recent developments are discussed in the analysis of cross-over trials, in particular regarding repeated measures. A piecewise linear model within the framework of mixed effects has been proposed in the analysis of cross-over trials. In this article, we report on a simulation study comparing performance of a piecewise linear mixed-effects (PLME) model against two commonly cited models-Grizzle's mixed-effects (GME) and Jones & Kenward's mixed-effects (JKME) models-used in the analysis of cross-over trials. Our simulation study tried to mirror real-life situation by deriving true underlying parameters from empirical data. The findings from real-life data confirmed the original hypothesis that high-dose iodine salt have significantly lowering effect on diastolic blood pressure (DBP). We further sought to evaluate the performance of PLME model against GME and JKME models, within univariate modeling framework through a simulation study mimicking a 2 × 2 cross-over design. The fixed-effects, random-effects and residual error parameters used in the simulation process were estimated from DBP data, using a PLME model. The initial results with full specification of random intercept and slope(s), showed that the univariate PLME model performed better than the GME and JKME models in estimation of variance-covariance matrix (G) governing the random effects, allowing satisfactory model convergence during estimation. When a hierarchical view-point is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive-definite. The PLME model is preferred especially in modeling an increased number of random effects, compared to the GME and JKME models that work equally well with random intercepts only. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters.

Interpenetration Phenomena via Anion Template Effects in Fe(II) and Co(II) Coordination Networks with a Bis-(1,2,4-triazole) Ligand.

Seven new coordination networks, [Fe(tbbt)3](BF4)2 (1), [Co(tbbt)3](BF4)2 (2), [Fe(tbbt)3](ClO4)2 (3), [Co(tbbt)3](ClO4)2 (4), [Fe(NCS)2(tbbt)2] (5), [Co(NCS)2(tbbt)2] (6), and [Fe(H2O)2(tbbt)2]Br2·2H2O (7), were synthesized with the linker 1,1'-(trans-2-butene-1,4-diyl)bis-1,2,4-triazole (tbbt) and structurally investigated. The structure of complexes 1-4 is composed of three interpenetrating, symmetry-related 3D networks. Each individual 3D network forms a primitive, nearly cubic lattice (pcu) with BF4- or ClO4- anions present in the interstitial spaces. The structure of compounds 5 and 6 is composed of two-dimensional sql layers, which are parallel to each other in the AB stacking type. These layers are interpenetrated by one-dimensional chains, both having the same formula unit, [M(NCS)2(tbbt)2] (M = Fe, Co). The structure of compound 7 consists of parallel, two-dimensional sql layers in the ABCD stacking type. The interpenetration in 1-6 is not controlled by π-π-interactions between the triazole rings or C=C bonds, as could have been expected, but by (triazole)C-H⋯F4B, C-H⋯O4Cl, and C-H⋯SCN anion hydrogen bonds, which suggests a template effect of the respective non-coordinated or coordinated anion for the interpenetration. In 7, the (triazole)C-H⋯Br anion interactions are supplemented by O-H⋯O and O-H⋯Br hydrogen bonds involving the aqua ligand and crystal water molecules. It is evident that the coordinated and non-coordinated anions play an essential role in the formation of the networks and guide the interpenetration. All iron(II) coordination networks are colorless, off-white to yellow-orange, and have the metal ions in the high-spin state down to 77 K. Compound 5 stays in the high spin state even at temperatures down to 10 K.

Glycemic Variability in Patients with Type 2 Diabetes Mellitus (T2DM): The Role of Melatonin in a Crossover, Double-Blind, Placebo-Controlled, Randomized Study.

BACKGROUND: Glycemic variability in patients with type 2 diabetes mellitus (T2DM) may be associated with chronic complications of the disease. Melatonin is a hormone that plays a crucial role in biological rhythms. Previous studies have indicated that individuals with T2DM often exhibit reduced melatonin production. In this study, our objective was to investigate whether nighttime melatonin supplementation could mitigate glycemic variability in these patients. METHODS: Crossover, double-blind, placebo-controlled, randomized study. A total of 30 patients were enrolled in this study. The study included 15 participants who followed the intervention sequence of placebo (7 days)-washout (7 days)-melatonin (3 mg) (7 days), and another 15 participants who followed the sequence of melatonin (3 mg) (7 days)-washout (7 days)-placebo (7 days). During the final three days of the first and third weeks, the participants measured their pre- and postprandial capillary blood glucose levels. This study was reported according to the CONSORT 2010 statement: extension to randomized crossover trials. RESULTS: There was a significant absolute difference in the breakfast blood glucose levels (p = 0.016) on Day 7. The use of melatonin determined a greater positive variation between pre- and postprandial glycemia than the placebo. The difference in glycemic amplitude between post-dinner Day 6 and pre-breakfast Day 7 was also significantly higher in the melatonin group (p = 0.032). CONCLUSIONS: Melatonin increased glycemic variability in individuals with type 2 diabetes mellitus (T2DM). These results can be attributed to the residual daytime effects of melatonin, prospective proximal effects, and damage to the prospective distal effects of exogenous melatonin. Therefore, caution should be exercised when administering melatonin supplementation to patients with T2DM, taking into consideration factors such as dosage, duration of use and genetic considerations.

Sex-specific responses in glucose-insulin homeostasis and lipoprotein-lipid components after high-dose supplementation with marine n-3 PUFAs in abdominal obesity: a randomized double-blind crossover study.

Background: Clinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs. Objective: To explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity. Methods: This was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity. Results: The between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: -11%*/-3.3%, p = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/-0.1%, p = 0.045), and arachidonic acid (-8.3%*/-12%*, p = 0.012), and after n-6 for total (+37%*/+2.1%, p = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p = 0.021), and lipoprotein (a) (-16%*/+0.1%, p = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: -2.1%/+3.9%*, p = 0.029), insulin (-31%*/+16%, p < 0.001), insulin C-peptide (-12%*/+13%*, p = 0.001), homeostasis model assessment of insulin resistance index 2 (-12%*/+14%*, p = 0.001) and insulin sensitivity index 2 (+14%*/-12%*, p = 0.001), and quantitative insulin sensitivity check index (+4.9%*/-3.4%*, p < 0.001). Conclusion: We found sex-specific responses after high-dose n-3 (but not n-6) supplementation in circulating markers of glycemic control/insulin sensitivity, which improved in females but worsened in males. This may partly be related to the sex differences we observed in several components of the lipoprotein-lipid profile following the n-3 intervention. Clinical trial registration: https://clinicaltrials.gov/, identifier [NCT02647333].

Effects of Melatonin on Glycemic Variability in Type 2 Diabetes Mellitus: Protocol for a Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Glycemic variability is recognized as a significant factor contributing to the development of micro- and macrovascular complications in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have shown that melatonin, a hormone involved in regulating various biological rhythms, including those related to glucose regulation, such as hunger, satiety, sleep, and circadian hormone secretion (ie, cortisol, growth hormone, catecholamines, and insulin), is deficient in individuals with T2DM. This raises an important question: Could melatonin replacement potentially reduce glycemic variability in these patients? This warrants investigation as a novel approach to improving glycemic control and reducing the risk of complications associated with T2DM. OBJECTIVE: We aimed to investigate whether melatonin replacement in individuals with T2DM who supposedly have melatonin deficiency can positively impact the regulation of insulin secretion rhythms and improve insulin sensitivity, ultimately resulting in a reduction in glycemic variability. METHODS: This study will use a crossover, randomized, double-blind, placebo-controlled trial design. Patients with T2DM in group 1 will receive 3 mg of melatonin at 9:00 PM in the first week, undergo a washout period in the second week, and receive a placebo in the third week (melatonin-washout-placebo). Group 2 will be randomized to receive a placebo-washout-melatonin sequence (3 mg). Capillary blood glucose levels will be measured at 6 different times before and after meals during the last 3 days of the first and third weeks. The study aims to compare the mean differences in blood glucose levels and the coefficient of glycemic variability in patients receiving melatonin and placebo during the first and third weeks. After analyzing the initial results, the number of needed patients will be recalculated. If the recalculated number is higher than 30, new participants will be recruited. Thirty patients with T2DM will be randomized into the 2 groups: melatonin-washout-placebo or placebo-washout-melatonin. RESULTS: Participant recruitment took place between March 2023 to April 2023. In all, 30 participants were eligible and completed the study. We expect that patients will show different glycemic variability on the days they receive placebo or melatonin. Studies on melatonin and glycemic control have shown both positive and negative results. We hope that there will be a positive outcome regarding glycemic variability (ie, a reduction in glycemic variability), as melatonin has a well-described chronobiotic effect in the literature. CONCLUSIONS: This study aims to determine whether melatonin supplementation can effectively reduce glycemic variability in patients with T2DM. The crossover design is necessary due to the multiple variables involved in the circadian variations of glucose, including diet, physical activity, sleep parameters, and pharmacological treatments. The relatively low cost of melatonin and its potential role in reducing the severe complications associated with T2DM have motivated this research effort. Furthermore, the indiscriminate use of melatonin in current times makes conducting this study essential to evaluate the effect of this substance in patients with T2DM. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials RBR-6wg54rb; https://ensaiosclinicos.gov.br/rg/RBR-6wg54rb. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47887.

Randomized Trial on the Effect of Oral Potassium Chloride Supplementation on the Thiazide-Sensitive Sodium Chloride Cotransporter in Healthy Adults.

Introduction: The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake. Methods: Healthy adults maintained on a high sodium (∼4.5 g [200 mmol]/d) low potassium (∼2.3 g [60 mmol]/d) diet underwent a 5-day run-in period followed by a crossover study, with 5-day supplementary KCl (active phase, Span-K 3 tablets (potassium 24 mmol) thrice daily) or 5-day placebo administrated in random order and separated by 2-day washout. Ambulatory blood pressure (BP) and biochemistries were assessed, and uEVs were analyzed by western blotting. Results: Among the 18 participants who met analysis criteria, supplementary KCl administration (vs. placebo) was associated with markedly higher levels of plasma potassium and 24-hour urine excretion of potassium, chloride, and aldosterone. KCl supplementation was associated with lower uEV levels of NCC (median fold change (KCl/Placebo) = 0.74 [0.30-1.69], P < 0.01) and pNCC (fold change (KCl/Placebo) = 0.81 [0.19-1.75], P < 0.05). Plasma potassium inversely correlated with uEV NCC (R2 = 0.11, P = 0.05). Conclusions: The lower NCC and pNCC in uEVs in response to oral KCl supplementation provide evidence to support the hypothesis of a functional "renal-K switch" in healthy human subjects.

Comparison of two brief mindfulness interventions for anxiety, stress and burnout in mental health professionals: a randomised crossover trial.

Background: Anxiety, stress and burnout are a growing reality among mental health professionals, impacting negatively on them and their clients. Mindfulness-based interventions (MBIs) have demonstrated effectiveness in mitigating these sufferings. Nevertheless, there is a lack of knowledge on the impact of MBIs in Cuba. Objectives: To compare the effectiveness of two brief mindfulness-based interventions for reducing anxiety, work stress and burnout. Methods: A total of 104 mental health professionals from Havana (Cuba) participated in a randomised crossover trial. Group A received first an intervention involving body-centred practices (body scan and Hatha yoga) and a second intervention involving mind-centred practices (focused attention and open monitoring meditation). Group B received the same interventions but in reverse order. Four measures (anxiety, stress, burnout syndrome, and antecedents of burnout) were measured at baseline, posttest1, posttest2, and 6-months follow-up. Results: After the first intervention, there was a between-group difference for burnout syndrome, but the ES was similar for both groups. After the second intervention (implementing both practises), groups showed the largest effect sizes, and there was a between-group difference for antecedents of burnout. Results were partially maintained at 6-month follow-up. Conclusion: These results suggest that mind-centred practises can be as effective as body-centred practises for stress, anxiety and burnout reduction. The combination of both types of practises could be the most effective way of teaching mindfulness. About the sequence of implementation, teaching mind-centred practises first and then body-centred practises could be most effective for reducing antecedents of burnout.Clinical Trial Registration: www.clinicaltrials.gov NCT03296254.

Effects of Tuina Combined With Moxibustion on Breast Cancer-Related Lymphedema: A Randomized Cross-Over Controlled Trial.

The objective of this study is to evaluate the effect of Tuina combined with moxibustion on relieving breast cancer-related lymphedema (BCRL). A randomized cross-over controlled trial was conducted at our institution. All patients with BCRL were assigned to 2 groups: Group A and Group B. In the first period (weeks 1-4), tuina and moxibustion were performed in Group A and pneumatic circulation and compression garment in Group B. The washout period took place from weeks 5 to 6. In the second period (weeks 7-10), pneumatic circulation and compression garment were performed in Group A, and tuina and moxibustion in Group B. Therapeutic efficacy was evaluated by measuring the affected arm volume, circumference, and Visual Analog Scale for swelling. Regarding the results, a total of 40 patients were included, and 5 cases were dropped. After treatment, both the traditional Chinses medicine (TCM) treatment and complete decongestive therapy (CDT) was found to reduce the volume of the affected arm (P < .05). At the endpoint (visit 3), compared with CDT, the effect of the TCM treatment was more evident than that of CDT (P < .05). After the TCM treatment, the arm circumference at the elbow crease and proximal 10 cm to elbow crease was reduced, which was statistically different from that before treatment (P < .05). Post-CDT treatment, the arm circumference at proximal 10 cm to wrist crease and the elbow crease and proximal 10 cm to elbow crease decreased, which was statistically different from that before treatment (P < .05). At the endpoint (visit 3), the arm circumference at proximal 10 cm to elbow crease of the patients treated with TCM was less than that of CDT (P < .05). Moreover, the VAS scores for swelling were better after compared with before TCM treatment and CDT (P < .05). At the endpoint (visit 3), the subjective relief of swelling by TCM treatment was greater than CDT (P < .05). Ultimately, tuina combined with moxibustion can alleviate BCRL symptoms, which is primarily reflected in reducing the affected arm volume and circumference and relieving swelling.Trial registration: Chinese Clinical Trial Registry (Registration Number ChiCTR1800016498).

Design and statistics of pharmacokinetic drug-drug, herb-drug, and food-drug interaction studies in oncology patients.

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.

Effectiveness of Shiatsu on Fatigue in Patients with Axial Spondyloarthritis: Protocol for a Randomized Cross-Over Pilot Study.

INTRODUCTION: Spondyloarthritis (SpA) is a serious chronic inflammatory rheumatism implying different painful and crippling symptoms that require a multidisciplinary approach for the patient. Fatigue is one of the less well treated symptoms, even if its repercussion on everyday life is noticeable. Shiatsu is a Japanese preventive and well-being therapy that aims to promote better health. However, the effectiveness of shiatsu in SpA-associated fatigue has never been studied yet in a randomized study. METHODS AND ANALYSIS: We describe the design of SFASPA (Etude pilote randomisée en cross-over évaluant l'efficacité du Shiatsu sur la FAtigue des patients atteints de SPondyloarthrite Axiale), a single-center, randomized controlled cross-over trial with allocation of patients according to a ratio (1:1) evaluating the effectiveness of shiatsu in SpA-associated fatigue. The sponsor is the Regional Hospital of Orleans, France. The two groups of 60 patients each will receive three "active" shiatsu and three sham shiatsu treatments (120 patients, 720 shiatsu). The wash-out period between the active and the sham shiatsu treatments is 4 months. PLANNED OUTCOMES: The primary outcome is the percentage of patients responding to the FACIT-fatigue score. A response to fatigue is defined as an improvement, i.e., an increase of ≥ 4 points in the FACIT-fatigue score, which corresponds to the "minimum clinically important difference" (MCID). Differences in the evolution of activity and impact of the SpA will be assessed on several secondary outcomes. An important aim of this study is also to gather material for further trials with higher proof of evidence. TRIAL REGISTRATION: NCT05433168, date of registration, June 21st, 2022 (clinicaltrials.gov).

Preliminary Comparison of Fractional Absorption of Zinc Sulphate, Zinc Gluconate, and Zinc Aspartate after Oral Supple-Mentation in Healthy Human Volunteers.

(1) Background: Zinc is generally used as a nutritional supplement for individuals at nutritional risk, such as older adults. This preliminary study investigated the fractional Zn absorption (FZA) after the supplementation on eight healthy volunteers with three different Zn complexes acquired with milk. (2) Methods: The design was a double-blind, three-period crossover trial. The volunteers were randomly divided into three groups. Each individual consumed 200 mL of bovine milk and rotated through a simultaneous administration of a single oral dose of 70ZnSO4, 70Zn-Gluconate (70Zn-Glu), and 70Zn-Aspartate (70Zn-Asp), equivalent to 2.0 mg 70Zn, followed by 2 weeks of wash-out. An estimation of the FZA for comparative purposes was computed by the isotopic ratio between 66Zn and 70Zn in urine collected before and 48 h after administration. (3) Results: The estimated FZA was found to be significantly higher for 70Zn-Asp when compared to the other forms, while the FZA of 70Zn-Glu was found to be significantly higher than 70ZnSO4. (4) Conclusions: The results of this study suggest that complexing Zn with aspartate in milk could be a useful tool to improve FZA in individuals at risk of Zn deficiency. These results provide a rationale for conducting further studies on Zn-Asp preparations.

Median Nerve Stimulation for Treatment of Tics: Randomized, Controlled, Crossover Trial.

A prior study showed that rhythmic, but not arrhythmic, 12 Hz stimulation of the median nerve (MNS) entrained the sensorimotor cortex EEG signal and found that 10 Hz MNS improved tics in Tourette syndrome (TS). However, no control condition was tested, and stimulation blocks lasted only 1 min. We set out to replicate the TS results and to test whether tic improvement occurs by the proposed cortical entrainment mechanism. Preregistration was completed at ClinicalTrials.gov, under number NCT04731714. Thirty-two people with TS, age 15-64, completed two study visits with repeated MNS on and off blocks in random order, one visit for rhythmic and one for arrhythmic MNS. Subjects and staff were blind to order; a video rater was additionally blind to stimulation and to the order of visits and blocks. Rhythmic MNS at 10 Hz improved tics. Both rhythmic and arrhythmic 12 Hz MNS improved tic frequency, intensity, and urges, but the two treatments did not differ significantly. Participant masking was effective, and there was no carryover effect. Several participants described a dramatic benefit. Discomfort was minimal. There was no evidence that the MNS benefit persisted after stimulation ended. These results replicate the tic benefit from MNS but show that the EEG entrainment hypothesis cannot explain that benefit. Another electrophysiological mechanism may explain the benefit; alternatively, these data do not exclude a placebo effect.

Efficacy and safety of Tuina (Chinese Therapeutic Massage) for knee osteoarthritis: A randomized, controlled, and crossover design clinical trial.

Background: Knee osteoarthritis (KOA) is a highly prevalent joint disease among the middle-aged and elderly population that can lead to pain, functional impairment, decreased quality of life, and a large number of medical expenses. Physical therapy is one of the main treatment methods for KOA. In China, Tuina has been widely used in the treatment of KOA, but up to now, there is no high-quality medical evidence to support its effectiveness and safety. The purpose of this study was to objectively evaluate the efficacy and safety of Tuina in the treatment of KOA. Methods: A crossover design clinical trial was performed on 96 patients. The test group and the control group in the trial were allocated randomly in a ratio of 1:1. The test group received Tuina treatment for 4 weeks first and then received health education intervention for another 4 weeks. The control group received health education intervention for 4 weeks first and then received Tuina treatment for another 4 weeks. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score was chosen as the primary outcome. The WOMAC pain score, WOMAC stiffness, WOMAC daily activity score, and visual analog scale (VAS) score were the secondary outcomes. Adverse events during the intervention were collected in both groups. Results: Compared with the baseline, the WOMAC total score, WOMAC pain score, WOMAC stiffness, WOMAC daily activity, and VAS score of patients in both groups were improved significantly at weeks 4 and 8 (p < 0.001). All patients who received Tuina treatment were significantly superior to those who received health education intervention in the WOMAC total score (194.96, 95% CI = 164.94-224.97, P < 0.001), WOMAC pain score (45.96, 95% CI = 35.82-56.09, P < 0.001), WOMAC stiffness (31.42, 95% CI = 26.37-36.46, P < 0.001), WOMAC daily activity (117.58, 95% CI = 97.56-137.61, P < 0.001), and VAS score (1.07, 95% CI = 0.83-1.32, P < 0.001). Both groups had no serious adverse events during the treatment. Conclusion: This trial demonstrated that Tuina can reduce joint pain in patients with KOA and improve the physical functions of the knee joint effectively and safely. Clinical trial registration: This trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR-TTRCC-13003157). http://www.chictr.org.cn/showproj.aspx?proj=6402.

The contralateral effects of foam rolling on range of motion and muscle performance.

A single bout of foam rolling (FR) can acutely increase joint range of motion (ROM) without detrimental effects on subsequent muscle performance. Similarly, long-term FR training can increase ROM, while muscle performance seems to be unaffected. Although the acute and long-term effects of FR on the treated muscle are understood, the impact of FR on the contralateral side is not well known. Therefore, this scoping review aims to summarize the current evidence on the acute and long-term effect of FR on the ipsilateral limb on ROM and muscle performance (i.e., maximum force, rate of force development, jump height) for the contralateral (non-treated) limb. Potential explanatory mechanisms are also discussed. There is evidence that a single bout of FR on the ipsilateral limb increases ROM of the contralateral limb; however, evidence is limited for long-term effects. The most likely mechanism for contralateral ROM increases is a reduced perception of pain. With regard to isolated muscle contractions, no changes in muscle performance (i.e., maximum voluntary isometric contraction, maximum voluntary dynamic contraction) were found in the contralateral limb after a single bout of FR on the ipsilateral limb. Notably, only one study reported large impairments in rate of force development of the contralateral limb following FR on the ipsilateral leg, possibly due to decreased motor unit recruitment. Furthermore, to date there are only two studies examining the long-term FR training of the ipsilateral limb on performance (i.e., maximal strength and jump performance) which reported moderate improvements. Although, trivial to very large changes on a variety of parameters were found in this study, the functional and practical relevance of our findings should be interpreted with caution.

Beneficial effects of celery seed extract (Apium graveolens), as a supplement, on anxiety and depression in hypertensive patients: a randomized clinical trial.

BACKGROUND: Anxiety and depression are crucial public health issues, affecting the rising in hospitalizations and death. Anxiety and depression can worsen hypertension and vice versa. OBJECTIVE: The current study has investigated the effects of celery seed extract, as a drug supplement, with the active ingredient of 3-n-butylphthalide, on mental problems primarily anxiety and secondary depression in hypertensive patients. DESIGN: The current study was a randomized, triple-blind, placebo-controlled, cross-over, 4-week clinical trial with a 4-week washout period. Fifty hypertensive patients received 4 placebo or celery seed extract capsules (1.34 g per day) for 4 weeks as a supplement to their usual medication regimen. The blood pressure parameters were assessed using 24-h ambulatory blood pressure monitoring device. Anxiety and depression and their wide range of symptoms were evaluated using Beck anxiety and depression inventories (BAI and BDI). RESULTS: In the celery treatment step, the mean reduction in BAI and BDI scores were 6.78 (P < 0.001) and 3.63 (P < 0.01), respectively. Some symptoms of anxiety including unable to relax, nervousness, numbness, dizziness, flushed face, sweating, and breathing difficulty were significantly improved by celery consumption (P < 0.001). Celery could decrease symptoms of depression such as sadness, crying, loss of energy, insomnia, irritability, fatigue, loss of interest in sex, and punishment feeling (P < 0.01). The mean reduction in blood pressure parameters was also significant during celery therapy (P < 0.001). CONCLUSIONS: The psychometric properties of anxiety and depression were investigated and the results were promising. The results indicated the anti-anxiety and anti-depressive properties of celery seed extract as a supplement in hypertensive patients. CLINICAL TRIAL REGISTRATION: Registry name: Iranian Registry of Clinical Trials (IRCT), Registration number: IRCT20130418013058N8, Registration link: https://www.irct.ir/trial/30021 . The study was carried out between 2018-09-21 and 2020-07-20.

Models predict change in plasma triglyceride concentrations and long-chain n-3 polyunsaturated fatty acid proportions in healthy participants after fish oil intervention.

Introduction: Substantial response heterogeneity is commonly seen in dietary intervention trials. In larger datasets, this variability can be exploited to identify predictors, for example genetic and/or phenotypic baseline characteristics, associated with response in an outcome of interest. Objective: Using data from a placebo-controlled crossover study (the FINGEN study), supplementing with two doses of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), the primary goal of this analysis was to develop models to predict change in concentrations of plasma triglycerides (TG), and in the plasma phosphatidylcholine (PC) LC n-3 PUFAs eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), after fish oil (FO) supplementation. A secondary goal was to establish if clustering of data prior to FO supplementation would lead to identification of groups of participants who responded differentially. Methods: To generate models for the outcomes of interest, variable selection methods (forward and backward stepwise selection, LASSO and the Boruta algorithm) were applied to identify suitable predictors. The final model was chosen based on the lowest validation set root mean squared error (RMSE) after applying each method across multiple imputed datasets. Unsupervised clustering of data prior to FO supplementation was implemented using k-medoids and hierarchical clustering, with cluster membership compared with changes in plasma TG and plasma PC EPA + DHA. Results: Models for predicting response showed a greater TG-lowering after 1.8 g/day EPA + DHA with lower pre-intervention levels of plasma insulin, LDL cholesterol, C20:3n-6 and saturated fat consumption, but higher pre-intervention levels of plasma TG, and serum IL-10 and VCAM-1. Models also showed greater increases in plasma PC EPA + DHA with age and female sex. There were no statistically significant differences in PC EPA + DHA and TG responses between baseline clusters. Conclusion: Our models established new predictors of response in TG (plasma insulin, LDL cholesterol, C20:3n-6, saturated fat consumption, TG, IL-10 and VCAM-1) and in PC EPA + DHA (age and sex) upon intervention with fish oil. We demonstrate how application of statistical methods can provide new insights for precision nutrition, by predicting participants who are most likely to respond beneficially to nutritional interventions.

Effect of puerarin supplementation on cardiovascular disease risk factors: A randomized, double-blind, placebo-controlled, 2-way crossover trial.

BACKGROUND: Cell culture and animal studies suggest puerarin could prevent cardiovascular disease (CVD). However, trials in human are scare, not primarily designed for prevention, and inadequately powered. We assessed the effect of puerarin supplementation on CVD risk factors in men using a crossover trial. METHODS: In total, 217 Chinese men aged 18-50 years without a history of CVD were recruited. They were randomized to take a puerarin supplement (90.2 mg daily) or a placebo, followed by a 4-week wash-out period, and then crossed over to the other intervention. An intention-to-treat analysis was used. Differences in primary outcomes (lipid profile such as low-density lipoprotein (LDL) cholesterol) and secondary outcomes (other CVD risk factors such as blood pressure and fasting glucose, and some potential mediating pathways such as testosterone) between supplementation and placebo within participants were compared using a paired t-test, or a crossover (CROS)-based analysis where a period effect existed. RESULTS: Lipid profile was similar after the puerarin supplementation or placebo (e.g., mean difference in LDL cholesterol: -0.02 mmol/L, 95% confidence interval (CI) -0.09 to -0.06). Conversely, fasting glucose was reduced after the puerarin supplementation (-0.13 mmol/L, 95% CI -0.25 to -0.008). There were no differences in blood pressure, testosterone, high-sensitive C-reactive protein, prothrombin time, liver or renal function. CONCLUSION: In young-to-middle-aged Chinese men, short-term puerarin supplementation did not improve the primary outcome of lipid profile, but an exploratory analysis suggested that puerarin could be beneficial for one of the secondary outcomes, i.e., fasting glucose.