Two-period Crossover Design Research Articles

In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

Novel bioequivalent oral disintegrating tablet of aripiprazole prepared by direct compression technique with shortened disintegration time

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1–5.2 kp hardness exhibited rapid disintegration (14.1–17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306–11051 and 0.9448–1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence.

A Bayesian approach to pilot-pivotal trials for bioequivalence assessment

BackgroundTo demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial.MethodsWe consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics.ResultsCompared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent.ConclusionsThe proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.

Validation of the Electronic Compassion Competence Scale: Paper-and-Pencil versus Web-Based Questionnaires

Purpose: This study aimed to determine the validity and reliability of the electronic Compassion Competence Scale (e-CCS).Methods: A cross-sectional, randomized, two-period crossover design was used. Nursing students from four South Korean universities were surveyed between June 2017 and April 2018. The participants were randomly assigned to one of three groups-paper/paper, electronic/electronic, and paper/electronic or electronic/paper-and a test-retest procedure was implemented. The reliability and validity of the e-CCS were evaluated using linear weighted kappa coefficients and intraclass correlation coefficients (ICCs). Internal consistency reliability was verified using linear weighted kappa coefficients and ICCs. Pearson’s correlation coefficients between the initial test and retest scores were all statistically significant.Results: The newly developed e-CCS was found to have good reliability and validity. We suggest that future research should increase sample heterogeneity by recruiting diverse age groups, nurses working in different nursing fields, and students from multiple colleges.Conclusion: This electronic instrument will help determine the differences in the level of compassion competence and devise interventions to improve compassion competence in nurses and nursing students. Further studies on enhancing compassion competence among nurses and nursing students may rely on the use of this electronic format.

The Lubricating Effect of Eye Drops Containing Hyaluronic Acid and Mallow Extract in Patients with Dry Eye Disease-A Pilot Study.

Background and Objectives: Mucilaginous substances from plants are known to be able to support the lubricating effect of hyaluronic acid (HA) in dry eye disease (DED). In this pilot study, the combined lubricating effect of HA and mallow extract (Malva sylvestris L.) in patients with DED was assessed. Materials and Methods: Twenty patients at five ophthalmological practices in Italy were treated with eye drops containing HA and mallow extract on the one hand, and with eye drops containing HA only, on the other hand, in a two-period crossover design. As primary endpoints, the tear film breakup time (TBUT), the reduction of lissamine green staining of the ocular surface (Oxford Scheme, OS), and the safety and efficacy assessment by the ophthalmologists were evaluated. As secondary variables, the patient symptom score, the ocular surface index (OSDI) and the satisfaction, preference and efficacy assessment by the patients were evaluated. All data were analysed descriptively in addition to an exploratory analysis being made of the target variables. Results: Both products were well-tolerated. There were no statistically significant differences with regard to the TBUT, OS and OSDI between the two treatments. Anyway, the efficacy and safety assessments by the ophthalmologists and the patients showed results in favour of the combined product. Conclusion: The addition of mallow extract to HA-containing eye drops enhances the treatment of DED, at least with respect to subjective measurements. Further assessments will have to be done to prove and explain this observation in terms of measurable parameters, e.g., markers for inflammatory cytokines.

Effectiveness of neurobic exercise program on memory performance in community-dwelling older adults with mild cognitive impairment: A randomized controlled crossover trial.

Mild cognitive impairment (MCI) is an early stage of cognitive decline in individuals who are still able to perform their activities of daily living. They are at increased risk of developing dementia. Improving and maintaining cognitive functions are essential goals for older people with MCI to delay or prevent the transition to dementia. This study investigated the effect of the neurobic exercise program on memory performance among community-dwelling older adults with MCI. A single-blind, randomized, controlled, two-period crossover design was used. Thirty-two older adults who met the study criteria were randomly assigned to one of two sequence groups, A (n =16) and B (n = 16). Group A received three weeks of neurobic exercise, followed by a three-week washout period, and then three weeks of the traditional brain exercise program. Group B received the treatments in the reverse order but otherwise in a similar manner. Two aspects of memory performance were evaluated: subjective memory and objective memory. Blinded evaluators measured the outcomes four times at baseline, post-intervention (week 3), follow-up stage (week 7), and the end of the study (week 9). Descriptive statistics, independent t-tests, and repeated measures ANOVA were employed for data analyses. For subjective memory, rmANOVA revealed a significant difference of within-subject (F1.437, 43.113 = 9.324, p <0.05) and interaction effect (time*group) (F1.437, 43.113 = 12.313, p <0.05) and also showed significant differences of within-subject (F1.794,53.811 = 28.931, p < .05) and interaction effect (time*group) (F1.794, 53.811 = 31.190, p <0.05) for objective memory. The study results revealed that the participants in both groups had significantly lower mean scores on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), indicating better or improved subjective memory. They also had significantly higher mean scores on the Common Objects Memory Test (COMT) after receiving the neurobic exercise program, indicating improvement in cognitive performance. The neurobic exercise intervention could improve subjective and objective memory among community-dwelling older adults with MCI more than those who received the traditional brain exercise program. Therefore, the neurobic exercise program can be used by nurses and multidisciplinary teams to enhance memory performance among older adults with MCI. Thai Clinical Trials Registry (TCTR) 20210326003.

Evaluation of the chromium-EDTA complex and creatinine as markers for urinary volume in cattle

ABSTRACT Creatinine and intravenously infused Cr-EDTA complex were compared as markers for urinary volume estimation in cattle fed diets containing different concentrate levels. Ten Nellore heifers were used in a two-period crossover design and fed with two diets of divergent maize silage to concentrate ratios (90:10 and 50:50). The urinary marker concentrations were strongly and positively associated with each other, and both correlated strongly and negatively with total urine volume. Creatinine excretion and chromium recovery did not vary according to diets, but chromium recovery exhibited a lower variance among animals. The evaluation of urine spot samples showed that sampling time affects both markers, with the lowest urinary concentrations obtained when samples were taken early in the morning. Both creatinine and the Cr-EDTA complex produce similar estimates of urine volume. However, despite the greater precision of the estimates obtained with chromium, the values obtained with creatinine exhibited less bias and are, therefore, more accurate.

Pharmacokinetic comparison of sitagliptin and metformin HCl extended-release tablets versus JANUMET® XR in healthy volunteers under fasting and fed conditions.

Background and Objectives: Janumet® XR is the combination of sitagliptin and extended metformin hydrochloride produced by Merck Sharp & Dohme. It is specially designed for diabetes mellitus patients taking both drugs already. Janumet® XR exhibited clinically significant blood glucose lowering efficacy and long-term use safety. However, no generic form of Janumet® XR has been approved in western countries. The relatively high cost made the medication less prescribed. A more affordable form of this drug may benefit an immense diabetes mellitus population. The current study compared the bioequivalence (BE) of sitagliptin 100mg and metformin 1000mg produced by Nanjing Chia-Tai Tianqing Pharmaceutical Company to Janumet® XR in healthy Chinese subjects. Methods: Twenty-eight healthy Chinese subjects were enrolled in Study 1 and 2, respectively. Both studies were conducted with an open, randomized, two-period crossover design using the test (T) or the reference (R) drug. Study 1 is conducted under the fasting state, and Study 2 is under the fed state. Subjects received an oral dose of sitagliptin 100mg and metformin 1000mg, and plasma concentrations of sitagliptin and metformin were determined up to 72h post-dose. Pharmacokinetic (PK) parameters, including maximum serum concentration (Cmax) and area under the concentration-time curve up to the last quantifiable concentration (AUC0-t) of both sitagliptin and metformin, were calculated and compared between the T and R treatments. Results: In the fasting study, the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ for sitagliptin were 109.42%, 101.93%, and 101.95%, respectively; the corresponding ratios for metformin were 98.69%, 94.12%, and 93.42%, respectively. In the fed study, the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ for sitagliptin were 98.41%, 100.30%, and 100.24%, respectively; the corresponding ratios for metformin were 97.79%, 99.28%, and 100.69%, respectively. The 90% CIs of Cmax, AUC0-t, and AUC0-∞ in both studies were all within acceptance limits (80.00%-125.00%). Conclusion: The results demonstrated for the first time that sitagliptin 100mg and metformin 1000mg produced by Nanjing Chia-Tai Tianqing Pharmaceutical Company was bioequivalent to the branded Janumet® XR, and both drugs were well tolerated.

Comparative Bioequivalence of Tablet and Capsule Formulations of Ulotaront and the Effect of Food on the Pharmacokinetics of the Tablet Form in Humans.

Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT1A receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC-MS/MS. PK parameters were calculated using Phoenix WinNonlin® software. For the BE study, geometric mean ulotaront Cmax values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. Cmax ratio was 107.25% (90% CI 101.84-112.94%). Geometric mean ulotaront area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) values were 868.8 and 829.3 ng·h/mL for tablet and capsule, respectively. AUC0-∞ ratio was 104.76% (90% CI 100.68109.01%). For the FE study, geometric mean ulotaront Cmax was 157.89 and 157.95 ng/mL under fed and fasted conditions, respectively. Geometric mean ratio of Cmax was 99.96% (90% CI 94.48-105.77%). Geometric mean ulotaront AUC0-∞ was 1584.2 ng·h/mL fed and 1589.2 ng·h/mL fasted. Geometric mean ratio for AUC0-∞ was 99.69% (90% CI 95.02-104.58%). There was a delay in tmax (median difference 1.47 h) in the fed condition. The results showed geometric mean ratios and 90% CIs for both Cmax and AUC0-∞ for ulotaront were well within typical bioequivalence criteria of 80-125% for both the BE and FE studies, thereby confirming the bioequivalence of the two dosage forms and no significant food effect.

The Effect of Spatial Uncertainty on Visual Search in Older School-Aged Children with and without ADHD.

Numerous studies support that simple visual search tests may not be sufficient to differentiate children with and without attention-deficit/hyperactivity disorder (ADHD), especially for older school-aged children. This study aimed to explore whether the high spatial uncertainty visual search tasks can effectively discriminate older school-aged children with ADHD from their typically developing (TD) peers. In a randomized, two-period crossover design, 122 school-aged children (61 ADHD and 61 TD subjects), aged 10-12years old, were measured using comparable visual search tasks with structured and unstructured layouts. First, the discriminant effectiveness of unstructured visual search tasks, which are associated with high-level spatial uncertainty, is superior to structured ones. Second, combining accuracy and speed into a Q score is a more sensitive measure than accuracy or time calculated alone in visual search tasks. A more in-depth ROC analysis showed that all variables could accurately identify ADHD from their TD peers under unstructured visual search tasks, with the index of the Q score performing best (AUR = 0.956). Third, the development of detectability, which represents the ability to distinguish between target and non-target, is approaching maturity in 10-12-year-old children with ADHD. However, these children showed severe deficits in dealing with disorganized distractors when performing visual search tasks with high-level spatial uncertainty. The findings of this study support that older school-aged children with ADHD demonstrate less efficient search performance than their TD peers in complex/difficult visual search tasks, especially under higher spatial uncertainty.

Efficacy of functional electrical stimulation in rehabilitating patients with foot drop symptoms after stroke and its correlation with somatosensory evoked potentials—a crossover randomised controlled trial

ObjectiveThe connectivity between somatosensory evoked potentials (SEPs) and cortical plasticity remains elusive due to a lack of supporting data. This study investigates changes in pathological latencies and amplitudes of SEPs caused by an acute stroke after 2 weeks of rehabilitation with functional electrical stimulation (FES). Furthermore, changes in SEPs and the efficacy of FES against foot drop (FD) stroke symptoms were correlated using the 10-m walk test and foot–ankle strength.MethodsA randomised controlled two-period crossover design plus a control group (group C) was designed. Group A (n = 16) was directly treated with FES, while group B (n = 16) was treated after 2 weeks. The untreated control group of 20 healthy adults underwent repeated SEP measurements for evaluation only.ResultsThe repeated-measures ANOVA showed a decrease in tibial nerve (TN) P40 and N50 latencies in group A after the intervention, followed by a decline in non-paretic TN SEP in latency N50 (p < 0.05). Moreover, compared to groups B and C from baseline to 4 weeks, group A showed a decrease in paretic TN latency P40 and N50 (p < 0.05). An increase in FD strength and a reduction in step cadence in group B (p < 0.05) and a positive tendency in FD strength (p = 0.12) and step cadence (p = 0.08) in group A were observed after the treatment time. The data showed a moderate (r = 0.50–0.70) correlation between non-paretic TN latency N50 and step cadence in groups A and B after the intervention time.ConclusionThe FES intervention modified the pathological gait in association with improved SEP afferent feedback.Registered on 25 February 2021 on ClinicalTrials.gov under identifier number: NCT04767360.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Abstract P114: Effects Of Losartan And The Dash Diet On Serum Urate

Background: The DASH diet and losartan each lower blood pressure (BP) and concurrently affect many cardiometabolic biomarkers. Whether these BP-lowering treatments reduce serum urate, a pro-oxidant associated with cardiovascular health and gout, is uncertain. Objective: To determine the independent effects of the DASH diet and losartan on serum urate. Methods: We randomized 55 participants with elevated BP in parallel fashion to the DASH or control diet, the standard American diet. While on their assigned diet, participants were randomized in a two-period cross-over design to losartan or placebo, each for 4-weeks. Serum urate was measured at baseline and at the end of each period. Diets were designed to maintain a constant weight constant. We examined the independent effects of DASH (vs control) or losartan (vs placebo) on serum urate, overall and among those with baseline serum urate ≥6 mg/dL, using generalized estimating equations. Results: Of 55 randomized participants, mean age of participants was 52 years, 58% were women, and 64% were Black. Mean (±SD) baseline SBP/DBP was 146±12/91±9 and mean (±SD) serum urate was 5.2±1.2 mg/dL. Losartan significantly decreased serum urate (overall mean difference -0.23 mg/dL; 95% CI: -0.40, -0.05). The DASH diet did not significantly reduce urate levels overall (mean difference -0.05 mg/dL; 95% CI: -0.39, 0.28), but did decrease levels in participants with elevated baseline urate levels (≥6 mg/dL), with a mean difference of -0.33 mg/dL (95% CI: -0.87, 0.21; P -interaction =0.007 across hyperuricemia groups). Conclusions: In adults with elevated BP, losartan significantly reduced serum urate, while the DASH diet only significantly decreased serum urate among participants with higher urate at baseline. Additional research should explore potential mechanisms, as well as the effects of these treatments on clinical outcomes (e.g. gout).

Double the dose, double the impact? Effects of iTBS on salivary cortisol in stressed healthy volunteers

There is a growing interest in applying double-dose repetitive transcranial Magnetic Stimulation (rTMS) as a therapeutic tool for stress-related psychiatric disorders. Such stimulation protocols may shorten the treatment duration and may result in faster symptom improvement. Currently, theta-burst stimulation (TBS) protocols have gained attention because of their significantly reduced treatment duration, compared to conventional rTMS. However, the effect of one or twice daily rTMS sessions remains unclear in relation to stress. Using a two-period cross-over design, we examined the impact of double-dosed intermittent (TBS) over the left dorsolateral prefrontal cortex on stress responses (salivary cortisol) in thirty-eight healthy participants after being stressed by a validated psychosocial stress task: the Trier Social Stress Test. After the first active iTBS session, as contrasted to sham, no differential effects on salivary output were observed. However, after the second active session, there was a significantly smaller decrease of salivary cortisol concentrations in the active iTBS condition compared to sham. Our results suggest that double-dosed iTBS after being stressed might differently affect stress recovery compared to a single session of iTBS.

Comparative effects of EMG-driven robot-assisted therapy versus task-oriented training on motor and daily function in patients with stroke: a randomized cross-over trial

BackgroundRobot-assisted hand training has shown positive effects on promoting neuromuscular control. Since both robot-assisted therapy and task-oriented training are often used in post-stroke rehabilitation, we raised the question of whether two interventions engender differential effects in different domains.MethodsThe study was conducted using a randomized, two-period crossover design. Twenty-four chronic stroke survivors received a 12-session robot-assisted intervention followed by a 12-session task-oriented intervention or vice versa. A 1-month washout period between each intervention was implemented. Outcome measures were evaluated before the intervention, after the first 12-session intervention, and after the second 12-session intervention. Clinical assessments included Fugl-Meyer Assessment for Upper Extremity, Wolf Motor Function Test, Action Research Arm Test and Motor Activity Log.ResultsOur findings suggested that EMG-driven robot-assisted therapy was as effective as task-oriented training in terms of improving upper limbs functional performance in activity domain, and robot-assisted therapy was more effective in improving movement duration during functional tasks. Task-oriented training showed better improvement in body function domain and activity and participation domain, especially in improving spontaneous use of affected arm during daily activities.ConclusionsBoth intervention protocol had their own advantages in different domains, and robot-assisted therapy may save manpower and be considered as an alternative intervention to task-oriented training. Combining the two approaches could yield results greater than either alone, which awaits further study.Trial registration: ClinicalTrials.gov Identifier: NCT03624153. Registered on 9th August 2018, https://clinicaltrials.gov/ct2/show/NCT03624153.

Efficacy of Low-frequency Monophasic Pulsed Microcurrent Stimulation Therapy in Undermining Pressure Injury: A Double-blind Crossover-controlled Study.

ABSTRACTObjectives:This double-blind crossover-controlled trial aimed to verify the effect of electrical stimulation therapy on pressure injuries with undermining.Methods: In this trial, we compared the healing rates between a sham period and a treatment period using monophasic pulsed microcurrent therapy. The participants were randomly assigned to the sham or treatment group and received stimulation for 2 weeks. All the participants, physical therapists, and researchers were blinded to the allocation. For the main analysis, data on the effect of the intervention on changes in weekly healing and contraction rates of the wound areas, including undermining, were analyzed based on a two-period crossover study design. The intervention effect was estimated by examining the mean treatment difference for each period using Wilcoxon’s signed-rank test.Results: The reduction of the entire wound area, including the undermining area, resulted in significantly higher healing and contraction rates in the treatment group (overall wound area reduction rate: contraction rate, P=0.008; period healing rate, P=0.002).Conclusions: Electrical stimulation therapy for pressure injuries, using conditions based on the findings of an in vivo culture study, was effective in reducing the wound area.

Effect of high nitrate vegetable juice supplementation on plasma nitrate and blood pressure in adults: a pilot randomized crossover intervention in healthy volunteers.

Beetroot juice (BRJ) has been demonstrated to decrease blood pressure (BP) due to the high inorganic nitrate content. This pilot randomized crossover trial aimed to investigate the effect of two different high nitrate vegetable juices on plasma nitrate concentrations and BP in healthy adults. Eighteen healthy volunteers were randomized to receive 115 ml of BRJ or 250 ml of green leafy vegetable juice for 7 d which contained similar amounts of nitrate (340 mg) daily. Blood samples were collected, and clinic BP measured at baseline and at the end of each juice consumption. Daily home BP assessment was conducted 2 h after juice consumption. Nitrate and nitrite concentrations were analysed using a commercially available kit on a Triturus automated ELISA analyser. Hills and Armitage analysis was used for the two-period crossover design and paired sample t-tests were performed to compare within-group changes. Plasma nitrate and nitrite concentrations significantly increased and there was a significant reduction in clinic and home systolic blood pressure (SBP) mean during the BRJ period (P-values 0⋅004 and 0⋅002, respectively). Home diastolic blood pressure (DBP) reduced significantly during green leafy vegetable juice consumption week (P-value 0⋅03). The difference between groups did not reach statistical significance during the formal crossover analysis adjusted for period effects. BRJ and green leafy vegetable juice may reduce SBP or DBP, but there was no statistically significant difference between the two juices, although this was only a pilot study.

Determination, comparison, and prediction of digestible energy, metabolizable energy, and standardized ileal digestibility of amino acids in novel maize co-products and conventional distillers dried grains with solubles for swine

The objectives of this study were to determine and compare the digestible energy (DE), metabolizable energy (ME), and the coefficient of standardized ileal digestibility (CSID) of amino acids (AA) in novel maize co-products and distillers dried grains with solubles (DDGS) for swine and to compare in vivo determined values with calculated values from published equations. Seven maize co-products were used including two sources of conventional DDGS (DDGS-A and DDGS-B), two sources of high protein distillers dried grains (HPDDG-A and HPDDG-B), two sources of high yeast and protein co-products (HYP-A and HYP-B), and one source of maize fiber and solubles (MFS). In Exp. 1, thirty-two barrows (initial body weight = 24.2 ± 3.4 kg) were housed individually in metabolism crates and randomly allotted to a maize-soybean meal basal diet or 1 of 7 diets, in which 300 g/kg of each co-product partially replaced a portion of maize and soybean meal, in a randomized two-period crossover design. Feces and urine were collected in two 7-d adaptation and 4-d collection periods. In Exp.2, sixteen ileal-cannulated barrows (initial body weight = 37.0 ± 3.8 kg) were housed in metabolism crates and assigned to a nitrogen-free diet or 1 of 7 diets containing 300 g/kg of each maize co-product as the sole crude protein (CP) source in a repeated 8 × 4 Youden square design to determine CSID of AA. Diets were fed for four consecutive 7-d periods (5-d adaptation and 2-d ileal digesta collection). Co-products contained 18.34–22.28 MJ/kg gross energy, 155.3–502.0 g/kg CP, 46.2–137.4 g/kg ether extract, 95.2–463.2 g/kg neutral detergent fiber, and 4.3–20.8 g/kg Lys on an as-fed basis. The HYP-A and HYP-B had the greatest DE (18.04 and 17.51 MJ/kg DM, respectively) and ME (17.24 and 16.63 MJ/kg DM, respectively) compared with other co-products (P < 0.05), and HPDDG-B had the lowest (P < 0.05) DE and ME. The CSID of Lys ranged from 0.30 to 0.70 among co-products. The CSID for Arg, His, Ile, Lys, Met, Thr, and Val were not different among DDGS-B, HPDDG-A, HYP-A, and HYP-B, while HPDDG-B had the lowest (P < 0.05) CSID for all AA. Use of published equations for DDGS resulted in low prediction accuracy and precision for estimating DE, ME, and SID AA compared with observed values. The high ME and SID Lys, Met, Thr, and Trp of HYP-A and HYP-B indicated greater feeding value for swine compared to other co-products evaluated.

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms: S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28±18.99, 230.76±29.16 and 352.67±42.94 μg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09±59.66, 524.50 ±72.87 and 822.68±95.21 μg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72±61.65, 536.06±78.13 and 832.07±96.91 μg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05±0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.

Anti-inflammatory Effect of Ketamine: A Double-Blind Placebo-Controlled Randomised Study

Considering the rapid antidepressant action of ketamine, we aimed to investigate its anti-inflammatory effect. As part of a randomised double-blind placebo-controlled study plasma samples from 31 healthy remitted depressed were collected before and 1.5 hours after ketamine (0.5 mg/kg) and saline (placebo) administration in a two-period cross-over design. Meso Scale Discovery was used to measure cytokines concentrations. Significant interaction effect between the treatment and time were found for IL-1beta (F=8.35, p=0.008), TNF-alpha (F=5.17, p=0.032), IFN-gamma (F=8.78, p=0.006) and GM-CSF (F=5.19, p=0.031). Following ketamine administration, there was a significant decrease in the levels of IFN-gamma (p<0.001) and GM-CSF (p=0.021); but not after placebo infusion (p>0.05). Delta for changes in cytokine concentration in response to ketamine showed statistical significance for IL-1beta, TNF-alpha, and IFN-gamma (p<0.05), and a trend for GM-CSF (p=0.072). Ketamine exhibits anti-inflammatory properties by the effect on the major proinflammatory cytokines including IL-1beta, TNF-alpha, IFN-gamma and GM-CSF. Ketamine could be useful for treatment resistant depression or suicidal thoughts, and our findings suggest that rapid changes in inflammatory markers to be studied as potential mediators of these effects, especially in patients with higher levels of inflammation.