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.

Background: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. Methods: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation–Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. Results: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence inter val [CI], 0.55– 0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% 0.56–0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79–1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65–2.17; P = 0.582). Conclusion In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.

Background: As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. Results: In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. Conclusions This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

We studied the effects of acetylcholinesterase inhibitors, donepezil and galantamine, and an N-methyl-D-aspartate (NMDA) receptor blocker, memantine, on sleep-wake architecture in rats. Screw electrodes were chronically implanted into the frontal and parietal cortex for the electroencephalography (EEG). EEG was recorded with a bio-potential amplifier for 8 h from 09:30 to 17:30. Vibration was recorded to monitor animal activity with a vibration measuring device. Sleep-wake states such as wake (W), slow-wave sleep (S) and paradoxical or rapid eye movement sleep (P), were scored every 10 sec by an experimenter. We measured mean episode duration and number of episode to determine which factor sleep disturbance was attributed to. Donepezil and memantine showed a significant increase in total W duration and decreases in total S and P duration and delta activity. Memantine showed increases in sleep latency and motor activity. Changes of S and P duration in memantine were attributed from changes of mean episode duration. Galantamine had little effect on sleep architecture. From these results, it is showed that galantamine may be an anti-dementia drug that does not cause sleep disturbances and memantine may be a drug that causes severe sleep disturbance.
Animals ; Cholinesterase Inhibitors ; Electrodes ; Electroencephalography ; Galantamine ; Indans ; Memantine ; Motor Activity ; N-Methylaspartate ; Organothiophosphorus Compounds ; Piperidines ; Rats ; Sleep, REM ; Vibration

Although quantitative EEG parameters, such as spectral band powers, are sensitive to centrally acting drugs in dose- and time-related manners, changes of the EEG parameters are redundant. It is desirable to reduce multiple EEG parameters to a few components that can be manageable in a real space as well as be considered as parameters representing drug effects. We calculated factor loadings from normalized values of eight relative band powers (powers of 0.5, 1.0~2.0, 2.5~4.0, 4.5~5.5, 6.0~8.0, 8.5~12.0, 12.5~24.5, and 25~49.5 Hz bands expressed as ratios of the power of 0.5-49.5 Hz band) of EEG during pre-drug periods (11:00~12:00) by factor analysis and constructed a two-dimensional canonical space (reference canonical space) by canonical correlation analysis. Eight relative band powers of EEG produced by either physostigmine or yohimbine were reduced to two canonical scores in the reference canonical space. While changes of the band powers produced by physostigmine and yohimbine were too redundant to describe the difference between two drugs, locations of two drugs in the reference canonical space represented the difference between two drug's effects on EEG. Because the distance between two locations in the canonical space (Mahalanobis distance) indicates the magnitude of difference between two different sets of EEG parameters statistically, the canonical scores and the distance may be used to quantitatively and qualitatively describe the dose-dependent and time-dependent effects and also tell similarity and dissimilarity among effects. Then, the combination of power spectral analysis and statistical analysis may help to classify actions of centrally acting drugs.
Animals ; Electroencephalography ; Factor Analysis, Statistical ; Physostigmine ; Rats ; Yohimbine

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.
Activin Receptors, Type II/*genetics ; Adult ; Alleles ; Angiography ; Antigens, CD/*genetics ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; Female ; Genetic Predisposition to Disease ; Humans ; Korea ; Male ; Middle Aged ; *Mutation ; Pedigree ; Receptors, Cell Surface/*genetics ; Smad4 Protein/*genetics ; Telangiectasia, Hereditary Hemorrhagic/diagnosis/*genetics/pathology ; Tomography, X-Ray Computed ; Young Adult

PURPOSE: Many medical centers routinely culture bronchoscopy samples for Mycobacterium tuberculosis, even when tuberculosis is not strongly suspected. The value of this practice, however, is controversial. We evaluated the role of that procedure in the diagnosis of pulmonary tuberculosis in an intermediate tuberculosis-burden country. PATIENTS AND METHODS: A prospective, observational study was conducted in a tertiary referral center and included 733 consecutive patients who underwent bronchoscopy examination. RESULTS: M. tuberculosis was isolated in 47 patients (6.4%). According to radiographic features, the rate of positive culture for M. tuberculosis was relatively high in patients with atelectasis (5/33, 15.2%) and those with pulmonary infiltrations of suspicious infections (26/183, 14.2%). M. tuberculosis was isolated even in patients with pulmonary masses (9/266, 3.4%) and those with pulmonary nodules (5/175, 2.9%). In 16/47 (34.0%) patients with positive cultures for M. tuberculosis, active pulmonary tuberculosis was not suspected at the time of bronchoscopy. CONCLUSION: These results suggest that routinely culturing for M. tuberculosis during bronchoscopy is still useful in the diagnosis of pulmonary tuberculosis in an intermediate tuberculosis-burden country.
Adult ; Aged ; Bacteriological Techniques/methods ; Bronchoscopy ; Female ; Humans ; Lung/microbiology/pathology ; Lung Neoplasms/microbiology ; Male ; Middle Aged ; Mycobacterium tuberculosis/growth & development/*isolation & purification ; Prospective Studies ; Pulmonary Atelectasis/microbiology ; Reproducibility of Results ; Sensitivity and Specificity ; Tuberculosis, Pulmonary/*diagnosis/microbiology

BACKGROUND: The purpose of this study was to survey the nasal colonization of methicillin-resistant Staphylococcus aureus (MRSA) among the patients admitted in a medical intensive care unit (MICU) and analyze risk factors associated with the colonization. METHODS: The study was carried out on patients admitted into the MICU in a 1,250-bed tertiary care university hospital from January through December 2006. Nasal surveillance cultures were obtained from patients within 24 hours of admission to the unit. Data were analyzed retrospectively by the review of medical records. RESULTS: A total of 312 patients were screened with active nasal cultures; 36 patients (11.6%) were positive for MRSA. Of these, 22 (7.1%) were positive in the nasal cultures only and 14 (4.5%) were positive in the cultures of other specimens (13, sputum; 1, joint fluid) in addition to the nasal swabs. Among the risk factors for MRSA nasal colonization were sex (man), route of admission (from other ICUs or wards), a history of ICU admission during the recent 12 months, and prolonged hospital days in ICU. CONCLUSION: MRSA nasal carrier rate was found higher in this study than in those reported in the literature. Most of the patients colonized with MRSA in the nostril were not colonized with the organism elsewhere in the body. Whether or not active surveillance for MRSA should be performed would depend on the nasal colonization rate of the patients at the time of admission to the ICU.
Colon* ; Humans ; Intensive Care Units* ; Critical Care* ; Joints ; Medical Records ; Methicillin Resistance* ; Methicillin-Resistant Staphylococcus aureus* ; Retrospective Studies ; Risk Factors ; Sputum ; Tertiary Healthcare

BACKGROUND: Bronchoscopy in patients on mechanical ventilation is being performed much more frequently. However, there is little data on the changes in physiologic parameters and no established mechanical ventilation protocol during bronchoscopy. A decreasing or the removal of positive end-expiratory pressure (PEEP) during bronchoscopy may precipitate severe hypoxemia and/or derecruitment. METHODS: Our standardized mechanical ventilation protocol, without changing the PEEP level, was used during bronchoscopy. The physiological parameters were measured during the bronchoscopic procedure. RESULTS: During bronchoscopy, respiratory acidosis, elevation of peak pressure, elevation of heart rate and auto-PEEP were developed, but were reversible changes. Procedure-related gross barotraumas or other severe complications did not developed. CONCLUSION: No serious complications developed during bronchoscopy under our standardized mechanical ventilation protocol when the PEEP level remained unchanged. The procedure time should be kept to a minimum to decrease the exposure time to undesirable physiological changes.
Acidosis, Respiratory ; Anoxia ; Barotrauma ; Bronchoscopes ; Bronchoscopy* ; Heart Rate ; Humans ; Intensive Care Units ; Intubation, Intratracheal ; Positive-Pressure Respiration ; Positive-Pressure Respiration, Intrinsic ; Pulmonary Gas Exchange ; Respiration, Artificial ; Respiratory Mechanics

BACKGROUND: Microscopic examination of sputum smears for acid-fast bacilli (AFB) is the most important and rapid diagnostic test for pulmonary tuberculosis. However, the AFB observed on the smear may represent either M. tuberculosis or nontuberculous mycobacteria (NTM). This study examined the clinical usefulness of a polymerase chain reaction test for M. tuberculosis (TB-PCR) for the differentiation of pulmonary tuberculosis and NTM lung disease in patients with smear-positive sputums in a tertiary hospital in Korea. MATERIAL AND METHODS: From January, 2003 to December, 2003, 826 AFB smear-positive and culture-positive sputum specimens were collected from 299 patients. RESULTS: NTM were recovered from 26.6% (220/826) of the smear-positive sputum specimens and 23.4% (70/299) of the patients with smear-positive sputum. All the patients with isolated NTM had clinically significant NTM lung disease; 38 patients (54.3%) had M. avium and 26 patients (37.1%). had M. abscessus. In the patients with pulmonary tuberculosis, 78.7% of the patients (74/94) showed TB-PCR positivity, and all the patients with NTM lung disease showed negative results on the TB-PCR test (p<0.001). A positive result of the TB-PCR test on the sputum or bronchial washing fluid specimens was able to predict pulmonary tuberculosis with 88.4% sensitivity, 100% specificity, a 100% positive predictive value and a 79.7% negative predictive value for the patients with smear-positive sputum. CONCLUSION: The TB-PCR test for sputum specimens or bronchial washing fluid specimens could be useful for differentiating pulmonary tuberculosis and NTM lung disease for the patients with smear-positive sputum in Korea.
Diagnostic Tests, Routine ; Humans ; Korea ; Lung Diseases* ; Lung* ; Mycobacterium tuberculosis ; Nontuberculous Mycobacteria ; Polymerase Chain Reaction* ; Sputum* ; Tertiary Care Centers ; Tuberculosis* ; Tuberculosis, Pulmonary*