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Dihydroxyaluminum aminoacetate, heavy magnesium carbonate, and aspirin tablets is a new combined aspirin preparation, each containing aspirin (81 mg), dihydroxyaluminum aminoacetate (11 mg), and heavy magnesium carbonate (22 mg). This study was conducted to evaluate the pharmacokinetic (PK) and bioequivalence in healthy Chinese subjects. This randomized, open‐label, single‐dose, 2‐sequence, and 2‐period crossover study included 78 healthy volunteers (fasting, n = 36; postprandial, n = 42). Blood samples were collected for PK analysis. Aspirin and salicylic acid concentrations in human plasma were determined by liquid chromatography‐tandem mass spectrometry. Safety and tolerability were monitored. There were no significant differences between the test and reference formulations in maximum plasma concentration, area under the plasma concentration‐time curve (AUC) from time 0 to time t, or AUC from time 0 to infinity. The 90% confidence intervals of the test and reference formulations of maximum plasma concentration, AUC from time 0 to time t, and AUC from time 0 to infinity were within the acceptable range (80%‐125%) under fasting and postprandial conditions. All adverse events were mild and no serious adverse events were observed in the study. Both compounds were well tolerated in healthy Chinese volunteers. [ABSTRACT FROM AUTHOR]

The study explored the effects of transcutaneous electrical spinal cord stimulation (tES) on postural control. Subjects were divided into field-dependent (FD) and field-independent (FI) groups according to their cognitive style. FD subjects use an exteroceptive afferent stream for spatial orientation, while FI subjects use an interoceptive stream. In darkness, vertical posture is maintained by head-trunk stabilization in FD subjects and by independent movements of body segments in FI subjects. Previously, we showed that tES at the L1-L2 vertebral level decreased postural stability in FD subjects. Now, stimulation was applied at the T11-T12 vertebral level (midline, above the left or right dorsal roots). Quiet standing was assessed using stabilometry in 18 FD and FI participants. Participants stood on a force platform in soundproof chamber with eyes closed during tES. Midline and left tES significantly improved postural stability by up to 28% in FD participants, while posture did not change significantly in FI participants. Pronounced differences between the effects of T11-T12 and L1-L2 stimulation are associated with selective topographical activation of proximal and distal leg muscles during tES of the lumbar enlargement. This study highlights the importance of considering cognitive style in postural control research. [ABSTRACT FROM AUTHOR]

To investigate the effect of a pulsed Nd:YAG laser on the forearm local skin temperature (LST) and electrophysiology in healthy adults. A total of 30 healthy subjects with a mean age of 21 ± 0.74 years, mass of 63 ± 9.97 kg, and height of 163.7 ± 6.24 cm participated in this study. The anterior surface of the left non-dominant forearm was scanned with a pulsed Nd:YAG laser at 20 Jcm−2 for a total of 2000 J in 15 min. The right forearm was considered as the control and was scanned with a placebo laser for the same time as the active laser. Forearm minimal, average, and maximum LST were measured using a thermographic camera. Electrophysiological assessment of the median nerve [distal motor latency (DML), motor nerve conduction velocity (MNCV), and sensory nerve conduction velocity (SNCV)] was performed on both forearms before and after the application of the pulsed Nd:YAG laser. Paired and unpaired t tests were used to compare within and between groups, respectively. The level of significance was set at p > 0.05. There were significant increases in the minimum, average, and maximum LST, as well as the MNCV and SNCV with a significant decrease in DML after laser application compared to the control. The average increase in LST and nerve conduction velocity post-treatment was 275.55 K and 4.8 ms−1, respectively. The application of a pulsed Nd:YAG laser significantly increased the forearm LST, MNCV, and SNCV and significantly decreased the DML in healthy subjects. The average increase in the LST was 275.55 K with an average increase of 5 ms−1 in the motor and 4 ms−1 in the sensory NCVS. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the pharmacokinetic parameters of single oral administration of postchange and prechange abexinostat (CRA‐024781) tosylate tablets in Chinese healthy subjects under fasting conditions, and assess the bioequivalence (BE) of the 2 formulations (Test [T1] and Reference [T2]). This study was a randomized, open‐label, 2‐formulation, fasting administration, single‐dose, 2‐sequence, 2‐cycle, crossover BE study. Thirty‐six subjects were enrolled in the study and 33 subjects completed 2 cycles. The plasma concentrations were determined by liquid chromatography‐tandem mass spectrometry. The 90% confidence intervals (CIs) for the Cmax, AUC0‐t, and AUC0‐∞ of CRA‐024781 and its 2 major metabolites (PCI‐27789 and PCI‐27887, both metabolites are pharmacologically inactive on HDAC1) fell within the acceptable range of 80%‐125%. The results suggest that the CRA‐024781 test preparation (Test [T1]) is bioequivalent to the reference preparation (Reference [T2]) in healthy Chinese subjects under fasting conditions. [ABSTRACT FROM AUTHOR]

Aims: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre‐clinical profiling suggests that time‐dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co‐administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time‐/dose‐dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. Methods: Open‐label, fixed‐sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug–drug interaction. Results: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co‐administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co‐administrations with two predicted therapeutically relevant doses of Atuliflapon. Conclusions: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs. [ABSTRACT FROM AUTHOR]

Introduction: This scoping review aimed to synthesize the fragmented evidence on ethical concerns related to the use of electrical and magnetic neuromodulation technologies, as well as brain-computer interfaces for enhancing brain function in healthy individuals, addressing the gaps in understanding spurred by rapid technological advancements and ongoing ethical debates. Methods: The following databases and interfaces were queried: MEDLINE (via PubMed), Web of Science, PhilPapers, and Google Scholar. Additional references were identified via bibliographies of included citations. References included experimental studies, reviews, opinion papers, and letters to editors published in peer-reviewed journals that explored the ethical implications of electrical and magnetic neuromodulation technologies and brain-computer interfaces for enhancement of brain function in healthy adult or pediatric populations. Results: A total of 23 articles were included in the review, of which the majority explored expert opinions in the form of qualitative studies or surveys as well as reviews. Two studies explored the view of laypersons on the topic. The majority of evidence pointed to ethical concerns relating to a lack of sufficient efficacy and safety data for these new technologies, with the risks of invasive procedures potentially outweighing the benefits. Additionally, concerns about potential socioeconomic consequences were raised that could further exacerbate existing socioeconomic inequalities, as well as the risk of changes to person and environment. Conclusion: This scoping review highlights a critical shortage of ethical research on electrical and magnetic neuromodulation technologies and brain-computer interfaces for enhancement of brain function in healthy individuals, with key concerns regarding the safety, efficacy, and socioeconomic impacts of neuromodulation technologies. It underscores the urgent need for integrating ethical considerations into neuroscientific research to address significant gaps and ensure equitable access and outcomes. [ABSTRACT FROM AUTHOR]

Background/objectives: Respiratory muscle training (RMT) was recognized as an effective means to improve respiratory muscle (RM) strength and enhance exercise performance. The purpose of this study was to examine the effect of low-intensity RMT on RM strength, pulmonary function, and performance. Methods: Fourteen healthy active adults were assigned randomly to either a training or placebo group. The training group completed six weeks of RMT, which consisted of a first week, 1 set of 15 min/d, 5 d/wk at 10–25% of maximal inspiratory pressure (PImax), and the remaining 5 weeks, 2 sets of 15 min/d, 5 d/wk, at 30% PImax. The placebo group followed the same protocol but with almost no additional ventilatory resistance. Measurement of RM strength and endurance, spirometry, and endurance exercise performance were obtained before and after the RMT program. Results: In the training group, PImax (+14%) and maximal expiratory pressure (PEmax, +27%), forced vital capacity (FVC, +3.6%), maximal oxygen uptake (VO2max, +11%), and time to exhaustion (Tlim90%, +25%) increased significantly from baseline values (P

Toll‐like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS‐7011a is an anti‐TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first‐in‐human, double‐blind, randomized, and placebo‐controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS‐7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS‐7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment‐emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS‐7011a, immunogenicity by measuring plasma anti‐drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin‐6 production ex vivo in whole blood. DS‐7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug‐related. DS‐7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target‐mediated drug disposition. Terminal half‐life was about 15‐17 days and Tmax upon SC administration was about 5 days. DS‐7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS‐7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE. [ABSTRACT FROM AUTHOR]

Bodily self-consciousness (BSC), a subject of interdisciplinary interest, refers to the awareness of one's bodily states. Previous studies have noted the existence of individual differences in BSC, while neglecting the underlying factors and neural basis of such individual differences. Considering that BSC relied on integration from both internal and external self-relevant information, we here review previous findings on individual differences in BSC through a three-level-self model, which includes interoceptive, exteroceptive, and mental self-processing. The data show that cross-level factors influenced individual differences in BSC, involving internal bodily signal perceptibility, multisensory processing principles, personal traits shaped by environment, and interaction modes that integrate multiple levels of self-processing. Furthermore, in interoceptive processing, regions like the anterior cingulate cortex and insula show correlations with different perceptions of internal sensations. For exteroception, the parietal lobe integrates sensory inputs, coordinating various BSC responses. Mental self-processing modulates differences in BSC through areas like the medial prefrontal cortex. For interactions between multiple levels of self-processing, regions like the intraparietal sulcus involve individual differences in BSC. We propose that diverse experiences of BSC can be attributed to different levels of self-processing, which moderates one's perception of their body. Overall, considering individual differences in BSC is worth amalgamating diverse methodologies for the diagnosis and treatment of some diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to analyze the role of each factor of the olfactory function as a predictor of cognitive impairment in relation to gender and age. Our results indicated that in men significant correlations were found in odor threshold versus language index score, as well as in odor identification versus language and executive index score. Instead, in women, odor discrimination and identification were related to visuospatial index score. Background: Different previous studies indicated olfactory function as a predictor of several types of cognitive impairment, in particular related to neurodegenerative disease. However, scanty data are available on the role of odor threshold (OT), odor discrimination (OD), and odor identification (OI) as a predictor of cognitive impairment. The aim of this study was to evaluate potential correlations between each factor of the olfactory function versus each specific cognitive domain of the Montreal Cognitive Assessment (MoCA) test on healthy subjects in relation to gender and age. Methods: Sniffin' Sticks and MoCA tests were used to determine olfactory function and cognitive abilities, respectively. Results: In men, significant correlations were found in OT versus language index score and OI versus language and executive index score, while in women, OD and OI were correlated to visuospatial index score. Conclusions: Our data suggested that olfactory function (OT, OD, and OI) may be considered a predictor for cognitive impairment in relation to gender and age. [ABSTRACT FROM AUTHOR]

Purpose: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps compare age-related changes in both cortical and sub-cortical regions with those in healthy individuals. Methods: We conducted retrospective analyses of brain volume using T1-weighted Magnetic Resonance Imaging (MRI) scans of a large cohort of PPMS patients and healthy subjects. The volume of brain parenchyma (BP), cortex, white matter (WM), deep gray matter, thalamus, and cerebellum were measured using the robust SynthSeg segmentation tool. Age- and gender-related regression curves were constructed based on data from healthy subjects, with the 95% prediction interval adopted as the normality threshold for each brain region. Results: We analyzed 495 MRI scans from 169 PPMS patients, aged 20–79 years, alongside 563 exams from healthy subjects aged 20–86. Compared to healthy subjects, a higher proportion of PPMS patients showed lower than expected brain volumes in all regions except the cerebellum. The most affected areas were BP, WM, and thalamus. Lower brain volumes correlated with longer disease duration for BP and WM, and higher disability for BP, WM, cortex, and thalamus. Conclusions: Constructing age- and gender-related brain volume maps enabled identifying PPMS patients at a higher risk of brain volume loss. Monitoring these high-risk patients may lead to better treatment decisions and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Respiratory muscle training (RMT) was recognized as an effective means to improve respiratory muscle (RM) strength and enhance exercise performance. The purpose of this study was to examine the effect of low-intensity RMT on RM strength, pulmonary function, and performance. Fourteen healthy active adults were assigned randomly to either a training or placebo group. The training group completed six weeks of RMT, which consisted of a first week, 1 set of 15 min/d, 5 d/wk at 10–25% of maximal inspiratory pressure (PImax), and the remaining 5 weeks, 2 sets of 15 min/d, 5 d/wk, at 30% PImax. The placebo group followed the same protocol but with almost no additional ventilatory resistance. Measurement of RM strength and endurance, spirometry, and endurance exercise performance were obtained before and after the RMT program. In the training group, PImax (+14%) and maximal expiratory pressure (PEmax, +27%), forced vital capacity (FVC, +3.6%), maximal oxygen uptake (VO2max, +11%), and time to exhaustion (Tlim90%, +25%) increased significantly from baseline values (P < 0.05). No significant changes were observed in the placebo group. Also, no significant interaction in maximum voluntary ventilation (MVV12), minute ventilation (VE), and respiratory rate (RR) were detected. These data suggest that low-intensity RMT is an effective tool to improve RM strength, pulmonary elastic properties and endurance exercise performance. [ABSTRACT FROM AUTHOR]

Several studies have investigated the mechanical behavior of the thoracolumbar spine. However, finding an accurate reference for the normal functional local alignment and segmental motion (SM) at the thoracolumbar junction (TLJ) is challenging. Therefore, this study aimed to assess age- and sex-related changes and differences in local alignment and SM at the TLJ. The study recruited healthy subjects aged 20 to 79 without complaints of back pain. Healthy subjects (60 males and 60 females) with appropriate imaging results were enrolled in the study. The subjects were divided into age groups (20–29, 30–39, 40–49, 50–59, 60–69, and 70–79 years); each group included 10 subjects of each sex. The SM at the TLJ was small but noticeable, and the motion gradually increased toward the lower level of the TLJ, closer to the lumbar region. No significant differences were observed between male and female subjects in any SM measurements at the TLJ. The SM at the TLJ gradually decreased with age, while local kyphosis of TLJ progressed. The results also showed that the thoracolumbar slope value did not change with age and remained at a mean of −12.8 ± 7.2° (P = 0.893). This study's results provide valuable guidance for appropriate surgical planning and rehabilitation of patients with spinal diseases or trauma. Furthermore, the results can be the basis for categorizing accurate criteria to evaluate the degree of disability after treatment. [ABSTRACT FROM AUTHOR]

Objective: Mucosal decongestion with nasal sprays is a common treatment for nasal airway obstruction. However, the impact of mucosal decongestion on nasal aerodynamics and the physiological mechanism of nasal airflow sensation are incompletely understood. The objective of this study is to compare nasal airflow patterns in nasal airway obstruction (NAO) patients with and without mucosal decongestion and nondecongested healthy subjects. Study Design: Cross‐sectional study of a convenience sample. Setting: Academic tertiary medical center. Methods: Forty‐five subjects were studied (15 nondecongested healthy subjects, 15 nondecongested NAO patients, and 15 decongested NAO patients). Three‐dimensional models of the nasal anatomy were created from computed tomography scans. Steady‐state simulations of airflow and heat transfer were conducted at 15 L/min inhalation rate using computational fluid dynamics. Results: In the narrow side of the nose, unilateral nasal resistance was similar in decongested NAO patients and nondecongested healthy subjects, but substantially higher in nondecongested NAO patients. The vertical airflow distribution within the nasal cavity (inferior vs middle vs superior) was also similar in decongested NAO patients and nondecongested healthy subjects, but nondecongested NAO patients had substantially less middle airflow. Mucosal cooling, quantified by the surface area where heat flux exceeds 50 W/m2, was significantly higher in decongested NAO patients than in nondecongested NAO patients. Conclusion: This pilot study suggests that mucosal decongestion improves objective measures of nasal airflow, which is consistent with improved subjective sensation of nasal patency after decongestion. [ABSTRACT FROM AUTHOR]

The study explored the effects of transcutaneous electrical spinal cord stimulation (tES) on postural control. Subjects were divided into field-dependent (FD) and field-independent (FI) groups according to their cognitive style. FD subjects use an exteroceptive afferent stream for spatial orientation, while FI subjects use an interoceptive stream. In darkness, vertical posture is maintained by head-trunk stabilization in FD subjects and by independent movements of body segments in FI subjects. Previously, we showed that tES at the L1-L2 vertebral level decreased postural stability in FD subjects. Now, stimulation was applied at the T11-T12 vertebral level (midline, above the left or right dorsal roots). Quiet standing was assessed using stabilometry in 18 FD and FI participants. Participants stood on a force platform in soundproof chamber with eyes closed during tES. Midline and left tES significantly improved postural stability by up to 28% in FD participants, while posture did not change significantly in FI participants. Pronounced differences between the effects of T11-T12 and L1-L2 stimulation are associated with selective topographical activation of proximal and distal leg muscles during tES of the lumbar enlargement. This study highlights the importance of considering cognitive style in postural control research.

In this study, the aim is to provide a more detailed understanding of vitamin D metabolism by evaluating the correlation between 1,25-dihydroxyvitamin D (1,25(OH)2D) and 25-hydroxyvitamin D (25(OH)D) according to the variations in measurement methods and clinical conditions.

Background: Effective rehabilitation of upper limb musculoskeletal disorders requires multimodal assessment to guide clinicians' decision-making. Furthermore, a comprehensive assessment must include reliable tests. Nevertheless, the interrelationship among various upper limb tests remains unclear. This study aimed to evaluate the reliability of easily applicable upper extremity assessments, including absolute values and asymmetries of muscle mechanical properties, pressure pain threshold, active range of motion, maximal isometric strength, and manual dexterity. A secondary aim was to explore correlations between different assessment procedures to determine their interrelationship. Methods: Thirty healthy subjects participated in two experimental sessions with 1 week between sessions. Measurements involved using a digital myotonometer, algometer, inclinometer, dynamometer, and the Nine-Hole Peg test. Intraclass correlation coefficients, standard error of the mean, and minimum detectable change were calculated as reliability indicators. Pearson's correlation was used to assess the interrelationship between tests. Results: For the absolute values of the dominant and nondominant sides, reliability was 'good' to 'excellent' for muscle mechanical properties, pressure pain thresholds, active range of motion, maximal isometric strength, and manual dexterity. Similarly, the reliability for asymmetries ranged from 'moderate' to 'excellent' across the same parameters. Faster performance in the second session was consistently found for the Nine-Hole Peg test. No systematic inter-session errors were identified for the values of the asymmetries. No significant correlations were found between tests, indicating test independence. Conclusion: These findings indicate that the sensorimotor battery of tests is reliable, while monitoring asymmetry changes may offer a more conservative approach to effectively tracking recovery of upper extremity injuries. [ABSTRACT FROM AUTHOR]

Case-control studies in major depression have established numerous regional grey and white matter effects in fronto-limbic brain regions. Yet, brain structural studies of dimensional depressive psychopathology within the subclinical spectrum are still limited, in particular for multi-modal imaging approaches. Using voxel-based and surface-based morphometry (cortical thickness) in combination with diffusion tensor imaging (DTI) in a large non-clinical sample (N = 300), we correlated grey and white matter structural variation with subclinical depressive symptoms assessed with Beck's Depression inventory (BDI). We found a significant decrease of axial diffusivity associated with higher BDI scores in the left hippocampal part of the cingulum bundle (p < 0.05, threshold free cluster enhanced [TFCE] p -value) and some grey matter trend results e.g., a non-linear negative correlation of cortical thickness with depressive symptom load in the right pre/postcentral cortex (pFWE = 0.054, family wise error [FWE] peak level corrected) and a trend in grey matter volume decrease in women in the inferior frontal gyrus (pFWE = 0.054). Since all grey matter effects disappear after FWE correction, we assume more stable effects in a larger, less homogenous sample enriched by help-seeking subjects covering a wider range of subclinical psychopathology. Our study adds correlations between single depressive symptoms and brain structure to a growing literature. Since subclinical depression is increasingly recognised to be relevant in our understanding of manifest depression, early detection and identification of potential brain correlates of minor depressive symptoms has the potential to expand and reveal possible biomarkers and early psychological treatment. • Subclinical depressive symptoms cause structural grey (trend effect) and white matter changes in healthy subjects. • Limbic/hippocampal brain regions are affected by singe depressive symptoms. • Brain structural changes might be relevant in risk states of depression. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance feature tracking (CMR-FT) is a novel technique for assessing myocardial deformation and dysfunction. However, a comprehensive assessment of normal values of strain parameters in all 4 cardiac chambers using different vendors is lacking. This study aimed to characterize the normal values for myocardial strain in all 4 cardiac chambers and identify factors that contribute to variations in FT strain through a systematic review and meta-analysis of the CMR-FT published reports. The investigators searched PubMed, Embase, and Scopus for myocardial strains of all 4 chambers measured by CMR-FT in healthy adults. The pooled means of all strain parameters were generated using a random-effects model. Subgroup analyses and meta-regressions were performed to identify the sources of variations. This meta-analysis included 44 studies with a total of 3,359 healthy subjects. The pooled means of left ventricular global longitudinal strain (LV-GLS), LV global radial strain, and LV global circumferential strain (GCS) were −18.4% (95% CI: −19.2% to −17.6%), 43.7% (95% CI: 40.0%-47.4%), and −21.4% (95% CI: −22.3% to −20.6%), respectively. The pooled means of left atrial (LA)-GLS (corresponding to total strain, passive strain, and active strain) were 34.9% (95% CI: 29.6%-40.2%), 21.3% (95% CI: 16.6%-26.1%) and 14.3% (95% CI: 11.8%-16.8%), respectively. The pooled means of right ventricular (RV)-GLS and right atrial global longitudinal total strain were −24.0% (95% CI: −25.8% to −22.1%) and 36.3% (95% CI: 15.5%-57.0%), respectively. Meta-regression identified field strength (P < 0.001; I 2 = 98.6%) and FT vendor (P < 0.001; I 2 = 98.5%) as significant confounders contributing to heterogeneity of LV-GLS. The variations of LA-GLS active were associated with regional distribution (P < 0.001; I 2 = 97.3%) and FT vendor (P < 0.001; I 2 = 97.4%). Differences in FT vendor were attributed to variations of LV-GCS and RV-GLS (P = 0.02; I 2 = 98.8% and P = 0.01; I 2 = 93.8%). This study demonstrated the normal values of CMR-FT strain parameters in all 4 cardiac chambers in healthy subjects. Differences in FT vendor contributed to the heterogeneity of LV-GLS, LV-GCS, LA-GLS active , and RV-GLS, whereas sex, age, and MR vendor had no effect on the normal values of CMR-FT strain measurements. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypoxia is mainly caused by cardiopulmonary disease or high-altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty-two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10-min practice and three 20-min randomized interventions: normoxic room air (21% FIO2) and medical air (21% FIO2) and hypoxic air (equal to 15% FIO2), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p < 0.0001), standard deviation of the RR interval (SDRR; p = 0.03), shortterm HRV (SD1; p < 0.0001), breathing rate (p = 0.01), and SpO2 (p < 0.0001) were all significantly different over the three gas interventions. Pairwise comparisons showed HR increased during hypoxic gas exposure compared to both normoxic interventions, while SDRR, SD1, breathing rate, and SpO2 were lower. Breathing hypoxic gas (15% FiO2, equivalent to 2710 m altitude) may not have a significant impact on driving behavior in healthy subjects. Furthermore, HRV was negatively affected by hypoxic gas exposure while driving suggesting further research to investigate the impact of breathing hypoxic gas on driving performance for patients with autonomic dysfunction. [ABSTRACT FROM AUTHOR]

Background/Aims: The physiological phenotype of individuals can influence and shape reallife phenomena in that it can contribute to the development of specific characteristics that can affect the immune response to specific stimuli. In this study we aimed to understand whether the sphingosine/sphingosine-1-phoshate (S1P) axis can modulate the immunotype of circulating cells. Methods: To pursue this goal, we performed bioinformatic analyses of public datasets. Results: The transcriptomic profile of healthy subjects of GSE192829 dataset identified two clusters with different transcriptional repertoire. Cluster 1 expressed higher levels of enzymes for S1P formation than cluster 0 which was characterized by enzymes that lead to ceramide formation, which represent the opposite metabolic direction. Inference analysis showed that cluster 1 was higher populated by monocytes, CD4+ T and B cells than cluster 0. Of particular interest was the phenotype of the monocytes in cluster 1 which showed an immunosuppressive nature compared to those in cluster 0. The role of S1P signature in healthy PBMCs was confirmed with other dataset analyses, supporting that circulating monocytes positive to the ceramidase, unlike the negative ones, had an immunosuppressive phenotype characterized by hub immunosuppressive markers (i.e. TYROBP, FCER1G, SYK, SIRPA, CSF1R, AIF1, FCGR2A, CLEC7A, LYN, PLCG2, LILRs, HCK, GAB2). This hub genes well discriminated the immunotype of healthy subjects. Conclusion: In conclusion this study highlights that S1P-associated hub markers can be useful to discriminate subjects with pronounced immunosuppression. [ABSTRACT FROM AUTHOR]

This study tried to assess the possibility of using the estimated levels of plasma expression of microRNAs (miR-) for distinguishing healthy subjects with latent pulmonary tuberculosis (LTB) from healthy controls (HC) and patients with active tuberculosis (ATB). Study participants included 30 newly diagnosed ATB patients, 30 of the households of ATB patients who were free of clinical manifestations, had normal chest radiography but had positive results on the whole-blood QuantiFERON tuberculosis (TB) Gold In-Tube (QFT-GIT) test (LTB patients), and 30 HC who were free of clinical symptoms and showed normal chest X-rays and negative QFT-GIT tests. All participants gave blood samples for quantitation of the plasma expression levels of miR- using the reverse transcription-quantitative polymerase chain reaction. Plasma levels of miR-150-5p were significantly downregulated in ATB samples than in other samples. However, miR-155-5p and miR-378-5p were significantly overexpressed in patients' samples compared to HC's samples and in ATB samples compared to LTB samples. On the contrary, plasma miR-4523-5p showed significant upregulation in LTB samples compared to ATB and HC samples, indicating insignificant in-between differences. The receiver operating characteristic curve analysis showed the ability of the estimated levels of the four miR- to differentiate TB patients from HC. Multivariate regression analysis defined expression levels of miR-155-5p and miR-378-5p as the significant biomarkers for distinguishing TB patients and levels of miR-378-5p and miR-4523-5p for identification of LTB patients. Pulmonary TB induces deregulated expression of miR-, according to the infection severity. An estimation of the expression levels of miR-378-5p and miR-4523-5p might be a reliable combination for identifying LTB patients.

Abstract With new advances in next generation sequencing (NGS) technology at reduced costs, research on bacterial genomes in the environment has become affordable. Compared to traditional methods, NGS provides high-throughput sequencing reads and the ability to identify many species in the microbiome that were previously unknown. Numerous bioinformatics tools and algorithms have been developed to conduct such analyses. However, in order to obtain biologically meaningful results, the researcher must select the proper tools and combine them to construct an efficient pipeline. This complex procedure may include tens of tools, each of which require correct parameter settings. Furthermore, an NGS data analysis involves multiple series of command-line tools and requires extensive computational resources, which imposes a high barrier for biologists and clinicians to conduct NGS analysis and even interpret their own data. Therefore, we established a public gut microbiome database, which we call Twnbiome, created using healthy subjects from Taiwan, with the goal of enabling microbiota research for the Taiwanese population. Twnbiome provides users with a baseline gut microbiome panel from a healthy Taiwanese cohort, which can be utilized as a reference for conducting case-control studies for a variety of diseases. It is an interactive, informative, and user-friendly database. Twnbiome additionally offers an analysis pipeline, where users can upload their data and download analyzed results. Twnbiome offers an online database which non-bioinformatics users such as clinicians and doctors can not only utilize to access a control set of data, but also analyze raw data with a few easy clicks. All results are customizable with ready-made plots and easily downloadable tables. Database URL: http://twnbiome.cgm.ntu.edu.tw/ .

Background: Saw palmetto extract (SPE) is one of the most widely used supplements for benign prostatic hyperplasia (BPH) due to its pharmacological effects. ß-sitosterol-enriched saw palmetto oil (VISPO™) contains more than 3% ß-sitosterol and 85% total fatty acids and has been shown to improve symptoms in patients with BPH. Lower urinary tract symptoms (LUTS) require primary preventive measures in countries with accelerated population aging, including Japan. VISPO™ is expected to be effective against the early symptoms of LUTS. However, the effect of VISPO™ on urinary function in healthy individuals has not been elucidated. Objective: This clinical study evaluated the efficacy and tolerability of VISPO™ in the management of urinary complaints among healthy middle-aged and older men who did not require treatment. Methods: We conducted a randomized, double-blind, placebo-controlled trial that included 54 male participants who were assigned to consume VISPO™ or placebo (olive oil) capsules for 12 weeks. Biometric data, uroflowmetry results, and salivary hormone levels were assessed at weeks 1 and 12. Urinary function and quality of life were assessed at weeks 1, 4, 8, and 12 using the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), Core Lower Urinary Tract Symptom Score (CLSS), and WHOQOL-26. Results: Two-way analysis of variance revealed that IPSS and OABSS were significantly lower in the VISPO™ group that in the placebo group. However, there were no significant differences in urine volume, urinary flow rate, or salivary hormone levels. In addition, no participants reported adverse effects (diarrhea, abdominal pain, etc.). Conclusion: The results of the present study, which is the first randomized controlled trial of VISPO™ conducted among healthy participants, demonstrate the effectiveness of VISPO™ in the management of lower urinary tract complaints that do not require treatment. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to determine the effect that different tDCS protocols have on pain processing in healthy people, assessed using quantitative sensory tests (QST) and evoked pain intensity. Methods: We systematically searched in EMBASE, CINAHL, PubMed, PEDro, PsycInfo, and Web of Science. Articles on tDCS on a healthy population and regarding QST, such as pressure pain thresholds (PPT), heat pain thresholds (HPT), cold pain threshold (CPT), or evoked pain intensity were selected. Quality was analyzed using the Cochrane Risk of Bias Tool and PEDro scale. Results: Twenty-six RCTs were included in the qualitative analysis and sixteen in the meta-analysis. There were no significant differences in PPTs between tDCS and sham, but differences were observed when applying tDCS over S1 in PPTs compared to sham. Significant differences in CPTs were observed between tDCS and sham over DLPFC and differences in pain intensity were observed between tDCS and sham over M1. Non-significant effects were found for the effects of tDCS on HPTs. Conclusion: tDCS anodic over S1 stimulation increases PPTs, while a-tDCS over DLPFC affects CPTs. The HPTs with tDCS are worse. Finally, M1 a-tDCS seems to reduce evoked pain intensity in healthy subjects. [ABSTRACT FROM AUTHOR]

Every brain is unique, having its structural and functional organization shaped by both genetic and environmental factors over the course of its development. Brain image studies tend to produce results by averaging across a group of subjects, under the common assumption that it is possible to subdivide the cortex into homogeneous areas while maintaining a correspondence across subjects. We investigate this assumption: can the structural properties of a specific region of an atlas be assumed to be the same across subjects? This question is addressed by looking at the network representation of the brain, with nodes corresponding to brain regions and edges to their structural relationships. Using an unsupervised graph matching strategy, we align the structural connectomes of a set of healthy subjects, considering parcellations of different granularity, to understand the connectivity misalignment between regions. First, we compare the obtained permutations with four different algorithm initializations: Spatial Adjacency, Identity, Barycenter, and Random. Our results suggest that applying an alignment strategy improves the similarity across subjects when the number of parcels is above 100 and when using Spatial Adjacency and Identity initialization (the most plausible priors). Second, we characterize the obtained permutations, revealing that the majority of permutations happens between neighbors parcels. Lastly, we study the spatial distribution of the permutations. By visualizing the results on the cortex, we observe no clear spatial patterns on the permutations and all the regions across the context are mostly permuted with first and second order neighbors. [ABSTRACT FROM AUTHOR]

Blonanserin is a novel oral antischizophrenic drug. Under fasting (n = 50) and fed (n = 60) conditions, this study compared the bioequivalence of the generic blonanserin tablet with the reference blonanserin tablet. In this single‐center, randomized, open‐label, 2‐period, 2‐sequence, crossover study, 110 patients were randomly given a 4‐mg dose of either the test or reference blonanserin tablet with a 14‐day washout period. Blood samples were taken before performing and up to 72 hours following. A validated high‐performance liquid chromatography‐tandem mass spectrometry technique was used to measure the levels of blonanserin in plasma. Safety was evaluated throughout the study. The study found no significant differences in the maximum observed drug concentration in the plasma (Cmax), the area under the plasma concentration‐time curve from time 0 to the last sampling time (AUC0‐t), and the area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) between the 2 blonanserin formulations. The 90% confidence intervals of the geometric mean ratio of the test/reference formulations for Cmax, AUC0‐t, and AUC0‐∞ were within the 80%‐125% limit. Food dramatically raised blonanserin exposure, and also significantly prolonged the lag time of absorption. No serious adverse events occurred. These results indicate that the 2 blonanserin formulations were bioequivalent and well tolerated in healthy Chinese subjects. In clinical treatment, it is necessary to consider the food effect of blonanserin. [ABSTRACT FROM AUTHOR]

With new advances in next generation sequencing (NGS) technology at reduced costs, research on bacterial genomes in the environment has become affordable. Compared to traditional methods, NGS provides high-throughput sequencing reads and the ability to identify many species in the microbiome that were previously unknown. Numerous bioinformatics tools and algorithms have been developed to conduct such analyses. However, in order to obtain biologically meaningful results, the researcher must select the proper tools and combine them to construct an efficient pipeline. This complex procedure may include tens of tools, each of which require correct parameter settings. Furthermore, an NGS data analysis involves multiple series of command-line tools and requires extensive computational resources, which imposes a high barrier for biologists and clinicians to conduct NGS analysis and even interpret their own data. Therefore, we established a public gut microbiome database, which we call Twnbiome, created using healthy subjects from Taiwan, with the goal of enabling microbiota research for the Taiwanese population. Twnbiome provides users with a baseline gut microbiome panel from a healthy Taiwanese cohort, which can be utilized as a reference for conducting case-control studies for a variety of diseases. It is an interactive, informative, and user-friendly database. Twnbiome additionally offers an analysis pipeline, where users can upload their data and download analyzed results. Twnbiome offers an online database which non-bioinformatics users such as clinicians and doctors can not only utilize to access a control set of data, but also analyze raw data with a few easy clicks. All results are customizable with ready-made plots and easily downloadable tables. Database URL: http://twnbiome.cgm.ntu.edu.tw/. [ABSTRACT FROM AUTHOR]

Objective: To establish reference values for the 6-minute walk test (6MWT) and 2-minute walk test (2MWT) distances, to investigate the correlation between these 2 tests, and to establish prediction equations for these distances in healthy populations of Belgium and Vietnam. Design: Cross-sectional study. Subjects and methods: The 6MWT and 2MWT were administered to a convenience sample of 239 Belgian and 303 Vietnamese participants between the ages of 18 and 80 years. Results: The mean (standard deviation; SD) 2MWT distances were 215 (32.8) m for Belgian participants and 156 (25.5) m for Vietnamese participants. The mean (SD) 6MWT distances were 625 (90.7) m for Belgian participants and 449 (70.4) m for Vietnamese participants. The Pearson correlation coefficient between the 2 tests was 0.901 (p

Abstract Hypoxia is mainly caused by cardiopulmonary disease or high‐altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty‐two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10‐min practice and three 20‐min randomized interventions: normoxic room air (21% FIO2) and medical air (21% FIO2) and hypoxic air (equal to 15% FIO2), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p

Objective To explore and analyze the reasons on the failure of subjects screening in Phase Ⅰ clinical trials. Methods The subjects screening data of 10 Phase I clinical trials conducted from February 2019 to December 2020 were summarized, and the reasons of screening failure were classified and analyzed to explore the possible influencing factors. Results The reasons of screening failure included laboratory examinations, other auxiliary examinations except the laboratory, vital signs and physical examination, compliance, etc. The main reasons were unqualified laboratory examinations(36.61%) and other auxiliary examinations(31.35%). Conclusion Scientific judgment of abnormal values in physical and chemical examinations, emphasis on recruitment, careful screening, establishment of a subject database, and strengthening of subject compliance management are effective measures to improve the pass rate of subject screening in Phase I clinical trials.

Bodily self-consciousness (BSC), a subject of interdisciplinary interest, refers to the awareness of one’s bodily states. Previous studies have noted the existence of individual differences in BSC, while neglecting the underlying factors and neural basis of such individual differences. Considering that BSC relied on integration from both internal and external self-relevant information, we here review previous findings on individual differences in BSC through a three-level-self model, which includes interoceptive, exteroceptive, and mental self-processing. The data show that cross-level factors influenced individual differences in BSC, involving internal bodily signal perceptibility, multisensory processing principles, personal traits shaped by environment, and interaction modes that integrate multiple levels of self-processing. Furthermore, in interoceptive processing, regions like the anterior cingulate cortex and insula show correlations with different perceptions of internal sensations. For exteroception, the parietal lobe integrates sensory inputs, coordinating various BSC responses. Mental self-processing modulates differences in BSC through areas like the medial prefrontal cortex. For interactions between multiple levels of self-processing, regions like the intraparietal sulcus involve individual differences in BSC. We propose that diverse experiences of BSC can be attributed to different levels of self-processing, which moderates one’s perception of their body. Overall, considering individual differences in BSC is worth amalgamating diverse methodologies for the diagnosis and treatment of some diseases.

Background: Different previous studies indicated olfactory function as a predictor of several types of cognitive impairment, in particular related to neurodegenerative disease. However, scanty data are available on the role of odor threshold (OT), odor discrimination (OD), and odor identification (OI) as a predictor of cognitive impairment. The aim of this study was to evaluate potential correlations between each factor of the olfactory function versus each specific cognitive domain of the Montreal Cognitive Assessment (MoCA) test on healthy subjects in relation to gender and age. Methods: Sniffin’ Sticks and MoCA tests were used to determine olfactory function and cognitive abilities, respectively. Results: In men, significant correlations were found in OT versus language index score and OI versus language and executive index score, while in women, OD and OI were correlated to visuospatial index score. Conclusions: Our data suggested that olfactory function (OT, OD, and OI) may be considered a predictor for cognitive impairment in relation to gender and age.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T).Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0–t and AUC0–∞) were used to evaluate relative bioavailability.Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0–∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0–t and AUC0–∞ of T over R were 98.7% (90% CI: 92.7%–105.2%), 102.6% (90% CI: 100.0%–105.3%) and 102.8% (90% CI: 100.1%–105.5%).Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT05336071

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects.Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis.Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120 mg. The t1/2 of HSK16149 is 3.7-6.4 h. In MAD, after a single and multiple administration of 15-80 mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05–1.44 and 1.07–1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration.Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80 mg twice daily (BID) was suggested as the highest target dose for further clinical development.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317

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Objective: Heart rate variability (HRV) and baroreflex sensitivity (BRS) are influenced by various internal and external factors, making it necessary to establish universal reference values. We aimed to identify independent factors affecting short-term HRV parameters and BRS, as well as determine appropriate reference ranges, which are lacking in Asian populations. Materials and Methods: A total of 117 healthy Thai participants (aged 20-72 years; final n=117) were recruited based on strict criteria, including normal medical history, physical examination (ascertained by a physician), and normal blood profile. Spontaneous 5-minute HRV parameters (time and frequency domains) and spontaneous cross-correlation BRS were measured. Results: Age and resting heart rate (HR) are independently and inversely correlated with BRS and all HRV parameters, except LFnu (normalized low-frequency component) and LF/HF ratio (ratio of low-to high-frequency component). Sex differences were observed only in LF, which was higher in men. However, multiple regression analysis showed that sex did not significantly contribute as an independent variable to either HRV or BRS. Remarkably, BRS exhibited moderate to strong correlations with all HRV values, indicating its prominent role in influencing HRV and surpassing the impact of age. Conclusion: Age and resting HR were identified as independent factors influencing 5-minute HRV and BRS. Our findings suggest that decreased baroreflex function associated with aging may contribute to reduced HRV among the elderly. Furthermore, we established reference ranges for each 5-minute HRV parameter and BRS, categorized by age group (20-39, 40-59, and =60 years old). These reference values offer valuable clinical insights, particularly for Asian populations where such normative ranges were previously unavailable. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical stimulation of the spinal cord is used to restore locomotion and body weight support in patients with severe motor disorders. We studied the effects of this non-invasive stimulation on postural control in healthy subjects. Stimulation at the L1–L2 vertebrae was performed to activate the extensor muscles of the lower limbs. Because postural regulation depends on the cognitive style, the effects of the stimulation were analyzed separately in field-dependent (FD) and field-independent (FI) participants. During the study, FD and FI participants (N = 16, 25 ± 5 years, all right dominant leg) stood on a force platform in a soundproof chamber with their eyes closed. Stimulation was applied in the midline between the L1 and L2 vertebrae or over the left or right dorsal roots of the spinal cord; under the control condition, there was no stimulation. Stimulation destabilized posture in healthy subjects, whereas patients with movement disorders usually showed an improvement in postural control. In the FD participants, left dorsal root and midline stimulation increased several postural parameters by up to 30%. Dorsal root stimulation on the side of the supporting leg reduced postural control, while stimulation on the side of the dominant leg did not. No significant changes were observed in the FI participants. [ABSTRACT FROM AUTHOR]

This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC0–24 h of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log10 cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

Aim: Healthy asymptomatic individuals can be screened for various diseases using medical check-up programs. On the other hand, the prevalence of diabetes mellitus (DM) and prediabetes (PD), which are common metabolic disorders, are increasing worldwide. In this context, this study aims to determine the prevalence of DM and PD among the asymptomatic participants of a medical check-up program. Material and Methods: The population of this cross-sectional study consisted of 440 healthy, asymptomatic volunteers aged 40 years or older who attended a medical check-up program conducted between January and August 2021. Patients with confirmed morbidities or regular medication use and pregnant women were excluded from the study. All study participants underwent physical examination, laboratory test, and sonographic assessment. The study participants were grouped according to their glycemic states, i.e., DM, PD, and normoglycemia (NG). The study's primary outcomes were the prevalence of DM and PD. Results: The prevalence of DM and PD among the study participants was 12.5% (n=55) and 58.9% (n=259), respectively. The number of males was significantly higher in Group DM than in Groups PD and NG (p=0.014). Additionally, Group DM was significantly older than Groups PD and NG (p<0.001). Furthermore, there were significantly more participants in Group DM with high urea, creatinine, uric acid, triglyceride, and very low-density lipoprotein (VLDL) levels (p>0.05 for all cases). Conclusion: The prevalence of DM and PD in presumed healthy asymptomatic participants was 12.5% and 58.9%, respectively, indicating unusually high prevalence in this population. In conclusion, the results of this study demonstrate that it is imperative that presumed healthy individuals are screened within the scope of medical check-up programs and followed closely afterward. [ABSTRACT FROM AUTHOR]

Background: The incidence of noncommunicable diseases (NCDs) has been rapidly ramped up worldwide. Hence, there is an urgent need to non-invasively detect NCDs possibly by exploiting saliva as a ‘liquid biopsy’ to identify biomarkers of the health status. Since, the absence of standardized procedures of collection/analysis and the lack of normal ranges makes the use of saliva still tricky, our purpose was to outline a salivary proteomic profile which features healthy individuals.Methods: We collected saliva samples from 19 young blood donors as reference population and the proteomic profile was investigated through mass-spectrometry.Results: We identified 1,004 proteins of whose 243 proteins were shared by all subjects. By applying a data clustering approach, we found a set of six most representative proteins across all subjects including Coronin-1A, F-actin-capping protein subunit alpha, Immunoglobulin J chain, Prosaposin, 78 kDa glucose-regulated protein and Heat shock 70 kDa protein 1A and 1B.Conclusion: All of these proteins are involved in immune system activation, cellular stress responses, proliferation, and invasion thus suggesting their use as biomarkers in patients with NCDs.

To assess safety in vaccine development, stricter grading scales, such as the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" issued by the U.S. Food and Drug Administration (FDA grading scale), are required. However, concern exists that their strictness may lead to an overestimation of some adverse events (AEs). We analyzed the details of AEs in a phase I clinical trial of a preventive vaccine for infectious diseases. In this trial, we observed the high occurrence of Grade 1 or greater AEs in hemoglobin changes from baseline value, and hypernatremia, and hypokalemia by FDA grading scale. The range considered as non-AE according to the FDA grading scale shifted or became narrower when compared to reference intervals, especially for a Japanese cohort. For sodium grading, the criterion for hypernatremia was around 2 to mEq/L lower than the upper limit of most standards in several countries. Also, the criterion for hypokalemia was around 0.2 mEq/L higher than the lower limit of most standards. Regarding a decrease in hemoglobin from baseline, the criterion of "any decrease" used for a Grade 1 AE was too strict and we suggest this be omitted. Upper and lower limits of AE criteria for sodium and potassium should be equal to, or 10–20% above, the reference interval consistent with other toxicities determined by laboratory tests. Consideration should be given to the issues surrounding the criteria that determine AEs before conducting clinical trials. [ABSTRACT FROM AUTHOR]

Aims: To verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference. Methods: This was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022. Results: After administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR10%max?11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated. Conclusions: The PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile. [ABSTRACT FROM AUTHOR]

Etrasimod (APD334) is an investigational, once‐daily, oral, selective sphingosine 1‐phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for treatment of various immune‐mediated inflammatory disorders. The disposition and mass balance of a single 2‐mg [14C]etrasimod dose were evaluated in 8 healthy males. An in vitro study was also conducted to identify etrasimod's oxidative metabolizing enzymes. Peak concentrations of etrasimod and total radioactivity in plasma and whole blood were typically reached 4–7 hours postdose. Etrasimod constituted 49.3% of total radioactivity plasma exposure, with multiple minor/trace metabolites making up the remainder. Etrasimod was slowly cleared mainly via biotransformation, predominantly by oxidative metabolism, with unchanged etrasimod recovered in feces accounting for only 11.2% of the dose and none in urine. The mean apparent terminal half‐lives of etrasimod and total radioactivity in plasma were 37.8 and 89.0 hours, respectively. Mean cumulative recovery of radioactivity in excreta over 336 hours was 86.9% of the dose, mostly in feces. The prevalent metabolites eliminated in feces were M3 (hydroxy‐etrasimod) and M36 (oxy‐etrasimod sulfate), accounting for 22.1% and 18.9% of the dose, respectively. From in vitro reaction phenotyping, the predominant enzymes involved in the oxidation of etrasimod were CYP2C8, CYP2C9, and CYP3A4, with minor contributions from CYP2C19 and CYP2J2. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of PPMX‐T003, a novel human monoclonal antibody for transferrin receptor 1 (TFR1), in healthy individuals. Forty participants were enrolled and randomized to PPMX‐T003 dose groups (n = 6/group) and the placebo group (n = 10). The safety and pharmacokinetics profiles were assessed according to the sequential, ascending single‐dose intravenous infusions of PPMX‐T003 from 0.008 mg/kg to 0.25 mg/kg. Adverse events (AEs) after PPMX‐T003 administration occurred in 16 of 30 participants. Any severe AE and AE incidence were not reported, but they tended to increase depending on the dose. Laboratory tests, vital signs, and standard 12‐lead electrocardiogram showed no clinically relevant changes. Five participants experienced an infusion‐related reaction but recovered on days 5–10. Regarding pharmacokinetics, PPMX‐T003 has a nonlinear elimination pattern. PPMX‐T003 in the 0.25 mg/kg group showed apparent (>50%) decreased serum levels of reticulocytes from day 3 and sustained moderate (<10%) fall of hematocrit and hemoglobin counts from day 7. In conclusion, the antibody‐mediated blockade of TFR1 elicited the expected fall in blood cell levels and showed an acceptable safety profile, supporting the continuing development of PPMX‐T003 as a new candidate for polycythemia vera treatment. [ABSTRACT FROM AUTHOR]

HSK16149 is a novel, potent gamma‐aminobutyric acid (GABA) analog for the treatment of neuropathic pain. The purpose of this study was to assess the effect of a high‐fat and high‐calorie meal on the pharmacokinetics of HSK16149 in healthy Chinese subjects. An open‐label, two‐period crossover design was applied in this study. Twenty‐six subjects were enrolled and were randomly divided into two groups: a fasted‐fed group and a fed‐fasted group, with 13 subjects in each group. Subjects took a single oral dose of 45 mg of HSK16149 under fasted or fed conditions on Day 1 and Day 4. A series of blood samples were collected for PK analysis. Safety was evaluated throughout the study by physical examinations, clinical laboratory tests, 12‐lead ECGs, vital signs, and adverse events (AEs). The parameters AUC0‐∞, AUC0‐t, and Cmax of HSK16149 were compared to assess the bioequivalence of HSK16149 under fasted and fed conditions. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of AUC0‐t and AUC0‐∞ under the fed condition compared with the fasted condition were 95.84% (91.94–99.90%) and 95.79% (91.89–99.84%), respectively, which were all within the bioequivalent interval (80.00–125.00%). The GMR (90% CI) of Cmax under the fed condition compared with the fasted condition was 66.04% (59.45–73.36%), which was not within the bioequivalent range (80.00–125.00%). All adverse events were transient and resolved. This study demonstrated that HSK16149 can be administered with or without food. [ABSTRACT FROM AUTHOR]