Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

The objective of this study was to investigate the effect-site concentration (Ce) of remimazolam at loss of response (LOR) and recovery of response (ROR) in patients underwent general anesthesia using simulation. In addition, the relationships between patient’s factors and simulated Ce at LOR and ROR were examined. Methods: The medical records of 81 patients who underwent elective surgery under general anesthesia using remimazolam with simulation of Ce between August 4, 2021 and October 12, 2021, were retrospectively reviewed. Remimazolam was administered as an induction dose of 6 or 12 mg/kg/h until the patient became unresponsive, followed by 0.3–2 mg/kg/ h to maintain BIS values below 60. Simultaneously, simulations of manual infusion mode were performed using Asan Pump software and the Ce of remimazolam was simulated using the Schüttler model. Whenever infusion rate of remimazolam was manually changed, the simulated Ce was confirmed almost simultaneously. LOR and ROR, defined as unresponsive and eye-opening to verbal commands, respectively, were recorded in the Asan Pump program. Results: The median (1Q, 3Q) simulated Ce at LOR and ROR were 0.7 (0.5, 0.9) and 0.3 (0.2, 0.4) μg/ml, respectively. LOR was achieved in 1.9 min after remimazolam infusion with cumulative doses of 0.3 mg/kg. There was a significant relationship between age and simulated Ce at ROR (Ce at ROR = –0.0043 × age + 0.57, r = 0.30, P = 0.014). Conclusions: For optimal dosage adjustment, simulating Ce while administering remimazolam with a weight-based dose during anesthesia is helpful. Elderly patients may recover from anesthesia at lower Ce of remimazolam.

Purpose: The probability of recurrence of cancer after adjuvant or definitive radiotherapy in patients with human papillomavirus-negative (HPV(–)) head and neck squamous cell carcinoma (HNSCC) varies for each patient. This study aimed to identify and validate radiation sensitivity signature (RSS) of patients with HPV(–) HNSCC to predict the recurrence of cancer after radiotherapy. Materials and Methods: Clonogenic survival assays were performed to assess radiosensitivity in 14 HNSCC cell lines. We identified genes closely correlated with radiosensitivity and validated them in The Cancer Genome Atlas (TCGA) cohort. The validated RSS were analyzed by ingenuity pathway analysis (IPA) to identify canonical pathways, upstream regulators, diseases and functions, and gene networks related to radiosensitive genes in HPV(–) HNSCC. Results: The survival fraction of 14 HNSCC cell lines after exposure to 2 Gy of radiation ranged from 48% to 72%. Six genes were positively correlated and 35 genes were negatively correlated with radioresistance, respectively. RSS was validated in the HPV(–) TCGA HNSCC cohort (n = 203), and recurrence-free survival (RFS) rate was found to be significantly lower in the radioresistant group than in the radiosensitive group (p = 0.035). Cell death and survival, cell-to-cell signaling, and cellular movement were significantly enriched in RSS, and RSSs were highly correlated with each other. Conclusion We derived a HPV(–) HNSCC-specific RSS and validated it in an independent cohort. The outcome of adjuvant or definitive radiotherapy in HPV(–) patients with HNSCC can be predicted by analyzing their RSS, which might help in establishing a personalized therapeutic plan.

Background: The performance of the pulse oximeter was evaluated based on the ISO 80601-2-61:2011 (E) guidelines. This study aimed to determine whether the various finger probes of the MP570T pulse oximeter (MEK-ICS Co., Ltd., Korea) would provide clinically reliable peripheral oxygen saturation (SpO2) readings over a range of 70100% arterial oxygen saturation (SaO2) during non-motion conditions. Methods: Each volunteer (n = 12) was connected to a breathing circuit for the administration of a hypoxic gas mixture. For frequent blood sampling, an arterial cannula was placed in a radial artery. The following seven pulse oximeter probes were simultaneously attached to each volunteer’s fingers: (1) WA-100 reusable finger probe (MEDNIS Co., Ltd., Korea), (2) MDNA disposable finger probe (MEDNIS Co., Ltd.), (3) IS-1011 disposable finger probe (Insung Medical Co., Ltd., Korea), (4) CJ340NA disposable finger probe (CHUN JI IN Medical Co., Ltd., Korea), (5) NellcorTM OxiMax DS-100A reusable finger probe (Medtronic, USA), (6) NellcorTM OxiMax MAX-N disposable finger probe (Medtronic), and (7) OXI-PRO DA disposable finger probe (Bio-Protech Inc., Korea). Results: A total of 275 SpO2-SaO2 pairs were included in the analysis. The accuracy of the root mean square (Arms) of each probe was 2.83%, 3.98%, 3.75%, 6.84%, 3.43%, 5.17%, and 3.84%, respectively. Conclusions The MP570T pulse oximeter with WA-100 reusable, MDNA disposable, IS-1011 disposable, NellcorTM OxiMax DS-100A reusable, and OXI-PRO DA disposable finger probes meets an acceptable standard of SpO2 accuracy under non-motion conditions.

Background: The international organization for standardization (ISO) 80601-2-61 dictates that the accuracy ofa pulse oximeter should be assessed by a controlled desaturation study. We aimed to characterize the relationshipbetween the fraction of inspired oxygen (FiO2) and peripheral oxygen saturation (SpO2) using a turnover modelby retrospectively analyzing the data obtained from previous controlled desaturation studies. Materials and Methods: Each volunteer was placed in a semi-Fowler’s position and connected to a breathingcircuit to administer the hypoxic gas mixture containing medical air, oxygen, nitrogen, and carbon dioxide.Volunteers were exposed to various levels of induced hypoxia over 70-100% arterial oxygen saturation (SaO2).The study period consisted of two rounds of hypoxia and the volunteers were maintained in room air betweeneach round. FiO2 and SpO2 were recorded continuously during the study period. A population pharmacodynamicanalysis was performed with the NONMEM VII level 4 (ICON Development Solutions, Ellicott City, MD,USA). Results: In total, 2899 SpO2 data points obtained from 20 volunteers were used to determine the pharmacodynamiccharacteristics. The pharmacodynamic parameters were as follows: kout = 0.942 1/min, Imax = 0.802, IC50 =85.3%, γ = 27.3. Conclusion The changes in SpO2 due to decreases in FiO2 well explained by the turnover model with inhibitoryfunction as a sigmoidal model.

BACKGROUND: Inaccuracies associated with target-controlled infusion (TCI) delivery systems are attributable to both software and hardware issues, as well as pharmacokinetic variability. However, little is known about the inaccuracy of the syringe pump operating in TCI mode. This study aimed to evaluate the accuracy of the TCI pump based on international standards.METHODS: A test apparatus for accuracy evaluation of a syringe pump (PION TCI®, Bionet Co. Ltd.) was designed to apply the gravimetric method. Pump accuracy was evaluated in terms of deviation defined by the following equation: infusion rate deviation (%) = (Rate(mea) − Rate(est)) / Rate(est) × 100, where Rate(mea) is the infusion rate (ml/h) as measured by the gravimetric system, and Rate(est) is the infusion rate (ml/h) as estimated by the pump. An infusion rate representing TCI mode was determined from previous clinical trial data which evaluated the predictive performance of the pharmacokinetic model. The PION TCI pump used in that clinical trial was used to evaluate accuracy of the syringe pump. The distribution of infusion rates obtained from the clinical trial was calculated, and the median value of the distribution was determined as the representative value.RESULTS: The representative infusion rate representing TCI mode was 31 ml/h, at which the infusion rate deviation was 4.5 ± 1.6%.CONCLUSIONS: The inaccuracy of the syringe pump contributing to TCI system inaccuracy is insignificant.
Mesons ; Methods ; Syringes

BACKGROUND: Process dissociation procedure has been used to evaluate explicit and implicit memories. Two process-dissociation measurement models are described. METHODS: This prospective study evaluated intraoperative memory formation in Korean patients undergoing elective surgery under general anesthesia and its relation to the depth of hypnotic state. A total of 270 patients enrolled were randomly assigned to three groups based on Bispectral Index (BIS) values in the following ranges: 30 to 40, BIS 40 to 50, and BIS 50 to 60 according to the level of hypnotic depth induced by propofol or sevoflurane during the presentation of wordlists. When the level of hypnotic depth was maintained at the target BIS range, words were played for 15 minutes via headphones to patients. Within 24 hours after the word presentation, memory was assessed using an auditory word stem completion test. The probability of explicit and implicit memory was calculated using original and extended measurement models. Brice interviews were performed within 1 and 24 hours after surgery. RESULTS: A total of 119 patients who did not deviate from the target BIS range were included in the analysis. The 95% confidence interval (CI) of the probability of occurrence of implicit memory evaluated by the original model did not include zero. However, when the extension model was used, 0 was included in the 95% CI. Explicit memory evaluated via Brice interviews did not occur in any group. CONCLUSIONS: When BIS was maintained in the range of 30 to 60 during surgery, no explicit or implicit memory was observed.
Anesthesia ; Anesthesia, General ; Humans ; Intraoperative Awareness ; Memory* ; Propofol ; Prospective Studies

A variety of drugs are continuously or intermittently administered to patients during general or regional anesthesia. Pharmacotherapy should also receive priority compared with several treatment modalities including nerve blocks for chronic pain control. Therefore, pharmacology may be fundamental to anesthesia as well as pain medicine. Pharmacokinetic equations quantitatively evaluating drug transfer in the body are essential to understanding pharmacological principles. In mammillary compartmental models, pharmacokinetic equations are easily derived from a few simple principles. The kinetics of drug transfer between compartments is determined initially. Ordinary, linear differential equations are constructed based on the kinetics. The Laplace transforms of these differential equations are used to derive functions for the calculation of drug amounts in the central or effect compartments in the Laplace domain. The inverse Laplace transforms of these functions are used to obtain pharmacokinetic equations in time domain. In this review, a two-compartment mammillary pharmacokinetic model is used to derive pharmacokinetic equations using the aforementioned principles.
Anesthesia ; Anesthesia, Conduction ; Chronic Pain ; Drug Therapy ; Humans ; Kinetics ; Models, Theoretical ; Nerve Block ; Pharmacokinetics ; Pharmacology

BACKGROUND: The aim of this retrospective study was to compare the clinical performance of the modified Marsh model for propofol between underweight and normal-weight patients with Crohn's disease. METHODS: The medical records of 50 patients who underwent elective surgery for Crohn's disease were reviewed retrospectively. Propofol and remifentanil were administered using target effect-site concentration (Ce)-controlled infusion with the modified Marsh and Minto models. Target Ce values of propofol were adjusted within a range of 2.5–3 µg/ml to maintain a bispectral index (BIS) value of less than 60 during anesthesia maintenance. Dosages of anesthetic agents administered during surgery were compared between underweight and normal-weight patients. The infusion profiles of patients were applied as inputs to calculate the Ce values in the Schnider model. RESULTS: The total midazolam and remifentanil dosages required for underweight patients were higher than those required for normal-weight patients to maintain BIS values at less than 60 within a target propofol Ce range of 2.5–3 µg/ml. Simulation results suggested that the Schnider model may be an appropriate pharmacokinetic model for target-controlled infusion in underweight patients, as the clearance was consistently higher in the Schnider model than the modified Marsh model, particularly in underweight patients. CONCLUSIONS: The modified Marsh model might cause inadvertent propofol underdosing in underweight patients. Future studies are necessary to compare the predictive performance of the modified Marsh and Schnider pharmacokinetic models in underweight patients.
Anesthesia ; Anesthetics ; Crohn Disease* ; Humans ; Medical Records ; Midazolam ; Pharmacokinetics ; Propofol* ; Retrospective Studies ; Thinness* ; Wetlands*

BACKGROUND: Only two pharmacokinetic models of propofol are commercially available in the category of target controlled infusion (TCI) pumps: the modified Marsh and Schnider models. Both models were developed using propofol-LCT (long chain triglyceride). Depending on the excipient, the pharmacokinetic properties of fast-acting drugs, such as propofol, vary. Hence, it is necessary to evaluate the predictive performances of both models using propofol-MCT (medium chain triglyceride)/LCT, which is frequently used in clinical practice. METHODS: This was a computer simulation study, using data collected in the previous clinical analysis used to evaluate the predictive performance of a pharmacokinetic model of propofol-MCT/LCT. The infusion profiles for each patient were applied as inputs to both models. Simulations were performed using TCI software, and the simulated plasma concentrations of both models were calculated. RESULTS: In total, 217 plasma samples, obtained from 35 patients, were used to determine the predictive performance. The pooled median (95% CI) biases and inaccuracies were 9.6 (−1.7 to 15.4) and 32.1 (22.6–38.2) respectively, for the modified Marsh model, and −5.9 (−8.9 to −0.7) and 26.3 (21.7–27.8) respectively, for the Schnider model. CONCLUSIONS: Although the pooled bias and inaccuracy of the Schnider models were clinically acceptable (< 10–20% and approximately 20–30%, respectively), the Schnider model consistently produced negatively biased predictions. Conversely, even though the pooled inaccuracy of the modified Marsh model failed to meet this criterion, the value did not deviate significantly from the standard. Therefore, it is reasonable to conclude that both TCI models can be used for propofol-MCT/LCT.
Bias (Epidemiology) ; Computer Simulation ; Humans ; Pharmacokinetics ; Plasma ; Propofol ; Wetlands*