Study In Volunteers Research Articles

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Advanced waveform analysis of the electrocardiogram signals using complementary signal processing techniques to investigate the response to a QTc prolonging drug vs control

Abstract Background Thorough QTc (TQT) studies using Electrocardiogram (ECG) data, are a well-established method for testing the pro-arrhythmic propensity of drugs performed during safety studies as part of drug development. ECG analysis is currently reduced to simplified biomarkers, such as rate, intervals and amplitudes. However, ECG waveforms are complex and generally sampled with high fidelity (125-1000 Hz). Our novel mathematical method, Symmetric Projection Attractor Reconstruction (SPAR) analyses the morphology and variability of such waveforms, using every data point to generate a new, faithful 2D waveform representation termed an ‘attractor’. Moxifloxacin is a reversible blocker of the rapid component of the delayed rectifier, potassium current of the cardiac IKr potassium channel and has been shown to cause a mean increase of the QTc interval of 10–14 ms after an oral single dose of 400 mg. Separately, studies have shown that meals can alter QT interval as well as altering the pharmacokinetic profile of moxifloxacin itself with gender and ethnicity impacting individual responses. In-depth knowledge of these physiological factors could support safer medicines development and clinical use. Purpose This project investigated the feasibility of SPAR analysis of ECG signals to detect drug induced changes which a higher degree of sensitivity, to support safety evaluation during medicines development. Methods High resolution triplicate 12 lead ECG time-series data from a Phase one study of healthy human volunteers cross over of placebo, moxifloxacin or moxifloxacin + food was retrospectively analysed using SPAR. Using a bespoke software tool was used to perform SPAR analyses to transform ECG time-series into corresponding attractors. Corresponding single point measurements were previously obtained as part of the original Phase one study. Results Initial evaluation of attractors revealed high inter-individual variation, consistent with previous SPAR ECG analysis. Nevertheless, we identified changes in subjects receiving Moxifloxacin (six hour time point) when compared to those receiving placebo control. These changes were not as evident in previously obtained QT intervals. Conclusion This pilot study illustrates that SPAR is highlighting changes on the ECG that are less obvious from QT data alone. Further evaluation of the whole dataset to identify generalisable SPAR features, and their comparison with existing markers is now necessary. The individualised nature of ECGs and corresponding attractors indicates the method may have highest utility in personalised medicine, evaluating each individual’s change and hence individual risk to drug induced arrhythmia.Visualisations of SPAR analysis of ECGs

A Wearable, Steerable, Transcranial Low-Intensity Focused Ultrasound System.

Transcranial low-intensity focused ultrasound (LIFU) offers unique opportunities for precisely neuromodulating small and/or deep targets within the human brain, which may be useful for treating psychiatric and neurological disorders. This article presents a novel ultrasound system that delivers focused ultrasound through the forehead to anterior brain targets and evaluates its safety and usability in a volunteer study. The ultrasound system and workflow are described, including neuronavigation, LIFU planning, and ultrasound delivery components. Its capabilities are analyzed through simulations and experiments in water to establish its safe steering range. A cohort of 20 healthy volunteers received a LIFU protocol aimed at the anterior medial prefrontal cortex (amPFC), using imaging and questionnaires to screen for adverse effects. Additional development after the study also analyzes the effect of the skull and sinus cavities on delivered ultrasound energy. Simulations and hydrophone readings agreed with <5% error, and the safe steering range was found to encompass a 1.8 cm × 2.5 cm × 2 cm volume centered at a depth 5 cm from the surface of the skin. There were no adverse effects evident on qualitative assessments, nor any signs of damage in susceptibility-weighted imaging scans. All participants tolerated the treatment well. The interface effectively enabled the users to complete the workflow with all participants. In particular, the amPFC of every participant was within the steering limits of the system. A post hoc analysis showed that "virtual fitting" could aid in steering the beams around subjects' sinuses. The presented system safely delivered LIFU through the forehead while targeting the amPFC in all volunteers, and was well-tolerated. With the capabilities validated here and positive results of the study, this technology appears well-suited to explore LIFU's efficacy in clinical neuromodulation contexts.

Preliminary study on the effects of boysenberry juice intake on brown adipose tissue activity in healthy adults

Brown adipose tissue (BAT) plays an important role in energy metabolism because it uses fatty acids for thermogenesis during cold exposure. Preclinical studies found that boysenberry anthocyanins (BoyACs) activate BAT. Therefore, the aim of this preliminary study was to evaluate how BoyAC intake affects BAT in humans. We performed an open-label single-arm nonrandomized study in healthy volunteers. Before and after 4 weeks of daily consumption of 100 ml boysenberry juice (BoyJ) containing 61 mg of BoyACs, participants were assessed at 24 °C and then after 1 h of mild cold exposure (18 °C). An infrared thermography camera was used to measure skin surface temperatures in the supraclavicular BAT region (Tscv) and the non-BAT region of the upper chest (Tch). Energy metabolism was measured by indirect calorimetry. For each endpoint, we calculated Δ as the difference between values before and after cold exposure and compared the values before and after BoyJ intake. 10 volunteers participated (age: 36.1 ± 4.1, body mass index (BMI): 20.9 ± 0.6). After BoyJ intake, ΔTscv-ch was significantly higher (p = 0.029), but Δ energy expenditure, Δ fat oxidation, and Δ carbohydrate oxidation were not significantly different. We found a significant positive correlation between BMI and Δfat oxidation with BoyJ intake. The results indicate that 4 weeks of BoyJ intake activates cold-induced thermogenesis in the scv-BAT but does not have a significant effect on energy metabolism. BoyJ intake may increase fat oxidation during cold exposure in individuals with higher BMI.Trial registry number: UMIN000043476, 05/03/2021.

Volunteers and their heritage – a heritage from within

ABSTRACT This article furthers research on heritage volunteering by focusing on the relationship between the volunteers and the heritage they produce and perform. It explores how volunteers engage with specific aspects of the past. Through an ethnographic study of contemporary heritage volunteers in Norway, we found a deeply personal connection between volunteers and their heritage. To better grasp the heritage produced by volunteers, we propose a conceptual framework for this heritage, reflecting that it derives from a characteristic personal engagement. We argue that volunteers’ heritage is a ‘heritage from within’, closely connected to the volunteers’ personal history and bodies. Accordingly, we frame and discuss volunteer heritage production as ‘care’ to emphasise the emotional and ethical commitment that affects how volunteers preserve and produce heritage. This concept of care is inspired by heritage and STS scholars who approach heritage as a ‘matter of care’ and care as an ethically and politically charged practice.

Cubosomes – A novel approach to taste masking using ibuprofen as a model drug

Taste masking of any pediatric oral formulation has always been a hurdle. Cubosomses, a type of lyotropic liquid crystal, have been used in this research to develop an oral formulation of ibuprofen. Ibuprofen cubosomes were prepared with glyceryl monooleate (GMO) and poloxamer 407 by high-pressure homogenization (HPH) technique. The formulation experiments were performed using a 2-level, 3-factor central composite design with drug loading, GMO concentration and HPH pressure as independent variables and vesicle size, entrapment efficiency and %drug content as the dependent variables. The most suitable ibuprofen cubosomes showed 94 nm vesicle size, −17.5 mV zeta potential, >75% drug content and >96% entrapment efficiency. The cubosomes released more than 80% of the drug within 2 hours. In vitro taste masking study showed significantly lower drug release than its bitterness threshold. An in vivo taste masking study in healthy adult volunteers showed significant taste masking compared to the marketed formulation and ibuprofen pure suspension. % of the volunteers observed cubosomes as not bitter. In contrast, 67% of the volunteers reported marketed suspension as very bitter. The developed cubosomes resulted in physical stability for three months of proper storage. The study has successfully achieved considerable taste-masking using cubosomes with GMO and Poloxmaer 407 formulation. This proof of concept can initiate a new field of research in taste-masked oral liquid formulation.

First fluorescence method for monitoring the doping stimulant drug solriamfetol in plasma and urine: A pharmacokinetic study in volunteers’ urine with greenness, whiteness, and blueness assessments

A green, sustainable, simple, and highly sensitive spectrofluorimetric method was developed to determine solriamfetol hydrochloride for the first time in biological fluids and dosage form. To the best of our knowledge, no Fluorimetric methods have been reported for solriamfetol determination in plasma and urine. The method is based on measuring the intrinsic fluorescence of solriamfetol hydrochloride at 522 nm after excitation at 260 nm in ammonium acetate buffer solution at pH 4. All factors influencing the response have been carefully investigated. The method was linear over a concentration range of 10 to 1800 ng/mL (r = 0.9998). The limit of detection (LOD) and limit of quantification (LOQ) values were found to be 3.2 and 9.8 ng/mL, respectively, indicating the excellent sensitivity of the proposed method. The pharmaceutical dosage form, spiked human plasma, and urine samples were successfully analyzed using the described method with average recoveries of 99.79 ± 0.739, 99.27 ± 1.885, and 99.57 ± 1.701, respectively. Plasma samples were first subjected to protein precipitation using 10 % perchloric acid, while urine samples were analyzed directly without any pretreatment. Furthermore, the suggested method was applied effectively on real human volunteers’ urine to measure renal clearance, the cumulative amount of solriamfetol excreted unchanged in the urine, and the percent of the dose recovered. The eco-friendly nature and sustainability of this work were evaluated using trending greenness, whiteness, and blueness assessment metrics. The greenness assessment tools, namely the Analytical GREEnness metric tool (AGREE), Analytical Eco-scale, and complementary green analytical procedure index (complex GAPI) were selected to prove the eco-friendly nature of the method. Additionally, whiteness and blueness assessments were conducted using the Red-Green-Blue model (RGB model), and high Blue Applicability Grade Index (BAGI), respectively. The proposed method is a promising analytical tool for routine analysis in quality control labs, therapeutic drug monitoring, and pharmacokinetics studies.

Thoracolumbar Sagittal Morphology and Segmental Inclination: A Cross-sectional Cohort Study of Asymptomatic Adult Volunteers.

A cross-sectional cohort study. To present a normative value reference of spinal segmental inclination stratified by age and pelvic incidence (PI), and to clarify the impact of segmental inclination on spinal sagittal morphology. Thoracolumbar segmental inclination has been shown to correlate with the clinical outcomes of adult spinal deformity surgery. However, there currently exists no normative value reference in a large sample of asymptomatic population. Asymptomatic adult volunteers were enrolled from the community. All volunteers underwent a standing full-spine anteroposterior and lateral radiograph. Lumbar tilt (LT) and thoracic tilt (TT) were measured to quantify the segmental inclination of the lumbar and thoracic spine. Regional curvature, global balance and thoracolumbar apex were analyzed across different age and PI groups. The correlation between sagittal parameters and age was analyzed using Pearson correlation tests. A total of 618 volunteers were included with a mean age of 38.7 ± 17.1 years (range 18 to 82y). As age increased, the LT and TT significantly increased (P<0.001). The LT was significantly correlated with PI (r=0.410, P<0.001), with the low PI group exhibiting a greater negative LT. The TT remained constant across different PI groups. Compared to the young and middle-age groups, the thoracic apex and lumbar apex were located more caudally in the elderly group (P<0.001). Subjects with a more caudal lumbar apex exhibited a greater negative LT, and those with a more caudal thoracic apex exhibited a greater positive TT. The thoracic spine naturally adapts to a relatively neutral position, yet it tends to tilt forward with aging. The physiological lumbar inclination is predominantly determined by the PI value with a slight backward tilt, and tends to counteract the anterior truncal inclination with advanced age. Physiological segmental inclination should be considered in spinal surgical planning.

Spesolimab, the first-in-class anti-IL-36R antibody: From bench to clinic.

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. Invitro and invivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need.

Wipe Disinfection of Reusable Elastomeric Half-Mask Respirators for Health Care Use.

During shortages, elastomeric half-mask respirators (EHMRs) are an alternative to reusing N95 filtering facepiece respirators but require between-use disinfection. The objectives of this study were to (a) measure microbial reductions on EHMR surfaces under laboratory conditions by a standardized procedure using wipes impregnated with health care disinfectants and to (b) measure microbial reductions on EHMRs disinfected by volunteer health care providers. We inoculated EHMR (Honeywell model RU8500) surfaces with Pseudomonas aeruginosa, Bacillus atrophaeus spores, and bacteriophages MS2 and Φ6, and disinfected them using two wipes with hydrogen peroxide (HP), alcohols, and quaternary ammonium compounds (QACs). Then, we randomized 54 volunteer subjects into three groups (Group 1: two wipes with instructions, Group 2: five wipes with instructions, Group 3: no instructions or set number of wipes) and used 0.5% HP wipes without precleaning on EHMRs inoculated with Raoultella terrigena and MS2. The laboratory study demonstrated that all organisms achieved at least 4 log10 median reductions (HP>QAC/alcohol>QAC>QAC/saline). Pseudomonas was highly susceptible to HP and QAC/alcohol and Φ6 to all disinfectants. MS2 reduction was highest using HP and lowest using QAC/saline. Bacillus was least susceptible. The volunteer study showed a 3 to 4 log10 average reductions of bacteria and virus; Raoultella reductions were greater than MS2, with variability within and between subjects. Conclusions: HP disinfectant wipes used in laboratory and by volunteers reduce bacteria and viruses on EHMRs by 3 to 4 log10 on average. Commercially available hospital disinfectant wipes reduce bacteria and viruses on EHMRs and can fill the need for between-use disinfection. HP and combination QAC/alcohol have the greatest efficacy under our test conditions.

Development and evaluation of machine-learning methods in whole-body magnetic resonance imaging with diffusion weighted imaging for staging of patients with cancer: the MALIBO diagnostic test accuracy study

Background Whole-body magnetic resonance imaging is accurate, efficient and cost-effective for cancer staging. Machine learning may support radiologists reading whole-body magnetic resonance imaging. Objectives To develop a machine-learning algorithm to detect normal organs and cancer lesions. To compare diagnostic accuracy, time and agreement of radiology reads to detect metastases using whole-body magnetic resonance imaging with concurrent machine learning (whole-body magnetic resonance imaging + machine learning) against standard whole-body magnetic resonance imaging (whole-body magnetic resonance imaging + standard deviation). Design and participants Retrospective analysis of (1) prospective single-centre study in healthy volunteers &gt; 18 years (n = 51) and (2) prospective multicentre STREAMLINE study patient data (n = 438). Tests Index: whole-body magnetic resonance imaging + machine learning. Comparator: whole-body magnetic resonance imaging + standard deviation. Reference standard Previously established expert panel consensus reference at 12 months from diagnosis. Outcome measures Primary: difference in per-patient specificity between whole-body magnetic resonance imaging + machine learning and whole-body magnetic resonance imaging + standard deviation. Secondary: per-patient sensitivity, per-lesion sensitivity and specificity, read time and agreement. Methods Phase 1: classification forests, convolutional neural networks, and a multi-atlas approaches for organ segmentation. Phase 2/3: whole-body magnetic resonance imaging scans were allocated to Phase 2 (training = 226, validation = 45) and Phase 3 (testing = 193). Disease sites were manually labelled. The final algorithm was applied to 193 Phase 3 cases, generating probability heatmaps. Twenty-five radiologists (18 experienced, 7 inexperienced in whole-body magnetic resonance imaging) were randomly allocated whole-body magnetic resonance imaging + machine learning or whole-body magnetic resonance imaging + standard deviation over two or three rounds in a National Health Service setting. Read time was independently recorded. Results Phases 1 and 2: convolutional neural network had best Dice similarity coefficient, recall and precision measurements for healthy organ segmentation. Final algorithm used a ‘two-stage’ initial organ identification followed by lesion detection. Phase 3: evaluable scans (188/193, of which 50 had metastases from 117 colon, 71 lung cancer cases) were read between November 2019 and March 2020. For experienced readers, per-patient specificity for detection of metastases was 86.2% (whole-body magnetic resonance imaging + machine learning) and 87.7% (whole-body magnetic resonance imaging + standard deviation), (difference −1.5%, 95% confidence interval −6.4% to 3.5%; p = 0.387); per-patient sensitivity was 66.0% (whole-body magnetic resonance imaging + machine learning) and 70.0% (whole-body magnetic resonance imaging + standard deviation) (difference −4.0%, 95% confidence interval −13.5% to 5.5%; p = 0.344). For inexperienced readers (53 reads, 15 with metastases), per-patient specificity was 76.3% in both groups with sensitivities of 73.3% (whole-body magnetic resonance imaging + machine learning) and 60.0% (whole-body magnetic resonance imaging + standard deviation). Per-site specificity remained high within all sites; above 95% (experienced) or 90% (inexperienced). Per-site sensitivity was highly variable due to low number of lesions in each site. Reading time lowered under machine learning by 6.2% (95% confidence interval −22.8% to 10.0%). Read time was primarily influenced by read round with round 2 read times reduced by 32% (95% confidence interval 20.8% to 42.8%) overall with subsequent regression analysis showing a significant effect (p = 0.0281) by using machine learning in round 2 estimated as 286 seconds (or 11%) quicker. Interobserver variance for experienced readers suggests moderate agreement, Cohen’s κ = 0.64, 95% confidence interval 0.47 to 0.81 (whole-body magnetic resonance imaging + machine learning) and Cohen’s κ = 0.66, 95% confidence interval 0.47 to 0.81 (whole-body magnetic resonance imaging + standard deviation). Limitations Patient whole-body magnetic resonance imaging data were heterogeneous with relatively few metastatic lesions in a wide variety of locations, making training and testing difficult and hampering evaluation of sensitivity. Conclusions There was no difference in diagnostic accuracy for whole-body magnetic resonance imaging radiology reads with or without machine-learning support, although radiology read time may be slightly shortened using whole-body magnetic resonance imaging + machine learning. Future work Failure-case analysis to improve model training, automate lesion segmentation and transfer of machine-learning techniques to other tumour types and imaging modalities. Study registration This study is registered as ISRCTN23068310. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 13/122/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 15. See the NIHR Funding and Awards website for further award information.

A Focused Group Human Volunteer Study on the Efficacy of a Novel Candyceutical Sleep Aid: “Restore Your Sleep"

A Focused Group Human Volunteer Study on the Efficacy of a Novel Candyceutical Sleep Aid: “Restore Your Sleep"

Essential Oil with Mosquito-Repellent Potential from Plectranthus Amboinicus Leaves Against Aedes Aegypti via Human Volunteer Study

Plectranthus amboinicus(PA) is a highly aromatic perennial shrub that belongs to the Lamiaceae family. It has thick, fleshy and succulent leaves and stem. The margins of the leaves contain numerous glandular hairs that produce essential oil. The essential oil of PA(PAEO) exhibits therapeutical, nutritional, antioxidant, antimicrobial, insecticidal, and insect repellent potentials. The objective of this study was to evaluate and compare the repellent properties of PAEO and DEET against Aedes aegypti mosquitoes, which are known carriers of dengue fever. The extraction of PAEO was carried out using hydrodistillation method while the chemical profile was analysed by gas chromatography-mass spectrometry (GC-MS) technique. The bioefficacy test was conducted according to the household insecticide products personal mosquito repellent evaluation method for biological efficacy (First revision) (MS1497:2007) provided by the Standard and Industrial Research Institute of Malaysia (SIRIM) with slight modification. 10% PAEO was used as test solution while 10% DEET was used as positive control. Fabric and patches treated with 10% PAEO were tested on human volunteers. Both the fabric and the patch, treated with 10% PAEO, exhibit excellent repellency (97 - 100%) against Ae. aegypti mosquitoes for a duration of up to 240 min (4 h) post-application. In contrast, 10% DEET, which initially showed a comparable repellency (99%) 30 min after application, experiences a gradual decline in repellency over time, reaching a 51% repellency rate at the end of the test (240 min post-application). A two-way ANOVA analysis indicates significant effect for type of treatment (p = 0.016) but with no significant difference between the exposure time. Tukey’s test showed significant differences between 10% PAEO-treated patches and 10% DEET (p = 0.016), and between 10% PAEO-treated fabric and 10% DEET (p = 0.026). These findings suggest that PAEO is potentially an effective natural repellent against Ae. aegypti.

Hyaluronic acid-solid lipid nano transporter serum preparation for enhancing topical tretinoin delivery: skin safety study and visual assessment of skin.

The use of nanosized particles is becoming more popular for the topical treatment of skin conditions. In this research work, we created and investigated the effects of solid lipid nanoparticles (SLN) containing hyaluronic acid and tretinoin. Solvent emulsification diffusion method was used to prepare the SLN formulation and characterized for their physicochemical properties. Fourier transform infrared spectroscopy was used to confirm that hyaluronic acid and tretinoin were incorporated in the SLN. Furthermore, X-ray diffractogram, thermal analysis including DSC and TGA and in vitro dissolution, permeation tests were also performed along with microbial assessment. Clinical studies in human were performed to evaluate the effect of the SLN on skin wrinkles. The SLN was 750 ± 31.29nm in size, with a zeta potential of 13.07 ± 0.75mV and a narrow polydispersity index of 0.24 ± 0.12. The entrapment efficiency of tretinoin was found to be 90.07 4.79%. Clinical studies in healthy human volunteers demonstrated that 90% of the tested individuals had improved skin conditions (reduction in wrinkles), by at least one grade after 4weeks of treatment. Regarding the development on SLN, it was found that the internal phase concentration did not considerably affect the physicochemical and microbiological properties. Therefore, Hyaluronic acid has potential for the development of SLN applicable to cosmetic formulations, especially for skin. These findings show that the developed SLN have potential for use as cosmetics in the future.

The recovery cycle of excitability assessed by a conventional electrodiagnostic machine: A study in healthy volunteers and in Charcot-Marie-Tooth 1A patients

ObjectiveTo validate the ‘paired pulses’ technique with a conventional electrodiagnostic machine (CEM) for studying the axonal excitability recovery cycle (ERC). MethodsPaired pulses, with a variable inter-stimulus interval, were delivered at the wrist along the median nerve. The CEM repeatability was verified in a group of 15 healthy volunteers (test/retest analysis). ERC was then applied in 40 healthy volunteers and 10 patients with Charcot-Marie-Tooth type 1A (CMT1A), using both the threshold tracking (TT) reference method and CEM (basal condition, during and after ischemia). ResultsCEM parameters evaluating absolute refractory and supernormal periods were reproducible (interclass correlation coefficient > 0.75). CEM results were consistent with TT method and literature data. In CMT1A, refractory and superexcitable periods were significantly reduced. According to receiving operator characteristic analysis, the CEM supernormal period area was the most relevant parameter for discriminating CMT1A from healthy volunteers (area under the curve = 0.98). ConclusionsCEM was a valid procedure for studying ERC. CMT1A patients exhibited ERC alterations due to modifications in passive membrane properties and of nodal ion channel distribution resulting from demyelination. SignificanceStudying ERC with CEM could be performed in routine practice in patients with peripheral neuropathies to provide information on motor axonal excitability.

Propofol disrupts the functional core-matrix architecture of the thalamus in humans

Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. Here we show a significant shift in this geometry during deep sedation, marked by a transmodal-deficient geometry. This alteration is closely linked to the spatial variations in the matrix cell composition within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core–matrix functional architecture in understanding the neural mechanisms of states of consciousness.

Single-point macromolecular proton fraction mapping using a 0.3T permanent magnet MRI system: phantom and healthy volunteer study.

In a 0.3T permanent-magnet magnetic resonance imaging (MRI) system, quantifying myelin content is challenging owing to long imaging times and low signal-to-noise ratio. macromolecular proton fraction (MPF) offers a quantitative assessment of myelin in the nervous system. We aimed to demonstrate the practical feasibility of MPF mapping in the brain using a 0.3T MRI. Both 0.3T and 3.0T MRI systems were used. The MPF-mapping protocol used a standard 3D fast spoiled gradient-echo sequence based on the single-point reference method. Proton density, T1, and magnetization transfer-weighted images were obtained from a protein phantom at 0.3T and 3.0T to calculate MPF maps. MPF was measured in all phantom sections to assess its relationship to protein concentration. We acquired MPF maps for 16 and 8 healthy individuals at 0.3T and 3.0T, respectively, measuring MPF in nine brain tissues. Differences in MPF between 0.3T and 3.0T, and between 0.3T and previously reported MPF at 0.5T, were investigated. Pearson's correlation coefficient between protein concentration and MPF at 0.3T and 3.0T was 0.92 and 0.90, respectively. The 0.3T MPF of brain tissue strongly correlated with 3.0T MPF and literature values measured at 0.5T. The absolute mean differences in MPF between 0.3T and 0.5T were 0.42% and 1.70% in white and gray matter, respectively. Single-point MPF mapping using 0.3T permanent-magnet MRI can effectively assess myelin content in neural tissue.

Differences in Somatosensory Function Related to Hand Dominance: Results of a Quantitative Sensory Testing Study in Healthy Volunteers.

Quantitative sensory testing commonly utilizes the unaffected, contralateral side as a control to detect somatosensory dysfunction. There is scant evidence that somatosensory function for the volar dominant and non-dominant hands is equivalent, therefore intra-patient comparisons are unwarranted. This study aimed to identify dominance-related differences in palmar hand somatosensation, thereby determining if the unaffected contralateral hand is a valid comparator in clinical populations. With ethical approval (IREC_13_1_10) and informed consent, 110 healthy adult volunteers' participated in this clinical measurement study. Somatosensory function was assessed with the German Research Network on Neuropathic Pain (DFNS) quantitative sensory testing (QST) protocol. Half of the participants were tested on the dominant hand. Thirteen parameters of thermal and mechanical detection and pain threshold were evaluated at both the dorsal and volar hand (distal middle finger). Tests were performed in the same order and instructions were read from a standardized script. Results for dorsal hand tests were compared to DFNS normative data to confirm participants met study inclusion criteria. Between-group differences for age and sex were investigated with the independent samples t-test and Chi-square test of independence, respectively. Group differences for dominant and non-dominant hands for all 13 continuous QST parameters were investigated with the Mann-Whitney U-test. Data for 106 participants were included in statistical analysis. Fifty percent of participants were tested on the dominant hand [n=53]; there were no differences for age or sex between groups (dominant or non-dominant hand test group). The dominant volar hand was significantly more sensitive to vibration detection threshold than the non-dominant hand (P=0.001). There were no significant differences related to dominance for other DFNS QST measures. For quantitative sensory testing with the DFNS protocol in healthy cohorts, the contralateral, unaffected hand is a valid control, with the exception of vibration detection threshold.

Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers.

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. Invitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

Abdominal MR Multitasking for radiotherapy treatment planning: A motion-resolved and multicontrast 3D imaging approach.

Radiotherapy treatment planning (RTP) using MR has been used increasingly for the abdominal site. Multiple contrast weightings and motion-resolved imaging are desired for accurate delineation of the target and various organs-at-risk and patient-tailored planning. Current MR protocols achieve these through multiple scans with distinct contrast and variable respiratory motion management strategies and acquisition parameters, leading to a complex and inaccurate planning process. This study presents a standalone MR Multitasking (MT)-based technique to produce volumetric, motion-resolved, multicontrast images for abdominal radiotherapy treatment planning. The MT technique resolves motion and provides a wide range of contrast weightings by repeating a magnetization-prepared (saturation recovery and T2 preparations) spoiled gradient-echo readout series and adopting the MT image reconstruction framework. The performance of the technique was assessed through digital phantom simulations and in vivo studies of both healthy volunteers and patients with liver tumors. In the digital phantom study, the MT technique presented structural details and motion in excellent agreement with the digital ground truth. The in vivo studies showed that the motion range was highly correlated (R2 = 0.82) between MT and 2D cine imaging. MT allowed for a flexible contrast-weighting selection for better visualization. Initial clinical testing with interobserver analysis demonstrated acceptable target delineation quality (Dice coefficient = 0.85 ± 0.05, Hausdorff distance = 3.3 ± 0.72 mm). The developed MT-based, abdomen-dedicated technique is capable of providing motion-resolved, multicontrast volumetric images in a single scan, which may facilitate abdominal radiotherapy treatment planning.