Healthy Volunteer Subjects Research Articles

Correlation of deglutitive striated esophagus motor function and pharyngeal phase swallowing biomechanical events.

The functional relationship of striated esophagus (St.Eso) motor function with pharyngeal deglutitive biomechanical events has not been systematically studied. The aim of this study was to determine the spatio-temporal characteristics of St.Eso function and its correlation with pharyngeal biomechanics and bolus transport. We studied 50 healthy volunteer subjects (age range: 21-82 years, 31 female) by digital videofluoroscopy. All subjects were studied in a seated, upright position. Thirteen of these 50 volunteers also underwent high-resolution manometry (HRM) concurrent with fluoroscopy. We used laryngeal excursion as a surrogate for St.Eso excursion. Median duration of St.Eso excursion was 2.35 [1.93,2.85, 5th and 95th percentile] seconds. Mean maximum extent of St.Eso excursion was 2.84 ± 0.72 cm. We identified four distinct periods in deglutitive St.Eso motor function: P1. Anterosuperior ascent without bolus or peristaltic activity, P2. Non-peristaltic bolus receiving at the apogee of St.Eso excursion concurrent with UES opening and pharyngeal peristalsis P3. Peristaltic bolus transport as St.Eso descends and P4. Continued peristalsis in resting position. 1. St.Eso motor function spans both pharyngeal and esophageal phases of swallowing for receiving and transporting the bolus, 2. Pressure signatures in HRM recordings currently attributed to St.Eso deglutitive motor activity does not represent the entirety of St.Eso peristalsis, only the part that occurs in its resting position. St.Eso peristalsis that occurs during its descent is recorded by pressure sensors initially in the pharynx. This finding needs to be considered when interpreting HRM recordings of the pharynx and proximal esophagus.

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

BackgroundSystemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.MethodsFourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.ResultsCultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).ConclusionsIn cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

The Oxidative Status and Na+/K+-ATPase Activity in Obsessive-Compulsive Disorder: A Case Control Study.

Oxidative stress is involved in pathogenesis of some psychiatric disorders. To examine the role of oxidative stress in the etiopathogenesis of obsessive-compulsive disorder (OCD), we aimed to determine oxidative stress indices, including malondialdehyde (MDA) levels in serum and red blood cells (RBC) membrane, total antioxidant capacity (TAC), serum glutathione (GSH) levels, serum antioxidant vitamins (A and E), and Na+/K+-ATPase activity, in patients with the mentioned disorder vs. healthy controls. 39 OCD patients diagnosed based on Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and 39 volunteer healthy subjects were included in this study. MDA levels in serum and RBC membrane were measured using fluorometric method. Serum TAC level, serum GSH level, and Na+/K+-ATPase activity were also measured using spectrophotometric methods. Serum levels of vitamins were calculated by reversed-phase high-performance liquid chromatography (RP-HPLC). There was a significantly higher MDA level in serum (p < 0.0001) and RBC membrane (p = 0.002) of OCD patients compared with those in controls. A significant reduction in vitamin A (p = 0.001) and vitamin E (p = 0.024) levels was found in OCD patients vs. controls. There was significantly lower activity of erythrocyte membrane Na+/K+-ATPase in RBC membrane of OCD patients vs. controls (p < 0.0001). Our findings indicate significantly higher levels MDA in both serum and RBC membrane, lower levels of serum vitamins A and E, and lower activity of membrane Na+/K+-ATPase in OCD patients compared to controls. These suggest an imbalance between oxidant and antioxidant factors in OCD patients that might play a fundamental role in the etiopathogenesis of OCD.

Shock waves modulate corticospinal excitability: A proof of concept for further rehabilitation purposes?

Focal extracorporeal shock wave therapy (fESWT) is a physical therapy vastly studied and used for various musculoskeletal disorders. However, the effect of fESWT on central nervous system is still to be determined. To elucidate spinal and supra-spinal mechanisms of fESWT in healthy subjects, in order to widen the spectrum of its clinical applications. In this quasi-experimental, unblinded, proof-of-concept clinical study, 10 voluntary healthy subjects underwent fESWT and were assessed immediately before (T0), immediately after (T1) and seven days after (T2) the intervention. As neurophysiological outcomes, motor evoked potentials (resting motor threshold, maximal motor evoked potential and maximal compound muscle action potential ratio, cortical silent period, total conduction motor time, direct and indirect central motor conduction time), F-waves (minimal and mean latency, persistence and temporal dispersion) and H-reflex (threshold, amplitude, maximal H reflex and maximal compound muscle action potential ratio, latency) were considered. Resting motor threshold and F-waves temporal dispersion significantly decreased, respectively, from T1 and T2 and from T0 and T2 (for both, p < 0.05). H-reflex threshold increase between T0 and T1. Analysis disclosed a strong negative correlation between Δ3 cortical silent period (i.e., T2 -T1 recordings) and Δ1 Hr threshold (i.e., T1 -T0 recordings) (r = -0.66, p < 0.05), and a positive strong relationship between Δ3 cortical silent period and Δ3 Hr threshold (r = 0.63, p < 0.05). fESWT modulates corticospinal tract excitability in healthy volunteers, possibly inducing an early inhibition followed by a later facilitation after one week.

Intra-abdominal Content Movement in Prone Versus Lateral Decubitus Position Lateral Lumbar Interbody Fusion (LLIF).

A prospective, anatomical imaging study of healthy volunteer subjects in accurate surgical positions. To establish if there is a change in the position of the abdominal contents in the lateral decubitus (LD) versus prone position. Lateral transpsoas lumbar interbody fusion (LLIF) in the LD position has been validated anatomically and for procedural safety, specifically in relation to visceral risks. Recently, LLIF with the patient in the prone position has been suggested as an alternative to LLIF in the LD position. Subjects underwent magnetic resonance imaging of the lumbosacral region in the right LD position with the hips flexed and the prone position with the legs extended. Anatomical measurements were performed on axial magnetic resonance images at the L4-5 disc space. Thirty-four subjects were included. The distance from the skin to the lateral disc surface was 134.9mm in prone compared with 118.7mm in LD ( P <0.0001). The distance between the posterior aspect of the disc and the colon was 20.3mm in the prone compared with 41.1mm in LD ( P <0.0001). The colon migrated more posteriorly in relation to the anterior margin of the psoas in the prone compared with LD (21.7 vs . 5.5mm, respectively; P <0.0001). 100% of subjects had posterior migration of the colon in the prone compared with the LD position, as measured by the distance from the quadratum lumborum to the colon (44.4 vs . 20.5mm, respectively; P <0.001). There were profound changes in the position of visceral structures between the prone and LD patient positions in relation to the LLIF approach corridor. Compared with LD LLIF, the prone position results in a longer surgical corridor with a substantially smaller working window free of the colon, as evidenced by the significant and uniform posterior migration of the colon. Surgeons should be aware of the potential for increased visceral risks when performing LLIF in the prone position. Level II-prospective anatomical cohort study.

Sequence variation of the Epstein-Barr virus nuclear antigen 1 (EBNA1) gene in chronic lymphocytic leukemia and healthy volunteer subjects.

Epstein-Barr virus-related malignancies have been linked to variations in the sequences of EBV genes, notably EBNA1. Therefore, the purpose of this study was to examine the DBD/DD domain and USP7 binding domain sequences at the C-terminus of the EBNA1 gene in patients with chronic lymphocytic leukemia (CLL). This study included 40 CLL patients and 21 healthy volunteers. Using commercial kits, total DNA was extracted from buffy coat samples, and each sample was tested for the presence of the EBV genome. The C-terminus of EBNA1 was then amplified from positive samples, using nested PCR. Sanger sequencing was used to identify mutations in the PCR products, and the results were analyzed using MEGA11 software. The mean ages of CLL patients and healthy individuals were 61.07 ± 10.2 and 59.08 ± 10.3, respectively. In the EBNA-1 amplicons from CLL patients and healthy individuals, 38.5% and 16.7%, respectively, harbored mutations in the DBD/DD domain of the C-terminal region of the EBNA1 gene (P = 0.378). The mutation frequency at locus 97,320 was significantly higher in CLL patients than in healthy individuals (P = 0.039). Three EBV subtypes based on residue 487 were detected. The frequency of alanine, threonine, and valine in both groups was 88, 8, and 4 percent, respectively (P = 0.207). Moreover, all of the isolates from healthy donors had alanine at this position. The findings indicated that the presence of threonine or valine at residue 487 as well as a synonymous substitution at residue 553 in the C-terminal region of EBNA1 might be involved in the pathogenesis of EBV in CLL patients.

Reference values of abdominal aorta wall thickness and Doppler indices in a Nigerian population

Introduction : There is a paucity of data on the association between Doppler indices, the wall thickness of the abdominal aorta and the development of atherosclerosis in Nigeria. This study aimed to establish reference data of the abdominal aorta wall thickness and their selected Doppler indices in Abuja, Nigeria.&#x0D; Methodology : This cross-sectional prospective study enlisted volunteer healthy subjects who consented and met the inclusion criteria by convenience sampling. The abdominal Aorta wall thickness (AAWT), as well as selected Doppler indices which are: the resistivity and pulsatility indices (RI &amp; PI) of the abdominal aorta (AA) of four hundred and twelve male and female volunteer healthy subjects, were measured sonographically using standard protocols. Data was analyzed using SPSS v 23 and inferential analysis was done with a level of significance set at 5 %.&#x0D; Results : The mean ± SD of the AAWT in the volunteer healthy subjects were 1.54 ± 0.33mm and 1.29 ± 0.32mm in male and female healthy volunteers respectively. The mean ± SD of the RI and PI for male volunteer healthy subjects were 0.81 ± 0.06, and 1.09 ± 0.20. Also, the mean + SD of the RI and PI for female healthy volunteers was 0.59 ± 0.06, and 1.10 ± 0.21 respectively.&#x0D; Conclusion : The reference AAWT, RI and PI in the locality were 1.51 ± 0.33mm, 0.6 ± 0.06 and 1.02 ± 0.19. The RI, PI and AAWT values were higher in males (p &gt;0.005) than in female volunteer healthy subjects.&#x0D;

Bioavailability and Antihyperglycemic Effect of Four Glibenclamide Tablets: A Comparative Study

This study compared the bioavailability and antihyperglycemic effect of 5 mg glibenclamide tablets available in Sudan. Nine healthy subjects were given a 5 mg dose of either micronized glibenclamide tablets (Euglucon®) or conventional non-micronized glibenclamide tablets (locally manufactured items). Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours and analyzed for glucose concentrations. The maximum mean serum concentration of the drug (Cmax) and the mean time to maximum serum concentration (Tmax) were calculated, and the area under the concentration versus time curve (AUC) and the drug clearance (Cl) were also recorded. The mean glucose concentration was also determined in different time intervals. The results show no significant difference in the mean Tmax between the tested items. However, the mean Cmax is significantly higher (p 0.001) when the non-micronized tablets are taken (456 ng/mL) rather than the micronized tablets (291 ng/mL). Similarly, the mean AUC0-8h is significantly higher (p 0.001) with the non-micronized tablets (1915 ng/mL.h) than with the micronized tablets (1163 ng/mL.h). After 8 hours, the subjects in the micronized group had a drug clearance of 0.0430 L/Kg.h, and a clearance of 0.0260 L/Kg.h was recorded in the unmicronized group. Both tablets lower the mean glucose concentrations of the nine volunteers after 8 hours, 99 mg/dL for micronized tablets and 98 mg/dL for non-micronized tablets. Overall, the non-micronized glibenclamide tablet used in this study similarly lowered the glucose concentrations in healthy volunteer subjects to that of imported micronized glibenclamide tablets.

Diffusion MRI of the facial-vestibulocochlear nerve complex: a prospective clinical validation study

ObjectivesSurgical planning of vestibular schwannoma surgery would benefit greatly from a robust method of delineating the facial-vestibulocochlear nerve complex with respect to the tumour. This study aimed to optimise a multi-shell readout-segmented diffusion-weighted imaging (rs-DWI) protocol and develop a novel post-processing pipeline to delineate the facial-vestibulocochlear complex within the skull base region, evaluating its accuracy intraoperatively using neuronavigation and tracked electrophysiological recordings.MethodsIn a prospective study of five healthy volunteers and five patients who underwent vestibular schwannoma surgery, rs-DWI was performed and colour tissue maps (CTM) and probabilistic tractography of the cranial nerves were generated. In patients, the average symmetric surface distance (ASSD) and 95% Hausdorff distance (HD-95) were calculated with reference to the neuroradiologist-approved facial nerve segmentation. The accuracy of patient results was assessed intraoperatively using neuronavigation and tracked electrophysiological recordings.ResultsUsing CTM alone, the facial-vestibulocochlear complex of healthy volunteer subjects was visualised on 9/10 sides. CTM were generated in all 5 patients with vestibular schwannoma enabling the facial nerve to be accurately identified preoperatively. The mean ASSD between the annotators’ two segmentations was 1.11 mm (SD 0.40) and the mean HD-95 was 4.62 mm (SD 1.78). The median distance from the nerve segmentation to a positive stimulation point was 1.21 mm (IQR 0.81–3.27 mm) and 2.03 mm (IQR 0.99–3.84 mm) for the two annotators, respectively.Conclusionsrs-DWI may be used to acquire dMRI data of the cranial nerves within the posterior fossa.Clinical relevance statementReadout-segmented diffusion-weighted imaging and colour tissue mapping provide 1–2 mm spatially accurate imaging of the facial-vestibulocochlear nerve complex, enabling accurate preoperative localisation of the facial nerve. This study evaluated the technique in 5 healthy volunteers and 5 patients with vestibular schwannoma.Key Points• Readout-segmented diffusion-weighted imaging (rs-DWI) with colour tissue mapping (CTM) visualised the facial-vestibulocochlear nerve complex on 9/10 sides in 5 healthy volunteer subjects.• Using rs-DWI and CTM, the facial nerve was visualised in all 5 patients with vestibular schwannoma and within 1.21–2.03 mm of the nerve’s true intraoperative location.• Reproducible results were obtained on different scanners.

Oxidative stress and genotoxicity in oral epithelial cells from subjects undergoing orthodontic treatment with fixed appliances.

The objective of this work was to evaluate the impact of fixed orthodontic appliances on oxidative stress (OS) and genotoxicity from oral epithelial cells. Samples of oral epithelial cells were obtained from fifty-one healthy voluntary subjects who had an indication for orthodontic treatment. The samples were obtained before treatment and after 6 and 9months of treatment. OS was evaluated by quantitating 8-hydroxy-2'deoxyguanosine (8-OHdG) and by performing relative gene expression with antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). DNA degradation and instability were evaluated by multiplex polymerase chain reaction (PCR) and fragment analysis for human identification. The quantitation results showed that 8-OHdG increased during treatment, although this increase was not statistically significant. SOD increased by 2.5- and 2.6-fold after 6 and 9months of treatment, respectively. CAT increased by threefold after 6months of treatment, while after 9months of treatment, the expression level decreased to a level similar to that before treatment. DNA degradation was found in 8% and 12% of DNA samples after 6 and 9months of treatment, respectively, while DNA instability was detected in only 2% and 8% of DNA samples after 6 and 9months of treatment, respectively. The results showed that OS and genotoxicity slightly changed after treatment with a fixed orthodontic appliance; in addition, a biological adaptation response to the treatment may occur after 6months. OS and genotoxicity in the buccal cavity are risk factors for oral and systemic diseases. This risk may be reduced through antioxidant supplementation, by using thermoplastic materials, or by reducing the orthodontic treatment time.

Abstract P1-05-35: Identification of Circulating Tumor Cells captured by the FDA Cleared Parsortix® PC1 System from the Peripheral Blood of Metastatic Breast Cancer Patients using Immunofluorescence and Cytopathological Evaluations

Abstract Background: Circulating tumor cells (CTCs) captured from the blood of cancer patients may serve as a non-invasive surrogate source of tumor material to investigate tumor characteristics in real-time. The Parsortix® PC1 System, the first FDA-cleared medical device for the capture and harvest of CTCs from peripheral blood of metastatic breast cancer (MBC) patients for use in subsequent user-validated downstream analyses, enables the epitope independent capture of CTCs with diverse phenotypes based on cell size and deformability. In this study, CTCs isolated from the blood of MBC patients by the Parsortix® PC1 System were identified using an immunofluorescence (IF) based assay for detection of epithelial CTCs followed by Wright-Giemsa staining and cytomorphological review. The aim of this study was to determine the proportion of MBC patients and self-declared female healthy volunteers (HVs) that had one or more CTCs identified in the population of cells harvested from their peripheral blood by the Parsortix® PC1 System. Methods: Peripheral blood from 75 HVs and 77 patients with MBC was prospectively collected into K2EDTA tubes at the University of Rochester Medical Center. The blood collected from each subject (8.6±1.2mL) was processed on a Parsortix® PC1 System within 8 hours of collection. The cells harvested by the system were cytospun onto a charged slide and IF stained using an optimised antibody panel. The IF panel consisted of a nuclear dye (DAPI), positive selection markers targeting epithelial CTCs (Cytokeratins (CK) and EpCAM), and negative selection markers targeting white blood cells, such as lymphocytes, macrophages, granulocytes, monocytes, fibroblasts, and cells of megakaryoblastic potential. The stained slides were imaged using fluorescence microscopy and CTCs were defined as nucleated cells (DAPI+) that were positive for CK and/or EpCAM and negative for the blood lineage markers. The IF slides were subsequently stained with Wright-Giemsa and analysed by a qualified pathologist using light microscopy. Morphological features of malignant cells were used to define and identify CTCs. All laboratory testing and analysis was performed by operators blinded to the clinical status of each subject. Results: On the evaluable IF-stained slides, cells classified as CTCs based on their IF staining pattern were identified in 45.3% (34/75) of the MBC patients (range = 0 – 125 CTCs, mean = 7) and in 5.6% (4/71) of the HVs (range = 0 – 8 CTCs, mean = 0). No EpCAM+, CK- CTCs were identified in either MBC patients or HVs. In the 34 MBC patients with one or more CTCs observed, 70.6% had only CK+, EpCAM- cells, while the remaining 29.4% had at least one CK+, EpCAM+ cell. In the HVs, one out of the four CTC-positive donors had only CK+, EpCAM+ cells while the other three had only CK+, EPCAM- cells. On the evaluable Wright-Giemsa stained slides, cells classified as CTCs by the pathologist were identified in 57.1% (40/70) of the MBC patients (range = 0 – 41 CTCs, mean = 4) and in 4.4% (3/68) of the HVs (range = 0 – 14, mean = 0). Conclusions: This study demonstrated the ability of ANGLE’s Parsortix® PC1 System to capture and harvest CTCs from a significantly larger proportion of MBC patients compared to HV subjects. The presence of epithelial cells in subjects without diagnosed disease has been previously described in the literature, with their significance being unclear. This study also demonstrated that the cells harvested by the Parsortix® PC1 System can be successfully evaluated using both IF staining and Wright-Giemsa cytomorphological assessment for the identification of CTCs. Interestingly, a high proportion of the identified CTCs did not express EpCAM, further highlighting the limitations of using EpCAM-based approaches to capture CTCs. Citation Format: Mariacristina Ciccioli, Richard Moore, Kyu Kwang Kim, Negar Khazan, Michael C. Miller, Anne-Sophie Pailhes-Jimenez. Identification of Circulating Tumor Cells captured by the FDA Cleared Parsortix® PC1 System from the Peripheral Blood of Metastatic Breast Cancer Patients using Immunofluorescence and Cytopathological Evaluations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-35.

Stature Estimation from Finger Length by Regression Equation

Background: Estimation of stature from mutilated body parts, as in mass disasters and in many heinous crimes, has always intrigued the Forensic Pathologist and investigating agencies. Every part of human being grows in correlation to each other. Many authors have conducted various studies to find the correlation amongst various body parts and found positive correlation. The present study has correlated the length of all fingers with the stature of the individual. Methodology: The study was carried out on 150 healthy voluntary subjects (75 male and 75 female) of age 18-25 years. Instruments like Stadiometer and Vernier caliper was used for height and finger length measurements respectively. Result: Mean values of stature and finger length were larger in males as compared to females. Positive and strong correlation was found between stature and right index finger length in females and left middle finger length in males whereas right and left middle finger length in total subjects showed statistically significant correlation (P-value &lt; 0.05). Conclusion: The findings of the study can be useful only when an intact finger is examined. As very less information is available related to correlation between finger length and stature of individual, there is need of more research from different geographical locations.

Evaluation of neck pain in patients with chronic obstructive pulmonary disease

In chronic obstructive pulmonary disease(COPD) patients use extensively supplementary respiratory muscles such as trapezium and scalenes muscles in order to facilitate ventilation. These situations cause pain restricting by the upper body mobility and neck movements. This study was conducted to investigate the presence of neck pain in individuals with COPD and to compare it with healthy individuals. The study included sixty-two patients with COPD(COPD group) and sixty-two healthy volunteer subjects(control group). Visual Analog Scale(VAS) to determine pain intensity were used. Severity of neck disability level and the effects of pain on daily life were evaluated by Neck Disability Index and Nordic Musculoskeletal System Questionnaire. Chest mobility was assessed by circumference measurement. VAS of the COPD group was higher than the control group (p

Influence of emotion on precision grip force control: A comparison of pleasant and neutral emotion.

The present study aimed to investigate the impact of emotion on force steadiness of isometric precision pinch grip that is not direction-specific. Thirty-two healthy volunteer subjects participated in the present study. Subjects were divided into two experimental groups: pleasant image group and neutral image group. The isometric precision pinch grip task was performed for three times. Specifically, the first task was performed before pleasant or neutral picture viewing, the second task was performed immediately after picture viewing, further the third task was performed 30 seconds after the second task. During the isometric precision pinch grip task, participants were asked to exert pinch grip force at 10% of maximal voluntary contraction with visual feedback. The coefficient of variation of force production and normalized root mean square value of electromyography activity were calculated. After pleasant picture viewing, coefficient of variation of pinch force production and normalized root mean square value of electromyography was decreased. While, in the neutral image condition, theses variables were not altered. More important, compared to the neutral image condition, pleasant emotion led to lower coefficient of variation of pinch grip force production. These findings indicate that pleasant emotion improves force control of isometric precision pinch grip. Therefore, in clinical settings, the emotional state of patients may affect the effectiveness of rehabilitation and should be taken into consideration.

Results From a Multiple Ascending Dose Study in Healthy Volunteers of ACD856, a Positive Modulator of Neurotrophin Trk‐Receptors

AbstractBackgroundACD856 is a novel positive allosteric modulator of Trk‐receptors in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired. The aim of this study was to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of ACD856.Method24 healthy volunteer subjects were administered ACD856 or placebo as a daily oral solution over 7 days in 3 cohorts of stepwise ascending doses. After each dose, the safety, tolerability, and pharmacokinetics of ACD856 were assessed by an internal Safety Review Committee to decide on the escalation of dose to the next cohort.ResultThere were no clinically significant changes from baseline in mean ECG, vital signs, physical examination findings, clinical chemistry, haematology, coagulation, or urinalysis parameters after receiving the 7 daily doses of ACD856. Occasional individual abnormal laboratory values were observed but all were assessed as not clinically significant. Most of the reported adverse events were of mild intensity, only a few were of moderate intensity and none of severe intensity. No serious adverse events were reported.The pharmacokinetic data confirmed the findings from the previously performed single ascending dose (SAD) study, including that ACD856 has a rapid absorption, long half‐life, high bioavailability, and a linear dose‐dependent exposure. The Cmax at steady state was approximately 1.6‐fold higher than the initial dose administration and no time‐dependent clearance was observed. Moreover, initial CSF data confirms CNS exposure of ACD856. Further PK, CSF and pharmacodynamic data will be shown at the time of presentation.ConclusionACD856 was shown to be safe and well tolerated in man at the tested dose levels and with a suitable pharmacokinetic profile for further clinical development. In the next step, ACD856 will be evaluated in a phase Ib study with the aim to further assess pharmacodynamic effects.

DS-P3SNet: An Efficient Classification Approach for Devanagari Script-Based P300 Speller Using Compact Channelwise Convolution and Knowledge Distillation

Deep convolution neural network and its ensemble variant-based classification methods of P300 in the Devanagari script (DS)-based P300 speller (DS-P3S) have generated numerous training parameters. This is likely to increase the problems like computational complexity and overfitting. The recent attempts of researchers to overcome these problems are further deteriorating the accuracy due to the dense connectivity and channel-mix group convolution. Moreover, compressing the deep models in these attempts also found losing vital information. Therefore, to mitigate these problems, an efficient compact classification model called “DS-P3SNet” along with a knowledge distillation (KD) and transfer learning (TL) is proposed in this article. It includes: 1) extraction of rich morphological information across temporal region; 2) combination of channelwise and channel-mix-depthwise convolution (C2-DwCN) for efficient channel selection and extraction of spatial information with less number of trainable parameters; 3) channelwise convolution (Cw-CN) for classification to provide sparse connectivity; 4) knowledge distillation to reduce the tradeoff between accuracy and the number of trainable parameters; and 5) subject-to-subject transfer of learning to reduce subject variability. The trial-to-trial transfer of learning to reduce the tradeoff between the number of trials and accuracy. The experimentations were performed on a self-generated dataset of 20 words comprising of 79 DS characters collected from ten volunteer healthy subjects. An average accuracy of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$95.32~{\pm }~0.85$ </tex-math></inline-formula> % and <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$94.64~{\pm }~0.68$ </tex-math></inline-formula> % were obtained for subject-dependent and subject-independent experiments, respectively. The trainable parameters were also reduced approximately by 2–34 times compared to existing models with improved or equivalent performance.

Salivary Exosomal MicroRNA-486-5p and MicroRNA-10b-5p in Oral and Oropharyngeal Squamous Cell Carcinoma.

Background and Objectives: The research aimed at evaluating the capacity of salivary exosomal miR-10b-5p and miR-486-5p for oral and oropharyngeal cancer detection. Materials and Methods: The saliva samples were harvested from histopathological diagnosed oral and oropharyngeal squamous cell carcinoma patients and healthy volunteer subjects. The exosomes were isolated by differential ultracentrifugation and quantified by Nano Track Analysis. The microRNAs were extracted and quantified from salivary exosomes by quantitative Real-Time Polymerase Chain Reaction. Results: This research comprised fifty participants. When compared to healthy controls, salivary exosomal miR-486-5p was elevated and miR-10b-5p was reduced in oral and oropharyngeal squamous cell carcinoma. Moreover, miR-486-5p had a high expression level in stage II of cancer in comparison to the other cancer stages. The cancer samples presented an increased exosome dimension compared to the control samples. Conclusions: Salivary exosomal miR-10b-5p and miR-486-5p have an altered expression in oral and oropharyngeal cancer.

Modulation of gut microbiota: The effects of a fruits and vegetables supplement.

The consumption of an optimal amount of fruits and vegetables is known to improve physical fitness and physiological body functions. Healthy eating habits, including intake of fruits and vegetables, can modify gut microbiota. This study aimed to demonstrate the effectiveness of a formulated fruit and vegetable supplement (FVS) in modulating the antioxidant capacity and the gut microbiota composition. We enrolled 30 healthy volunteer subjects, matched for age, gender, BMI, and smoking habits, and randomized them into the FVS and the placebo (PLA) groups. Among the serum vitamins, the folic acid level was significantly higher (p = 0.001) in the FVS group than in the PLA group, whereas the vitamin B2 level was significantly higher in the PLA group than in the FVS group (p = 0.028). The antioxidant capacity, measured by using the oxygen radical absorbance capacity (ORAC) method, was also slightly higher in the FVS group than in the PLA group but did not reach statistical significance. The dietary intake, assessed by 24-h recalls, did not show any significant changes after the supplementation in both the groups. The gut microbiome composition, measured by 16S rDNA sequencing, showed no difference in both alpha and beta diversities, whereas the LEfse analysis revealed a microbial shift after the treatment, with a decreased abundance of the genus Ruminococcus from the Lachnospiraceae family (p = 0.009), and the unclassified genus from the family Erysipelotrichaceae (UC36, p = 0.003) in the FVS group compared with the PLA group (confirmed by SIAMCAT analysis, AUC = 74.1%). With a minor effect, the genus Faecalibacterium and unclassified genus and family from the order Lactobacillales (UC31) were also increased in the FVS group compared with the PLA group (p = 0.0474, p = 0.0352, respectively). SCFA measurement by gas chromatography–mass spectrometry showed an increased level of 2-methylbutyrate in the FVS group compared with the PLA group (p = 0.0385). Finally, the Spearman correlation analysis showed that in the FVS group, the genus Faecalibacterium positively correlated with 2-methyl butyrate (p = 0.040). In the PLA group, none of the significant bacteria correlated with either SCFA or serum biomarkers. The network analysis confirmed the positive correlation between genus Faecalibacterium and 2-methyl butyrate. We can conclude that the FVS in healthy individuals modified the gut microbiota composition and metabolites, and it can potentially contribute to reduce the pro-inflammatory response along with the antioxidant capacity.

Association between expression of ZBP1, AIM2, and MDA5 genes and severity of COVID-19.

Antiviral and inflammatory responses following the detection of the virus genome by nucleic acid sensors play a vital role in the pathogenesis and outcome of diseases. In this study, we investigated the ZBP1, AIM2, and MDA5 expression levels in COVID-19 patients with different intensities of the disease. 75 quantitative Real-Time PCR (qRT-PCR)-confirmed COVID-19 patients were included consecutively and divided into 3 groups of mild, severe, and critical based on the severity of the disease. Also, 25 healthy volunteer subjects were included. PBMCs were collected from the whole blood, and RNA was extracted using commercial kit. The expression of ZBP1, AIM2, and MDA5 genes was investigated using qRT-PCR technique. The mean age of the patients and healthy volunteers was 52.73±13.78 and 49.120±12.490, respectively. In each group, 13 out of 25 participants were male. The expression levels of ZBP1 (P=0.001), AIM2 (P=0.001), and MDA5 (P= 0.003) transcript were significantly higher in COVID-19 patients than the control group. The results also revealed that the expression levels of ZBP1, AIM2, and MDA5 were significantly higher in the critical and severe COVID-19 patients compared to those with mild disease (P<0.05). Moreover, regarding the gender, the expression levels of AIM2 and MDA5 were significantly elevated in male severe (P=0.04 and P=0.003, respectively) and critical (P=0.005 and P=0.0004, respectively) patients than the female ones. The results indicated that ZBP1, AIM2, and MDA5 genes might have an important role in the severity of COVID-19 disease. Moreover, the severity of COVID-19 disease in male and female patients might be related to AIM2, and MDA5 expression levels. More studies are recommended to be conducted to clarify this issue.

Interim Analysis of an Open-Label, Ascending-Dose, Phase 1 Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses of the Subcutaneously Administered Human Monoclonal Antibody Pozelimab in Combination with Single Doses of the Subcutaneously Administered siRNA Cemdisiran in Healthy Volunteers

Introduction. Pozelimab (REGN3918) and cemdisiran (ALN-CC5) are C5 inhibitors under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), and other diseases in which tissue damage is mediated by terminal complement pathway activity. Pozelimab is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, and cemdisiran is a synthetic small interfering RNA (siRNA) targeting C5 mRNA. Both agents can be administered via subcutaneous (SC) injection. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling based on observed data from both pozelimab and cemdisiran healthy volunteer studies (NCT03115996, NCT02352493) suggests that, by combining cemdisiran and pozelimab, the dose of both agents may be significantly reduced and the interval for SC dosing of pozelimab may be significantly increased.Objectives. To provide initial safety and tolerability data for a SC cemdisiran/pozelimab combination approach.Methods. This is an ongoing phase 1, open-label, parallel-dose cohort combination study (NCT04601844) assessing the safety and tolerability of ascending doses of SC pozelimab in combination with SC cemdisiran when administered on the same day or sequentially, on different days, in healthy subjects.Cohort Descriptions. Three parallel ascending-dose cohorts, consisting of six subjects each, were selected based on PK/PD modeling using observed data from both pozelimab and cemdisiran non-combination healthy volunteer studies: •Cohort 1: Cemdisiran low dose SC followed by pozelimab low dose SC, administered on different days•Cohort 2: Cemdisiran high dose SC followed by pozelimab low dose SC, administered on different days•Cohort 3: Cemdisiran high dose SC and pozelimab high dose SC, both administered on the same dayDose regimens were designed to limit the duration of >50% complement inhibition for no longer than 8 weeks, to mitigate risk in the enrolled healthy subjects. An optional additional Cohort 4 was included in the study design and this interim analysis was planned to review safety data to guide the decision regarding whether to enroll this cohort and to inform its dose selection.Interim Analysis: An interim safety analysis was performed with a data cut-off corresponding to study day 127 for Cohort 1, study day 85 for Cohort 2, and study day 71 for Cohort 3. Eighteen healthy volunteer subjects, nine female and nine male, with a mean age of 36 years (standard deviation 9.5 years), were randomized to one of the three cohorts. Demographic and baseline characteristics were comparable for subjects in each cohort. A total of 47 treatment emergent adverse events (TEAEs) were reported, with comparable distribution across cohorts, all mild to moderate in severity with no severe TEAEs. “Nervous system disorders” was the TEAE System Organ Class with the most subjects for all three cohorts, occurring in 12 (66.7%) of the 18 subjects. “Headache” was the most frequent MedDRA Preferred Term for all three cohorts, occurring in 11 (61.1%) of the 18 subjects. All TEAEs were recovered or recovering at the time of data cut-off, and there were no study drug discontinuations or interruptions of treatment due to TEAEs. There were no serious TEAEs or deaths. There were no clinically meaningful findings or treatment-emergent changes reported on the vital signs or laboratory safety tests.Conclusions: The combined SC administration of pozelimab and cemdisiran represents a promising approach to achieve therapeutically significant complement inhibition for extended durations. •An interim safety analysis demonstrated that the combined administration was generally safe and well tolerated.•Final PK/PD analysis from this healthy volunteer study will allow for assessment of agreement between modeling predictions and observed data, and further inform combination dose regimens for studies in target patient populations. Disclosuresvan Zyl: Regeneron Pharmaceuticals, Inc.: Current Employment. Weyne: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Harari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Levy: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Miller: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chen: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Meagher: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodgers: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Perlee: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morton: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Weinreich: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yancopoulos: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company.