Dissipation Kinetics and Risk Assessment of Diniconazole, Dinotefuran, Metconazole, and Tebuconazole in Raphanus sativus L.

This study investigated the degradation characteristics and conducted a risk assessment of four pesticides (Diniconazole, Dinotefuran, Metconazole, and Tebuconazole) in the leaves and roots of radish. Radish was cultivated in two greenhouse fields, and samples were collected at 0, 1, 2, 3, 5, 7, and 10 days after pesticide application. Sample analysis was performed using LC-MS/MS, and the recovery rates ranged from 70.1% to 118.6%. The biological half-life of Diniconazole was found to be 6.2 days (leaf and root), Dinotefuran was 5.3 days (leaf) and 4.6 days (root), Metconazole was 9.3 days (leaf) and 3.2 days (root), and Tebuconazole was 8.0 days (leaf) and 5.1 days (root). After comparing the maximum residue limits (MRL) of each pesticide in Korea with the residues during the pre-harvest interval (PHI), Diniconazole showed a Hazard quotient (HQ) exceeding 1, indicating potential risks for true consumers. Furthermore, Tebuconazole showed an HQ of 0.3 or higher, indicating a significant level of risk.

Pharmacokinetics and Safety of Single-Dose Amphotericin B Colloidal Dispersion in Healthy Chinese Subjects and Population Pharmacokinetic/Pharmacodynamic Analysis to Inform Clinical Efficacy in Invasive Infections Caused by Candida albicans.

PURPOSE: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. METHODS: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. FINDINGS: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. IMPLICATIONS: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.

Assessment of medical students' clinical performance using high-fidelity simulation: comparison of peer and instructor assessment.

BACKGROUND: High-fidelity simulators are highly useful in assessing clinical competency; they enable reliable and valid evaluation. Recently, the importance of peer assessment has been highlighted in healthcare education, and studies using peer assessment in healthcare, such as medicine, nursing, dentistry, and pharmacy, have examined the value of peer assessment. This study aimed to analyze inter-rater reliability between peers and instructors and examine differences in scores between peers and instructors in the assessment of high-fidelity-simulation-based clinical performance by medical students. METHODS: This study analyzed the results of two clinical performance assessments of 34 groups of fifth-year students at Ajou University School of Medicine in 2020. This study utilized a modified Queen's Simulation Assessment Tool to measure four categories: primary assessment, diagnostic actions, therapeutic actions, and communication. In order to estimate inter-rater reliability, this study calculated the intraclass correlation coefficient and used the Bland and Altman method to analyze agreement between raters. A t-test was conducted to analyze the differences in evaluation scores between colleagues and faculty members. Group differences in assessment scores between peers and instructors were analyzed using the independent t-test. RESULTS: Overall inter-rater reliability of clinical performance assessments was high. In addition, there were no significant differences in overall assessment scores between peers and instructors in the areas of primary assessment, diagnostic actions, therapeutic actions, and communication. CONCLUSIONS: The results indicated that peer assessment can be used as a reliable assessment method compared to instructor assessment when evaluating clinical competency using high-fidelity simulators. Efforts should be made to enable medical students to actively participate in the evaluation process as fellow assessors in high-fidelity-simulation-based assessment of clinical performance in situations similar to real clinical settings.

Validity of the GOLD 2017 classification in the prediction of mortality and respiratory hospitalization in patients with chronic obstructive pulmonary disease.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) released an updated document in 2017 that excluded the spirometric parameter in the classification of patients. The validity of this new classification system in predicting mortality and respiratory hospitalization is still uncertain. Methods: Outpatients (n=149) with chronic obstructive pulmonary disease (COPD) who underwent spirometry and six-minutes walking test from October 2011 to September 2013 were enrolled. The overall mortality and rate of respiratory hospitalization over a median of 61 months were analyzed. Kaplan-Meier survival analyses, receiver operaing curve analyses with areas under the curve (AUCs), and logistic regression analyses for GOLD 2007, GOLD 2011, GOLD 2017, and/or BODE index were performed to evaluate their abilities to predict mortality and respiratory hospitalization. Results: Forty-two (53.2%) patients in 2011 GOLD C or D group were categorized into 2017 GOLD A or B group. The odds ratios of GOLD 2017 group C and group D relative to group A were 7.55 (95% CI, 1.25-45.8) and 25.0 (95% CI, 6.01-102.9) for respiratory hospitalization. Patients in GOLD 2017 group A and group B had significantly better survival (log-rank test, p<0.001) compared with patients in group D; however, survival among patients in GOLD 2007 groups and GOLD 2011 groups was comparable. The AUC values for GOLD 2007, GOLD 2011, GOLD 2017, and BODE index were 0.573, 0.624, 0.691, 0.692 for mortality (p=0.013) and 0.697, 0.707, 0.741, and 0.754 for respiratory hospitalization (p=0.296), respectively. Conclusion: The new GOLD classification may perform better than the previous classifications in terms of predicting mortality and respiratory hospitalization.

Preliminary report on Sichuan golden snub-nosed monkeys (Rhinopithecus roxellana roxellana) at Laohegou Nature Reserve, Sichuan, China.

Comparative studies of subspecies under different ecological environments offer insights into intraspecies evolutionary adaptive mechanisms. Golden snub-nosed monkeys (Rhinopithecus roxellana) include three subspecies in China classified mainly by their morphological variations: R. r. roxellana (Sichuan and Gansu province), R. r. qinlingensis (Shaanxi province) and R. r. hubeiensis (Hubei province). These three subspecies live in three isolated area with different environments. Past works focused on the last two subspecies, but little information of habitat and behaviors of the nominated subspecies (R. r. roxellana) is available to date. We conducted a two-year study on the diet, activity budget, home range and social organization of 4 herds of R. r. roxellana, based on a total of 106 days' observation in Laohegou (LHG) Nature Reserve, Sichuan province. By using scan sampling method, our results suggest that the R. r roxellana feeds predominantly on leaves (77.5%), and spends more time feeding (40.0%) and resting (27.0%) while compared to the other two subspecies. Kernel Density Estimation Method based on GPS technology confirms that R. r roxellana has relatively larger home ranges (49.1 km2). The unit size (8.3 ± 3.5 individuals) of R. r roxellana is also smaller. Therefore, it is possible that differences in food availability in relation to habitats have important impacts on the feeding strategy and social system of the golden snub-nosed monkey. These results provide data to further explore intraspecific adaptations of living primates.

Methemoglobin-Based Biological Dose Assessment for Human Blood.

Methemoglobin is an oxidative form of hemoglobin in erythrocytes. The authors' aim was to develop a new biological dosimeter based on a methemoglobin assay. Methemoglobin in peripheral blood (of females or males) that was exposed to a Co source (0.20 Gy min) was quantified using an enzyme-linked immunosorbent assay. The dose range was 0.5-8.0 Gy. In a time-course experiment, the time points 0, 0.02, 1, 2, 3, 7, 15, 21, and 30 d after 4-Gy irradiation of heparinized peripheral blood were used. Methemoglobin levels in a lysed erythrocyte pellet from the irradiated blood of females and males increased with the increasing dose. Methemoglobin levels in female blood irradiated with γ-doses more than 4 Gy were significantly higher than those in male samples at the same doses. Two dose-response relations were fitted to the straight line: one is with the correlation coefficient of 0.98 for females, and the other is with the correlation coefficient of 0.99 for males. The lower limit of dose assessment based on methemoglobin is about 1 Gy. Methemoglobin levels in blood as a result of auto-oxidation increase after 7-d storage at -20 °C. The upregulation of methemoglobin induced by γ-radiation persists for ∼3 d. The absorbed doses that were estimated using the two dose-response relations were close to the actual doses. The results suggest that methemoglobin can be used as a rapid and accurate biological dosimeter for early assessment of absorbed γ-dose in human blood.

Single-Molecule Studies in Live Cells.

Live-cell single-molecule experiments are now widely used to study complex biological processes such as signal transduction, self-assembly, active trafficking, and gene regulation. These experiments' increased popularity results in part from rapid methodological developments that have significantly lowered the technical barriers to performing them. Another important advance is the development of novel statistical algorithms, which, by modeling the stochastic behaviors of single molecules, can be used to extract systemic parameters describing the in vivo biochemistry or super-resolution localization of biological molecules within their physiological environment. This review discusses recent advances in experimental and computational strategies for live-cell single-molecule studies, as well as a selected subset of biological studies that have utilized these new technologies.

Predictive Mortality Index for Community-Dwelling Elderly Koreans.

There are very few predictive indexes for long-term mortality among community-dwelling elderly Asian individuals, despite its importance, given the rapid and continuous increase in this population. We aimed to develop 10-year predictive mortality indexes for community-dwelling elderly Korean men and women based on routinely collected clinical data.We used data from 2244 elderly individuals (older than 60 years of age) from the southwest Seoul Study, a prospective cohort study, for the development of a prognostic index. An independent longitudinal cohort of 679 elderly participants was selected from the Korean Genome Epidemiology Study in Ansan City for validation.During a 10-year follow-up, 393 participants (17.5%) from the development cohort died. Nine risk factors were identified and weighed in the Cox proportional regression model to create a point scoring system: age, male sex, smoking, diabetes, systolic blood pressure, triglyceride, total cholesterol, white blood cell count, and hemoglobin. In the development cohort, the 10-year mortality risk was 6.6%, 14.8%, 18.2%, and 38.4% among subjects with 1 to 4, 5 to 7, 8 to 9, and ≥10 points, respectively. In the validation cohort, the 10-year mortality risk was 5.2%, 12.0%, 16.0%, and 16.0% according to these categories. The C-statistic for the point system was 0.73 and 0.67 in the development and validation cohorts, respectively.The present study provides valuable information for prognosis among elderly Koreans and may guide individualized approaches for appropriate care in a rapidly aging society.

Comparing the clinical outcomes in stereotactic body radiotherapy for lung tumors between Ray-Tracing and Monte-Carlo algorithms.

PURPOSE: The purpose of this study was to compare the clinical outcomes between the groups using Ray-Tracing (RAT) and Monte-Carlo (MC) calculation algorithms for stereotactic body radiotherapy (SBRT) of lung tumors. MATERIALS AND METHODS: Thirty-five patients received SBRT with CyberKnife for 47 primary or metastatic lung tumors. RAT was used for 22 targets in 12 patients, and MC for 25 targets in 23 patients. Total dose of 48 to 60 Gy was prescribed in 3 to 5 fractions on median 80% isodose line. The response rate, local control rate, and toxicities were compared between RAT and MC groups. RESULTS: The response rate was lower in the RAT group (77.3%) compared to the MC group (100%) (p = 0.008). The response rates showed an association with the mean dose to the gross tumor volume, which the doses were re-calculated with MC algorithm in both groups. However, the local control rate and toxicities did not differ between the groups. CONCLUSIONS: The clinical outcome and toxicity of lung SBRT between the RAT and MC groups were similar except for the response rate when the same apparent doses were prescribed. The lower response rate in the RAT group, however, did not compromise the local control rates. As such, reducing the prescription dose for MC algorithm may be performed but done with caution.

Optimal Drift Correction for Superresolution Localization Microscopy with Bayesian Inference.

Single-molecule-localization-based superresolution microscopy requires accurate sample drift correction to achieve good results. Common approaches for drift compensation include using fiducial markers and direct drift estimation by image correlation. The former increases the experimental complexity and the latter estimates drift at a reduced temporal resolution. Here, we present, to our knowledge, a new approach for drift correction based on the Bayesian statistical framework. The technique has the advantage of being able to calculate the drifts for every image frame of the data set directly from the single-molecule coordinates. We present the theoretical foundation of the algorithm and an implementation that achieves significantly higher accuracy than image-correlation-based estimations.

Nitric oxide synthase inhibitors: a review of patents from 2011 to the present.

INTRODUCTION: Nitric oxide synthases (NOSs) are a family of enzymes that play an essential role in synthesizing nitric oxide (NO) by oxidizing l-arginine. As previously reported, NO is a significant mediator in cellular signaling pathways. It serves as a crucial regulator in insulin secretion, vascular tone, peristalsis, angiogenesis, neural development and inflammation. Due to its important role, the inhibition of these vital enzymes provides, as tools, the opportunity to gain an insight into potential therapeutic applications targeting NOSs. AREAS COVERED: This paper reviews the patent literature between 2011 and mid-2014 that specified inhibitors of NOS family members as the significant targets. Google and Baidu search engines were used to find relevant patents and clinical information using NOSs or NOS inhibitor as search terms. EXPERT OPINION: Considerable recent progress has been made in the development of NOS inhibitors with pharmacodynamic and pharmacokinetic properties, and such development is likely to continue. The patented compounds attenuated mostly embodying evidence from in vitro and in vivo trials that demonstrate good potential for future clinical human trials and industrial applications. Furthermore, new techniques such as X-ray ligand crystallographic study and structure-activity relationship were popularly utilized, which give new insights for developing novel, safe, efficient and selective NOS inhibitors.

Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 µg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 µg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 µg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 µg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Assessment of corneal biomechanical behavior under posterior and anterior pressure.

PURPOSE: To determine the biomechanical response of the rabbit cornea to inflation under posterior and anterior pressure. METHODS: Twelve Japanese white rabbits were included in the study. A randomly selected eye from each animal was subjected to posterior pressure in an inflation test rig, and the other eye was subjected to anterior pressure after manually reversing its curvature. Specimens were loaded by cycles of pressure up to 40 mmHg, and the experimentally obtained pressure-deformation data were used to derive the stress-strain behavior of each eye using an inverse modeling procedure. RESULTS: The differences between the two groups in corneal thickness, diameter, and intraocular pressure (IOP) were not statistically significant (P=.935, .879 and .368, respectively). Corneas tested under posterior pressure displayed significantly higher stiffness (as measured by the tangent modulus) than those inflated by anterior pressure (P<.001). CONCLUSIONS: Cornea is a nonlinear viscoelastic tissue that presents different mechanical properties when tested under posterior and anterior pressure. The determination of the behavior under both forms of pressure could contribute to the construction of accurate finite element simulations of corneal behavior and the correction of tonometric IOP measurements. The difference in mechanical behavior between anteriorly and posteriorly loaded corneas in the study, although significant, could have been partly affected by the changes in microstructure possibly caused by changing corneal form to enable anterior loading.

Assessment of deceased donor kidneys using a donor scoring system.

PURPOSE: Marginal grafts should be used more actively in Asian countries where deceased donor transplantation is unpopular. We modified a quantitative donor scoring system proposed by Nyberg and his colleagues and developed a donor scoring system in order to assess the quality of deceased donor grafts and their prognostic value as an initial effort to promote usage of marginal donors. MATERIALS AND METHODS: We retrospectively evaluated 337 patients. RESULTS: A scoring system was derived from six donor variables [age, 0-25; renal function, 0-4; history of hypertension, 0-4; Human Leukocyte Antigen (HLA) mismatch, 0-3; body weight, 0- 1; cause of death, 0-3 points]. Donor grafts were stratified by scores: grade A, 0-10; grade B, 11-20; grade C, 21-30; and grade D, 31-40 points. Donor grades significantly correlated with estimated glomerular filtration rate (eGFR) at 6 months (A, 64.0 mL/min/1.73 m(2); B, 57.0 mL/min/1.73 m(2); C, 46.8 mL/min/1.73 m(2); p < 0.001). The five-year graft survival rate was also lower in grade C than grade A (74% vs. 93%, p = 0.002). Donors in grade C and D were regarded as marginal donors. The proportion of marginal donors was much lower in Korea, compared with data from the United Network for Organ Sharing (15.2% vs. 29%). CONCLUSION: Considering the scarcity of deceased donor kidneys and the relatively better graft outcome with lower grade-donors in Korea, it is worth increasing the usage of marginal grafts.