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This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test‐reference or reference‐test order, before being switched to another study drug sequence after 7 drug‐free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration‐time curve (AUC) from time 0 to infinity (AUC0‐∞), AUC from time 0 to the last detectable concentration (AUC0‐t), and the maximum plasma concentration (Cmax) fell within the range 80%‐125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0‐∞, AUC0‐t, and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%‐125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug‐related AEs in the test and reference‐avanafil groups (all P >.05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions. [ABSTRACT FROM AUTHOR]

Abstract Background Several studies addressed the association between fragmented QRS (fQRS) on 12-lead EKG and left ventricular (LV) dysfunction in patients with a variety of cardiovascular disorders. We tested such association in healthy individuals. Methods Out of 500 healthy participants without -overt cardiovascular disease from the Shiraz Heart Study cohort, we identified 20 subjects with fQRS (cases) and 20 peers without fQRS (controls). Global LV longitudinal strain (GLS) was measured by speckle tracking echocardiography in the two groups. Comparison was made between case and control groups by using chi-square or independent sample t-test or ANOVA. Results Age, gender, ejection fraction, LV volume and dimensions did not differ between the case and the control groups. Overall, 14 subjects out of 40 had reduced GLS (≤20%) and 10 of them (25%) had fQRS. GLS was significantly lower in the group with fQRS than in the control group (19.9 ± 1.8 vs 21.4 ± 1.6; p = 0.009). Conclusions Healthy subjects with fQRS present regional LV systolic dysfunction, assessed by GLS, in the presence of a normal ejection fraction. These data suggest that fQRS may be a promising tool to identify apparently healthy subjects with regional LV systolic dysfunction.

The aim of the study was to investigate whether visual stimuli have the same potency to increase electroencephalography (EEG) delta wave power density during non-rapid eye movement (NREM) sleep as do auditory stimuli that may be practical in the treatment of some sleep disturbances. Nine healthy subjects underwent two polysomnography sessions—adaptation and experimental—with EEG electrodes positioned at Fz–Cz. Individually adjusted auditory (pink noise) and visual (light-emitting diode (LED) red light) paired 50-ms signals were automatically presented via headphones/eye mask during NREM sleep, shortly (0.75–0.90 s) after the EEG wave descended below a preset amplitude threshold (closed-loop in-phase stimulation). The alternately repeated 30-s epochs with stimuli of a given modality (light, sound, or light and sound simultaneously) were preceded and followed by 30-s epochs without stimulation. The number of artifact-free 1.5-min cycles taken in the analysis was such that the cycles with stimuli of different modalities were matched by number of stimuli presented. Acoustic stimuli caused an increase (p < 0.01) of EEG power density in the frequency band 0.5–3.0 Hz (slow waves); the values reverted to baseline at post-stimuli epochs. Light stimuli did not influence EEG slow wave power density (p > 0.01) and did not add to the acoustic stimuli effects. Thus, dim red light presented in a closed-loop in-phase fashion did not influence EEG power density during nocturnal sleep.

Meng-Jie Yang, Hong-Rong Xu, Hui Li, Wei-Li Chen, Fei Yuan, Xue-Ning Li Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 31587861Fax +86 21 64437963Email li.xuening@zs-hospital.sh.cnPurpose: Aprepitant is used to prevent nausea and vomiting associated with moderately and highly emetogenic chemotherapy. In this open-label, 2-period study, the safety, tolerability, and pharmacokinetics (PK) of aprepitant (EMEND®) were evaluated in healthy Chinese and Caucasian subjects.Patients and Methods: Twelve Chinese and 12 Caucasian subjects were to receive a 125 mg single-dose of aprepitant during period 1; subsequently, after 15 days washout, only Chinese subjects were to receive the 3-day regimen in period 2. In each period, serial blood samples were collected and analyzed by a validated liquid chromatographic and mass spectrometric method to characterize aprepitant PK across both groups.Results: In both Chinese and Caucasian subjects, there were no serious adverse events. AUC0-∞, Cmax, Tmax, and t1/2 were largely comparable between the two ethnicities. Comparing the result of period 1 in Chinese and Caucasian subjects, the geometric least-squares mean maximum plasma concentrations (Cmax) were 1482 ng/mL and 1435 ng/mL, and the area under the concentration–time curve (AUC0-∞) 34,035 hr·ng/mL and 34,188 hr·ng/mL. In period 2, the geometric mean AUC0– 24 on Day 1 and Day 3 were 19,446 hr·ng/mL and 27,843 hr·ng/mL, and the geometric mean Cmax on Day 1 and Day 3 were 1423 ng/mL and 1757 ng/mL, respectively.Conclusion: Aprepitant is generally safe and well tolerated in healthy Chinese and Caucasian subjects. Aprepitant PK is comparable between Chinese and Caucasian subjects following single-dose administration. The PK following a clinical 3-day regimen on healthy Chinese subjects has been characterized.Keywords: pharmacokinetics, aprepitant, chemotherapy-induced nausea and vomiting, ethnicity, healthy subjects

While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.

This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48 hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (C max ) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC 0-t ) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants., (© 2024, The American College of Clinical Pharmacology.)

Objective. To determine the optimal frequency and site of stimulation for transcutaneous vagus nerve stimulation (tVNS) to induce acute changes in the autonomic profile (heart rate (HR), heart rate variability (HRV)) in healthy subjects (HS) and patients with heart failure (HF). Approach. We designed three single-blind, randomized, cross-over studies: (1) to compare the acute effect of left tVNS at 25 Hz and 10 Hz ( n = 29, age 60 ± 7 years), (2) to compare the acute effect of left and right tVNS at the best frequency identified in study 1 ( n = 28 age 61 ± 7 years), and (3) to compare the acute effect of the identified optimal stimulation protocol with sham stimulation in HS and HF patients ( n = 30, age 59 ± 5 years, and n = 32, age 63 ± 7 years, respectively). Main results. In study 1, left tragus stimulation at 25 Hz was more effective than stimulation at 10 Hz in decreasing HR (-1.0 ± 1.2 bpm, p < 0.001 and -0.5 ± 1.6 bpm, respectively) and inducing vagal effects (significant increase in RMSSD, and HF power). In study 2, the HR reduction was greater with left than right tragus stimulation (-0.9 ± 1.5 bpm, p < 0.01 and -0.3 ± 1.4 bpm, respectively). In study 3 in HS, left tVNS at 25 Hz significantly reduced HR, whereas sham stimulation did not (-1.1 ± 1.2 bpm, p < 0.01 and -0.2 ± 2.9 bpm, respectively). In HF patients, both active and sham stimulation produced negligible effects. Significance. Left tVNS at 25 Hz is effective in acute modulation of cardiovascular autonomic control (HR, HRV) in HS but not in HF patients (NCT05789147)., (© 2024 Institute of Physics and Engineering in Medicine.)

The microbial profile of patients with periimplantis to inqure any unique composition of microorganisms in them is of interest to dentists. Hence, we evaluated the microbial profile of patients with peri-implantitis, patients with periodontitis and normal healthy subjects. 180 subjects were included in this study. Plaque samples were collected from 60periodontically healthy (PH) participants, 60 periodontitis (PT) subjects, and 60 periimplantitis (PI) subjects. Final concentrations were obtained for seven most common periodontal pathogens namely Aggregatibacter actinomycetemcomitans , Fusobacterium nucleatum , Treponema denticola , Porphyromonas gingivalis , Prevotella intermedia , Staphylococcus aureus and Haemophilus parainfluenzae . The abundance of microorganisms was represented in the form of Log10CFU (x103). The abundance of periopathogens evaluated in this research was different in periimplantitis patients, periodontitis patients and normal healthy subjects with slight greater abundance of peripathogens in patient with periimplantitis., (© 2024 Biomedical Informatics.)

BACKGROUND: Mindfulness-based interventions (MBIs) are known for their beneficial effects on positive and negative psychological factors. When applied in an occupational context, MBIs might help workers to cope with stress, increase their professional outcomes and wellbeing. OBJECTIVE: In this two-groups pre-post experimental design we tested the effect of our MBI, called Integral Meditation (IM), among the employers of an Italian service company by measuring positive and negative aspects of psychological wellbeing related to mindfulness and workplace functioning through eight self-report questionnaires (CORE-OM, FFMQ, WEMWBS, MAIA, PSS, PANAS, STAI-X1, SCS). METHOD: Forty-two voluntary non-clinical employers of the company, randomly assigned to the experimental or the control group, were analyzed. The experimental group underwent our IM program, which consists of 12 weekly meditation classes given after the afternoon shift, while the control group did not receive any intervention. Data was analyzed via linear mixed models. RESULTS: Statistically significant results were obtained for FFMQ observing subscale (β= 0.49, p = 0.014), WEMWBS (β= 5.31, p = 0.02), PSS (β= –3.31, p = 0.03), the whole scale of SCS (β= 0.47, p = 0.01) and self-judgment (β= 0.68, p = 0.003) and isolation (β= –0.66, p = 0.01) SCS subscales. Statistically significant results were also found in four out of eight subscales of MAIA: emotional awareness (β= 1.26, p < 0.001), self-regulation (β= 1.28, p < 0.001), body listening (β= 1.08, p < 0.001) and trusting (β= 1.1, p < 0.001). CONCLUSION: Our intervention has demonstrated to bring beneficial effects in a mindfulness subdomain, in perceived stress, self-compassion, interoception and psychological wellbeing. Based on our results, we conclude that our intervention was effective in increasing the positive aspects of wellbeing and in reducing stress. [ABSTRACT FROM AUTHOR]

Aims: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated in healthy subjects the safety, and pharmacokinetics of a liquid service formulation (LSF) and immediate release (IR) tablet of emodepside in 2 randomised, parallel‐group, placebo‐controlled, Phase I studies. Methods: Seventy‐nine subjects in 10 cohorts in the single ascending dose study and 24 subjects in 3 ascending‐dose cohorts in the multiple ascending dose study were enrolled. Emodepside as LSF was administered orally as single 1–40‐mg doses and for 10 days as 5 or 10 mg once daily and 10‐mg twice daily doses, respectively. Pharmacokinetics and safety were assessed up to 21 and 30 days, respectively. In addition, IR tablets containing 5 or 20 mg emodepside were tested in the single ascending dose study. Results: Emodepside as LSF was rapidly absorbed under fasting conditions, with dose‐proportional increase in plasma concentrations at doses from 1 to 40 mg. Terminal half‐life was > 500 hours. In the fed state, emodepside was absorbed more slowly but overall plasma exposure was not significantly affected. Compared to the LSF, the rate and extent of absorption was significantly lower with the tablets. Conclusions: Overall, emodepside had acceptable safety and tolerability profiles, no major safety concerns, after single oral administration of 20 mg as LSF and after multiple oral administration over 10 days at 5 and 10 mg OD and at 10 mg twice daily. For further clinical trials, the development of a tablet formulation overcoming the limitations observed in the present study with the IR tablet formulation is considered. [ABSTRACT FROM AUTHOR]

To assess the normative values of subfoveal choroidal thickness (SFCT) in healthy Turkish subjects using spectral -domain optical coherence tomography (SD-OCT, Spectralis®, Heidelberg Engineering, Germany) and its relationship with age and gender. One hundred sixty-nine emmetropic healthy subjects (84 men; 49.7%, 85 women 50.3%) underwent a detailed ophthalmological examination. The subjects were divided into 5 groups according to age; Group 1 (n = 42): 18-29 years, group 2 (n = 34): 30-39 years, group 3 (n = 33): 40-49 years, group 4 (n = 34): 50-59 years, group 5 (n = 26): 60 years and older. There were statistically significant differences in mean SFCT values among different age groups (p <0.05). Mean SFCT was highest in subjects under 30 years (364.87 ± 71.24 µm) and lowest in subjects over 60 years (261.25 ± 52.39 µm). There was a statistically significant negative correlation be tween age and SFCT values (r= -0.52, p< 0.001). Slope of change in SFCT over time in the subjects was -2.59 µm per year. When all subjects were evaluated, the mean SFCT value was 322.73 ± 64.00 µm in men and 310.47 ± 60.11 µm in women (p= 0.34). Except group 4, SFCT did not differ between men and women. SFCT decreases with aging and sex does not seem to alter the measurements. Our normative data according to age groups and gender might be used to demonstrate SFCT changes in various retinal and choroidal diseases in Turkish population. [ABSTRACT FROM AUTHOR]

Joint manipulation is generally used to reduce musculoskeletal pain; however, evidence has emerged challenging the effects associated with the specificity of the manipulated vertebral segment. The aim of this study was to verify immediate hypoalgesic effects between specific and non-specific cervical manipulations in healthy subjects. Twenty-one healthy subjects (18–30 years old; 11 males, 10 females) were selected to receive specific cervical manipulation at the C6-7 segment (SCM) and non-specific cervical manipulation (NSCM) in aleatory order. A 48h interval between manipulations was considered. Pressure pain threshold (PPT) was measured pre- and post-manipulation with a digital algometer on the dominant forearm. The SCM produced a significant increase in the PPT (P < 0.001) however no difference was observed in the PPT after the NCSM (P = 0.476). The difference between the two manipulation techniques was 37.26 kPa (95% CI: 14.69 to 59.83, p = 0.002) in favor of the SCM group Specific cervical manipulation at the C6-7 segment appears to increase PPT on the forearm compared to non-specific cervical manipulation in healthy subjects. [ABSTRACT FROM AUTHOR]

Background: The Hexoskin is a smart shirt that can take continuous and objective measurements and could be part of a potential telemonitoring system. Objective: The aim of this study was to determine the accuracy of the calibrated Hexoskin in measuring tidal volumes (TVs) in comparison to spirometry during various tasks. Methods: In a cross-sectional study, the TV of 15 healthy subjects was measured while performing seven tasks using spirometry and the Hexoskin. These tasks were performed during two sessions; between sessions, all equipment was removed. A one-time spirometer-based calibration per task was determined in session 1 and applied to the corresponding task in both sessions. Bland-Altman analysis was used to determine the agreement between TV that was measured with the Hexoskin and that measured with spirometry. A priori, we determined that the bias had to be less than ±5%, with limits of agreement (LOA) of less than ±15%. Lung volumes were measured and had to have LOA of less than ±0.150 L. Results: In the first session, all tasks had a median bias within the criteria (±0.6%). In the second session, biases were ±8.9%; only two tasks met the criteria. In both sessions, LOA were within the criteria in six out of seven tasks (±14.7%). LOA of lung volumes were greater than 0.150 L. Conclusions: The Hexoskin was able to correctly measure TV in healthy subjects during various tasks. However, after reapplication of the equipment, calibration factors were not able to be reused to obtain results within the determined boundaries. [ABSTRACT FROM AUTHOR]

This study aimed to explore the relationship between exercise and circulating microparticles (CMPs). PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until August 13, 2020, using the terms "exercise" and "cell-derived microparticles." The Cochrane tool of risk of bias and the Methodological Index for Non-Randomized Studies were used to grade the studies. Twenty-six studies that met criteria were included in this review, including one before–after self-control study, 2 cohort studies, 4 randomized control trials, 5 case–control studies, and 14 descriptive studies. The studies were divided into a single bout and long-term exercise. The types of MPs contained endothelium-derived microparticles (EMPs), leukocyte-derived microparticles (LMPs), platelet-derived microparticles (PMPs), and erythrocyte-derived microparticles (ErMPs). This first systematic review found that the levels of CMPs continued to increase after a single bout of exercise in untrained subjects and were lower in trained subjects. PMPs expressed a transient increase after a single bout of exercise, and the proportion and duration of PMPs increment reduced in long-term exercise. Most studies showed a decline in LMPs in trained subjects after a single bout and long-term exercise, and variable changes were found in EMPs and ErMPs after exercise. A single bout of exercise drives the vessels exposed to high shear stress that promotes the formation of CMPs. However, the decline in CMPs in trained subjects may be attributed to the fact that they have a better ability to adapt to changes in hemodynamics and cellular function during exercise. [ABSTRACT FROM AUTHOR]

Brain reorganization patterns associated with language recovery after stroke have long been debated. Studying mechanisms of spontaneous and treatment-induced language recovery in post-stroke aphasia requires a network-based approach given the potential for recruitment of perilesional left hemisphere language regions, homologous right hemisphere language regions, and/or spared bilateral domain-general regions. Recent hardware, software, and methodological advances in functional near-infrared spectroscopy (fNIRS) make it well-suited to examine this question. fNIRS is cost-effective with minimal contraindications, making it a robust option to monitor treatment-related brain activation changes over time. Establishing clear activation patterns in neurotypical adults during language and domain-general cognitive processes via fNIRS is an important first step. Some fNIRS studies have investigated key language processes in healthy adults, yet findings are challenging to interpret in the context of methodological limitations. This pilot study used fNIRS to capture brain activation during language and domain-general processing in neurotypicals and individuals with aphasia. These findings will serve as a reference when interpreting treatment-related changes in brain activation patterns in post-stroke aphasia in the future. Twenty-four young healthy controls, seventeen older healthy controls, and six individuals with left hemisphere stroke-induced aphasia completed two language tasks (i.e., semantic feature, picture naming) and one domain-general cognitive task (i.e., arithmetic) twice during fNIRS. The probe covered bilateral frontal, parietal, and temporal lobes and included short-separation detectors for scalp signal nuisance regression. Younger and older healthy controls activated core language regions during semantic feature processing (e.g., left inferior frontal gyrus pars opercularis) and lexical retrieval (e.g., left inferior frontal gyrus pars triangularis) and domain-general regions (e.g., bilateral middle frontal gyri) during hard versus easy arithmetic as expected. Consistent with theories of post-stroke language recovery, individuals with aphasia activated areas outside the traditional networks: left superior frontal gyrus and left supramarginal gyrus during semantic feature judgment; left superior frontal gyrus and right precentral gyrus during picture naming; and left inferior frontal gyrus pars opercularis during arithmetic processing. The preliminary findings in the stroke group highlight the utility of using fNIRS to study language and domain-general processing in aphasia. [ABSTRACT FROM AUTHOR]

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants' individual demographics (mean age 38 ± 11.5 years, range 23–65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) of the brain is an effective clinical treatment for psychiatric disorders. Noninvasive neuroimaging during rTMS allows visualization of cortical brain activations and responses, and it is a potential tool for investigating the neurophysiological response occurring actively during stimulation. In this paper, we present a fast diffuse optical tomography (DOT) approach for three-dimensional brain mapping of hemodynamics during rTMS. Eight healthy subjects were enrolled in the study. These subjects received 10 Hz stimulation with 80%and 100%of resting motor threshold (rMT), respectively, for 4 seconds for each stimulation. Significant hemodynamic activation was observed in all cases with the strongest response when 100%rMT stimulation was applied. This work demonstrates that fast DOT has the potential to become a powerful tool for noninvasive three-dimensional imaging of the brain during rTMS. [ABSTRACT FROM AUTHOR]

Background/aims: Recently, it was suggested that skin microbiome is related to some skin disease. The possibility of affecting the skin might be high, but there were few reports of the influence on the skin condition in healthy subjects. Our aim was to evaluate the relationship between skin condition and skin microbiome in healthy subjects. Methods: Experiment 1: 293 Japanese healthy women were divided into two groups, good skin properties and poor skin properties by 14 skin physiology parameter values on the cheek using noninvasive method. Differences of abundance of bacterial species on the cheek between the two groups were evaluated. Experiment 2: 11 Japanese healthy women were applied Staphylococcus hominis (S. hominis) on half‐side of cheek for eight times in 1 month. Difference of change of physiology parameter values comparing to placebo side was evaluated. Results: Experiment 1: Multiple skin bacterial species were found to be significantly relevant in 14 physiology parameters. The abundance of S. hominis on the cheek with good skin properties group was significantly higher than poor skin properties group. Experiment 2: The application of S. hominis improved significantly the conspicuous pore number, melanin index, and the wrinkle count compared to placebo side. Conclusion: We found many skin bacterial species that might improve the skin condition in healthy women. In particular, S. hominis might have the potential to improve multiple skin beauty problems. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about the relationship between left atrium (LA) volumes and contractility features along the cardiac cycle. The present study aimed to assess, by three-dimensional speckle-tracking echocardiography (3DSTE), correlations between LA volumes, volume-based functional properties, and strains during the cardiac cycle in healthy adults.Methods: We included 217 healthy adult volunteers (mean age 33.4 ± 12.7 years, 112 males) who underwent complete two-dimensional Doppler echocardiography with 3DSTE.Results: LA stroke volumes were greater in subjects with the greater maximum LA volume (Vmax ) in reservoir, conduit, and booster pump phases of LA function. While LA emptying fraction in LA reservoir phase was not different between subjects depending in their Vmax value, a significantly lower LA emptying fraction could be detected in LA conduit phase in subjects whose Vmax was >50 mL. In booster pump function, LA emptying fraction was not significantly different whatever the Vmax . Only global and mean segmental peak LA radial strain (RS) and 3D strain (3DS) and the same strains at atrial contraction appeared greater in subjects with greater Vmax , whereas the other strain parameters were not different.Conclusions: In healthy subjects, LA-RS and LA-3DS, objective features of LA contractility, are greater in subjects with greater LA volumes up to a point beyond which this association disappears. [ABSTRACT FROM AUTHOR]

Fatigue is a key factor that affects human motion and modulates physiology, biochemistry, and performance. Prolonged cyclic human movements (locomotion primarily) are characterized by a regular pattern, and this extended activity can induce fatigue. However, the relationship between fatigue and regularity has not yet been extensively studied. Wearable sensor methodologies can be used to monitor regularity during standardized treadmill tests (e.g., the widely used Bruce test) and to verify the effects of fatigue on locomotion regularity. Our study on 50 healthy adults [27 males and 23 females;

Brain reorganization patterns associated with language recovery after stroke have long been debated. Studying mechanisms of spontaneous and treatment-induced language recovery in post-stroke aphasia requires a network-based approach given the potential for recruitment of perilesional left hemisphere language regions, homologous right hemisphere language regions, and/or spared bilateral domain-general regions. Recent hardware, software, and methodological advances in functional near-infrared spectroscopy (fNIRS) make it well-suited to examine this question. fNIRS is cost-effective with minimal contraindications, making it a robust option to monitor treatment-related brain activation changes over time. Establishing clear activation patterns in neurotypical adults during language and domain-general cognitive processes via fNIRS is an important first step. Some fNIRS studies have investigated key language processes in healthy adults, yet findings are challenging to interpret in the context of methodological limitations. This pilot study used fNIRS to capture brain activation during language and domain-general processing in neurotypicals and individuals with aphasia. These findings will serve as a reference when interpreting treatment-related changes in brain activation patterns in post-stroke aphasia in the future. Twenty-four young healthy controls, seventeen older healthy controls, and six individuals with left hemisphere stroke-induced aphasia completed two language tasks (i.e., semantic feature, picture naming) and one domain-general cognitive task (i.e., arithmetic) twice during fNIRS. The probe covered bilateral frontal, parietal, and temporal lobes and included short-separation detectors for scalp signal nuisance regression. Younger and older healthy controls activated core language regions during semantic feature processing (e.g., left inferior frontal gyrus pars opercularis) and lexical retrieval (e.g., left inferior frontal gyrus pars triangularis) and domain-general regions (e.g., bilateral middle frontal gyri) during hard versus easy arithmetic as expected. Consistent with theories of post-stroke language recovery, individuals with aphasia activated areas outside the traditional networks: left superior frontal gyrus and left supramarginal gyrus during semantic feature judgment; left superior frontal gyrus and right precentral gyrus during picture naming; and left inferior frontal gyrus pars opercularis during arithmetic processing. The preliminary findings in the stroke group highlight the utility of using fNIRS to study language and domain-general processing in aphasia.

Viscosity and elasticity represent biomechanical properties of soft tissues that suffer changes during the pathophysiological alterations of the tissue in various conditions. This study aimed to determine average viscosity values for the thyroid gland and to evaluate the potential influences of age, gender and body mass index (BMI), using a recent technique Viscosity Plane-wave UltraSound (Vi PLUS). A total of 85 healthy Caucasian volunteers (56 women and 29 men, median age of 29 years, range 17–81 years) were included in this prospective monocentric study conducted between January 2022 and March 2022. Thyroid viscosity was measured using the SuperSonic MACH 30® Ultrasound system (Aixplorer, SuperSonic Imagine, Aix-en-Provence, France), equipped with a curvilinear C6-IX transducer that allows simultaneous quantification of the viscosity and stiffness. The mean thyroid viscosity measurement value was 2.63 ± 0.47 Pa.s. No statistically significant differences were detected between the left and the right lobes of the thyroid gland. A significant positive correlation was found between thyroid viscosity and elasticity (r = 0.685, p < 0.0001). There was no statistically significant correlation between body mass index (BMI) and thyroid gland viscosity and elasticity values (r = 0.215, p = 0.053; r = 0.106, p = 0.333). No correlation between viscosity and gender was established (p > 0.05). Vi PLUS represents a new and promising ultrasonographic technique that can provide helpful information for evaluating the thyroid parenchyma, similar to elastography. The effect of the potential confounding factors on thyroid viscosity was negligible, except for BMI.

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level.Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis.Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects.Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19.

Cerebrovascular reactivity (CVR) is defined as the change in cerebral blood flow induced by a change in a vasoactive stimulus. CVR using BOLD MRI in combination with changes in end-tidal CO2 is a very useful method for assessing vascular performance. In recent years, this technique has benefited from an advanced gas delivery method where end-tidal CO2 can be targeted, measured very precisely, and validated against arterial blood gas sampling (Ito et al., 2008). This has enabled more precise comparison of an individual patient against a normative atlas of healthy subjects. However, expected control ranges for CVR metrics have not been reported in the literature. In this work, we calculate and report the range of control values for the magnitude (mCVR), the steady state amplitude (ssCVR), and the speed (TAU) of the BOLD response to a standard step stimulus, as well as the time delay (TD) as observed in a cohort of 45 healthy controls. These CVR metrics maps were corrected for partial volume averaging for brain tissue types using a linear regression method to enable more accurate quantitation of CVR metrics. In brief, this method uses adjacent voxel CVR metrics in combination with their tissue composition to write the corresponding set of linear equations for estimating CVR metrics of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). After partial volume correction, mCVR and ssCVR increase as expected in gray matter, respectively, by 25 and 19%, and decrease as expected in white matter by 33 and 13%. In contrast, TAU and TD decrease in gray matter by 33 and 13%. TAU increase in white matter by 24%, but TD surprisingly decreased by 9%. This correction enables more accurate voxel-wise tissue composition providing greater precision when reporting gray and white matter CVR values.

BackgroundSeasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown.ObjectiveThis double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants.Design62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed.ResultsMean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04).ConclusionsDaily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation.Clinical Trial Registrationhttps://www.isrctn.com, identifier (ISRCTN 73114576).

• Lumbar lordosis occurred most frequently in the lower lumbar region (L4–S1). • L3–L4 to L5–S1 were conspicuous as mobile segments, exhibiting larger ROM. • Loss of local ROM with increasing age was most prominent at L3–L4 to L5–S1 levels. • Age-related degenerative disc height loss was most prominent at L4/L5. The aim of this study was to determine age-related changes and sex-specific differences in sagittal alignment, range of motion (ROM), and intervertebral disc height of the thoracolumbar spine in healthy subjects. Lateral neutral and flexion–extension radiographs of the thoracolumbar spine of 627 asymptomatic subjects (307 males and 320 females; average age, 49.6 ± 16.5 years) were evaluated. We included at least 50 males and 50 females in each decade of life between the 20s and the 70s. Intervertebral disc height from T10/T11 to L5/S1, local lordotic alignment, and ROM from T10–T11 to L5–S1 were measured. T10–L2 kyphosis and T12–S1 lordosis as well as flexion, extension, and total ROM were measured. T10–L2 kyphosis did not markedly change with age in subjects of either sex but a sudden increase was noted in the 70s females. T12–S1 lordosis increased with age in both sexes, except the 70s. Flexion, extension, and total ROM at T10–L2 and T12–S1 decreased with age in most subjects. The levels from L3–L4 to L5–S1 were conspicuous as mobile segments. Intervertebral disc height gradually increased from T10/T11 to L4/L5; the shortest was at T10/T11 and the longest at L3/L4 or L4/L5 in all subjects. Age-related decreases in intervertebral disc height were most prominent at L4/L5 in middle-aged and elderly individuals of both sexes. Normative values of sagittal alignment, ROM, and intervertebral disc height at each segmental level were established in both sexes and all age groups in healthy subjects. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of low-frequency magnetic stimulation at Shenmen (HT 7) acupoint on blood oxygen levels in the prefrontal cortex of healthy subjects. Methods: Functional near-infrared spectroscopy (fNIRS) technology was used to collect real-time data of oxygenated hemoglobin (oxy-Hb) in the prefrontal cortex of 16 healthy subjects at resting state and low-frequency magnetic stimulation of Shenmen. The mean and integral values of blood oxygen concentration were analyzed. Results: Compared with the resting state, the mean and integral values of blood oxygen concentration were decreased during the task period, recovery period, and the whole process in the magnetic stimulation of Shenmen acupoint (P<0.05). In particular, the difference was statistically significant in the recovery period (P<0.01). Conclusions: The prefrontal cortex was widely activated and produced an immediate effect by reducing the local blood oxygen concentration at low-frequency magnetic stimulation of Shenmen acupoint, which verifies the sedative effect of Shenmen acupoint. [ABSTRACT FROM AUTHOR]

Aims: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. Methods: This randomized, double‐blind, placebo‐controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1–35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross‐over design in 14 healthy subjects. Results: Pharmacokinetics of HTL0018318 were well‐characterized showing dose proportional increases in exposure from 1–35 mg. Single doses of HTL0018318 were associated with mild dose‐related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2–16.3], 35‐mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9–18.9], 15‐mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. Conclusion: HTL0018318 showed well‐characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias. [ABSTRACT FROM AUTHOR]

Objectives: To determine the 6-minute walk test (6MWT) for healthy volunteers in our population and find out the factors affecting 6MWT. Furthermore, comparing our results with published National and International data. Materials and Methods: This cross-sectional study was carried in the physiology department of Rawalpindi Medical College, from 1st July 2019 to 31st December 2019A total of 129 adult healthy volunteers between 18 and 60 years of age were included in this study after the application of inclusion and exclusion criteria. A 6-minute walk test (6MWT) was carried out in a standardized procedure. The height, weight, and BMI were recorded on predesigned Performa. Distance covered in 6-minute, heart rate, systolic BP, Diastolic BP, SPO2, Borg Scale Dyspnea score, Borg Scale Fatigue score were recorded before and after the 6-minute walk test. Correlation and its significance were calculated among anthropometric and physiological variables. Results: Seventy (54%) men and Fifty-nine (46%) women participated in the study. The mean distance covered for all subjects was 430.412±63.0150. The distance covered by the female subject was 388.720±30.104 and 439.533±68.355 by male subjects. The mean age of the subjects was 31.64 ±12.36, while the mean BMI was 22.06 ±4.15. The mean heart rate value before the test is 77.72±1.48 and after the test is 92.84±1.12. The mean systolic BP value before the walk was 122.65±11.75 and after the walk, it was 106.5±9.83. Mean diastolic BP before the walk was 80.55±12.61 and after the walk, it was 76.5±9.83. SPO2 mean value before the walk was 96.23±1.4 and after the walk is 98.2±1.17. Borg scale dyspnea score mean value before the test is 0 ± 0 and after the test it was 0.67±0.76 and Borg scale fatigue score mean value before the walk is 1.32±0.73 and after the walk is 1.62±0.92. A positive correlation was noted with height, while a negative correlation was noted with age and BMI. Gender also showed a significant relationship with the 6MWD. Conclusion: The distance covered in 6-minute is shorter than the studies carried out in different parts of the world. Age, gender, height, and BMI showed a significant relationship with 6MWD. Those reference values for the 6MWD should not be used in our population, as it overestimates the distance and may interfere with the significance of the test. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the intra and inter-rater and inter-analyzer reliability of neuromuscular variables and functional tests. Cross-sectional crossover design. Two independent raters and analyzers evaluated twenty-two healthy subjects. Knee-extensor strength was assessed from three maximal voluntary isometric contractions. Muscle activation was obtained from the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM) muscles. VL and RF muscles' architecture [fascicle length (FL), pennation angle (PA), muscle thickness (MT)] was obtained at rest by ultrasound. The time from five sit-to-stand (STS) trials, and the distance from the 6-min walk test (6MWT) were obtained. Intraclass correlation coefficient was determined and classified as strong (r = 0.75–1.00), moderate (r = 0.40–0.74), and weak (r < 0.40). Strong intra-rater reliability values were observed for strength (r = 0.97), muscle activation [VL (r = 0.91); RF (r = 0.92); VM (r = 0.80)], VL [FL (r = 0.90); PA (r = 0.94); MT (r = 0.99)] and RF [MT (r = 0.85)] muscle architecture, STS (r = 0.95), and 6MWT (r = 0.98). Inter-rater reliability also presented strong values for strength (r = 0.97), muscle activation [VL (r = 0.94); RF (r = 0.79); VM (r = 0.78)], muscle architecture VL [PA (r = 0.81) and MT (r = 0.88)] and RF [MT (r = 0.80)], STS (r = 0.93), and 6MWT (r = 0.98). A moderate correlation VL muscle architecture [FL (r = 0.69)]. Inter-analyzer muscle architecture reliability presented strong VL [FL (r = 0.77); PA (r = 0.76); MT (r = 0.91)] and RF [MT (r = 0.99)]. The high intra and inter-rater and inter-analyzer reliability values for most variables is evidence that they can be used for clinical evaluation. Muscle architecture might need a longer training period by different raters and analyzers to increase reliability. [ABSTRACT FROM AUTHOR]

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Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. Clinical Trial Registration: https://www.isrctn.com , identifier (ISRCTN 73114576). [ABSTRACT FROM AUTHOR]

Background: IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.Methods: This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.Discussion: LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.Trial Registration: This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ). [ABSTRACT FROM AUTHOR]

Cerebrovascular reactivity (CVR) is defined as the change in cerebral blood flow induced by a change in a vasoactive stimulus. CVR using BOLD MRI in combination with changes in end-tidal CO2 is a very useful method for assessing vascular performance. In recent years, this technique has benefited from an advanced gas delivery method where end-tidal CO2 can be targeted, measured very precisely, and validated against arterial blood gas sampling (Ito et al., 2008). This has enabled more precise comparison of an individual patient against a normative atlas of healthy subjects. However, expected control ranges for CVR metrics have not been reported in the literature. In this work, we calculate and report the range of control values for the magnitude (mCVR), the steady state amplitude (ssCVR), and the speed (TAU) of the BOLD response to a standard step stimulus, as well as the time delay (TD) as observed in a cohort of 45 healthy controls. These CVR metrics maps were corrected for partial volume averaging for brain tissue types using a linear regression method to enable more accurate quantitation of CVR metrics. In brief, this method uses adjacent voxel CVR metrics in combination with their tissue composition to write the corresponding set of linear equations for estimating CVR metrics of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). After partial volume correction, mCVR and ssCVR increase as expected in gray matter, respectively, by 25 and 19%, and decrease as expected in white matter by 33 and 13%. In contrast, TAU and TD decrease in gray matter by 33 and 13%. TAU increase in white matter by 24%, but TD surprisingly decreased by 9%. This correction enables more accurate voxel-wise tissue composition providing greater precision when reporting gray and white matter CVR values. [ABSTRACT FROM AUTHOR]

Recently introduced, the Heidelberg Engineering™ high magnification module enables in vivo visualization of cone photoreceptor cells. Currently, a reliable analysis of cone mosaic on high magnification module images is hindered by an unfavorable signal-to-noise ratio. In this paper, we describe how a novel high magnification module high-pass filter may enhance cone signals in healthy participants and patients. We compared the cone counts of our filter-based algorithm to the counts of two human graders. We found a good to excellent intragrader and intergrader correlation in both patients and healthy participants. We identified a good correlation between the average cone counts of both graders and high-pass filter cone counts in patients and healthy participants. We observed no significant difference between manual and filter-based counts via the Bland–Altman analysis. In conclusion, a quantitative cone analysis on high magnification module images is feasible manually by human graders and automatically by a filter-based algorithm. However, larger datasets are needed to improve repeatability and consistency by training human graders. [ABSTRACT FROM AUTHOR]

Susanne Prothon,1 Ulrika Wählby Hamrén,1 Ulrika Tehler,2 Esther Yoon,3 Henrik Forsman,4 Cecilia Arfvidsson,5 Ajay Aggarwal,6 Yingxue Chen7 1Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 2Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 3Early Phase Clinical Unit, PAREXEL, Glendale, CA, USA; 4Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Clinical Sample and Bioanalytical Science, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 6Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA; 7Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Boston, MA, USACorrespondence: Susanne ProthonClinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SwedenEmail susanne.prothon@astrazeneca.comIntroduction: AZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator (SGRM), currently in development for the treatment of asthma and chronic obstructive pulmonary disease. This paper reports a randomized placebo-controlled dose escalation study in healthy Japanese male subjects.Methods: Inhaled AZD7594 was administered as one single dose at day 1 (day 1–4), with subsequent multiple daily doses (day 5–16) via a multiple-dose dry powder inhaler for 12 days of once-daily treatment. At each dose level, subjects were randomized to AZD7594 (n=7) or placebo (n=2). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 were evaluated.Results: Inhaled AZD7594 was safe and well tolerated up to and including the highest dose 1600 μg tested. Plasma exposure suggested dose-proportional PK. The urinary excretion of AZD7594 was negligible (

The training surface can modulate the body’s response to training stimuli. The purpose of the article was to determine the influence of two types of training programs on stable/unstable surfaces on postural stability. 20 physically active participants with no history of lower limb injuries were randomly assigned to 3 groups (Control, Unstable Training, Stable Training), and performed supervised training in 16 sessions. Dynamic postural stability and static stability were assessed and tests were performed at baseline after completion of the training and 1, 2 and 4 weeks after the training process. The stable surface training group improved dynamic stability between the pre-test and the two first retention tests performed (p = .037, d = .780; p = .011, d = .989). The unstable training group significantly improved its dynamic stability level between the post-test and the retention test (2). The improvements found after the training session for the unstable training group do not mean an increase in stability higher than that obtained by the stable surface training group. The dynamic postural stability test seems more appropriate than the static tests for analyzing small changes related to the training of postural stability in healthy young people.

Date palm (Phoenix dactylifera) is one of the oldest trees cultivated by human; Egypt has been ranked as the first country in the production of dates, soft, semi dry and dry date cultivars are cultivated in wide area of Egypt. Therefore, this work was carried out to determine the Glycemic Index (GI) and Glycemic Load (GL) of five Egyptian varieties of date fruit in healthy subjects. Chemical composition analysis was carried out for five types of date fruit (Partamoda, Malakabi, Saadi, Zaghluol and Samani); also, antioxidant power was determined. The study subjects were ten healthy volunteers, each subject was tested on six separate visits with 50 g of glucose and 50 g equivalent of available carbohydrates from the five date varieties. Capillary glucose was measured in the healthy subjects at 0, 30, 60 and 120 min. The GI was determined as ratios of the incremental areas under the response curves for the dates compared to glucose. Collecting data showed that Egyptian varieties of date fruit contain a good nutrients and antioxidant power. Among the five Egyptian varieties of date fruit, the chemical characteristics by moisture content in fruits was the highest in Samani date fruit and lowest in Partamoda dates; also, the five Egyptian varieties of date fruit contain available carbohydrate (7.4% - 69.2%), proteins (1.85 % - 7.0 %), total dietary fiber, TDF (11.82% - 15.63%) and Energy value (76.2 - 297.9 Kcal/100g). The antioxidant activity ranged between 52.61 and 79.12% as scavenging activity for free radicals; also, dates rich in phenols. The medium GI was recorded by Malakabi followed by Saadi and Partamoda which had high GL; while, the lowest GI was recorded for soft date fruit (Zaghluol and Samani) which had medium GL. These findings point to the potential benefits of Egyptian date fruit for healthy subjects when used in a stable healthy diet.

Antonina I Volikova1, Barry J Marshall1, J M A Yin2, Robert Goodwin2, Peter Ee-Pan Chow1, Michael J Wise1,3 1Marshall Centre for Infectious Disease Research and Training, School of Biological Sciences, University of Western Australia, Perth, Australia; 2Urology Department, Sir Charles Gairdner Hospital, Perth, Australia; 3Department of Computer Science and Software Engineering, School of Physics, Mathematics and Computing, University of Western Australia, Perth, AustraliaCorrespondence: Antonina I VolikovaUniversity of Western Australia, 35, Stirling Highway, Crawley WA 6009, AustraliaTel +61 845 015 4041Email Antonina.volikova@uwa.edu.auAim: The aim of this study was to apply and evaluate three ultrasound methods to measure the bladder wall in a healthy population using high-resolution applications and to establish reference points and baselines for future research into lower urinary tract diseases, specifically to understand how lower urinary tract disorders affect the bladder wall and to find objective, non-invasive diagnostic tests. Methods: The study was conducted on 116 healthy volunteers aged 19–79 years old with approximately 10 participants in each decade group. Results: The following bladder parameters were recorded and measured using a GE LOGIQ E9 XDclear 2.0 ultrasound machine (GE Healthcare, Wauwatosa, WI, USA): Full bladder wall thickness (BWT) and each of three bladder wall layers thickness (BWLT) – serosa, detrusor and mucosa;Shear Wave Velocity (SWV) in m/s, using 2D Shear Wave Elastography (2D-SWE); andBladder wall blood circulation (Resistive Index, RI), using Duplex Doppler ultrasound. All of the above measurements were recorded at three different urine filling volumes: V0 (20–50 mL), V2 (180–200 mL) and V4 (380–400 mL) with ten repeats for each measured parameter. As expected, BWT and BWLT correlated inversely with increasing bladder volume.While there are no large differences in the healthy bladders of men compared with women, or with age, some small, but statistically significant, differences revealed. BWT at V0 is greater in men, as is the detrusor thickness at VO, but there are no differences at other volumes or for other layers. There is a small, but statistically significant thickening ofBWTand detrusor layer and increase in SWVwith age in men at V0. SWE showed increase in SWVmeasured at 400 mL bladder volume across all gender and age groups. There was no change in bladder wall vessels RI with age, between gender groups or increasing bladder volume. Conclusion: We used three ultrasound applications to obtain bladder wall reference data in healthy individuals and investigated the relationships between BWT, BWLT, SWV, RI and gender, age at three bladder volumes, for further studies into identifying and diagnosing different urinary bladder disorders. With further research, ultrasound could be used as a diagnostic test to differentiate bladder pathology in clinical practice. Keywords: urinary bladder, healthy subjects, reference data, high-frequency ultrasound, duplex doppler, shear wave elastography

Background: Pulse oximeter is a simple and noninvasive standard device to monitor the saturation of peripheral oxygen (SpO2) and heart rate. The nail polish of different colors may result in inaccurate oximetry reading and interpretation of oxygen saturation. This study aimed at determining the effect of different colors of glittered nail polish on SpO2in healthy students. Materials and Methods: This is a randomized clinical trial on 30 healthy students with SpO2≥95% and without any complications on nail beds and environmental perfusion. SpO2was measured on 10 fingers of the participants after sitting and resting on a seat for 10 min in a room with normal temperature. Then they were asked to apply 10 colors of glittered nail polish randomly to their fingernails as all colors were used. After drying the two-layer nail polish, SpO2was measured again. Results: Of 10 glittered nail-polishes, dark green and purple did not change SpO2reading significantly. All other colors lowered SpO2significantly based on Wilcoxon test (red: p = 0.003; orange: p = 0.002; yellow: p = 0.015; pink: p = 0.017; dark blue: p = 0.001; violet: p = 0.001; brown: p = 0.001; black: p = 0.001). However, those changes were not clinically significant because SpO2differences before and after nail polish were in acceptable range (less than a 2% change). Conclusions: We conclude that different colors of glittered nail polishes do not result in a clinically significant change in pulse oximetry measurements in healthy subjects; therefore, it is not necessary to remove the glittered nail polish routinely in clinical, surgical, and emergency settings.

Biological soft tissues are characterized by viscoelastic properties. The propagation of shear waves within tissues is influenced by both elasticity, which is linked to the shear wave speed, and viscosity, which is linked to the shear wave dispersion. This study aimed to functionally assess the parotid glands (PG) and submandibular glands (SMG) in a group of 40 healthy subjects using the novel Viscosity PLUS (Vi.PLUS) and 2D Shear-Wave Elastography PLUS (2D-SWE.PLUS) techniques. The viscosity and stiffness of PG and SMG were measured before and after gustatory stimulation with a sialagogue agent (commercially available lemon juice) using the new SuperSonic MACH 30 ultrasound system equipped with a curvilinear C6-1X transducer. PG presented a mean basal viscosity and elasticity of 2.10 ± 0.19 Pa.s and 11.32 ± 1.91 kPa, respectively, which significantly increased poststimulation to 2.39 ± 0.17 Pa.s (p < 0.001) and 12.58 ± 1.92 kPa (p < 0.001), respectively. SMG did not present statistically increased values of viscosity and elasticity following stimulation (2.31 ± 015 Pa.s vs. 2.37 ± 0.18 Pa.s, p = 0.086, and 10.40 ± 1.64 kPa vs. 10.90 ± 1.98 kPa, p = 0.074, respectively). Vi.PLUS measurements presented a good positive correlation with 2D-SWE.PLUS values for PG and SMG, before and after stimulation. Gender and BMI were not confounding factors for these two parameters. Vi.PLUS represents an innovative non-invasive imaging technique that, together with 2D-SWE.PLUS proves to be useful in functionally assessing the major salivary glands in healthy subjects.

The gut microbiota is implicated in diverse interactions affecting human health. The present study reports a randomized, double-blind, placebo-controlled clinical study conducted by administering a new synbiotic formulation composed of two Lactobacillus strains (L. plantarum and L. acidophilus) and one Bifidobacterium strain (B. animalis subsp. lactis) and two types of fructans (fructo-oligosaccharides with a degree of polymerization of 3–5 and inulin-type fructans with 10 DP). The effects of this synbiotic were evaluated on healthy subjects for 28 days and the maintenance of its efficacy was evaluated at the end of a follow-up period of 28 days. The synbiotic treatment contributes to higher biodiversity of the gut microbiota, increasing the community richness with respect to the group with the prebiotics alone and the placebo group. Its positive effect is also reflected in the variation of microbial community structure favoring the beneficial short-chain fatty acids bacterial producers. The amelioration of the health status of the subjects was also established by the reduction of common infectious disease symptom incidence, the stimulation of the gut immune system showing a noteworthy variation of fecal β-defensin2 and calprotectin levels, and the modulation of the response of the respiratory tract’s immune system by salivary IgA as well as total antioxidant capacity biomarkers.

Liver fibrosis is the most significant prognostic factor in chronic liver disease (CLD). Clinical practice guidelines recommend the use of non-invasive techniques, such as two-dimensional shear-wave elastography (2D-SWE), to assess liver stiffness as a marker of fibrosis. Several other factors influence liver stiffness in addition to liver fibrosis. It is presumed that changes due to necro-inflammation modify the propagation of shear waves (dispersion). Therefore, new imaging techniques that investigate the dispersion properties of shear waves have been developed, which can serve as an indirect method of measuring liver viscosity (Vi PLUS). Defining the reference values in healthy subjects among different age groups and genders and analyzing the factors that influence these values is essential. However, published data on liver viscosity are still limited. This is the first study that aimed to assess the normal range of liver viscosity values in subjects with healthy livers and analyze the factors that influence them. One hundred and thirty-one consecutive subjects with healthy livers were enrolled in this prospective study. The results showed that Vi PLUS is a highly feasible method. Liver stiffness, age and BMI influenced the liver viscosity values. The mean liver viscosity by Vi PLUS in subjects with healthy livers was 1.59 Pa·s.

Stress is inevitably linked to life. It has many and complex facets. Notably, perception of stressful stimuli is an important factor when mounting stress responses and measuring its impact. Indeed, moved by the increasing number of stress-triggered pathologies, several groups drew on advanced neuroimaging techniques to explore stress effects on the brain. From that, several regions and circuits have been linked to stress, and a comprehensive integration of the distinct findings applied to common individuals is being pursued, but with conflicting results. Herein, we performed a volumetric regression analysis using participants’ perceived stress as a variable of interest. Data shows that increased levels of perceived stress positively associate with the right amygdala and anterior hippocampal volumes.

Purpose: Albendazole is a benzimidazole carbamate drug with anthelmintic and antiprotozoal activity against intestinal and tissue parasites. It has been described that the administration with meals increases albendazole absorption. Our aim was to compare the systemic exposure in healthy volunteers of two albendazole formulations after a single oral dose under fed conditions and to evaluate the effect of breakfast composition on albendazole and albendazole sulfoxide bioavailability.Methods: 12 healthy volunteers were included in a 4-period, 4-sequence, crossover, open, randomized, bioequivalence clinical trial, including two stages to compare two formulations of albendazole. Single oral doses of 400 mg albendazole were administered under fed conditions (a low-fat breakfast in first stage and a high-fat breakfast in the second) separated by 7-day washout periods. Plasma albendazole and albendazole sulfoxide concentrations were measured by HPLC-MS/MS.Findings: Albendazole absorption was clearly influenced by the meal composition. A high-fat breakfast increased albendazole and albendazole sulfoxide area under the concentration–time curve (AUC) and maximum concentration (Cmax) by double, compared to a low-fat breakfast. The bioavailability of the two formulations was very similar, although the sample size was not sufficient to demonstrate bioequivalence because the intraindividual variability of albendazole was approximately 60%.Implications: The higher albendazole and albendazole sulfoxide levels when administered with a high-fat meal could be of importance in clinical practice. Since albendazole labeling recommends its administration with meals, it is necessary to insist on taking it with a fatty meal so that the effectiveness of albendazole is not compromised.

Background The burden of tuberculosis (TB) and cardiovascular disease (CVD) is enormous worldwide. Public health programs have been challenged with the overlapping of TB and CVD epidemics.Mycobacterium tuberculosis (MTB) is also a main driver of atherogenesis, suggesting a potential pathogenic role of tuberculosis in cardiovascular disease. The objective of this study was to compare the serum levels of apolipoprotein B (apo B), apolipoprotein B48 (apo B48) and apolipoprotein B100 (apo B100) between patients with tuberculosis and healthy subjects. Methods A cross-sectional study was conducted involving 251 subjects consisting of 120 treatment naïve active TB patients [26 HIV co infected (TB+HIV+) and 82 TB+), 12 malaria parasite co-infected (TB+MP+)], 26 latent TB infected (LTB) and 105 healthy controls. Their body mass index (BMI) was calculated. Mycobacterium tuberculosis infection was determined by Ziehl-Nelseen (ZN) sputum smear microscopy and confirmed positive using GeneXpert. Latent TB was determined by Mantoux test, MP was evaluated by microscopy while HIV by immunochromatographic techniques using serial algorithm. Apolipoproteins were determined using spectrophotometry. A one-way ANOVA test and LSD’s post hoc multiple comparisons were used for statistical analyses. Results Significantly lower mean levels of BMI were observed in LTB, TB+, TB+HIV+ and TB+MP+ compared with the controls (p

Introduction: A number of studies defined normal reference values of three‐dimensional (3D) speckle‐tracking echocardiography (3DSTE)‐derived left ventricular (LV) strains. The present study aimed to quantify normal reference values of LV strains in healthy adult population in real clinical world settings in different age groups, and to determine age‐ and gender‐dependence of these variables in a high volume single center. Methods: The present prospective study included 296 healthy adult subjects. Among them, 124 were excluded due to inferior image quality during the 6‐year recruitment period (2011‐2017). The remaining population was further divided into four subgroups based on age decades. Results: While global radial (RS) strain showed an increase‐decrease‐increase pattern with age, circumferential, longitudinal, and area strains (CS, LS, AS, respectively) were nonsignificantly lower in older ages. Only global LV‐LS showed gender‐dependency with higher values in females. Although moderately higher RS and 3DS and lower LS, and AS were observed in males, clear gender‐dependency could not be detected in different age decades. Conclusions: This study provides normal reference values of 3DSTE‐derived global, segmental, mean segmental, and regional LV strains in healthy adult subjects based on real‐life clinical experience. Age‐, gender‐, and functional nonuniformity of LV strains were also defined. [ABSTRACT FROM AUTHOR]