Adult Human Volunteers Research Articles

Reducing individual differences in task fMRI with OGRE (One-step General Registration and Extraction) preprocessing.

Volumetric analysis methods continue to enjoy great popularity in the analysis of task-related functional MRI (fMRI) data. Among these methods, the software package FSL (FMRIB, Oxford, UK) is omnipresent throughout the field. However, it remains unknown what advantages might be gained by integrating FSL with alternative preprocessing tools. Here we developed the One-step General Registration and Extraction (OGRE) pipeline to apply FreeSurfer brain extraction for simultaneous registration and motion correction ("one-step resampling"), for FSL volumetric analysis of fMRI data. We compared three preprocessing approaches (OGRE, FSL, and fMRIPrep) in a dataset wherein adult human volunteers (N=39) performed a precision drawing task during fMRI scanning. The three approaches produced grossly similar results, but OGRE's preprocessing led to lower inter-individual variability across the brain and greater detected activation in primary motor cortex contralateral to movement. This demonstrates that FreeSurfer tools and one-step resampling can improve FSL's volumetric analysis of fMRI data. The OGRE pipeline provides an off-the-shelf method to apply FreeSurfer-based brain extraction and one-step resampling of motion correction and registration for FSL analysis of task fMRI data.

2-iminobiotin, a selective inhibitor of nitric oxide synthase, improves memory and learning in a rat model after four vessel occlusion, mimicking cardiac arrest.

Survivors of out-of-hospital cardiac arrest (OHCA) experience between 30% and 50% cognitive deficits several years post-discharge. Especially spatial memory is affected due to ischemia-induced neuronal damage in the hippocampus. Aim of this study was to investigate the potential neuroprotective effect of 2-iminobiotin (2-IB), a biotin analogue, on memory and learning in a four-vessel occlusion model of global ischemia using the Water Maze test. Sprague-Dawley rats were randomly assigned to either sham operation (n = 6), vehicle treatment (n = 20), 1.1 (n = 15), 3.3 (n = 14), 10 (n = 14), or 30 mg/kg/dose 2-IB treatment (n = 15). Treatment was subcutaneously (s.c.) administered immediately upon reperfusion, at 12h, and at 24h after reperfusion. Memory function on day 32 was significantly preserved in all doses of 2-IB rats compared to vehicle, as was the learning curve in the 1.1, 3.3 and 30 mg/kg dose group. Adult rats treated s.c. with 3 gifts of 2-IB every 12 h in a dose range of 1.1-30 mg/kg/dose directly upon reperfusion showed significant improved memory and learning after four vessel occlusion compared to vehicle-treated rats. Since 2-IB has already shown to be safe in a phase 1 clinical trial in adult human volunteers, it is a suitable candidate for translation to a human phase 2 study after OHCA.

Repositioning forward-leaning vehicle occupants with a pre-pretensioner belt and a startle-based warning in pre-crash scenarios

Objective Pre-pretensioner (PPT) seatbelts have been found to be effective in controlling vehicle occupants’ motion response to disturbances in optimally positioned occupants, but it is not clear how the PPT performs when the occupant is initially forward leaning. Previous work demonstrated that an acoustic startling pre-stimulus (ASPS) reduced trunk out-of-position in sled-simulated pre-crash maneuvers. Therefore, the aim of this study was to determine if coupling the PPT with the ASPS could reduce the needed magnitude and rate of belt tension of the PPT to reposition forward leaning occupants to their optimal position within the seatbelt. Methods Sixteen belt-restrained adult human volunteers (8 males and 8 females) restrained by a 3-point seatbelt on a vehicle seat in a forward leaning posture on a sled simulating pre-crash braking (approx. 1 g of maximum acceleration and 0.3 s duration) were exposed to sled perturbations with three belt configurations (low and high force PPT and no PPT), and two warning conditions (ASPS and no-ASPS). Head and trunk positions were extracted from the 3D motion-capture data. Repeated measure ANOVAs were used to understand the effect of sex, PPT, ASPS, and repetition on head and trunk positions. A survival analysis was also performed to understand the probability of the occupants moving rearward in the different conditions. Results The probability of the head and trunk to move rearward from the initial position was greater with the PPT than without the PPT (p = 0.01) and with the high force level than the low force level (p = 0.01). The interaction effect of ASPS x PPT showed that with no PPT, there was a greater probability for the head to move rearward from the initial position with ASPS than without ASPS (p < 0.03). The trunk shows a similar trend to the head, but the ASPS vs no-ASPS differences were not statistically significant (p = 0.06). No sex differences were found. Conclusions The PPT, particularly the high level, may be an effective countermeasure on its own to reduce trunk and head out-of-position in forward leaning postures in pre-crash scenarios. The ASPS reduced the occupants’ head forward position when the PPT was not available.

Plant formulation ATRICOV 452 in improving the level of COVID-19 specific inflammatory markers in patients

ImportanceDue to the huge demand for healthcare facilities, there is a need for safe therapeutic intervention which can reduce the need for extensive healthcare support. ObjectiveIn phase 1, to determine the safety of plant formulation in healthy volunteers and in phase 2, to validate its potential to improve the level of COVID-19 specific inflammatory markers. DesignSetting, and Participants: The phase 1 single fasting dose study was conducted on 24 healthy adult human volunteers to evaluate the safety and tolerability of plant formulation. The usage of plant formulation in humans was found safe and encouraged conducting Phase 2 clinical trial to evaluate the efficacy in 100 COVID-19 patients along with the standard of care. InterventionsPhase 1: plant formulation capsule of 500 mg single dose; Phase 2: plant formulation 1 gm thrice a day for 14 days. ResultsDuring the Phase 1 trial no adverse event was observed and all organ systems were normal in function. During the Phase 2 trial, 100 patients underwent randomization, 50 were assigned to receive plant formulation, and 50 to receive placebo. Three patients in the placebo and two patients in the plant formulation group had dropped out of the study. Hence, the primary analysis population included 95 patients (48 allocated to plant formulation and 47 to placebo). The COVID-19-specific inflammatory markers improved faster and became normal in the plant formulation treatment group. No one needed hospital care or oxygen. Conclusionsand Relevance: The investigational product, plant formulation (ATRICOV 452) has been found to be safe in phases 1 and 2. Further, in the phase 2 trial, ATRICOV 452 was effective at the dose of 1 mg, three times a day dose frequency to improve the level of COVID-19 specific inflammatory markers. Trial registrationPhase 1: CTRI Registration number: CTRI 2020/09/027660 Phase 2: CTRI Registration number: CTRI/2021/01/030795.

Foetal amplitude-integrated electroencephalography: proof of principle of a novel foetal monitoring technique in adult volunteers

Peripartum hypoxic neonatal brain injury cannot be accurately predicted with current foetal monitoring techniques. Neonatal brain monitoring through amplitude-integrated electroencephalography (aEEG) is utilised when brain injury is suspected. Intrapartum aEEG assessment may improve detection of foetal hypoxia, facilitating earlier intervention. Using different engineered configurations in adult volunteers (n = 18), we monitored aEEG through application of two foetal scalp electrodes (FSEs). This aided development of a novel signal splitter, our Foetal heart rate and aEEG Monitoring System (FEMS) to monitor aEEG intrapartum. We then compared FEMS with gold-standard EEG monitoring simultaneously in two adults. Average percentage of interpretable aEEG signal was 61.3%, with the FEMS obtaining 72.15%. EEG signal on the aEEG device consistently showed a similar trace to gold standard EEG. This study demonstrates feasibility of aEEG monitoring in adults with FEMS utilising FSE inputs. An intrapartum foetal study utilising FEMS is due to commence shortly. IMPACT STATEMENT What is already known on this subject? Cardiotography, the current gold standard in foetal monitoring, is not associated with a reduction in cerebral palsy or infant mortality rates. Neonatal amplitude-integrated electroencephalography (aEEG) is an established method of monitoring brain function to guide commencing cooling therapy in suspected hypoxic brain injury. Intrapartum animal studies have illustrated foetal EEG changes reflecting evolving hypoxia. What do the results of this study add? This study demonstrates aEEG monitoring in human adult volunteers through application of foetal scalp electrodes and use of a novel signal splitter. This Foetal heart rate and aEEG Monitoring System (FEMS) provided a good overall percentage of aEEG signal, consistently showing a similar trace to gold standard EEG. What the implications are of these findings for clinical practice and/or further research? This proof of principle study provides the first step in developing a novel intrapartum foetal monitoring technique to monitor foetal aEEG in labour. This provides an exciting prospect of transferring well established neonatal monitoring techniques to facilitate accurate brain function assessment intrapartum and early intervention to reduce hypoxic brain injury. An intrapartum foetal study of this technology is due to begin in the near future.

Superior Bioavailability of a Novel Lutein and Zeaxanthin Formulation in Healthy Human Subjects.

IntroductionLutein (L) and zeaxanthin (Z) are carotenoids that are found in the macula of the human eye and are known to improve visual functions. However, poor bioavailability of supplemental L and Z poses a challenge to achieving significant benefits after consumption. We developed a novel patented formulation of L and Z (Ocusorb®) and demonstrated the improved bioavailability in a pharmacokinetic clinical study.MethodsNinety adult human volunteers were recruited in this randomized, double-blind, parallel, comparative bioavailability study. Volunteers were randomly assigned to receive single dose of 10 mg lutein and 2 mg zeaxanthin from test (LZO) or reference (LZC) formulations after breakfast. Blood samples were collected pre-dose at − 48, − 24, and 0 h and at 2, 4, 6, 8, 10, 12, 16, 20, 24, 48, and 72 h post-dose. Serum concentrations of L and Z were quantified by using a validated HPLC method. The LZO and LZC formulations were compared for L and Z on the basis of Cmax, AUC0–72, and AUC0–t.ResultsAll 90 subjects completed the study. The LZO group demonstrated significantly higher levels of L and Z in serum at several time points as compared to LZC group. The LZO group showed significantly higher bioavailability for lutein (2.5 times higher Cmax, 2.9 times higher AUC0–72, and 3.2 times higher AUC0–t) and zeaxanthin (1.8 times higher Cmax, 2.2 times higher AUC0–72, and AUC0–t) as compared to the LZC group. No safety issues were reported.ConclusionThe study results show superior bioavailability of lutein and zeaxanthin from our novel LZO formulation as compared to LZC. The enhanced bioavailability from the LZO formulation can be advantageous for individuals looking to quickly improve their L and Z status and enhance their vision performance.Trial Registrationhttp://ctri.nic.in/. Identifier: CTRI/2019/11/022082.

The interaction between endogenous GABA, functional connectivity, and behavioral flexibility is critically altered with advanced age.

The flexible adjustment of ongoing behavior challenges the nervous system’s dynamic control mechanisms and has shown to be specifically susceptible to age-related decline. Previous work links endogenous gamma-aminobutyric acid (GABA) with behavioral efficiency across perceptual and cognitive domains, with potentially the strongest impact on those behaviors that require a high level of dynamic control. Our analysis integrated behavior and modulation of interhemispheric phase-based connectivity during dynamic motor-state transitions with endogenous GABA concentration in adult human volunteers. We provide converging evidence for age-related differences in the preferred state of endogenous GABA concentration for more flexible behavior. We suggest that the increased interhemispheric connectivity observed in the older participants represents a compensatory neural mechanism caused by phase-entrainment in homotopic motor cortices. This mechanism appears to be most relevant in the presence of a less optimal tuning of the inhibitory tone as observed during healthy aging to uphold the required flexibility of behavioral action. Future work needs to validate the relevance of this interplay between neural connectivity and GABAergic inhibition for other domains of flexible human behavior.

Checklist to select contract Research Organization for early phase Bioavailability/Bioequivalence Clinical Studies in Healthy Adult Human Volunteers

Nowadays health agencies of regulated markets are becoming stringent regarding the bio-studies. So clinical/contract research organization (CRO) need to be selected carefully after their detailed assessment. As per requirement of bio-study CRO should be assessed with the study specific checklist of questions before awarding the bio-study. Questions related to various services of study like: Clinic phase, analytical phase, Pharmacokinetic and statistical phase, ethics approval, QA/QC, record handing etc. and related to CRO capabilities are discussed here with their relevance to conclude the abilities of CRO for successful execution of bio-study. Hence, this paper focuses all possible questions which need to be assessed before selection of CRO mainly for Bioavailability/Bioequivalence (BABE) study in healthy adult volunteers. Properly selected CRO will help for smooth execution of study and quality report and subsequently, hassle-free approval of dossier submitted to regulatory agency.

Optimized copolymeric microstructured platforms for smart controlled delivery of an anticoagulant drug: Preparation, in vitro assessment and crossover study in healthy adult human volunteers

In the present study, novel micro-structured copolymeric carriers were developed based on the grafting technology where acrylamide was chemically crosslinked with different types of Eudragits® (NE30D, L100, RL30D, or RS30D) based on a 41*21 factorial design. The designed systems efficiently engulfed the anticoagulant drug dipyridamole (DIP), within their formed entangled mesh of crosslinked polymeric network. An optimized formulation, ECOP4 with a desirability-value of 0.706, (in which DIP is engulfed within a copolymeric network of acrylamide and Eudragit® RS30D) showed high engulfment capacity (97.13 ± 1.34%) and controlled DIP release over 8 h. FTIR studies revealed absence of interactions between DIP and the formed copolymer. ECOP4 was further inserted within an easily-administered safe raft forming system composed of a mixture of LM-pectin and gellan gum. A pharmacokinetic study was performed using human volunteers to determine DIP concentration in their plasma after administering the designed formulation using the high-performance liquid chromatography (HPLC) method. A crossover design was adopted comparing the designed formulation with Persantin® 25 mg tablets as a reference standard. Superior results were obtained for the optimized formulation regarding the measured pharmacokinetic parameters (AUC0-24h, Cmax, and Tmax) with a 2.31 fold increase in relative bioavailability, which reveals the usefulness of the designed grafted dipyridamole formulation in site-specific delivery system.

Free-breathing Accelerated Cardiac MRI Using Deep Learning: Validation in Children and Young Adults.

Background Obtaining ventricular volumetry and mass is key to most cardiac MRI but challenged by long multibreath-hold acquisitions. Purpose To assess the image quality and performance of a highly accelerated, free-breathing, two-dimensional cine cardiac MRI sequence incorporating deep learning (DL) reconstruction compared with reference standard balanced steady-state free precession (bSSFP). Materials and Methods A DL algorithm was developed to reconstruct custom 12-fold accelerated bSSFP cardiac MRI cine images from coil sensitivity maps using 15 iterations of separable three-dimensional convolutions and data consistency steps. The model was trained, validated, and internally tested in 10, two, and 10 adult human volunteers, respectively, based on vendor partner-supplied fully sampled bSSFP acquisitions. For prospective external clinical validation, consecutive children and young adults undergoing cardiac MRI from September through December 2019 at a single children's hospital underwent both conventional and highly accelerated short-axis bSSFP cine acquisitions in one MRI examination. Two radiologists scored overall and volumetric three-dimensional mesh image quality of all short-axis stacks on a five-point Likert scale and manually segmented endocardial and epicardial contours. Scan times and image quality were compared using the Wilcoxon rank sum test. Measurement agreement was assessed with intraclass correlation coefficient and Bland-Altman analysis. Results Fifty participants (mean age, 16 years ± 4 [standard deviation]; range, 5-30 years; 29 men) were evaluated. The mean prescribed acquisition times of accelerated scans (non-breath-held) and bSSFP (excluding breath-hold time) were 0.9 minute ± 0.3 versus 3.0 minutes ± 1.9 (P < .001). Overall and three-dimensional mesh image quality scores were, respectively, 3.8 ± 0.6 versus 4.3 ± 0.6 (P < .001) and 4.0 ± 1.0 versus 4.4 ± 0.8 (P < .001). Raters had strong agreement between all bSSFP and DL measurements, with intraclass correlation coefficients of 0.76 to 0.97, near-zero mean differences, and narrow limits of agreement. Conclusion With slightly lower image quality yet much faster speed, deep learning reconstruction may allow substantially shorter acquisition times of cardiac MRI compared with conventional balanced steady-state free precession MRI performed for ventricular volumetry. © RSNA, 2021 Online supplemental material is available for this article.

Superior Bioavailability of a Patented Lutein &amp; Zeaxanthin Macular Carotenoid (MC) Formulation

Abstract Objectives Lutein (L) and Zeaxanthin (Z) are the only dietary carotenoids exclusively deposited in the macula and supplementation of these nutrients is associated with visual and cognitive benefits. Ensuring their bioavailability is an important consideration for efficacy. We developed and patented a unique LZ formulation designed for enhanced MC absorption (Test). Our objective was to clinically measure the bioavailability of this Test formulation in comparison to a commercially available formulation (Reference). Methods This randomized, double-blind, parallel study involved ninety healthy, adult human volunteers. All subjects stayed within the study facility three days before administration of the study products and three days post-dose. Volunteers consumed a single-dose of the Test or Reference product, each comprising of 10 mg L and 2 mg Z immediately after breakfast. Blood samples were collected prior to dosing @ −48, −24 &amp; 0 hrs and subsequently at 2, 4, 6, 8, 10, 12, 16, 20, 24, 48 and 72 hrs post-dose. L and Z levels were measured in serum using the validated HPLC method. The primary outcomes of the study included Cmax, AUC0–72, AUC0-T. Secondary outcomes included AUC0-12, AUC0-24, AUC0-48, AUC0-inf, Tmax and t1/2. Results All subjects completed the study with 100% compliance and no drop-outs. Serum L and Z levels were significantly higher in the Test group vs. the Reference group with a 2-fold and 1.5-fold greater absorption of L and Z levels, respectively, at all time points. Cmax, AUC0-72 and AUC0-T for serum L levels were 2.5, 2.9 and 3.2-fold greater, respectively, in the group receiving the Test formula. Similarly, the Cmax, AUC0-72 and AUC0-T for serum Z were also significantly greater with the Test formula. Finally, the Cmax and AUC parameters were significantly higher than the 80–125% criteria established by the FDA for bioequivalence confirming the superior bioavailability of Test product compared to Reference product. Conclusions These clinical findings support the superior bioavailability of this novel and uniquely formulated L Z dietary supplement product. The enhanced bioavailability behavior of this proprietary formulation can be advantageous for individuals looking to quickly improve their L and Z status and enhance their vision protection and performance. Funding Sources OmniActive Health Technologies.

A Recombinant BCG Vaccine Is Safe and Immunogenic in Neonatal Calves and Reduces the Clinical Disease Caused by the Respiratory Syncytial Virus.

The human respiratory syncytial virus (hRSV) constitutes a major health burden, causing millions of hospitalizations in children under five years old worldwide due to acute lower respiratory tract infections. Despite decades of research, licensed vaccines to prevent hRSV are not available. Development of vaccines against hRSV targeting young infants requires ruling out potential vaccine-enhanced disease presentations. To achieve this goal, vaccine testing in proper animal models is essential. A recombinant BCG vaccine that expresses the Nucleoprotein of hRSV (rBCG-N-hRSV) protects mice against hRSV infection, eliciting humoral and cellular immune protection. Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. Here, we evaluated the safety, immunogenicity, and protective efficacy of the rBCG-N-hRSV vaccine in a neonatal bovine RSV calf infection model. Newborn, colostrum-replete Holstein calves were either vaccinated with rBCG-N-hRSV, WT-BCG, or left unvaccinated, and then inoculated via aerosol challenge with bRSV strain 375. Vaccination with rBCG-N-hRSV was safe and well-tolerated, with no systemic adverse effects. There was no evidence of vaccine-enhanced disease following bRSV challenge of rBCG-N-hRSV vaccinated animals, suggesting that the vaccine is safe for use in neonates. Vaccination increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in PBMCs and lymph nodes at 7dpi. Furthermore, rBCG-N-hRSV vaccinated calves developed reduced clinical disease as compared to unvaccinated control calves, although neither pathology nor viral burden were significantly reduced in the lungs. These results suggest that the rBCG-N-hRSV vaccine is safe in neonatal calves and induces protective humoral and cellular immunity against this respiratory virus. These data from a newborn animal model provide further support to the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.

Retention, stability, iron bioavailability and sensory evaluation of extruded rice fortified with iron, folic acid and vitamin B12.

Fortification of rice with micronutrients using extrusion technology is considered a sustainable strategy to prevent nutritional deficiencies in general population. The objective of the present study is to assess the retention, stability and iron bioavailability from indigenously developed triple fortified rice (iron, folic acid and vitamin B12) during rinsing and different cooking methods. Further, we also assessed the acceptability of fortified rice in adult human volunteers. The retention of iron during rinsing with excess water was ≥90%, whereas folic acid and vitamin B12 levels were reduced by ~25% during rinsing. Watertight cooking of rice (in electric cooker or on flame) had no additional effect on the nutrient levels as compared with rinsed rice, implying their stability during cooking. However, cooking with excess water followed by decanting led to loss of 45% iron and ≥70% folic acid and vitamin B12. The dialyzable iron and ferritin synthesis in Caco‐2 cells was significantly (P < .01) higher from fortified rice compared with unfortified rice. In addition, inclusion of ascorbic acid significantly (P < .01) increased the iron bioavailability from the fortified rice. Triangle tests in adult human subjects revealed that there are no significant sensory differences among fortified and unfortified rice. Further, fortified rice consumption appears to bridge the gaps in dietary iron intake deficits in children and women of reproductive age. These results suggest that the iron‐, folic acid‐ and vitamin B12‐fortified rice has higher retention and stability of fortified nutrients and is acceptable for consumption in adult human volunteers.

Determination of lacosamide in human plasma by LC–MS/MS and its application to a human pharmacokinetic study

AbstractA highly sensitive, specific, and rapid liquid chromatography–tandem mass spectrometry method for determination of lacosamide in human plasma has been developed using lacosamide d6 as an internal standard with 50 µL of human plasma. Protein precipitation technique was used to extract the analyte from human plasma. The chromatographic separation was achieved on ZODIAC C18, 4.6 × 100 mm, 5 µm column using an isocratic mobile phase composition of acetonitrile and 0.1% formic acid buffer (80:20, v/v) at a flow rate of 0.9 mL/min. A detailed method validation was performed as per the recent US FDA guidelines and the calibration curve obtained was linear (r2 = 998) over the concentration range 0.075–25.461 µg/mL. API‐4500 liquid chromatography with tandem mass spectrometry was operated with multiple reaction monitoring mode during the entire analysis. The proposed method was successfully applied to a pharmacokinetic study in healthy, adult human volunteers after oral administration of lacosamide 200 mg film‐coated tablet under fed conditions.

Wide-vergence, multi-spectral adaptive optics scanning laser ophthalmoscope with diffraction-limited illumination and collection.

Visualizing and assessing the function of microscopic retinal structures in the human eye is a challenging task that has been greatly facilitated by ophthalmic adaptive optics (AO). Yet, as AO imaging systems advance in functionality by employing multiple spectral channels and larger vergence ranges, achieving optimal resolution and signal-to-noise ratios (SNR) becomes difficult and is often compromised. While current-generation AO retinal imaging systems have demonstrated excellent, near diffraction-limited imaging performance over wide vergence and spectral ranges, a full theoretical and experimental analysis of an AOSLO that includes both the light delivery and collection optics has not been done, and neither has the effects of extending wavefront correction from one wavelength to imaging performance in different spectral channels. Here, we report a methodology and system design for simultaneously achieving diffraction-limited performance in both the illumination and collection paths for a wide-vergence, multi-spectral AO scanning laser ophthalmoscope (SLO) over a 1.2 diopter vergence range while correcting the wavefront in a separate wavelength. To validate the design, an AOSLO was constructed to have three imaging channels spanning different wavelength ranges (543 ± 11 nm, 680 ± 11 nm, and 840 ± 6 nm, respectively) and one near-infrared wavefront sensing channel (940 ± 5 nm). The AOSLO optics and their alignment were determined via simulations in optical and optomechanical design software and then experimentally verified by measuring the AOSLO's illumination and collection point spread functions (PSF) for each channel using a phase retrieval technique. The collection efficiency was then measured for each channel as a function of confocal pinhole size when imaging a model eye achieving near-theoretical performance. Imaging results from healthy human adult volunteers demonstrate the system's ability to resolve the foveal cone mosaic in all three imaging channels despite a wide spectral separation between the wavefront sensing and imaging channels.

The effect of vehicle countermeasures and age on human volunteer kinematics during evasive swerving events

Objective: Emergency maneuvers such as evasive swerving often precede a crash. These events are typically low-acceleration, time-extended events where the inertial forces have the potential to cause changes to the occupant’s initial state (initial posture, position, muscle tension). The objective of this study was to systematically quantify the kinematics of pediatric and adult human volunteers during simulated pre-crash evasive swerving maneuvers and evaluate the effect of age and two vehicle-based countermeasures.Methods: A novel laboratory device was designed to expose subjects to non-injurious loading conditions that mimic real-world evasive swerving events. A four-cycle oscillatory lateral pulse with a maximum acceleration of 0.72 g (0.53 g for the first lateral movement in the first cycle) was applied. Forty seat belt restrained subjects across four age groups – 9-11 years (n = 10), 12-14 years (n = 10), 15-17 years (n = 10) and 18-40 years (n = 10) – were exposed to a series of test conditions (baseline, pre-pretensioned seat belt, sculpted vehicle seat with and without inflated torso bolsters) while their kinematics were captured using 3 D motion capture and muscle activity was recorded. Reaction loads were collected from the shoulder belt and footrest. Data are presented for the first cycle only.Results: Pre-pretensioning the shoulder belt before the onset of acceleration had the greatest restraining effect on the head and trunk for all age groups. In the pre-pretensioning trials, compared to baseline, subjects exhibited 34% and 33% less head excursion, into and out of the shoulder belt respectively. Similar reductions were observed with pre-pretensioning for trunk excursion (45% and 53% reductions, in and out of the belt respectively). Inflating seat torso bolsters reduced lateral kinematics relative to baseline but to a lesser extent than the pre-pretensioner (Head Out of belt: 11%; Head Into Belt: 32% and Trunk Out of Belt: 15%; Trunk Into Belt: 27%). Although there was no overall effect of age on the magnitude of lateral displacement, different age groups employed various neuromuscular strategies to control their kinematics.Conclusion: A pre-pretensioner was an effective vehicle countermeasure during evasive swerving maneuvers as it substantially reduced lateral head and trunk displacement for all age groups. Providing lateral restraint via a sculpted vehicle seat was less effective as the geometry of the torso bolsters when inflated did not provide substantial lateral support.

Evaluating the Antimicrobial Efficacy of an Innovative, Novel Herbal Formulation on Dental Caries and Plaque Microorganisms - A Clinical Research.

To develop a novel, innovative herbal formulation that can prevent both dental caries and periodontal diseases simultaneously. This clinical research involved in vitro studies to determine Minimum Inhibitory Concentration (MIC) of combinations of Acacia nilotica, Murraya koenigii Linn Sprengel, Eucalyptus hybrid, and Psidium Guajava on dental caries and plaque bacteria followed by evaluation of phytochemical constituents in these plant extracts. MIC was determined using broth dilution method. Then, an animal experimentation was carried out to determine median lethal dose and adverse drug reactions following single oral administration of polyherbal extract which was followed by human experimentation. A short term double blind randomized double blind study on 34 adult human volunteers was undertaken to assess antiplaque efficacy of a novel polyherbal mouth rinse using 0.2% chlorhexidine as positive control.MIC of the polyherbal combinations on S. mutans, S. sanguis, S. salivarius, L. acidophilus, F. nucleatum and P. gingivalis was found to be 0.25%, 0.05% , 0.05%, 0.1%, 0.25% and 0.25% respectively. Median lethal dose (LD50) for herbal formulation was found to be more than 2000mg/kg body weight. In vivo study found that the polyherbal mouth rinse group had lesser plaque buildup, S mutans and total viable count in comparison with saline group with no significant difference in plaque build-up and total viable count between polyherbal rinse group and 0.2% chlorhexidine. Polyherbal mouth rinse containing Acacia nilotica, Murraya koenigii L.sprengel, Eucalyptus hybrid and Psidium guajava was effective against dental caries and plaque induced dental diseases.

S100B Serum Level is Independent of Moderate Alcohol Intoxication.

In Germany, among patients with minor head injury (MHI), the incidence of coexisting alcohol intoxication is indicated up to 50%. The neurological symptoms of patients with MHI may be caused or altered by alcohol intoxication, this could mislead to further, potential harmful, diagnostic steps or to misinterpretation of the symptoms and to non-execution of necessary treatments. In order to decide which patients need further diagnostics by CCT, S100B has been proposed as a potential selection criterion. On the other hand, studies have hypothesized that alcohol intoxication may lead to elevated S100B serum levels. Therefore, the present study aims to investigate the relationship between the blood ethyl alcohol concentration and the S100B serum concentration in an experimental setting in young human adult volunteers. In a cohort of 58 healthy volunteers, serum S100B concentration and blood ethyl alcohol concentration were measured before and after liberately drinking alcohol. The study was approved by the local Ethics Committee of the Medical Faculty Mannheim (Ethics Committee II, AZ 2012-272 N-MA). Instantaneous analysis of the samples was carried out using state-of-the art automated measuring systems. (Analyzer Cobas e411, Roche and Analyzer Dimension Vista 1500, Siemens). After drinking, alcohol levels ranged from 0,23 to 1,92 g/l. The S100B value ranged from to 0,021 to 0,115 µg/l after alcohol consumption (S100B standard value < 0,11 µg/l). By calculating the Pearson correlation of empirical correlation after drinking alcohol with r = 0.01181, a correlation between serum S100B concentration and ethyl alcohol concentration is not probable. The S100B concentrations were independent on the alcohol intake in low to medium alcohol levels. A relevant alcohol blood concentration (~ 1 g/l), in otherwise healthy volunteers, does not affect the serum concentration of S100B. S100B may be a useful brain injury marker in low to moderate drunken patients.

Attentional amplification of neural codes for number independent of other quantities along the dorsal visual stream.

Humans and other animals base important decisions on estimates of number, and intraparietal cortex is thought to provide a crucial substrate of this ability. However, it remains debated whether an independent neuronal processing mechanism underlies this 'number sense', or whether number is instead judged indirectly on the basis of other quantitative features. We performed high-resolution 7 Tesla fMRI while adult human volunteers attended either to the numerosity or an orthogonal dimension (average item size) of visual dot arrays. Along the dorsal visual stream, numerosity explained a significant amount of variance in activation patterns, above and beyond non-numerical dimensions. Its representation was selectively amplified and progressively enhanced across the hierarchy when task relevant. Our results reveal a sensory extraction mechanism yielding information on numerosity separable from other dimensions already at early visual stages and suggest that later regions along the dorsal stream are most important for explicit manipulation of numerical quantity.