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Acute pancreatitis (AP) ranges in severity from mild to severe with high mortality. Severe AP, similar to other critical illnesses, is associated with changes in cortisol level. Early increase of high-sensitivity C-reactive protein (hs-CRP) as an inflammatory marker could be an indicator of AP progression. We aimed to assess the level of cortisol and hs-CRP on initial diagnosis of AP and identify their prognostic value.This case-control study included patients with AP and a control group of healthy subjects. Laboratory tests such as liver profile, kidney functions, blood picture, lactate dehydrogenase, blood glucose, and lipogram were evaluated, the severity of AP was determined, the duration of hospitalization, complications, and outcomes were identified, and the serum levels of cortisol and hs-CRP were assessed.There were 90 patients with AP and 60 controls with a higher percent of females in both groups. Serum cortisol and hs-CRP were significantly higher in AP relative to controls and were higher in severe AP relative to mild AP. Significant positive correlation was present between high cortisol and severity of AP (r = 0.520 and p0.001) and negatively with pancreatic necrosis (r= - 0.303 and p = 0.007) and morality (r= - 0.432, p = 0.005) while hs-CRP did not show significant correlation.Different levels of serum cortisol in early AP should be considered on initial diagnosis. High cortisol level was a good prognostic indicator for AP with low mortality. This could have further implications on the appropriate initiation of steroid therapy to prevent necrotizing pancreatitis and lower the mortality. Meanwhile, hs-CRP has a low prognostic value in early AP.

Patients with hallux rigidus (HR) tend to develop a characteristic alteration in walking to lessening pain and compensate for the limited range of motion at the first metatarsophalangeal (MTP1) joint that might be affected balance and gait. The goal of this study was to perform an integrated biomechanical description of gait and balance of symptomatic patients with either grade as III or IV HR in comparison with healthy subjects. Eleven patients (7 men) with HR (60 ± 7 years, 1.60 ± 0.07 m, and 70 ± 13 kg) and 16 (7 men) healthy subjects (70 ± 8 years, 1.66 ± 0.10 m, and 74 ± 14 kg) were included. Subjects performed 2 tasks: walking (5 trials of straight walking for at least 6 meters) and bipedal quiet standing for 30 seconds. For these 2 tasks the following variables were measured: range of motion of the MTP1 joint, plantar pressure distribution during the stance phase of walking, and the postural sway during quiet standing. Plantar pressure was measured in up 15 walking trials with a mat pressure sensor. The MTP1 joint range of motion for flexion/extension during walking was significantly smaller for the patients with HR than for the control group (HR: 14 ± 8°, control: 44 ± 5°; t(17) = -9.7, p.001). The forefoot plantar pressure distribution among different regions of the foot in patients with HR was not statistically different than the control group, but there was a tendency of higher pressures in the lateral metatarsal heads (p = .06). As description of the postural sway during quiet standing, the center of pressure area was not different between HR and the control group (p.05). Decreased MTP1 joint range of motion for flexion/extension during walking in symptomatic high-grade HR patients can be associated with higher pressure in the lateral metatarsal heads while the impact on postural sway is not affected.

To mitigate artifactual choriocapillaris flow deficits in optical coherence tomography angiography, which are a side effect of inverse structural optical coherence tomography compensation.In a modified algorithm, we set pixels in the original structural optical coherence tomography that were greater than one SD above the mean intensity (hyperreflective regions) to the mean pixel intensity of the image to remove hyporeflective regions in the inverse slab. We compared this algorithm to the original using flow deficit density and multiscale structural similarity index obtained from three distinct thresholding methods (local Phansalkar, global MinError (I), and global Li).We included 16 eyes of 16 healthy subjects (31.1 ± 6.9 years, 10 females). Using the modified optical coherence tomography correction, flow deficit density was lower compared with the original algorithm using Phansalkar (P0.001) but higher using Li thresholding (P = 0.049). Multiscale structural similarity index was increased after applying the modified algorithm with all three thresholding methods (P0.001), indicating a closer relationship to the original optical coherence tomography angiography scan.We demonstrate a new method that significantly reduced the introduction of artifactual flow deficits in the choriocapillaris during postprocessing. Given the improved multiscale structural similarity index, we believe our algorithm more accurately represents the choriocapillaris.

Background Autoantibodies (AAbs) against immunoglobulin E (IgE) antibodies (Abs) and their high-affinity receptor alpha subunits (FceRIα) are key factors in the elicitation of type IIb autoimmune chronic spontaneous urticaria (type IIb aiCSU). In this study, we aimed to develop a new method to detect functional anti-FceRIα and anti-IgE AAbs, which can crosslink the plural FceRІα molecules and IgE Abs on the surface of mast cells and basophils, in sera from aiCSU patients using the amplified luminescence proximity homogeneous assay (Alpha). Methods Sera were obtained from 14 aiCSU patients, as diagnosed by recurrent chronic spontaneous urticaria episodes and positive results for the autologous serum skin test and/or histamine release test (HRT). The AAbs to FceRIα and IgE Abs were determined in sera from aiCSU patients using enzyme-linked immunosorbent assay (ELISA) and Alpha by cross-linking (AlphaCL) of IgE Abs and/or FceRІα. Results Serum anti-FceRIα and anti-IgE AAb levels were not significantly different between aiCSU patients and healthy subjects in ELISA. Anti-FceRIα AAbs were detected in 10 of 14 aiCSU patients who displayed positive (5/5) and negative (5/9) results in the HRT for anti-FceRIα AAbs by AlphaCL, whereas no signals were observed in healthy subjects. Additionally, anti-IgE AAbs were detected in two of four aiCSU patients who displayed positive results in the HRT for anti-IgE AAbs. Conclusions A new assay method using AlphaCL can detect anti-FceRIα and anti-IgE AAbs with FceRIα- and IgE-crosslinking abilities in sera from aiCSU patients. This simple and practical assay method may be available as a diagnostic tool for urticaria patients.

BACKGROUND Chitotriosidase and YKL-40, also called chitinase 3-like protein 1, are homologs of family 18 glycosyl hydrolases, secreted by human macrophages and granulocytes under inflammatory conditions. Although increased levels of chitotriosidase and YKL-40 are linked with several inflammatory diseases, the physiological utility of these two enzymes is still not fully characterized. This study aims to analyze the serum YKL-40 and chitotriosidase levels of acute pancreatitis patients to assess whether their activity correlates with acute pancreatitisand its severity. METHODS Chitotriosidase and YKL-40 levels, along with routine laboratory parameters, were determined from the serum samples of 41 acute pancreatitis patients, at both onset and remission (male/female: 22/19), and 39 healthy subjects (male/female: 19/20). The Modified Glasgow Prognostic Score was used to predict the severity of the disease, and a correlation analysis was performed between study variables. RESULTS A statistically significant increase in both chitotriosidase and YKL-40 levels was observed in acute pancreatitis patients compared to healthy controls (P < 0.001). Higher levels of YKL-40, chitotriosidase and C-reactive protein were found in patients with acute pancreatitis at onset than in remission. The correlation analysis showed a statistically significant association between YKL-40 and chitotriosidase (p = 0.039, r = 0.323). The cut-off point for YKL-40, for detecting acute pancreatitis, was 60.3 with a sensitivity and specificity of 84.9% and 84.6% (AUC: 0.890). The optimum cut-off point for chitotriosidase, for detecting acute pancreatitis, was 33.5 with a sensitivity and specificity of 79.5% and 78.4% (AUC: 0.899). CONCLUSION Elevated YKL-40 and chitotriosidase levels in acute pancreatitis patients demonstrate the importance of possible macrophage involvement in the pancreatic microenvironment during acute pancreatitis progression.

Sungyeun Bae,1 Jihoon Kwon,2 Si-Beum Lee,3 In-Jin Jang,1 Kyung-Sang Yu,1 SeungHwan Lee1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Statistics Team, APACE, Seoul, Republic of Korea; 3Addpharma Pharmaceutical Corp, Seongnam-si, Gyeonggi, Republic of KoreaCorrespondence: SeungHwan LeeDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of KoreaTel +82-2-2072-1920Fax +82-2-742-9252Email leejh413@snu.ac.krPurpose: Proton pump inhibitors (PPIs) are used for the treatment of acid-related disorders. Demands for enhanced stability and faster onset led to the development of AD-206, a fixed-dose combination of a PPI (esomeprazole) with an antacid salt (calcium carbonate). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of AD-206 (Addpharma) with conventional esomeprazole (Nexium®, AstraZeneca).Materials and Methods: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with 2 different doses of esomeprazole at 20 and 40 mg with a fixed calcium carbonate dose of 600 mg in AD-206. Forty-four subjects were included in each dose group and randomly received either AD-206 or the conventional esomeprazole for 7 consecutive days in each period. After a single- and multiple-dose, blood samples for the PK analysis were analyzed, and 24-hour intragastric pH monitoring was conducted.Results: The systemic exposure of esomeprazole after a multiple-dose of AD-206 was similar to that of the conventional esomeprazole in both doses, but the time to reach the peak concentration was faster in AD-206. The percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the dose was not significantly different between the AD-206 and the conventional esomeprazole after a single- and multiple-dose for both doses, and the time to reach pH 4 was faster for AD-206.Conclusion: AD-206 showed a similar systemic exposure and suppression of gastric acid secretion after a multiple-dose compared to the conventional esomeprazole.Keywords: proton pump inhibitors, randomized controlled study, crossover design, healthy subjects, intragastric pH monitoring

Background : : Transcutaneous electrical acupoint stimulation (TEAS) improves autonomic balance and reduces oxidative stress in subjects with chronic diseases, that decreases the risk of low-grade chronic inflammatory diseases, including cardiovascular diseases. However, these beneficial effects have never been demonstrated in healthy subjects. Objectives: To evaluate the acute effects of TEAS on autonomic balance and oxidative stress of healthy subjects. Methods : : A randomized clinical trial was conducted with male healthy subjects (18-30 years old), randomly allocated to control (no intervention; n = 14), placebo (placebo intervention; n = 14) and TEAS group (at PC5 and PC6 acupoints; n = 13). The protocol consisted of accommodation (20 min), intervention (40 min), and recovery (30 min) periods. The acute effects of TEAS on hemodynamics were studied through measurements of heart rate, blood pressure and double product; on the autonomic nervous system by assessing heart rate variability; and on oxidative stress by quantifying reactive oxygen species in saliva samples, collected at the end of each period. Results : : TEAS increased heart rate and double-product compared to control and placebo groups (p < 0.01). Moreover, TEAS increased sympathetic and reduced parasympathetic tonus, increasing the sympathovagal balance compared to the control and placebo groups. However, TEAS exerted no effect on oxidative stress in saliva samples. Conclusion : : In healthy subjects, TEAS at PC5 and PC6 acupoints acutely improved autonomic balance, increasing sympathetic and reducing parasympathetic tonus, reflecting little improvement on hemodynamic responses. Whether it could be used as a cardioprotective strategy remains uncertain since it exerted no effect on oxidative stress.

Objectives Trace elements (TrEL) are nutritionally essential components in maintaining health and preventing diseases. There is a lack of reliable biological variation (BV) data for TrELs, required for the diagnosis and monitoring of TrEL disturbances. In this study, we aimed to provide updated within- and between-subject BV estimates for zinc (Zn), copper (Cu) and selenium (Se). Methods Weekly serum samples were drawn from 68 healthy subjects (36 females and 32 males) for 10 weeks and stored at −80 °C prior to analysis. Serum Zn, Cu and Se levels were measured using inductively-coupled plasma mass spectrometry (ICP-MS). Outlier and variance homogeneity analyses were performed followed by CV-ANOVA (Røraas method) to determine BV and analytical variation estimates with 95% CI and the associated reference change values (RCV) for all subjects, males and females. Results Significant differences in mean concentrations between males and females were observed, with absolute and relative (%) differences for Zn at 0.5 μmol/L (3.5%), Cu 2.0 μmol/L (14.1%) and Se 0.06 μmol/L (6.0%). The within-subject BV (CVI [95% CI]) estimates were 8.8% (8.2–9.3), 7.8% (7.3–8.3) and 7.7% (7.2–8.2) for Zn, Cu and Se, respectively. Within-subject biological variation (CVI) estimates derived for male and female subgroups were similar for all three TrELs. Marked individuality was observed for Cu and Se. Conclusions The data of this study provides updated BV estimates for serum Zn, Cu and Se derived from a stringent protocol and state of the art methodologies. Furthermore, Cu and Se display marked individuality, highlighting that population based reference limits should not be used in the monitoring of patients.

Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity. We conclude that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype in CRPS. PERSPECTIVE: This article describes an upregulation of MMPs in CRPS and pain controls and shows different expression of MMP-2 and -9 depending on clinical phenotype in CRPS. These results provide evidence that MMP-2 and -9 play a key role in CRPS pathophysiology.

Many recent studies have showed that morphological changes are one of the key signs of meibomian gland disease (MGD). These changes can be seen even before symptom onset, potentially underestimating the prevalence of MGD; however, until now, there is no conclusive information about the impact of meibomian gland (MG) morphology in tear film physiology and disease. This study aimed to investigate the prevalence of anatomical and morphological MG alterations between patients with evaporative dry eye disease (DED) and healthy controls. Retrospective chart review of seventy-five patients with evaporative DED and healthy individuals who had dry eye assessments included Ocular Surface Disease Index questionnaire, meibum quality, meibum expressibility, lid margin abnormality, ocular staining, non-invasive tear film break-up time, and meibography. We did not find significant differences in MG alterations in the upper lid between healthy and DED subjects. Patients with evaporative DED presented MG alterations in the lower lid more frequently than healthy subjects (54.8 vs. 30.3%; p = 0.03). The presence of shortened glands was the only MG alteration that was more prevalent in the lower lid in dry-eye patients than in healthy subjects (p

Objective This proof-of-principle-study evaluated the extent to which spontaneous activity (SA) of the muscle can be detected via non-invasive magnetomyography (MMG) with optically pumped magnetometers (OPM). Methods Five patients, who together exhibited all forms of SA (fibrillations, positive sharp waves, fasciculations, myotonic discharges, complex-repetitive discharges) with conventional needle electromyography (EMG), were studied by OPM-MMG and simultaneous surface EMG (sEMG) while at rest, during light muscle activation, and when a muscle stretch reflex was elicited. Three healthy subjects were measured as controls. SA was considered apparent in the OPM-MMG if a signal could be visually detected that corresponded in shape and frequency to the SA in the respective needle EMG. Results SA in the context of fasciculations could be detected in 2 of 5 patients by simultaneous OPM-MMG/sEMG. Other forms of SA could not be detected at rest, during light muscle activation, or after provocation of a muscle stretch reflex. Conclusions This proof-of-principle study shows that fasciculations could be detected non-invasively via a new method (OPM). Significance We show that other forms of SA are not detectable with current OPM and propose necessary technical solutions to overcome this circumstance. Our results motivate to pursue OPM-MMG as a new clinical neurophysiological diagnostic.

Objective The aim was to find a sensitive method to highlight the remodeling of the brain’s bioelectric activity in post-stroke repair. Methods Fifteen mild upper limb paretic stroke patients and age-matched healthy controls were included. Repeated trials of finger tapping around the 10th and 100th days after stroke onset were recorded with a 128-channel EEG. Power spectra and Inter Trial Coherence (ITC) calculations were synchronized to tappings. ITC was correlated with motor performance. Results ITC, in low frequency bands, designates the motor related bioelectric activity in channel space in both healthy subjects and patients. Ten days after stroke onset, delta-theta ITC was severely reduced compared to baseline, while three months later ITC reorganized partially over the ipsilesional central-parietal areas reflecting the improvement of motor networks. Decreased ITC in the central-parietal area remained significant compared to controls. Delta band ITC over the dorsolateral-prefrontal cortex correlates with the performance on Nine Hole Peg Test. At post-recovery, non-paretic hand tappings show significantly decreased delta-theta ITC over the supplementary motor area, which reflects network remodeling. Conclusions Inter Trial Coherence is a useful measure of brain reorganization during stroke recovery. Significance Delta- theta ITC is a sensitive indicator of impaired motor execution.

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 CONCLUSION: Specific cervical manipulation at the C6-7 segment appears to increase PPT on the forearm compared to non-specific cervical manipulation in healthy subjects.

Context Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms. Objective To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults. Design and Setting A cross-sectional case-control study was conducted at a tertiary medical center. Participants We enrolled 12 consecutive patients with acromegaly along with 12 age- and sex-matched controls in the discovery phase of the study and then extended this cohort to 47 patients with acromegaly and 28 healthy controls for the validation study. Main Outcome Measures Plasma miRNAs were quantified by next-generation sequencing (NGS) in the discovery phase. Levels of selected miRNAs were validated on extended cohorts using reverse transcription quantitative polymerase chain reaction (RT-qPCR), compared between groups, and correlated with clinical parameters. Results Based on NGS data, we selected 3 plasma miRNAs downregulated in patients with acromegaly compared to healthy controls: miR-4446-3p −1.317 (P = 0.001), miR-215-5p −3.040 (P = 0.005), and miR-342-5p −1.875 (P = 0.013) without multiplicity correction for all 3 miRNAs. These results were confirmed by RT-qPCR in the validation phase for 2 miRNAs out of 3: miR-4446-3p (P < 0.001, Padjusted < 0.001), area under the receiver-operator curve (AUC) 0.862 (95% CI 0.723-0.936; P < 0.001) and miR-215-5p (P < 0.001, Padjusted < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) to differentiate patients with acromegaly from healthy controls. Conclusions In a 2-phase experiment using 2 different techniques we found and validated the downregulation of plasma miR-4446-3p and miR-215-5p in patients with acromegaly compared to healthy subjects, which makes them promising biomarkers for further research.

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub‐second dynamics of resting‐state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA‐related changes in resting‐state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting‐state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12–51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median‐split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo‐parietal junctions (TPJ). FRDA patients with an ASO 11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute‐long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub‐second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub‐second network activity and functional brain integration over long timescales., This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub‐second dynamics of resting‐state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA‐related changes in resting‐state functional brain connectivity (rsFC) over long timescales. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo‐parietal junctions (TPJ). The temporal dynamics of the DMN state also correlated with minute‐long DMN rsFC. FRDA patients with an ASO

PURPOSE Despite the importance of anterior chamber depth (ACD) measurements in disease and ageing, the repeatability and their threshold for change is not known. Our purpose was to determine the intra-session repeatability of Pentacam Scheimpflug photography for measuring the ACD across the chamber width in healthy subjects and thus inform expected limits of normality. METHODS Pentacam Scheimpflug photography was used to obtain ACD measurements at 57 points across the central 8mm of the chamber width from one randomly selected eye of 130 healthy (normal vision and no ocular diseases, except age-normal cataracts) subjects (median age 58.0 years, interquartile range 46.3-63.0 years; 48 males, 82 females). Intra-session ACD measurements were compared. Univariate and multivariate linear regression was performed to identify categorical and continuous variables demonstrating a significant relationship with ACD and its repeatability. RESULTS Bland-Altman analyses showed no directional or depth-dependent bias in the difference between the first and second tests (mean bias -0.003 mm, 95% limits of agreement -0.115 to +0.109 mm). Multivariate analysis found gender to be a significant factor (p 60-year-old age groups found 8.1-11.5 steps for females, and 7.5-9.2 steps for males. CONCLUSIONS Scheimpflug imaging using the Pentacam has excellent intra-session repeatability. Only gender appeared to affect repeatability characteristics, manifesting with a greater number of meaningful steps of change between two extremes of age range in females compared to males, which provides guidance for identifying clinically significant and measurable change between tests.

Objective: This study aims to investigate the elements of wayfinding in indoor complex healthcare environments. Background: The study replicates Ghamari and Pati’s 2018 study to identify the environmental attributes that attract eye fixation during wayfinding by objectively tracking eye movements and fixation as healthy subjects navigate through a complex, unfamiliar indoor healthcare setting. The study addressed what do people look at while navigating in unfamiliar healthcare environments? What are the relative time periods of eye fixations on different visual environmental elements of the healthcare-designed environments? And what role do visual environmental attributes in healthcare facilities, such as configuration, color, art, directories, maps, furniture, and so on, play during the wayfinding process. Method: Twenty-four adults in different genders and various age groups participated in this study and navigated five routes with different degrees of difficulty. The sequence of the destinations in this study was randomized. The data were collected by tracking gaze fixations while human subjects navigated an indoor complex healthcare environment. Results: The findings show that identifying signs (29.1%), informative signs (20.8%), and architectural features (11.3%) constituted the most frequent elements attracting gaze, substantially more than the other classes of information. Four types of signage (identifying signs, informative signs, directional, and safety/regulatory signs) were accounted for 62.3% of the total gaze fixation time. Conclusions: The comparison of the ordered list based on frequencies and time of eye fixations on various elements developed in Ghamari and Pati’s study shows a vast degree of similarities.

Jimaixin™ (Jintan Ltd, China) is a biosimilar of recombinant erythropoietin (rEPO) now authorized for therapeutic application in China. With a risk of abuse by athletes, a clear evaluation of its detection using the electrophoretic methods in use in antidoping laboratories was necessary. In a previous work, we showed that Jimaixin™ electrophoretic profile presented slight changes compared with the original drug (first generation rEPO) and that a spike of Jimaixin™ in urine and serum was well identified by SDS-PAGE but with less performance by IEF-PAGE unless a neuraminidase treatment was applied first. The aims of this research were to perform an intravenous administration of Jimaixin™ on three healthy subjects (one microdose [10 IU/kg] and three therapeutic doses [50 IU/kg]) and to evaluate the detection in urine and blood up to 7 days post administration. Analysis of the samples showed that Jimaixin™ detection was complicated by IEF-PAGE due to the loss of the most distinctive basic isoforms. In addition, a neuraminidase treatment did not improve detection (contrary to the observations from spike experiments). On the contrary, Jimaixin™ was very efficiently detected in blood and urine by SDS-PAGE: up to 40 h after a microdose and up to 7 days after the therapeutic doses. The effect of Jimaixin™ on hematological parameters was limited to a clear but transitory increase of the reticulocytes. These data give new elements to better survey a potential misuse of Jimaixin™ by athletes.

Objective A large N20 and P25 of the median nerve somatosensory evoked potential (SEP) predicts short survival in amyotrophic lateral sclerosis (ALS). We investigated whether high frequency oscillations (HFOs) over N20 are enlarged and associated with survival in ALS. Methods A total of 145 patients with ALS and 57 healthy subjects were studied. We recorded the median nerve SEP and measured the onset-to-peak amplitude of N20 (N20o-p), and peak-to-peak amplitude between N20 and P25 (N20p-P25p). We obtained early and late HFO potentials by filtering SEP between 500 and 1 kHz, and measured the peak-to-peak amplitude. We followed up patients until endpoints (death or tracheostomy) and analyzed the relationship between SEP or HFO amplitudes and survival using a Cox analysis. Results Patients showed larger N20o-p, N20p-P25p, and early and late HFO amplitudes than the control values. N20p-P25p was associated with survival periods (p = 0.0004), while early and late HFO amplitudes showed no significant association with survival (p = 0.4307, and p = 0.6858, respectively). Conclusions The HFO amplitude in ALS is increased, but does not predict survival. Significance The enlarged HFOs in ALS might be a compensatory phenomenon to the hyperexcitability of the sensory cortex pyramidal neurons.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)—omega-3 fatty acids with various functions—influence sleep in children and young adults. However, only limited studies on their effects on sleep in middle- and old-aged adults have been reported. Therefore, we investigated the effects of DHA and EPA on sleep quality in subjects aged ≥ 45 years. We performed a randomized, placebo-controlled, double-blinded, parallel-grouped study, in which we randomly assigned 66 healthy Japanese males and females. Each individual received six 480 mg capsules containing 576 mg DHA and 284 mg EPA per day (DHA/EPA group, n = 33), or corn oil (placebo group, n = 33), for 12 weeks. Before and after the intervention, the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA) and the sleep state test were conducted. In the DHA/EPA group, factor III (frequent dreaming) scores among the OSA-MA scores were significantly improved compared to the placebo group. Additionally, sleep state tests revealed that sleep efficiency improved in the DHA/EPA group. To our knowledge, this study is the first to report that DHA/EPA improves sleep quality in middle- and old-aged individuals, even at doses lower than those administered in previous studies.

STUDY DESIGN Retrospective cohort study on prospectively implemented EOS protocol. OBJECTIVE This study aims to audit and compare existing radiological definitions of gaze direction-chin brow vertical angle (CBVA), McGregor slope (McGS), slope of line of sight (SLS), orbital-internal occipital protuberance (OIOP) slope angle, and Tangent to the hard palate (THP) in a neutral, healthy, and asymptomatic cohort. SUMMARY OF BACKGROUND DATA The ability to accurately define direction of gaze is the first step when striving for horizontal gaze restoration in any affected individual with rigid sagittal deformity. Yet, the radiological definition of gaze direction remains poorly standardized. METHODS Hundred healthy subjects who could achieve horizontal gaze underwent whole-body standing EOS radiographs taken under a strictly standardized protocol. Radiographic measurements of global spinal sagittal parameters and surrogate measures of horizontal gaze were analyzed and compared. RESULTS The mean age was 45 ± 15.9 years, with a balanced male-to-female-ratio. Their C7 SVA was -7.7 mm ± 24.8 mm, PI was 51.0o ± 11.4o, PI-LL was -0.9o ± 13.0o and T1-slope was 21.2o ± 9.2o. Measured horizontal gaze parameters were as follows: CBVA (1.07o ± 5.48o), McGS (-3.23o ± 5.63o), SLS (0.45o ± 5.34o), OIOP (5.03o ± 4.66o), THP (-0.17o ± 6.27o). CBVA correlated strongly with McGS (r = 0.679, P

We analyze changes in circulating platelets in COVID-19 positive patients who received conventional treatment Dexamethasone and Enoxaparin (Dexa-Enoxa) compared to patients treated with conventional therapy plus nebulization with alkaline hypertonic ibuprofenate (AHI). Results show that after 24 h of nebulization with AHI, circulating platelets shows an increase about 40% at 24 h and reach 65% at 96 h. In patients with platelets content below 200,000 by microliter the increase was 49% and 79% at 24 and 96 h respectively. In patients with platelets above 200,000 by microliter the increase was 24% and 31% at 24 and 96 h, respectively. The increase of platelets via AHI was similar in both, men and women.To evaluate whether this action of AHI was related to platelets from COVID-19 positive patients or also for healthy people, two controls were included: one of them with 10 healthy volunteers and another one with COVID-19 positive patients hospitalized and treated only with Dexa-Enoxa. Results show that, in healthy volunteers, the number of circulating platelets remains unchanged even after 7 days of treatment with AHI. In COVID-19 positive patients treated only with Dexa-Enoxa for 4 days, platelets increased only 16%.

The purpose of this study was to compare the morphology of the central and peripheral choroid of eyes with central serous chorioretinopathy (CSC) to that of normal eyes using ultra-widefield optical coherence tomography (UWF-OCT). We reviewed the medical records of 29 eyes of 25 patients (23 men, 2 women; average age 44.4 years) with CSC and 34 eyes of 22 healthy subjects (19 men, 3 women; average age, 49.5 years) with normal eyes. The images obtained by a prototype swept source UWF-OCT (Topcon, Tokyo, Japan) of about 31.5-mm wide and a depth of 10.9 mm were analyzed. The choroidal thickness was measured for each sector of the eye using the conventional automated layer analysis method. The local morphological differences were quantified by the maximum steepness (µm/deg) which was obtained by differentiating the changes in the choroidal thickness from the periphery to the fovea. Only the vertical scans were evaluated to avoid the influence of the optic disc. The choroid was thicker in the macular area than the peripheral area in both normal and CSC eyes. The choroid at the subfovea was significantly thicker in the CSC eyes than that of the normal eyes (P

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Chelation of excessive copper is recommended but data on the pharmacokinetics of trientine are limited. The aim of this study was to compare the pharmacokinetics of a new trientine tetrahydrochloride formulation (TETA 4HCl) with those of an established trientine dihydrochloride (TETA 2HCl) salt. A randomised single-centre crossover study to evaluate the pharmacokinetics, safety and tolerability of two different oral formulations of trientine (TETA 4HCl tablets vs TETA 2HCl capsules) in 23 healthy adult subjects receiving a single dose equivalent to 600 mg of trientine base was performed. Following oral administration, the median time to reach maximum plasma concentration (Tmax) was 2.00 h (TETA 4HCl) and 3.00 h (TETA 2HCl). The rate (maximum plasma concentration [Cmax]) and extent (area under the plasma concentration-time curve from time zero to infinity [AUC0–∞]) of absorption of the active moiety, trientine, were greater (by approximately 68% and 56%, respectively) for TETA 4HCl than for the TETA 2HCl formulation. The two formulations presented a similar terminal elimination rate (λz) and a similar terminal half-life (t½) for trientine. Differences between TETA 4HCl and TETA 2HCl in the levels of the two main mono- and diacetylated metabolites were less than seen for trientine. For both tested formulations, healthy male volunteers demonstrated higher trientine plasma levels but lower mono- and diacetylated metabolite levels compared with females, with no sex differences in terminal half-life (t½) observed. Single oral doses of both formulations were safe and well tolerated. Compared with an identical dose of a TETA 2HCl formulation, the TETA 4HCl formulation provided more rapid absorption of trientine and greater systemic exposure in healthy subjects. Clinical Trials Number EudraCT # 2015-002199-25.

Purpose ABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects. Methods This randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing. Results A total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study. Conclusions This study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab. Clinical trial listing EudraCT 2018-002903-33.

Summary Background & Aims High quality and precise methods are needed when monitoring changes in body composition among colorectal cancer (CRC) patients and healthy subjects. The aim of this study was to estimate precision of the Dual-energy X-ray absorptiometry (Lunar iDXA, GE Healthcare software enCORE version 16) in measuring body composition in CRC patients and healthy subjects. Methods Precision error of iDXA in measuring body composition was investigated in the current study. Thirty CRC patients and 30 healthy subjects, including both men and women underwent two consecutive whole-body DXA scan with repositioning. Precision estimates of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in the abdominal region, and total fat mass (FM), fat-free mass (FFM), lean mass (LM), bone mineral density (BMD) and bone mineral content (BMC) were calculated. Results Precision error expressed as coefficient of variation (% CV) of VAT and SAT were estimated to be 3.56 % and 3.28 % among CRC patients, and 5.30 % and 3.46 % among healthy subjects. Estimated precision errors for body masses in the total region ranged between 0.49-1.01 % and 0.40-0.88 % in CRC patients and healthy subjects, respectively. Least significant change (LSC) in VAT mass, SAT mass, FM and LM were 140.9 g, 121.4 g, 637.0 g and 701.0 g, respectively, among CRC patients. Among healthy subjects the LSC in VAT, SAT, FM and LM were 80.93 g, 98.90 g, 484.0 g and 618.0 g, respectively. Only minor and non-significant differences between the two consecutive measurements for each body compartment were observed within both populations, and we found no systematic bias in the distribution of the differences. Conclusion The Lunar iDXA demonstrated high precision in body composition measurements among both CRC patients and healthy subjects. Hence, iDXA is a useful tool in clinical following-up and interventions targeted towards changes in body composition.

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.

Background: Oral Lichen Planus (OLP) is one of the most common oral mucosal diseases. However, the current diagnostic method for OLP has limitations, and sometimes it is easy to be misdiagnosed. Salivary metabolomics may provide new ideas for the diagnosis of OLP. Objective: To identify the biomarkers for the early detection of OLP. Methods: A non-targeted metabolomic analysis method was established based on UHPLC-Q-Orbitrap HRMS (Ultra-performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry) to analyze the differential metabolites in saliva samples of patients with OLP and healthy subjects. Saliva samples were collected from 120 OLP patients and 125 healthy subjects. Results: A total of 19 differential metabolites were identified, including 6 amino acid metabolites, 2 carnitines, 2 lipid metabolites and 9 other metabolites. The integrated biomarkers were constructed by 3 metabolites according to Receiver Operating Characteristic (ROC). Meanwhile, multiple metabolic pathways were found to be involved in the occurrence and development of OLP. Conclusion: Metabolomics can be used to characterize the characteristics of metabolic disorders in patients with OLP, which is also helpful to the early diagnosis of OLP and reveal the pathological process of OLP.

PURPOSE: This study aimed to examine the effect of head-down tilt (HDT) on vascular autoregulation in different age groups and determine its effects on intraocular pressure (IOP) and central corneal thickness (CCT).METHODS: Included were 43 eyes of 23 men. The optic nerve head and parafoveal vascular densities were measured by optical coherence tomography angiography before and after 20 min 10 HDT. Also, the study comprised an examination of the IOP and CCT in a subset of 8 participants (14 eyes) in the sitting position and during 15 min of 10 HDT.RESULTS: Grid-based inside disc all-vessel density (GBID) was statistically significantly lower after the HDT test in subjects under 30 yr (1.26). Whole image and peripapillary capillary vessel density (WICVD, PCVD), and whole image and peripapillary all-vessel density (WIAVD, PAVD) were significantly higher after the HDT test in subjects ages 30-39 yr (1.34, 2.16, 1.05, 1.72, respectively). Inside disc capillary, all-vessel density (IDCVD, IDAVD) and GBID were significantly higher after HDT in subjects over 40 yr (2.48, 2.15, 1.52, respectively). In a subset of eight participants, IOP was significantly higher (3.7 mmHg) and CCT was unchanged after 15 min of HDT.CONCLUSION: Our study showed that simulated microgravity induced optic nerve head vessel density at the inside disc area, especially in persons over 40 years. In addition, IOP was increased by HDT, although no change in CCT was observed.Özelbaykal B, Öğretmenoğlu G, Tunçez I.H. Ocular outcomes in healthy subjects undergoing a short-term head-down tilt test. Aerosp Med Hum Perform. 2021; 92(8):619-626.

The most reliable head and neck position for cervical vestibular-evoked myogenic potentials (cVEMPs) measurements yet to be determined.To assess how four body positions used during clinical recordings of cVEMPs affect cVEMP parameters.cVEMPs of 10 healthy subjects (26-50 years old) were recorded in four body positions:Mean background sternocleidomastoid muscle (SCM) electrical activity was significantly higher in positions C and D than in positions A and B. The latencies of p13 and n23 differed significantly among the four positions. Raw p13-n23 complex amplitude was significantly greater in positions C and D than in A and B. These differences were reduced when amplitudes were corrected by SCM activity. For positions A and B, one and two subjects, respectively, had an abnormal raw asymmetry ratio (AR). After correction, all subjects had normal ARs in all positions.Body positions in which the head is elevated produce a quicker and larger cVEMP response compared to positions in which the head is not elevated. The difference in ARs among positions can be ignored as long as the correction is made.

Background Although structured exercise training is strongly recommended in cardiac patients, uncertainties exist about the methods for determining exercise intensity (EI) and their correspondence with effective EI obtained by ventilatory thresholds. We aimed to determine the first (VT1 ) and second ventilatory thresholds (VT2 ) in cardiac patients, sedentary subjects, and athletes comparing VT1 and VT2 with EI defined by recommendations. Methods We prospectively enrolled 350 subjects (mean age: 50.7±12.9 years; 167 cardiac patients, 150 healthy sedentary subjects, and 33 competitive endurance athletes). Each subject underwent ECG, echocardiography, and cardiopulmonary exercise testing. The percentages of peak VO2 , peak heart rate (HR), and HR reserve were obtained at VT1 and VT2 and compared with the EI definition proposed by the recommendations. Results VO2 at VT1 corresponded to high rather than moderate EI in 67.1% and 79.6% of cardiac patients, applying the definition of moderate exercise by the previous recommendations and the 2020 guidelines, respectively. Most cardiac patients had VO2 values at VT2 corresponding to very-high rather than high EI (59.9% and 50.3%, by previous recommendations and 2020 guidelines, respectively). A better correspondence between ventilatory thresholds and recommended EI domains was observed in healthy subjects and athletes (90% and 93.9%, respectively). Conclusions EI definition based on percentages of peak HR and peak VO2 may misclassify the effective EI, and the discrepancy between the individually determined and the recommended EI is particularly relevant in cardiac patients. A ventilatory threshold-based rather than a range-based approach is advisable to define an appropriate level of EI.

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT‐P17 to United States‐licensed adalimumab (US‐adalimumab) and European Union‐approved adalimumab (EU‐adalimumab). This double‐blind, parallel‐group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT‐P17, US‐adalimumab, or EU‐adalimumab. Primary end points were PK equivalence in terms of: area under the concentration–time curve from time zero to infinity (AUC0–inf); AUC from time zero to the last quantifiable concentration (AUC0–last); and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80–125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT‐P17; 103 US‐adalimumab; 106 EU‐adalimumab), 308 subjects received study drug. AUC0–inf, AUC0–last, and Cmax were equivalent among CT‐P17, US‐adalimumab, and EU‐adalimumab, because 90% CIs for the ratios of GLSMs were within the 80–125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single‐dose administration of CT‐P17, EU‐adalimumab, and US‐adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Context: Serratus anterior tightness is associated with scapular dyskinesis and overall shoulder dysfunction, which affects the range of motion. The most effective intervention to stretch the serratus anterior is unknown. Objective: To evaluate the effect of a therapist-administered novel serratus anterior stretch (SAS) on shoulder range of motion. Method: This study recruited 30 healthy subjects of age 21.20 (1.69) years, height 1.65 (0.11) m, and weight 60.90 (10.36) kg in equal ratio of males and females who scored 1 or 2 on the shoulder mobility test of functional movement screening. A single intervention of a novel SAS was applied to the shoulder. Outcome variables before and after the SAS included the following: shoulder ROM (flexion, abduction, internal rotation, and external rotation) and functional movements of reaching up behind the back and reaching down behind the neck. Results: A paired t test was used to analyze the data. Following the acute SAS intervention, all shoulder ROM improved significantly (P 1) was observed across most of the variables. Conclusion: An acute SAS intervention improves shoulder mobility in healthy individuals. It is recommended for the trial on the prevention and rehabilitation of shoulder pathologies with restriction in shoulder mobility.

Hongquan Zheng,1,2 Yan Xia,3 Shengjun Qu,4 Lin Fan,2 Jingjing Zhang,1 Zhixiang Ma,1 Yangsheng Chen,4 Hongwei Fan1,2 1Department of Clinical Pharmacology Lab, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 3Jiangsu Leeway Biological Technology Co., Ltd, Nanjing, Jiangsu, People’s Republic of China; 4CP Pharmaceutical Qingdao Co., Ltd, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Hongwei FanNanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People’s Republic of ChinaTel +86 25 5288 7030Fax +86 25 5288 7031Email fanhongwei178@sina.comYangsheng Chen 3601 Tuanjie Road, Economic and Technological Development Zone, Qingdao, People’s Republic of ChinaTel +86 18766396996Email chenys@cppqd.comPurpose: The present report describes findings from a Phase I clinical study that evaluated the single- and multiple-dose pharmacokinetics of frovatriptan succinate tablet in Chinese healthy subjects.Methods: A total of 24 healthy subjects were enrolled. In single-dose study, 2.5, 5, and 10 mg oral doses of frovatriptan succinate tablet were administrated. A 2.5 mg frovatriptan succinate tablet was administrated 12 times in 7 days in the multiple-dose study. Blood samples were collected at scheduled time points.Results: The results in single-dose study indicated that the blood levels were proportional to the administered dose, with the mean Cmax and AUClast ranging from approximately 6.27 ng/mL– 17.35 ng/mL and 92.52 h⋅ng/mL – 287.40 h⋅ng/mL over the dose range. In the multiple-dose study, moderate drug accumulation was noted, which was attributable to forvatriptan’s long t1/2 of about 26.47 to 30.63 h. Gender differences were noticed in both single- and multiple-dose study; exposure PK parameters were consistently higher in female than in male.Conclusion: These pharmacokinetic evaluations in healthy Chinese subjects found that frovatriptan succinate tablet has an acceptable pharmacokinetic profile in Chinese subjects.Keywords: frovatriptan succinate, pharmacokinetics, single-dose, multiple-dose

Background Reference intervals (RIs) are normal ranges of clinical indicators established from healthy subjects, and comparing test results with RIs is the first step for clinicians in differentiating between healthy and diseased subjects. Capillary blood is widely used in complete blood count (CBC) tests in children; however, capillary blood-based RIs for the CBC parameters are still lacking for all pediatric populations. The aim of this study was to establish capillary blood-based RIs for the CBC parameters in children aged 3 months to 18 years in Beijing. Methods A total of 6799 capillary blood specimens from children were collected, including 3832 males and 2967 females aged 3 months to 18 years, and CBC parameters were analyzed. Data analysis, RI calculations, and 90% confidence interval (CI) calculations were performed according to CLSI C28-A3 guidelines. Results Capillary blood RIs for 22 CBC parameters were established in children aged 3 months to 18 years. The levels of most red blood cell-related parameters increased with age and were generally higher in males than in females. White blood cell counts were relatively stable, with no obvious upward or downward trends from 3 months to 18 years of age. Platelet levels decreased within the first year and tended to be stable thereafter. Further validation with 458 healthy children illustrated that the verified results were within the established RIs with a 90%-100% proportion. Conclusion We established capillary blood RIs for 22 CBC parameters in children across a broad age range in Beijing.

lt;bgt;Background and Objective:lt;/bgt; A well-established treatment for childhood epilepsy, the Ketogenic Diet (KD) is increasingly gaining acceptance as a preventative tool for obesity. The current study aims to compare the effects of a ketogenic diet on some of the immunological parameters among obese individuals and contrast them with non-obese individuals. This includes finding the absolute numbers of white blood cells and estimating the efficacy of phagocytic cells and serum IgA concentration.lt;bgt;Materials and Methods:lt;/bgt; Twenty healthy persons were chosen for the study, with an age range between 18-45 years, a weight range before the ketogenic diet of 80-115 kg and after the ketogenic diet 60-80 kg with a height range between 155-180 cm during a period between 8-16 weeks. Their daily food was composed of high fats (80%), moderate protein (15%) and small amounts of carbohydrates (5%). The control sample included twenty healthy subjects, their food consisted of different types of food carbohydrates (75-80%), proteins (10%) and fats (10%).lt;bgt;Results:lt;/bgt; The results showed a significant increase in the White Blood Cells (WBC) count in KD individuals. Additionally, no significant difference was noticed in the absolute number of neutrophils and lymphocytes. Conversely, a significant increase in the absolute number of monocytes was observed. Moreover, the study showed a significant decrease in IgA concentration in KD individuals compared with control.lt;bgt;Conclusion:lt;/bgt; In the ketogenic system users indicated a rise in the number of monocytes and a decrease in the concentration of IgA. This provides a strong sign that autoimmune disorders are emerging.

Omecamtiv mecarbil (OM) is a cardiac myosin activator under clinical development for the treatment of heart failure. Two modified-release (MR) novel OM minitablet formulations were developed to support the planned investigation of chronic heart failure in pediatric patients. The primary objective of this study was to determine the bioavailability of the minitablets relative to the adult matrix MR formulation tablets. In a randomized, 5-period, crossover study, 20 healthy subjects received each of the following treatments orally: one 25-mg adult matrix MR tablet, 25 1-mg slow-release minitablets, 25 1-mg fast-release minitablets, six 1-mg slow-release minitablets, or six 1-mg fast-release minitablets after an overnight fast of at least 10 h with a minimum washout of 7 days between treatments. Blood samples were collected for up to 168 h. OM pharmacokinetic parameters were estimated using non-compartmental methods. When OM was administered as 25 1-mg OM slow-release minitablets, AUClast, AUCinf, and Cmax were 0.998-, 1.00-, and 1.29-fold of a single 25-mg OM matrix MR tablet, respectively. When OM was administered as 25 1-mg OM fast-release minitablets, AUClast, AUCinf, and Cmax were 1.26-, 1.25-, and 2.21-fold of a single 25-mg OM matrix MR tablet, respectively. The slow- and fast-release minitablets display approximately dose-proportional pharmacokinetics. There were no serious adverse events or treatment-emergent adverse events leading to discontinuation from the study. Relative bioavailability of slow-release minitablets was demonstrated to be similar to the adult matrix MR formulation.

Summary Objective Molecular information derived from dynamic [18F]sodium fluoride ([18F]NaF) PET imaging holds promise as a quantitative marker of bone metabolism. The objective of this work was to evaluate physiological mechanisms of [18F]NaF uptake in subchondral bone of individuals with and without knee osteoarthritis (OA). Methods Eleven healthy volunteers and twenty OA subjects were included. Both knees of all subjects were scanned simultaneously using a 3T hybrid PET/MRI system. MRI MOAKS assessment was performed to score the presence and size of osteophytes, bone marrow lesions, and cartilage lesions. Subchondral bone kinetic parameters of bone perfusion (K1), tracer extraction fraction, and total tracer uptake into bone (Ki) were evaluated using the Hawkins 3-compartment model. Measures were compared between structurally normal-appearing bone regions and those with structural findings. Results Mean and maximum SUV and kinetic parameters Ki, K1, and extraction fraction were significantly different between Healthy subjects and subjects with OA. Between-group differences in metabolic parameters were observed both in regions where the OA group had degenerative changes as well as in regions that appeared structurally normal. Conclusions Results suggest that bone metabolism is altered in OA subjects, including bone regions with and without structural findings, compared to healthy subjects. Kinetic parameters of [18F]NaF uptake in subchondral bone show potential to quantitatively evaluate the role of bone physiology in OA initiation and progression. Objective measures of bone metabolism from [18F]NaF PET imaging can complement assessments of structural abnormalities observed on MRI.

Objectives Onychomycosis is the general term to define fungal nail infections that arise from dermatophytes, non-dermatophytic moulds and yeasts. Thiol/disulphide homeostasis is a new indicator of oxidative stress. In this study, we aimed to investigate the role of thiol/disulphide balance in the pathogenesis of onychomycosis. Methods This cross-sectional study included adult patients with onychomycosis who were admitted to the dermatology department and healthy adult volunteers without any dermatologic or systemic condition. The patients and controls were evaluated in terms of native thiol, total thiol, and disulphide levels, and disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios. The possible association between these parameters and clinical subtypes of onychomycosis and demographic characteristics was also investigated. Results A total of 52 patients with onychomycosis and 50 healthy subjects were enrolled in the study. The patient group showed lower levels of total thiol, native thiol and native thiol/total thiol ratio, and higher ratios of disulphide/native thiol and disulphide/total thiol. No statistically significant relationship was found between the parameters, clinical subtypes of onychomycosis and demographic characteristics (p > .05). Conclusion Patients with onychomycosis showed a shifted thiol/disulphide homeostasis towards oxidative stress with a reduction in thiols and an increase in disulphide/native thiol, and disulphide/total thiol ratios. These findings may indicate the role of oxidative stress in the pathogenesis of onychomycosis.

GLPG1205 is a modulator of GPR84, a G‐protein–coupled receptor reported to be associated with several diseases. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1205 in healthy subjects were evaluated in 2 randomized, double‐blind, placebo‐controlled, single‐site, phase 1 studies. In study 1, 16 (aged 21‐48 years) and 24 (24‐50 years) healthy men received single doses of GLPG1205 10 to 800 mg, and GLPG1205 50, 100, or 200 mg once daily for 14 days, respectively, or placebo. Study 2 evaluated the effect of aging on GLPG1205 pharmacokinetics: 24 healthy men (aged 37–83 years), weight‐matched into 3 age cohorts (65‐74, ≥75, and 18‐50 years), received GLPG1205 50 mg or placebo once daily for 14 days; an open‐label part of this study evaluated a GLPG1205 250‐mg loading dose followed by 50 mg once daily for 13 days in 8 healthy men (aged 68‐74 years). Single (up to 800 mg) and multiple (maximum tolerated dose 100 mg once daily) GLPG1205 doses had favorable safety and tolerability profiles. After single administration of GLPG1205, median time to occurrence of maximum observed plasma concentration and arithmetic mean apparent terminal half‐life ranged from 2.0 to 4.0 and from 30.1 to 140 hours, respectively. Age did not affect GLPG1205 exposure. GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205.

Background Physical growth during childhood and adolescence is influenced by both genetic and environmental factors. Heritability, the proportion of phenotypic variance explained by genetic factors, has been demonstrated for stature and weight status. The aim of this study was to explore the heritability of body composition. Methods A real-life, observational study of the children and adolescents referred to the Endocrine Unit in a tertiary medical center. In January 2018, body composition by means of bioimpedance analysis (BIA) was implemented as part of the standard intake assessment of subjects referred for endocrine consultation. The clinic BIA database was searched for subjects with the term “observation of growth” as the sole reason for referral. BIA of 114 triads of healthy subjects aged 5–18 years and their parents were analyzed. The BIA report included the following data: fat mass, fat percentage, truncal fat percentage and muscle mass. Calculated variables included: appendicular skeletal muscle mass (ASMM = the sum of muscle mass of four limbs), muscle-to-fat ratio [MFR = ASMM (kg)/fat mass (kg)] and sarcopenic index [(SI = ASMM(kg)/height (meter)²]. Data collection from medical files included pubertal stage and home address for socioeconomic position grading. Results There were sex differences in body composition parameters in both the prepubertal and pubertal subjects. The boys among the prepubertal subjects had a lower fat percentage on average than girls (p = 0.020). Among the adolescents, boys on average had lower fat percentage (p = 0.011), higher sarcopenic index (p = 0.021), and higher muscle-to-fat ratio (p p = 0.050; boys-mothers: r = 0.435, p = 0.026; girls-fathers: r = 0.462, p = 0.012; girls-mothers: r = 0.365, p = 0.050) and adiposity indices (fat percentage, truncal fat percentage and muscle-to-fat ratio) of prepubertal boys and their mothers (r = 0.438, p = 0.025; r = 0.420, p = 0.033, and r = 0.478, p = 0.014, respectively). There were no associations between body composition parameters of adolescents and their parents. Socioeconomic position adversely affected fat percentage in adolescent girls and mothers. Conclusions Heritable body composition traits were demonstrated in childhood but not in adolescence, suggesting that environmental influence has a more telling effect during teenage years.

Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 μg beraprost SR under fasting conditions. The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85–1.48) and 1.40 (1.05–1.86) in Chinese, and 1.18 (0.90–1.55) and 1.18 (0.89–1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

Previous pathologic studies evaluated the substantia nigra pars compacta (SNpc) of a limited number of idiopathic Parkinson's disease (IPD) patients with relatively longer disease durations. Therefore, it remains unknown which region of the SNpc is most significantly affected in early‐stage IPD. We hypothesized that a voxelwise analysis of thin‐section neuromelanin‐sensitive MRI (NM‐MRI) may help determine the significantly affected regions of the SNpc in early‐stage IPD and localize these areas in each nigrosome on high‐spatial‐resolution susceptibility map‐weighted imaging (SMwI). Ninety‐six healthy subjects and 50 early‐stage IPD patients underwent both a 0.8 × 0.8 × 0.8 mm3 NM‐MRI and a 0.5 × 0.5 × 1.0 mm3 multi‐echo gradient‐recalled echo imaging for SMwI. Both NM‐MRI and SMwI templates were created by using image data from the 96 healthy subjects. Permutation‐based nonparametric tests were conducted to investigate spatial differences between the two groups in NM‐MRI, and the results were displayed on both NM‐MRI and SMwI templates. The posterolateral and anteromedial regions of the SNpc in NM‐MRI were significantly different between the two groups, corresponding to the nigrosome 1 and nigrosome 2 regions, respectively, on the SMwI template. There were the areas of significant spatial difference in the hypointense SN on SMwI between early‐stage IPD patients and healthy subjects. These areas on SMwI were slightly greater than those on NM‐MRI, including the areas showing group difference on NM‐MRI. Our voxelwise analysis of NM‐MRI suggests that two regions (nigrosome 1 and nigrosome 2) of the SNpc are separately affected in early‐stage IPD., Ninety‐six healthy subjects and 50 early‐stage IPD patients underwent both a 0.8 × 0.8 × 0.8 mm3 NM‐MRI and a 0.5 × 0.5 × 1.0 mm3 multi‐echo gradient‐recalled echo imaging for SMwI. Using both NM‐MRI and SMwI templates, we conducted voxelwise analysis of NM‐MRI between healthy subjects and IPD patients, and found that two regions (nigrosome 1 and nigrosome 2) of the substantia nigra pars compacta are separately affected in early‐stage IPD.

MT-1207 is a novel multitarget blocker of α1 receptor, 5-HT2A receptor, and calcium channel that is currently under development for the treatment of hypertension. In this study, we evaluated the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MT-1207 in healthy Chinese subjects.We examined the effects of a single-ascending dose (SAD) of MT-1207 (5-40 mg) and MT-1207 (40 mg) administered in combination with food in 56 healthy subjects.No serious adverse events or discontinuations due to adverse events (related to MT-1207) occurred in either study. MT-1207 was rapidly absorbed (median Tmax: 0.5-1.25 h). The mean tMT-1207 was well tolerated in all subjects. PD measurements demonstrated the antihypertensive effects of MT-1207.

Harlan, KG, Merucci, RB, Weaver, JJ, Windle, TC, and Malek, MH. Pre-exhaustion exercise differentially influences neuromuscular fatigue based on habitual physical activity history. J Strength Cond Res 35(3): 739-745, 2021-Although there is anecdotal evidence of a potential physiological benefit of pre-exhaustion exercise to enhance muscular recruitment, few studies have systematically examined the effect on neuromuscular activity. Moreover, a subject's habitual physical activity history may, in part, contribute to the muscle's response on a subsequent workbout after a single pre-exhaustion workbout. To date, no studies have examined the effect of pre-exhaustion exercise on the electromyographic fatigue threshold (EMGFT). The purpose of this study, therefore, is to determine whether pre-exhaustion exercise influences the EMGFT. Specifically, we were interested in determining whether or not there is a dichotomous response to pre-exhaustion exercise based on the individual's habitual physical activity history. Thus, we hypothesized that healthy active subjects would have reduced EMGFT values, whereas elite runners would have increased EMGFT values as a result of the pre-exhaustion exercise. Eight healthy college-aged men (mean ± SEM, age = 24.5 ± 0.3 years; body mass = 83.1 ± 3.0 kg; and height = 1.80 ± 0.02 m) and 9 elite runners (mean ± SEM, age = 23.4 ± 0.7 years; body mass = 70.3 ± 2.7 kg; and height = 1.79 ± 0.03 m) participated in current study. Each subject visited the laboratory on 2 occasions separated by 7 days and performed the single-leg knee-extensor ergometry test. For one of the visits, the subjects performed the Thorstensson test (50 continuous, concentric knee extensions) before the single-leg knee-extensor ergometry. The EMGFT was measured on both visits for all subjects. For healthy subjects, we found that the EMGFT was significantly reduced after performing the 50 isokinetic knee extensions (control: 27 ± 6 W vs. Thorstensson: 21 ± 6.0 W; p = 0.001), whereas for elite runners, there was no significant mean differences between the 2 visits (control: 38 ± 3 W vs. Thorstensson: 39 ± 2 W; p = 0.813). These results suggest that 50 repetition of isokinetic muscle action, as a method of pre-exhausting the quadriceps femoris muscles, may be influenced by the subject's habitual exercise history.

The pandemic of COVID-19 is continuously spreading, becoming a worldwide emergency. Early and fast identification of subjects with a current or past infection must be achieved to slow down the epidemiological widening. Here we report a Raman-based approach for the analysis of saliva, able to significantly discriminate the signal of patients with a current infection by COVID-19 from healthy subjects and/or subjects with a past infection. Our results demonstrated the differences in saliva biochemical composition of the three experimental groups, with modifications grouped in specific attributable spectral regions. The Raman-based classification model was able to discriminate the signal collected from COVID-19 patients with accuracy, precision, sensitivity and specificity of more than 95%. In order to translate this discrimination from the signal-level to the patient-level, we developed a Deep Learning model obtaining accuracy in the range 89–92%. These findings have implications for the creation of a potential Raman-based diagnostic tool, using saliva as minimal invasive and highly informative biofluid, demonstrating the efficacy of the classification model.

Schizophrenia is a biologically complex disorder with multiple regional deficits in cortical brain morphology. In addition, interindividual heterogeneity of cortical morphological metrics is larger in patients with schizophrenia when compared to healthy controls. Exploiting interindividual differences in the severity of cortical morphological deficits in patients instead of focusing on group averages may aid in detecting biologically informed homogeneous subgroups. The person-based similarity index (PBSI) of brain morphology indexes an individual’s morphometric similarity across numerous cortical regions amongst a sample of healthy subjects. We extended the PBSI such that it indexes the morphometric similarity of an independent individual (eg, a patient) with respect to healthy control subjects. By employing a normative modeling approach on longitudinal data, we determined an individual’s degree of morphometric dissimilarity to the norm. We calculated the PBSI for sulcal width (PBSI-SW) in patients with schizophrenia and healthy control subjects (164 patients and 164 healthy controls; 656 magnetic resonance imaging scans) and associated it with cognitive performance and cortical sulcation index. A subgroup of patients with markedly deviant PBSI-SW showed extreme deficits in cognitive performance and cortical sulcation. Progressive reduction of PBSI-SW in the schizophrenia group relative to healthy controls was driven by these deviating individuals. By explicitly leveraging interindividual differences in the severity of PBSI-SW deficits, neuroimaging-driven subgrouping of patients is feasible. As such, our results pave the way for future applications of morphometric similarity indices for subtyping of clinical populations.

Transcranial static magnetic stimulation (tSMS) has been focused as a new non-invasive brain stimulation, which can suppress the human cortical excitability just below the magnet. However, the non-regional effects of tSMS via brain network have been rarely studied so far. We investigated whether tSMS over the left primary motor cortex (M1) can facilitate the right M1 in healthy subjects, based on the hypothesis that the functional suppression of M1 can cause the paradoxical functional facilitation of the contralateral M1 via the reduction of interhemispheric inhibition (IHI) between the bilateral M1. This study was double-blind crossover trial. We measured the corticospinal excitability in both M1 and IHI from the left to right M1 by recording motor evoked potentials from first dorsal interosseous muscles using single-pulse and paired-pulse transcranial magnetic stimulation before and after the tSMS intervention for 30 min. We found that the corticospinal excitability of the left M1 decreased, while that of the right M1 increased after tSMS. Moreover, the evaluation of IHI revealed the reduced inhibition from the left to the right M1. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of tSMS in human.