Volenrelaxin (LY3540378) increases Renal Plasma Flow: A Randomized Phase 1 Trial.

BACKGROUND AND HYPOTHESIS: Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. METHODS: In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n = 56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n = 77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. RESULTS: Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p < 0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and + 4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. CONCLUSION: Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

Baseline glycated albumin level and risk of type 2 diabetes mellitus in Healthy individuals: a retrospective longitudinal observation in Korea.

Glycated albumin (GA) reflects glycemic status for the past three weeks. GA level demonstrates a strong correlation with HbA1c level and is used as an adjunctive biomarker for diagnosis and monitoring of type 2 diabetes mellitus (T2DM). In this study, we validated the predictive performance of baseline GA for development of T2DM in healthy individuals in Korea. From August 2013 to September 2014, the medical records of 3,771 healthy Koreans were retrospectively reviewed. Each participant was categorized into tertiles based on initial GA level. During the follow-up period through May 2020, study participants were evaluated for T2DM using HbA1c, fasting glucose level, and a self-reported diagnosis history. Baseline GA level by tertile (T1 to T3) was 10.4 ± 0.8% (mean ± SD), 12.1 ± 0.3%, and 13.7 ± 0.9%, respectively. The median follow-up was 5.97 years, during which 4.9% (186 of 3,771) of the participants developed T2DM. After adjusting for confounding factors, the hazard ratio for the development of T2DM in the highest GA level group (T3) compared to the reference group (T1) was 2.46 (95% CI, 1.7 to 3.58, p < 0.001 for trend) with a Harrell's C index of 0.80 (95% CI, 0.76 to 0.83). Also, within highest group of baseline HbA1c and FG levels, higher GA levels were associated with an increased HRs for T2DM. In conclusion, Our study confirms that the risk of T2DM increases with baseline GA level. Additional follow-up of the cohort is warranted to investigate the correlations between GA and other clinical indicators including diabetic complications.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

AIMS: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. METHODS: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. RESULTS: In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. CONCLUSIONS: The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Reference jitter values for the sternocleidomastoid muscle with concentric needle electrodes.

BACKGROUND: The aim of this study was to establish reference jitter values for the voluntary activated sternocleidomastoid (SCM) muscle using a concentric needle electrode (CNE). METHODS: The study included 39 healthy participants (20 female and 19 male) aged 18-77 y. Jitter was expressed as the mean consecutive difference (MCD) of 80-100 consecutive discharges. Filters were set at 1 and 10 kHz. The mean MCDs for all participants were pooled, and the mean value +2.5 SD was accepted as the upper limit for the mean MCD. The upper limit for individual MCD was calculated using +2.5 SD of the upper 10th percentile MCD for individual participants. RESULTS: Mean age of the participants was 45 ± 14.5 y. Mean MCD was 16.20 ± 2.23 µs (range: 12-21 µs), and the upper limit of normal for mean MCD was 21.8 µs. The mean value for 823 individual jitters was 23.3 ± 4.61 µs (range: 6.6-36.9 µs), and the upper limit of normal for each individual jitter was 34.6 µs. CONCLUSIONS: The present findings indicate that upper normal limit for mean MCD is 22 µs and for individual data it is 35 µs.

Comparative analysis of the autonomic nervous system response during movement representation in healthy individuals and patients with chronic low back pain: a prospective cohort study.

OBJECTIVE: The primary objective was to compare the difference in autonomic nervous system (ANS) response between motor imagery (MI) group and action observation (AO) group. Both consisted of two subgroups: the control subgroup (CG), which consisted of asymptomatic individuals, and the patient subgroup (PG), which consisted of patients with chronic low back pain (CLBP). The secondary objective was to assess ANS activity during AO and MI training according to the fear-of-movement levels of the PGs. METHODS: Sixty participants were randomly assigned. The autonomic outcome measures included skin conductance (SC), respiration rate (RR), and heart rate (HR). RESULTS: Results showed that intergroup differences in RR were higher in the PG, with a large effect size (p = .007, d = 1.71). Only the PGs showed intragroup differences in SC (p <.05). In terms of ANS activity during the training, there were no statistically significant intergroup differences (p <.05). However, the strongest intragroup differences were among the AOPG with greater levels of kinesiophobia. For the SC and HR variables, only this condition showed significant differences between baseline and the first and second movements, with a large effect size (p <.001 and p = .002, respectively, and d >.80). CONCLUSIONS: The results showed that AO and MI training in the PG and CG resulted in similar but not identical ANS activation, with slightly higher activation in the PG. The differences in the PG could be associated with kinesiophobia when visually exposed to low-back movements that could be interpreted as hazardous or unsafe.

The Timed Swallowing Proficiency for Eating and Drinking (SPEAD) Test: Development and Initial Validation of an Instrument to Objectify (Impaired) Swallowing Capacity in Head and Neck Cancer Patients.

Objective swallowing outcomes measure the physical swallowing function, while subjective outcomes measure swallowing perception. A test for swallowing capacity, measuring the ingestion of all consistencies is currently not available. Therefore, the Swallowing Proficiency for Eating And Drinking (SPEAD) test was developed. It entails the timed ingestion of thin liquid, thick liquid and solid. In this study, its feasibility, reliability and validity were evaluated in patients with dysphagia after treatment for head and neck cancer (HNC) and healthy participants. Thirty-eight HNC patients and forty healthy participants were enrolled in this study and performed the SPEAD test three times. Video recordings of the test were evaluated three times by one observer, and once by three additional observers, to assess test-retest, intra-rater and inter-rater reliability. Validity was assessed by calculating effect sizes for the difference between results of patients and healthy participants and by evaluating correlations with objective (e.g., videofluoroscopy and functional oral intake scale) and subjective (e.g., SWAL-QOL) swallowing outcomes. Test-retest, intra-rater and inter-rater reliability of ingestion duration was good to excellent. All hypotheses with regard to magnitude and direction of correlations were confirmed, supporting construct validity of the test. Our initial results suggest that the SPEAD test reliably measures the transport capacity of the upper digestive tract (in grams per second) and that this test can be useful to objectively evaluate and monitor the (safe) swallowing capacity in HNC patients, in both research as well as daily clinical practice.

The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants.

Background The third-generation tyrosine kinase inhibitor lorlatinib is approved for the treatment of ALK-positive metastatic NSCLC. CYP3A plays a major role in lorlatinib metabolism; therefore, a drug-drug interaction study was warranted to evaluate the impact of the strong CYP3A inhibitor, itraconazole, on lorlatinib plasma exposure. Methods This phase 1, open-label, 2-period, crossover study estimated the effects of itraconazole on the plasma pharmacokinetics and safety of lorlatinib in healthy participants (NCT02838264). Single-dose lorlatinib 50 mg (n = 2), 75 mg (n = 2) and 100 mg (n = 12) was administered in Period 1. In Period 2, itraconazole oral solution 200 mg/day was administered on Days 1-11, and single-dose lorlatinib on Day 5. Blood samples were collected up to 168 h after lorlatinib dosing. Results During daily dosing with itraconazole (Period 2), the ratios of the adjusted geometric means for area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of single-dose lorlatinib 100 mg were 141.79% (90% confidence interval, 128.71%, 156.21%) and 124.39% (110.20%, 140.41%), respectively, compared with Period 1 (lorlatinib alone). Lorlatinib was well tolerated alone and with itraconazole. No serious adverse events or withdrawals were reported. Conclusions Co-administration of itraconazole and lorlatinib increased the plasma exposure of lorlatinib relative to lorlatinib alone in healthy participants. Therefore, concomitant use of lorlatinib with strong CYP3A inhibitors should be avoided. If this combination is unavoidable, the starting dose of lorlatinib should be reduced from 100 mg to 75 mg.

Intermachine Variation of Ultrasound Strain Elastographic Measures of the Quadriceps and Patellar Tendons in Healthy Participants: Implications for Clinical Practice.

OBJECTIVES: To evaluate intermachine variation and compare intraoperator and interoperator agreement and repeatability characteristics of 2 ultrasound (US) systems for measurements of quadriceps and patellar tendons by strain elastography (SE). METHODS: Forty tendons from 20 healthy participants were investigated by operators with different experience (operator 1, 12 years of US experience and >50 SE examinations; operator 2, no US experience and 1 day of SE training). Repeated measures were performed on GE Healthcare (Waukesha, WI) and Esaote (Genoa, Italy) US systems. The percentage of agreement, Cohen κ, intraclass correlation coefficient, and correlation tests assessed agreement, repeatability, and associations of SE measures. A paired t test and Wilcoxon signed rank test assessed differences in SE measures. RESULTS: The study participants included 5 male and 15 female volunteers (mean [range] age, 29.3 [21-39] years). Better agreement and repeatability characteristics were observed for the patellar compared to the quadriceps tendon and the color score (CS) method over the elasticity ratio (ER). Intraoperator agreement was better for the experienced operator. Intraoperator repeatability was achieved in 55% of ER (intraclass correlation coefficient, 0.40-0.91; P < .05) and 77% to 85% (κ = -0.25-1) of CS measures. Interoperator repeatability was achieved in 35% (t/z, -2.93-7.94; P < .001-.048) of all ER measures. No significant differences in proximal (z, -0.13- -0.78) and distal patellar (z, -1.52-2.26; P > .5) patellar ER measures were observed. Seventy-four percent to 75% mean agreement (κ = 0-0.5) for CS measures comparable across both US systems was observed. Intermachine ER associations were poor (r = -0.39-0.13; P > .05), whereas greater than 70% agreement (κ = -0.87-0.53) for the CS was achieved. CONCLUSIONS: The reproducibility of knee tendon SE measurements is influenced by the operator experience, US system, and tendon site.

Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults.

BACKGROUND: Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. METHODS: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18-50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. RESULTS: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. CONCLUSION: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. TRIAL REGISTRATION: NA.

The inter-rater and test-retest reliability of skin thickness and skin elasticity measurements by the DermaLab Combo in healthy participants.

BACKGROUND: For several purposes, skin parameters like thickness and elasticity can be measured. However, little is known about the accuracy of those measurements. AIM: The aim of this study was to determine the intrarater and test-retest reliability of skin thickness and elasticity measurements performed with the DermaLab Combo®. METHODS: A total of 49 participants were included in this study. Skin thickness and elasticity were measured at six defined locations on the dominant arm. Measurements were repeated two times by the same observer to determine the test-retest reliability. To determine the inter-rater reliability, a second observer repeated the measurements once. RESULTS: Inter-rater and test-retest reliability for elasticity measurements fluctuates per location and per parameter: Inter-rater intraclass correlation coefficient (ICC) ranged from 0.23 to 0.80, and test-retest ICC ranged from 0.25 to 0.84. Skin thickness was measured reliable by every observer on every location, with a test-retest ICC ranging from 0.71 to 0.83 and an inter-rater ICC ranging from 0.69 to 0.80. CONCLUSION: The DermaLab Combo® showed a good inter-rater reliability when measuring skin thickness and elasticity. Not all locations are suitable for reliable inter-rater or test-retest measurements. The device is difficult to use by inexperienced users, as the echo probe is sensitive to small movements.

Acute and repetitive fronto-cerebellar tDCS stimulation improves mood in non-depressed participants.

Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation, which allows for selective inhibition or excitation of neural structures. It has demonstrated some efficacy in the treatment of mood disorders. However, these studies have predominately focused on stimulation of the prefrontal cortex (PFC). The cerebellum has an increasingly recognized role in emotional control, affective state, and some psychopathologies. As such, tDCS research into mood modulation needs to expand beyond conventional PFC-focused paradigms. Using a contralateral stimulation electrode placement [anodal left dorsolateral(dl)PFC, cathodal right cerebellum], and a single-blind, repeated-measures design, we initially assessed changes in the mood of healthy participants in response to acute stimulation (n = 44) and three repeated stimulations delivered second-daily (n = 21). In a second experiment, we separately investigated the influence of reversed polarity upon these same measures, in response to acute stimulation (n = 23) and repeated stimulation (n = 11). We observed a systematic elevation of mood in both active conditions following single and repeated tDCS, the latter of which displayed a progressive elevation of mood from baseline. No mood change was noted in response to either single or repeated stimulation in the sham condition. Frontocerebellar tDCS stimulation advantageously influences mood in healthy participants, with an accumulative and potentiated effect following successive stimulations. The possibility that frontocerebellar stimulation may provide a novel therapeutic adjunctive or pre-emptive intervention in stress-related disorders and mood-related psychopathologies should be considered.

Assessing harmonized intelligence measures in a multinational study.

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to measure IQ across a five-site, multinational study and demonstrate the harmonized measure's cross-site validity. Culturally appropriate intelligence measures were selected: four short-form Wechsler intelligence tests (Brazil, Netherlands, South Africa, United States) and the Binet Kamat (India). Analyses included IQ scores from 255 healthy participants (age 18-50; 42% male). Regression analyses tested between-site differences in IQ scores, as well as expected associations with sociodemographic factors (sex, socioeconomic status, education) to assess validity. Harmonization (e.g., a priori selection of tests) yielded the compatibility of IQ measures. Higher IQ was associated with higher socioeconomic status, suggesting good convergent validity. No association was found between sex and IQ at any site, suggesting good discriminant validity. Associations between higher IQ and higher years of education were found at all sites except the United States. Harmonized IQ scores provide a measure of IQ with evidence of good validity that can be used in neurocognitive and circuit-based studies to control for intelligence across global sites.

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants.

Elezanumab is a fully human monoclonal antibody, which is directed against repulsive guidance molecule A. The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab were assessed in 2 Phase 1 clinical studies. The objective of this study was to assess the PK, safety, tolerability, and immunogenicity following intravenous infusion of elezanumab in healthy adult Japanese, Han Chinese, and Caucasian participants as well as Western participants from the single-ascending-dose study. Elezanumab exposures were approximately 20% higher in Japanese and Han Chinese participants compared to White participants without controlling for body weight. After statistically controlling for body weight by including it as a covariate, the PK of elezanumab in White participants were comparable to those in Japanese and Han Chinese participants. The clinical implications of these exposure differences are yet to be determined. All adverse events were assessed by the investigator as having no reasonable possibility of being related to the study drugs and were mild in severity. No positive immunogenicity effect was observed that impacted elezanumab exposure or safety.

Test-Retest Reliability of a Protocol for Assessment of Local Tissue Water in the Head and Neck Area.

Background: Lymphedema measurement is vital to select appropriate treatment and monitor its progress. Quantifying lymphedema in the head and neck area is challenging. The use of tissue dielectric constant (TDC) measurements has shown promising results in other body areas. This study aims to determine the test-retest reliability of a TDC measurement protocol developed for the head and neck area. Methods and Results: A detailed measurement protocol, including eight measurement points per side, was developed. Subsequently, the reliability of the protocol was tested in a sample of healthy participants (n = 50, 28 males). Using the LymphScanner (Delfin, Finland), participants were subjected to two measurement sessions. Each measurement point was measured three times per session. Test-retest reliability for each point was evaluated using intraclass correlation coefficients (ICCs) and standard errors of measurement (SEMs). Using the average of three measurements, reliability was good to excellent for all points (ICCs 0.81-0.95), with small measurement errors (SEMs 1.51-2.86). The reliability of a single measurement was moderate to excellent for all measurement points (ICCs 0.58-0.87), with larger, but still small, measurement errors (SEMs 1.65-3.39). When using single measurements, the lowest ICCs were found for the temporal (left 0.73 and right 0.67) and submandibular (left 0.58 and right 0.77) locations. Conclusion: Measurements with the LymphScanner, taken according to the developed protocol, are reliable in healthy participants. We recommend using the average of three measurements to optimize reliability. The protocol is fit for further testing in patient populations and for determining normal values in a larger scale study with healthy subjects.

SARS-CoV-2 Contamination on Healthy Individuals' Hands in Community Settings During the COVID-19 Pandemic.

Introduction Hand hygiene is an infection control measure for COVID-19 in our daily lives; however, the contamination levels of SARS-CoV-2 in the hands of healthy individuals remain unclear. Thus, we aimed to evaluate SARS-CoV-2 contamination levels by detecting viral RNA and viable viruses in samples obtained from the hands of 925 healthy individuals. Methods Swab samples were collected from the palms and fingers of healthy participants, including office workers, public officers, university students, university faculty and staff, and hospital staff between December 2022 and March 2023. The collected swab samples were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for SARS-CoV-2 RNA detection. Viral RNA-positive samples were subjected to plaque assay to detect viable viruses. Results We collected 1,022 swab samples from the hands of healthy participants. According to the criteria for data collection, 97 samples were excluded, and 925 samples were analyzed using RT-qPCR. SARS-CoV-2 RNA was detected in three of the 925 samples. The viral RNA detection rate was 0.32% (3/925), and the viral RNA copy numbers ranged from 5.0×103 to 1.7×105 copies/mL. The RT-qPCR-positive samples did not contain viable viruses, as confirmed by the plaque assay results. Conclusions The detection rate of SARS-CoV-2 RNA from the hands of healthy individuals was extremely low, and no viable viruses were detected. These results suggest that the risk of contact transmission via hands in a community setting is extremely rare.

Comparison Between Effects of Galvanic and Vibration-Based Vestibular Stimulation on Postural Control and Gait Performance in Healthy Participants: A Systematic Review of Cross-Sectional Studies.

Electricity and vibration were two commonly used physical agents to provide vestibular stimulation in previous studies. This study aimed to systematically review the effects of galvanic (GVS) and vibration-based vestibular stimulation (VVS) on gait performance and postural control in healthy participants. Five bioscience and engineering databases, including MEDLINE via PubMed, CINAHL via EBSCO, Cochrane Library, Scopus, and Embase, were searched until March 19th, 2023. Studies published between 2000 and 2023 in English involving GVS and VVS related to gait performance and postural control were included. The procedure was followed via the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The methodological quality of included studies was assessed using the NIH study quality assessment tool for observational cohort and cross-sectional studies. A total of 55 cross-sectional studies met the inclusion criteria and were included in this study. Five studies were good-quality while 49 were moderate-quality and 1 was poor-quality. There were 50 included studies involving GVS and 5 included studies involving VVS. GVS and VVS utilized different physical agents to provide vestibular stimulation and demonstrated similar effects on vestibular perception. Supra-threshold GVS and VVS produced vestibular perturbation that impaired gait performance and postural control, while sub-threshold GVS and VVS induced stochastic resonance phenomenon that led to an improvement. Bilateral vestibular stimulation demonstrated a greater effect on gait and posture than unilateral vestibular stimulation. Compared to GVS, VVS had the characteristics of better tolerance and fewer side effects, which may substitute GVS to provide more acceptable vestibular stimulation.

Comparability of Foslevodopa/Foscarbidopa Pharmacokinetics in Healthy Asian and White Participants.

This phase 1 study assessed the safety, tolerability, and pharmacokinetics of a single 24-hour continuous subcutaneous dose of foslevodopa/foscarbidopa in healthy adult Japanese (N = 24), Han Chinese (N = 8), and White (N = 24) participants. Three doses of foslevodopa/foscarbidopa were evaluated in healthy participants for this study: 480/24, 960/48, and 1440/72 mg/day. Serial blood samples for measurement of levodopa, carbidopa, foslevodopa, foscarbidopa, and 3-O-methyldopa concentrations were collected for 48 hours after foslevodopa/foscarbidopa administration. Safety and tolerability were assessed throughout the study. Point estimates for ratios of central values indicated that the exposure difference between Japanese and White participants was <10%. The maximum concentration and area under the plasma concentration-time curve for both LD and CD following foslevodopa/foscarbidopa continuous subcutaneous infusion were comparable between Han Chinese and White participants. Point estimates for ratios of central values indicated that the exposure difference between Han Chinese and White participants was <14%. The regimens tested were generally well tolerated, and no new safety issues were identified in this study. There were no clinically meaningful differences in LD and CD exposures or pharmacokinetics following administration of foslevodopa/foscarbidopa among White, Japanese, and Han Chinese participants.

Validation of the BLOC test: A computerized oral line bisection task in French healthy participants.

Line bisection is one of the most commonly used tasks to assess spatial neglect. More recently, line bisection has been recommended as a task to monitor for spatial neglect during awake brain tumor surgery, but the operative constraints hamper the normal test conditions. We developed and validated in 118 healthy participants the BLOC test, a computerized version of line bisection, suppressing the motor component, in both sitting and lying positions. The results showed that the computerized line bisection task is strictly comparable to manual bisection and that it can be used in the sitting or lying position with the same significance threshold. The BLOC test therefore represents a relevant tool for clinical practice in a variety of contexts.

Activity of deep trunk muscles for postural control to predictable and unpredictable sagittal plane perturbations: Electromyographic analysis.

BACKGROUND: The activity of deep trunk muscles (psoas major; PM, quadratus lumborum; QL, transverse abdominis; TrA, and lumbar multifidus; MF) in response to external perturbation is not clearly known. OBJECTIVE: This study aimed to record the onset and amount of activity of the deep trunk muscles during sagittal plane perturbations. METHODS: Fourteen healthy males participated in this study. The activity of the right deep trunk muscles was recorded using wire electrodes. In standing, the participants performed three tasks: a pendulum impacted from anterior with predictable and unpredictable and posterior with unpredictable. RESULTS: In predictable anterior perturbation, the TrA and PM demonstrated feedforward activation, while all deep trunk muscles demonstrated feedback activation in unpredictable anterior and posterior perturbations. In the anticipatory postural adjustment phase, the activity of the TrA was large in predictable anterior perturbation, while that of all deep trunk muscles was slight in other perturbations. In the compensatory postural adjustment phase, the activity of the PM, QL, and TrA in unpredictable anterior perturbation and those of the PM, QL, and MF in unpredictable posterior perturbation were large. CONCLUSIONS: These results showed that the onset and magnitude of deep trunk muscle activity changed depending on both predictable or unpredictable perturbation and the direction of perturbation.