Adult Subjects Research Articles

Exposure Matching-Based Pediatric Dose Selection for Drugs with Renal Excretion - Lessons Learned from Pediatric Development of Direct Oral Anticoagulants.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

Bioequivalence Analysis of Ondansetron Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open-Label, Two-Period Crossover Phase I Study.

Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug. The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects. In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K2-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00-125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software. The geometric mean ratio (GMR) of the maximum observed concentration (Cmax), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC0-t), and the AUC from time zero to infinity (AUC0-∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75-97.79, 82.64-98.95, and 82.25-99.03, respectively. The GMRs of Cmax, AUC0-t, and AUC0-∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43-106.07, 87.35-100.24, and 87.35-100.68, respectively. The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.

Construction of new polygon mesh-type phantoms based on adult Japanese voxel phantoms.

To construct adult Japanese phantoms applicable to individual exposure dose assessments, we created adult Japanese polygon mesh-type male (JPM) and female (JPF) phantoms through modification of the adult Japanese voxel phantoms, JM-103 (male) and JF-103 (female). The body sizes and masses of organs, tissues, and organ contents in JPM and JPF were adjusted to the Japanese averages, except for those unimportant for radiation protection or risks. The JPM and JPF data were converted to tetrahedral mesh-type data and incorporated into the Particle and Heavy Ion Transport code System (PHITS) for dose calculations. The dosimetric characteristics of the JPM and JPF phantoms were validated by calculating their effective doses in the anterior-posterior geometry for the external irradiation of photons with energies of 0.01-20 MeV and compared with those of JM-103 and JF-103 or the reference values given in ICRP Publication 116. The results confirmed no problems applying JPM and JPF to dose assessments in adult Japanese subjects. Furthermore, it was found that JPM and JPF can also accurately calculate the absorbed doses for entire organs and high radiosensitive cell regions with thin, small, and complicated structures.

Perioperative adjuvant therapy with short course of dupilumab with ESS for recurrent CRSwNP.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with a high rate of disease recurrence following endoscopic sinus surgery (ESS). Type 2 disease is associated with a higher incidence of recurrence and is believed to impact disease resolution via interference with epithelial healing and pathogen immunity. We wished to verify if perioperative control of Type 2 inflammation with an anti-IL4/IL13 targeting monoclonal antibody and during the resolution period following surgery leads to better control of the disease long term. In this prospective, placebo-controlled, double-blinded trial. Thirty adult subjects with recurrent CRSwNP underwent ESS plus or minus 14 weeks of perioperative dupilumab, initiated 4 weeks (two injections) pre-ESS. Subjective and objective parameters of nasal patency, olfaction, quality of life (QoL), and adverse events were monitored up to 52 weeks post-ESS. Microbiological culture was performed to characterize pathogens colonization under both conditions. ESS safely improved subjective and objective measures of nasal patency, olfaction, and QoL in both groups. Olfaction was conserved longer in the dupilumab-treated group, with 33.3% of subjects presenting anosmia at 12 months after ESS in the dupilumab group compared to 50.0% with placebo. This was associated with persistent decreases in serum IgE, which were not seen with placebo treatment. No unusual safety signals were observed. Short-course adjuvant perioperative treatment with dupilumab is associated with improved long-term olfactory outcomes and persistent lowering of serum IgE.

Psychological conditions of caregivers of adult subjects with Prader-Willi syndrome

BackgroundPrader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder. Individuals with PWS face a range of cognitive, behavioral, and emotional challenges that require comprehensive and lifelong care, posing significant demands on their caregivers. The study is not only aimed to assess the psychological conditions of caregivers of adult subjects with PWS focusing on psychological distress and coping, but also to shed light on a crucial yet often overlooked aspect of healthcare. This study aims to compare the psychological well-being of individuals with PWS and their caregivers, providing valuable insights that can potentially improve the quality of care for these individuals. The sample recruited at the Division of Auxology, IRCCS Istituto Auxologico Italiano, was composed of 30 adult subjects with PWS (11 men and 19 women; mean age ± SD: 36.4 ± 10.31 years; mean Body Mass Index (BMI): 35.7 ± 8.92: kg/m2) and their caregivers (10 men and 20 women). To assess the psychological condition of caregivers, the Italian-validated versions of the Depression Anxiety and Stress Scale (DASS-21) and the Coping Orientation to the Problems Experiences (COPE) were used, while to assess the psychological well-being of individuals with PWS and their caregivers, the Italian validated version of the Psychological General Well-Being Index (PGWBI) was used.ResultsDepression (p < 0.001), Stress (p = 0.050), and Total score (p = 0.009) of DASS 21 were higher in the caregivers of subjects with PWS than in the general population. PGWBI scores of caregivers were significantly lower than in individuals with PWS in Positive Well-being (p < 0.001), General Health (p = 0.006), Vitality (p = 0.004), and the total score (p = 0.006). The depression subscale of PGWBI was higher in caregivers than in subjects with PWS. Correlations between the subscales of COPE and the total score of PGWBI in caregivers revealed that the Avoidance subscale of COPE had a negative significant correlation with the total score of PGWBI (p = 0.003).ConclusionsOur results highlighted several critical insights into the profound emotional and psychological challenges faced by the caregivers of individuals with PWS.

Gamma-glutamyl transferase: A potential biomarker for pancreas steatosis in patients with concurrent obesity, insulin resistance and metabolic dysfunction-associated steatotic liver disease.

To evaluate the relationship between serum gamma-glutamyl transferase (GGT) levels and fatty pancreas in subjects with concurrent obesity, insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) without a history of pancreatitis. From March 2019 to September 2021, 31 adult subjects with concurrent obesity and MASLD were recruited as part of the study investigating the biological impact of bariatric surgery and lifestyle modification on obesity. Chemical shift encoded MRI of the abdomen, LiverMultiScan, anthropometric, clinical and blood biochemistry analyses were performed prior to any intervention at baseline. GGT (p <.001) was significantly different between those 'with fatty pancreas' and 'without fatty pancreas' groups. GGT (p <.001) was significantly different between those 'with both metabolic syndrome and fatty pancreas' and those 'with metabolic syndrome but without fatty pancreas.' GGT (p <.001) was also significantly different between those 'with both diabetes and fatty pancreas' and those 'with diabetes but without fatty pancreas'. Logistic regression analysis showed that abnormal GGT levels (p = .010) and Hypertension (p = .045) were significant independent predictors of fatty pancreas. GGT was associated with fatty pancreas by an odds ratio 7.333 (95% [CI]: 1.467-36.664), while the AUROC of GGT in determining fatty pancreas was 0.849. Elevation in serum GGT might be a potential marker to identify fatty pancreas.

Image of Social World in Metaphors and Narratives of Adults

The image of the social world is a predictor of social behavior and its development during stable social transitivity, i.e., COVID-19 pandemic, economic crises, local military conflicts, etc. It can also be interpreted as a variable linguistic phenomenon. However, very little empirical research has featured its integral structural and content characteristics through the prism of narratives, metaphors, and social representations. The author used the methods of thematic narrative analysis and content analysis of metaphors to identify the narrative constructions used by adult subjects to describe their image of the social world. The data obtained were subjected to frequency analysis and hierarchical cluster analysis. The experiment involved 193 respondents aged 35–49 years old, employed in the city of Rostov-on-Don, Russia. In their metaphors and narratives, they described the social world as balancing between stability and dynamism, predictability and stochasticity, as well as endowed it with differentiation in the absence of universal laws. The rationality of the metaphors reflected the age identity while the subject of biographical narratives reflected the subjective adaptation to current social processes.

Innate immune response in COVID-19: single-cell multi-omics profile of NK lymphocytes in a clinical case series

BackgroundCOVID-19 pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) represents the biggest global health emergency in recent decades. The host immune response to SARS-CoV-2 seems to play a key role in disease pathogenesis and clinical manifestations, with Natural Killer (NK) lymphocytes being among the targets of virus-induced regulation.MethodsThis study performed a single-cell multi-omics analysis of transcripts and proteins of NK lymphocytes in COVID-19 patients, for the characterization of the innate immunological response to infection. NK cells were isolated from peripheral blood samples collected from adult subjects divided into 3 study groups: (1) non-infected subjects (Naïve group, n = 3), (2) post COVID-19 convalescent subjects (Healed group, n = 3) and (3) patients that were vaccinated against SARS-CoV-2 (Vaccine group, n = 3). Cells were then analysed by the BD Rhapsody System for the single-cell multi-omics investigation of transcriptome and membrane proteins.ResultsThe bioinformatic analysis identified 5 cell clusters which differentially expressed gene/protein markers, defining NK cell subsets as “Active NK cells” and “Mature NK cells”. Calculating the relative proportion of each cluster within patient groups, more than 40% of the Naïve group cell population was found to belong to Mature NKs, whereas more than 75% of the Vaccine group cell population belonged to the cluster of Active NKs. Regarding the Healed group, it seemed to show intermediate phenotype between Active and Mature NK cells. Differential expression of specific genes, proteins and signaling pathways was detected comparing the profile of the 3 experimental groups, revealing a more activated NK cell phenotype in vaccinated patients versus recovered individuals.ConclusionsThe present study detected differential expression of NK cell markers in relation to SARS-CoV-2 infection and vaccine administration, suggesting the possibility to identify key molecular targets for clinical-diagnostic use of the individual response to viral infection and/or re-infection.

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare and severe complication of SARS-CoV-2 infection that is characterized by multi-organ involvement and substantial inflammation. The immunological responses in MIS-C are not fully known. Antibody-mediated viral clearance in which innate immune cells interact with antibodies via their Fc receptors to remove the virus is an important mechanism for reducing SARS-CoV-2 viral load. However, little is known about how antibody-mediated cellular responses in MIS-C compared to acute COVID-19 infection and direct testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Therefore, we focused on the antibody-mediated cellular responses in MIS-C relative to children and adults that had acute COVID-19 infection with spectrum of symptoms. We hypothesized that cells that bind antibodies to help clear the virus are dysfunctional in MIS-C patients, preventing the virus from being fully cleared. Methods We collected samples from MIS-C children along with pediatric and adult subjects with a clinical spectrum of COVID-19 symptoms and uninfected controls. Through these controls, we can compare Fc-mediated antibody functions between ages and clinical symptoms. We utilized high dimension flow cytometry to assess phenotype and function of innate immune cells that bind to antibodies and sequencing to study Fc receptor genetic. This data was then correlated with matched clinical data. Results Monocytes in MIS-C were hyperfunctional for antibody-dependent cellular phagocytosis and production of proinflammatory cytokines. In contrast, natural killer (NK) cells in MIS-C were hypofunctional for antibody-dependent cellular cytotoxicity and cytokine production. To provide some preliminary insight into mechanism, we show multiple ways leading to decreased cytotoxicity for NK cells, including phenotypic exhaustion of NK cells, variants in CD16 (NK cell Fc receptor) genetics that reduce Fc binding to IgG, and cytokine-induced associations. Using a novel anti-CD16 novel bispecific reagent that we developed, we could rescue the hypofunctional antibody-mediated NK cell function in MIS-C to the same levels as control. Conclusion Together, our results reveal dysregulation in antibody-mediated responses that are unique to MIS-C and may contribute to the immune pathology of this disease. Specifically, we find that monocytes are hyperfunctional with NK cells are hypofunctional. In the case of the MIS-C antibody-mediated response, while it is likely that multiple pathogenetic mechanisms contribute to MIS-C, our data suggest an imbalance of the antibody-mediated cellular response as a mechanistic correlate of this rare, but life-threatening outcome of SARS-COV-2 in children. Our results highlight that targeted therapies to reduce viral burden and/or boost NK cells responses while decreasing cytokine levels may be effective in preventing MIS-C.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies

BackgroundSHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects.MethodsTwo randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg).ResultsSixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed.ConclusionsA single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development.Trial registrationNCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.

Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3months to < 18 years old) with chronic pain. Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference. The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM, and OCT1 on CLMO. Simulation scenarios includingdifferent CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8mg/kg, respectively. In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.

Efficacy and safety of a lipid-containing artificial tear compared with a non-lipid containing tear: a randomized clinical trial.

Dry eye disease (DED) is a prevalent condition affecting over 16 million patients in the USA. DED and the symptoms of ocular discomfort are debilitating and a significant burden on patients. If left untreated, DED can progress to cause severe pathology. Treatment is often initiated by patients without consulting a healthcare professional. This study investigated the safety and efficacy of a novel lipid-containing eye drop (BTC), which might better mimic the components of natural tears. This was a multicenter, randomized, double-masked, active control, two arm, parallel group study of eye drops in adult subjects with self-reported DED. Subjects were randomly assigned to BTC or control (commercially available non-lipid eye drops; NLED) arm and were followed for 30 days. Assessments using visual analog scale and patient-reported outcomes (PRO) questionnaires, non-invasive tear break up time, slit-lamp examination, and subject-reported ocular symptoms were conducted at baseline and at days 7 and 30. The primary endpoint was change in overall ocular comfort score from baseline to day 30. 158 subjects were randomized, of whom 130 completed the study per protocol (PP). Mean (SD) age was 47.8 (14.14) years. The mean (95% CI) change in overall comfort scores at the 30-day follow-up in the PP population was 21.4 (15.1, 27.7) for the test drop and 10.0 (3.9, 16.1) for the comparator. The mean (95% CI) treatment difference was 11.3 (2.6, 20.1); this met the pre-defined requirements for non-inferiority. There was no significant difference in the proportion of eyes with reported ocular symptoms between the groups. At day 7, the OR (95% CI) was 0.967 (0.528, 1.770) and at day 30 was 1.160 (0.610, 2.203). There were no Grade 3 or higher corneal edema, corneal neovascularization, corneal staining, conjunctival injection, tarsal abnormalities or any other biomicroscopy findings, and no corneal infiltrates observed during the study. The investigational lipid eye drop BTC was noninferior to the commercially available non-lipid comparator in all parameters measured and has the potential to provide an effective therapy for subjects with symptoms of dry eye who would benefit from a lipid-based artificial tear. NCT03995355 ( http://www. gov ), registered June 24, 2019.

Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling.

The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii. The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii. A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices. The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population. The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

Dose-dependent effects of transcranial photobiomodulation on brain temperature in patients with major depressive disorder: a spectroscopy study.

This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm2, medium: 300 mW/cm2, high: 850 mW/cm2) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy (1H-MRS). A voxel with a volume of 30 × 30 × 15 mm3 was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing 1H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant temperature differences for any t-PBM-active or sham groups post-irradiation (p-value range = 0.105 and 0.781). We also tested for potential differences in the pre-post variability of brain temperature in each group. As for t-PBM active groups, the lowest fluctuation (variance) was observed for the medium dose (σ2 = 0.29), followed by the low dose (σ2 = 0.47), and the highest fluctuation was for the high dose (σ2 = 0.67). t-PBM sham condition showed the overall lowest fluctuation (σ2 = 0.11). Our 1H-MRS thermometry results showed no significant brain temperature elevations during t-PBM administration.

Correlation of Reaction Time Differences in Naïve vs. Scientific Concept Conflict Task with the Stroop Interference Effect: Exploring the Concepts that “Moving Things are Alive” or “Stationary Things are Not”

ABSTRACTRecent studies have proposed that the automatic activation of naïve concepts, which persist even after learning scientific concepts, must be inhibited to successfully output scientific concepts. This model assumes that individual differences in inhibitory control (IC) within executive functions represent differences in conceptual change. However, the reported correlations between concept conflict and IC tasks are weak, casting doubt on this assumption. This study improves on previous methodologies by focusing on the performance of adult subjects in living and nonliving concept tasks presumed to have successfully achieved conceptual change and quantifying semantic‐level IC through the Stroop interference effect. The results revealed that the correlations between the Stroop interference effect and reaction time (RT) differences between conditions of the concept conflict task, which are assumed to represent the time required to inhibit naïve concepts, were relatively stronger compared with findings reported in previous studies. These findings suggest that individual differences in fluent inhibition of naïve concepts after acquiring scientific concepts align with those in IC, thereby supporting the validity of the inhibition model of naïve concepts.

A-328 Accuracy of the Glucose Test in the i-STAT® G Cartridge Using the i-STAT 1 System for Venous, Arterial and Capillary Whole Blood Specimens in Clinical Settings

Abstract Background Precise and accurate measurements of whole blood glucose levels are important for the diagnosis, monitoring and treatment of carbohydrate metabolism disorders, such as diabetes and hypoglycemia. This study demonstrates the accuracy of the glucose test in the i-STAT G cartridge with the i-STAT 1 System in arterial, venous, and capillary whole blood specimens in point of care or clinical laboratory settings. Methods The accuracy of the glucose test in the i-STAT G cartridge was assessed at external clinical sites in a method comparison study using whole blood specimens across the measurement range of 20 - 700 mg/dL. Specimens used in this study were venous, arterial, and capillary specimens prospectively collected under Institutional Review Board-approved informed consent or were leftover de-identified venous or arterial specimens. The study included venous whole blood samples from 164 adult subjects (≥ 18 years) and arterial whole blood samples from 173 adult subjects at 3 clinical sites, and capillary whole blood samples from 211 adult subject at 3 clinicals sites and 23 neonate subjects (birth to 28 days) at 2 clinical sites. For venous and arterial whole blood, samples were collected and tested in duplicate on the i-STAT G cartridge and on the i-STAT CHEM8+ cartridge (comparator). For capillary whole blood samples, adult fingerstick samples and neonate heel-stick samples were collected in capillary tubes and tested in singlicate on the i-STAT G cartridge and in singlicate on the epoc® Blood Analysis System (comparator). Passing-Bablok linear regression was performed for venous and arterial whole blood samples using the first replicate from the i-STAT G cartridge versus the mean result of the comparator, and for capillary whole blood samples (adult and neonate combined) using the singlicate result from the i-STAT G cartridge versus the singlicate result of the comparator. Results Passing-Bablok regression of i-STAT G cartridge results versus the comparator was used to calculate slope and correlation coefficient (r). Adult venous whole blood results had slope = 1.00 and r = 1.00, and adult arterial whole blood results had slope = 1.00 and r = 1.00. Adult and neonate capillary whole blood results had slope = 1.00 and r = 1.00. Conclusions These results demonstrate that the i-STAT 1 System delivers accurate glucose test results within ∼2 minutes using the i-STAT G cartridge for venous, arterial and capillary whole blood samples for adult and neonate subjects across a glucose range of 20-700 mg/dL when tested by end-users in a point of care or clinical laboratory setting. This study was funded by Abbott Laboratories.

A-329 Accuracy of the pH, PO2, and PCO2 Tests in the i-STAT® G3+ Cartridge Using the i-STAT 1 System for Venous, Arterial and Capillary Whole Blood Specimens in Clinical Settings

Abstract Background Precise and accurate measurements of blood gases are important for the diagnosis, monitoring and treatment of respiratory, metabolic, and acid-base disturbances. This study demonstrates the accuracy of the pH, partial pressure of oxygen (PO2), and partial pressure of carbon dioxide (PCO2) tests in the i-STAT G3+ cartridge with the i-STAT 1 System in arterial, venous, and capillary whole blood specimens in point of care or clinical laboratory settings. Methods The accuracy of the PO2, and PCO2 tests in the i-STAT G3+ cartridge was assessed at external clinical sites in a method comparison study using whole blood specimens across the measurement range for each test: pH 6.5-7.8, PO2 5-700 mmHg, PCO2 5.0-130.0 mmHg. Specimens used in this study were venous, arterial, and capillary specimens prospectively collected under Institutional Review Board-approved informed consent or were leftover de-identified venous or arterial specimens. The study included venous and arterial whole blood samples from ∼140 adult subjects (≥ 18 years) at 3 clinical sites, and capillary whole blood samples from ∼180 adult subject at 3 clinicals sites and ∼25 neonate subjects (birth to 28 days) at 2 clinical sites. The RapidPoint System was used as comparator. For venous and arterial whole blood, samples were collected and tested in duplicate on the i-STAT G3+ cartridge and in singlicate on the RapidPoint System. For capillary whole blood samples, adult fingerstick samples and neonate heel-stick samples were collected in capillary tubes and tested in singlicate on the i-STAT G3+ cartridge and on the RapidPoint System. Passing-Bablok regression was performed for venous and arterial whole blood samples combined, using the first replicate from the i-STAT G3+ cartridge versus the singlicate result from the comparator, and for capillary whole blood samples (adult and neonate combined) using the singlicate result from the i-STAT G3+ cartridge versus the singlicate result from the comparator. Results Passing-Bablok regression of i-STAT G3+ cartridge results versus the comparator was used to calculate slope and correlation coefficient (r). For adult venous and arterial whole blood results, pH had slope = 0.96 and r = 0.99, PO2 had slope = 1.05 and r = 1.00, and PCO2 had slope = 1.04 and r = 0.98. For adult and neonate capillary whole blood results, pH had slope = 1.02 and r = 0.98, PO2 had slope = 1.09 and r = 0.99, and PCO2 had slope = 1.07 and r = 0.96. Conclusions These results demonstrate that the i-STAT 1 System delivers accurate pH, PO2, and PCO2 test results with ∼2 minutes using the i-STAT G3+ cartridge for venous, arterial and capillary whole blood samples for adult and neonate subjects when tested by end-users in a point of care or clinical laboratory setting. This study was funded by Abbott Laboratories.

A-342 Precision Evaluation of the pH, PO2 and PCO2 tests in the i-STAT® G3+ Cartridge using the i-STAT 1 System for Venous, Arterial and Capillary Whole Blood Specimens in Clinical Settings

Abstract Background Precise and accurate measurements of blood gases are important for the diagnosis, monitoring and treatment of respiratory, metabolic, and acid-base disturbances. This study demonstrates the precision of the pH, partial pressure of oxygen (PO2), and partial pressure of carbon dioxide (PCO2) tests in the i-STAT G3+ cartridge with the i-STAT 1 System in arterial, venous, and capillary whole blood specimens in point-of-care or clinical laboratory settings. Methods The precision of the i-STAT pH, PO2, and PCO2 tests in the i-STAT G3+ cartridge was assessed at external clinical sites by end-users using whole blood specimens across the measurement range for each test: pH (6.500 - 7.800 pH units), PO2 (5 - 700 mmHg), PCO2 (5.0 - 130.0 mmHg). The study included venous whole blood samples from ∼140 adult subjects (≥ 18 years) and arterial whole blood samples from ∼140 adult subjects at 3 clinical sites. Each whole blood sample was run in duplicate on the i-STAT G3+ cartridge. In addition, ∼140 specimens were collected in capillary tubes using two fingerstick draws from adult subjects and ∼20 capillary heel-stick specimens were collected into two capillary tubes from neonate subjects (birth - 28 days) at two clinical sites. Specimens used in this study were prospectively collected venous, arterial, or capillary specimens under an Institutional Review Board approved informed consent or were de-identified leftover venous or arterial specimens. For each specimen type, duplicates from each subject were grouped into subintervals based on their mean values. The subintervals included the medical decision levels of 7.300, 7.350 and 7.450 pH units for pH, 30, 45 and 60 mmHg for PO2 and 35, 45, 50 and 70 mmHg for PCO2. The estimates of the pooled standard deviation (SD) and pooled coefficient of variation (%CV), as well as their respective 95% confidence intervals were calculated for each subinterval. Results Across all specimen types (excluding outliers), the pooled SD for pH ranged from 0.00591 - 0.01747 pH units for subintervals 6.500 - 7.300, &amp;gt;7.300 - 7.450, &amp;gt;7.450 - 7.800 pH units. For PO2, the pooled SD ranged from 0.71 - 3.76 mmHg for subintervals 10 - 40 mmHg and &amp;gt;40 - 50 mmHg and the pooled %CV ranged from 1.63 - 8.76 %CV for subintervals &amp;gt;50 - 100 mmHg, &amp;gt;100 - 250 mmHg and &amp;gt;250 - 700 mmHg. For PCO2, the pooled SD ranged from 0.000 - 1.709 mmHg for subintervals 5.0 - 35.0 mmHg, &amp;gt;35.0 - 50.0 mmHg and &amp;gt;50.0 - 62.5 mmHg and the pooled %CV ranged from 1.10 - 3.62 %CV for subinterval &amp;gt;62.5 - 130.0 mmHg. Conclusions The precision study demonstrated that the pH, PO2 and PCO2 tests in the i-STAT G3+ cartridge when tested using the i-STAT 1 System deliver precise results within ∼2 minutes for venous, arterial, and capillary whole blood patient specimens when tested by end users in a point-of-care or clinical laboratory setting. These studies were funded by Abbott Laboratories.

A-341 Precision Evaluation of the i-STAT® Glucose Test in the i-STAT G Cartridge using thei-STAT 1 System for Venous, Arterial and Capillary Whole Blood Specimens in Clinical Settings

Abstract Background Precise and accurate measurements of whole blood glucose levels are important for the diagnosis and treatment of patients suffering from diabetes and hypoglycemia. This study demonstrates the precision of the i-STAT G cartridge with the i-STAT 1 System in arterial, venous, or capillary whole blood in point of care or clinical laboratory settings. Methods The precision of the i-STAT G cartridge was assessed at external clinical sites by intended end users with whole blood specimens across the measurement range of 20 - 700 mg/dL. The study included testing venous whole blood samples from 154 adult (≥ 18 years) patients and arterial whole blood samples from 173 adult patients at three clinical sites. Each whole blood sample was run in duplicate on the i-STAT G cartridge. In addition, 139 capillary whole blood specimens from both adult subjects and neonate subjects (birth - 28 days) were collected and tested for capillary whole blood precision. Duplicate fingerstick draws were collected in capillary tubes from 119 adult subjects at two clinical sites and duplicate heel-stick specimens were collected in capillary tubes from 20 neonate subjects at two clinical sites. Specimens used in this study were prospectively collected venous, arterial, or capillary specimens under an Institutional Review Board approved informed consent or were de-identified leftover venous or arterial specimens. For each specimen type, duplicates from each subject were grouped into subintervals based on their mean values. The subintervals included the glucose medical decision levels of 45 mg/dL, 120 mg/dL and 180 mg/dL. The estimates of the pooled standard deviation (SD) and pooled coefficient of variation (%CV), as well as their respective 95% confidence intervals (CI) were calculated for each subinterval (20-90 mg/dL, &amp;gt;90-150 mg/dL, &amp;gt;150-250 mg/dL, &amp;gt;250-700 mg/dL or &amp;gt;250-400 mg/dL and &amp;gt;400-700 mg/dL, as applicable). The precision estimates for each subinterval were compared against an acceptance criteria of the greater of 3 mg/dL or 5% of the mean (mg/dL) of the subinterval. Results The whole blood precision was found to be less than or equal to 5.00 %CV for all subintervals for each specimen type. For venous specimens, the %CV ranged from 0.35% to 0.43%; for arterial specimens the %CV ranged from 0.26% to 0.46% and for capillary specimens (adult and neonate combined), the %CV ranged from 1.38% to 2.71%. Conclusions The study demonstrated that the i-STAT Glucose test in the i-STAT G cartridge when tested using the i-STAT 1 System delivers precise results within ∼2 minutes for venous, arterial, and capillary whole blood patient specimens across a glucose range of 20 - 700 mg/dL when tested by end users in a point of care or clinical laboratory setting. The studies were funded by Abbott Laboratories.

Age and Gender Related Changes on Total Antioxidant/Oxidant Status and Electrolyte Composition of Saliva in Individuals

BackgroundSaliva is used as an important biological material in the diagnosis and treatment of various diseases to collect easily, to be cheap, to have a minimal risk of infection. Here in that study we aimed to evaluate age and gender-related changes on total antioxidant/oxidant status and electrolyte composition of saliva levels in individuals. MethodsA total of 30 young adult (21.2± 2.47 years) and 14 adult (51.6±9.35 years) subjects were included in the study. Stimulated saliva samples were collected. Cortisol, amylase, oxidative stress biomarkers (total antioxidant status and total oxidant status) were measured by ELISA and spectrophotometric manual methods and electrolyte level of saliva samples were determined by autoanalyzer. ResultsSalivary concentrations of biomarkers of young adults were compared to adult subjects, there was a statistically significant difference between cortisol (μg/dL) (p=0.003), Ca+2(mg/dL) (p=0.004), TAS (mmol Trolox Equiv/L) (p=0.001), BUN (mg/dL) (p=0.02), Mg+2 (mg/dL) (p=0.02), and K+ (mmol/L) (p=0.05) levels , but there was no significant difference was found between uric acid (mg/dL) (p=0.44), Cl- (mmol/L) (p=0.07), amylase (ng/mL) (p=0.47), phosphate (mg/dL) (p=0.63), Na+(mmol/L)( p=0.21), and TOS (μmol H2O2 Equiv/L) ( p=0.70) levels. We evaluated salivary cortisol, amylase, and electrolyte levels of groups that we commented on their relationship between oxidant-antioxidant defense systems of the saliva and their correlations with age and gender. ConclusionsThis study could suggest the use of saliva samples to correlate with age and representing the levels of the most common biological parameters for routine use and antioxidant-oxidant enzymes for clinical trials.