•SMART analysis model considering primary and secondary systems is developed using MARS-KS without the boundary conditions.•The turbine models of MARS-KS that can affect the turbine work are improved ...by modifying the governing equations.•The shell side of feedwater heater wherein complex two phase flow phenomena occurs is modeled by multi-dimension model.•The developed model reasonably predicts the dynamic behavior of thermal hydraulic variables under the steam extraction operation at the secondary system.
The flexibility of nuclear energy can be achieved by the load following operation and the thermal energy utilization for hydrogen production, desalination, district heating, and Thermal Energy Storage (TES). Thermal energy utilization is performed by transferring the remaining thermal energy over the energy required for electric power generation without changing the reactor power level significantly. For the Pressurized Water Reactor (PWR), it becomes possible by extracting steam from the secondary system and circulating it to a thermal energy application such as the TES system. However, the steam extraction operation affects the behavior of all thermal–hydraulic (TH) variables in the secondary system and further influences the primary system in terms of coolant temperature, reactivity, and reactor power. For thermal energy utilization, it is necessary to secure a technology that can examine the overall stability of the primary and secondary systems in a Nuclear Power Plant (NPP). In this study, based on the system analysis code MARS-KS, an NPP analysis model for SMART, a small-sized integral type PWR, was developed that can simulate major TH variables behavior in the primary and secondary systems at once. Its strength is that major components in the secondary system are modeled without any boundary conditions under matching the heat and mass balance. From the verification calculation of the steady state, it was confirmed that this SMART analysis model can predict the main TH variables of the primary and secondary systems similarly to the plant data. Furthermore, an example calculation was performed for the TES application. The analysis results show that the analysis model is sufficiently applicable to the transient calculation of the primary and secondary systems during the steam extraction operation. This analysis model is expected to be used for the development of technologies such as load following operation and thermal energy utilization in the future.
Single-use duodenoscopes have been recently developed to eliminate risk of infection transmission from contaminated reusable duodenoscopes. We compared performances of single-use and reusable ...duodenoscopes in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP).
Patients with native papilla requiring ERCP were randomised to single-use or reusable duodenoscope. Primary outcome was comparing number of attempts to achieve successful cannulation of desired duct. Secondary outcomes were technical performance that measured duodenoscope manoeuvrability, mechanical-imaging characteristics and ability to perform therapeutic interventions, need for advanced cannulation techniques or cross-over to alternate duodenoscope group to achieve ductal access and adverse events.
98 patients were treated using single-use (n=48) or reusable (n=50) duodenoscopes with >80% graded as low-complexity procedures. While median number of attempts to achieve successful cannulation was significantly lower for single-use cohort (2 vs 5, p=0.013), ease of passage into stomach (p=0.047), image quality (p<0.001), image stability (p<0.001) and air-water button functionality (p<0.001) were significantly worse. There was no significant difference in rate of cannulation, adverse events including mortality (one patient in each group), need to cross-over or need for advanced cannulation techniques to achieve ductal access, between cohorts. On multivariate logistic regression analysis, only duodenoscope type (single-use) was associated with less than six attempts to achieve selective cannulation (p=0.012), when adjusted for patient demographics, procedural complexity and type of intervention.
Given the overall safety profile and similar technical performance, single-use duodenoscopes represent an alternative to reusable duodenoscopes for performing low-complexity ERCP procedures in experienced hands.
Clinicaltrials.gov number: NCT04143698.
Lumen‐apposing metal stents (LAMS) are integrated in a single‐step delivery platform and can be deployed under endoscopic ultrasound‐guidance for the drainage of intra‐abdominal fluid collections, ...decompression of obstructed ductal systems, establishment of anastomosis or creation of fistulous tracts between organs that can facilitate further endoscopic interventions if required. A unique feature of LAMS is their ability to approximate the adjoining structures, thereby minimizing the potential for leak and perforation. Consequently, the innovation has advanced our ability to carry out complex therapeutic interventions and obviate the need for high‐risk surgical procedures, particularly in morbid patients. However, a keen awareness of the technical design of LAMS and its implication on treatment effect is important to minimize adverse events and to improve clinical outcomes. This review outlines the technical approach to placement of LAMS, procedural challenges, adverse events, current clinical indications and emerging applications.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has no cure. Although mesenchymal stem cells (MSCs) have been reported to ameliorate lung inflammation and fibrosis in ...mouse models, their mechanisms of action remain unknown. Therefore, we aimed to determine the changes in various immune cells, especially macrophages and monocytes, involved in the effects of MSC treatment on pulmonary fibrosis.
We collected and analyzed explanted lung tissues and blood from patients with IPF who underwent lung transplantation. After establishing a pulmonary fibrosis model via the intratracheal administration of bleomycin (BLM) to 8-week-old mice, MSCs derived from human umbilical cords were administered intravenously or intratracheally on day 10 and the lungs were immunologically analyzed on days 14 and 21. Flow cytometry was performed to analyze the immune cell characteristics, and gene expression levels were examined using quantitative reverse transcription-polymerase chain reaction.
In the histological analysis of explanted human lung tissues, the terminally fibrotic areas contained a larger number of macrophages and monocytes than the early fibrotic areas of the lungs. When human monocyte-derived macrophages (MoMs) were stimulated with interleukin-13 in vitro, the expression of type 2 macrophage (M2) markers was more prominent in MoMs from the classical monocyte subset than in those from intermediate or non-classical monocyte subsets, and MSCs suppressed M2 marker expression independent of MoM subsets. In the mouse model, the increased number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung fibrosis observed in BLM-treated mice were significantly reduced by MSC treatment, which tended to be more prominent with intravenous administration than intratracheal administration. Both M1 and M2 MoMs were upregulated in BLM-treated mice. The M2c subset of M2 MoMs was significantly reduced by MSC treatment. Among M2 MoMs, M2 MoMs derived from Ly6C
monocytes were most effectively regulated by the intravenous administration, not intratracheal administration, of MSCs.
Inflammatory classical monocytes may play a role in lung fibrosis in human IPF and BLM-induced pulmonary fibrosis. Intravenous rather than intratracheal administration of MSCs may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages.
Carbon monoxide (CO) is recently accepted as a therapeutic molecule that exhibits remarkable biological actions, including anti‐inflammation, antiapoptosis, and cytoprotection, at a physiological ...level. For clinical use without the side effect of tissue hypoxia, which arises from the uncontrolled administration of CO in the human body, CO‐releasing molecules (CORMs) are developed to ensure safe and efficient CO‐delivery. Herein, a syringe‐injectable CO‐releasing peptide hydrogel (COH) and a corresponding bioadhesive hydrogel patch (COHP), developed by rational supramolecular chemistry, to enhance the therapeutic efficacy of CO with controllable CO‐release to a specific tissue is report. The injectable COH is prepared by self‐assembly of the CORM‐attached peptides with a gel‐forming diphenylalanine‐derivative, resulting in fibrillar networks and exhibiting prolonged CO‐release compared with CORMs. Furthermore, Ca2+‐chelating and mussel‐derived catechol‐functionalized peptides are introduced to afford a mechanically rigid, bioadhesive COHP that elicits cytoprotective and anti‐inflammatory activities. The supramolecular COHP can be utilized in the efficient CO‐delivery to the site of interest by conformal contacts, making it a promising scaffold for biomedical applications.
A therapeutic carbon monoxide (CO)‐releasing hydrogel patch is fabricated by self‐assembly of rationally designed peptides. Increase in mechanical strength and adhesive force of hydrogel enables the local CO‐delivery with its sustained release. The hydrogel patch elicits effective cytoprotective and anti‐inflammatory effects on cardiomyocytes by conformally contacting with the desired tissues, resulting in an efficient nanoplatform for a medical gas therapy.
Objective
Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. In this study, we aimed to identify the genetic risk load using ...clinical and serological manifestations in SLE patients.
Methods
We genotyped a total of 1,655 Korean patients with SLE (n = 1,243 as a discovery set and n = 412 as a replication set) using a customized genome‐wide single‐nucleotide polymorphism (SNP) array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well‐validated non‐HLA SNPs and HLA haplotypes of SLE‐risk loci. We analyzed associations between individual wGRS and clinical SLE subphenotypes and autoantibodies using multivariable linear or logistic regression adjusted by onset age, sex, and disease duration.
Results
Childhood‐onset SLE (<16 years) conferred the highest genetic risk compared with adult‐onset (16–50 years) or late‐onset (>50 years) SLE (P = 6.8 × 10−6). High wGRS significantly increased associations with SLE manifestations, regardless of onset age, sex, and disease duration. Individual wGRS significantly correlated positively with more clinical American College of Rheumatology criteria (β = 0.143, P = 1.8 × 10−6). Subphenotype analysis revealed significant associations between the highest and lowest wGRS quartile with risk of renal disorder (hazard ratio HR 1.74, P = 2.2 × 10−8) and anti–Sm antibody production (HR 1.85, P = 2.8 × 10−5). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis class III or IV (HR 1.98, P = 1.6 × 10−5) and class V (HR 2.79, P = 1.0 × 10−3), but especially lupus nephritis class V in anti–Sm‐positive SLE (area under the curve 0.68, P = 1.8 × 10−4).
Conclusion
Patients with SLE and high wGRS tended to have earlier age of SLE onset, higher anti–Sm antibody positivity, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and a diverse clinical course in SLE patients.
Objectives
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry into the host cells depends on the expression of angiotensin‐converting enzyme 2 (ACE2) and transmembrane protease serine ...2 (TMPRSS2). We investigated the distribution of ACE2‐ and TMPRSS2‐expressing cells in various oral tissues to identify the underlying mechanism of oral manifestations in patients with coronavirus disease 2019.
Subjects
We analyzed the expression patterns of ACE2 and TMPRSS2 in the oral mucosa (tongue, palate, and buccal mucosa), trigeminal ganglion, vessels, and salivary glands of 9 Sprague‐Dawley rats using immunohistochemistry and immunofluorescence.
Results
ACE2 and TMPRSS2 were strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa. ACE2‐ and TMPRSS2‐positive cells were observed in the taste buds of the tongue. Additionally, ACE2 and TMPRSS2 were co‐expressed in the ductal epithelium and acinar cells of salivary glands. Furthermore, both ACE2 and TMPRSS2 were stained in the neuronal cell body of trigeminal ganglia, but not in Schwann cells. Moreover, ACE2 and TMPRSS2 were expressed in capillaries, but not in venules/arterioles.
Conclusions
SARS‐CoV‐2 can spread the suprabasal area of squamous epithelia of the oral mucosa, invades taste bud, trigeminal nerve, parotid gland, and microvessel, resulting in oral manifestations.
Background
Although lung macrophages are directly exposed to external stimuli, their exact immunologic roles in asthma are still largely unknown. The aim of this study was to investigate the ...anti‐asthmatic effect of Acinetobacter lwoffii in terms of lung macrophage modulation.
Methods
Six‐week‐old female BALB/c mice were sensitized and challenged with ovalbumin (OVA) with or without intranasal administration of A. lwoffii during the sensitization period. Airway hyperresponsiveness and inflammation were evaluated. Using flow cytometry, macrophages were subclassified according to their activation status. In the in vitro study, a murine alveolar macrophage cell line (MH‐S) treated with or without A. lwoffii before IL‐13 stimulation were analysed by quantitative RT‐PCR.
Results
In a murine asthma model, the number of inflammatory cells, including macrophages and eosinophils, decreased in mice treated with A. lwoffii (A. lwoffii/OVA group) compared with untreated mice (OVA group). The enhanced expression of MHCII in macrophages in the OVA group was decreased by A. lwoffii treatment. M2 macrophage subtypes were significantly altered. A. lwoffii treatment decreased CD11b+M2a and CD11b+M2c macrophages, which showed strong positive correlations with Th2 cells, ILC2 and eosinophils. In contrast, CD11b+M2b macrophages were significantly increased by A. lwoffii treatment and showed strong positive correlations with ILC1 and ILC3. In vitro, A. lwoffii down‐regulated the expression of M2 markers related but up‐regulated those related to M2b macrophages.
Conclusions and Clinical Relevance
Intranasal A. lwoffii exposure suppresses asthma development by suppressing the type 2 response via modulating lung macrophage activation, shifting M2a and M2c macrophages to M2b macrophages.
Flow cytometry was performed on a murine asthma model to assess the phenotype of macrophages, innate lymphoid cells and T cells. Intranasal administration of Acinetobacter lwoffii alleviated Th2 inflammation through modulation of macrophage polarization: the lung macrophages tended to be M2b and less M2a, M2c. A. lwoffii also modulated innate lymphoid cells and T cells resulting in a lowered type 2 immune response.
Characteristics of fuel relocation and its effect on safety margin in a loss-of-coolant accident (LOCA) safety analysis have been analyzed. Packing fraction model developed by Quantum Technology was ...validated and slight modification was conducted based on the formation of high burnup structure model. FAMILY computer code that is an integrated code with FRAPTRAN and MARS-KS is used for the evaluation. The peak cladding temperature (PCT) and peak local oxidation (PLO) of the APR1400 nuclear power plant with the PLUS7 fuel during LOCA were evaluated by a best-estimate plus uncertainty analysis methodology up to 60 MWd/kgU. Fuel relocation resulted in an increase in 95 %/95 % probability/confidence level of the reflood PCT (95/95 reflood PCT) and the PLO (95/95 PLO) until the fuel burnup of ∼ 50 MWd/kgU. Maximum increase of 95/95 reflood PCT was about 130 K at 30 MWd/kgU burnup. This results in the minimum safety margin of the reflood PCT at that burnup with respect to the U.S. NRC proposed 10CFR50.46c PCT limit. Maximum increase of 95/95 PLO was 3.9 percent point at 30 MWd/kgU. However, minimum safety margin was observed at different burnups such as 40 MWd/kgU and 60 MWD/kgU. Regarding the cladding burst characteristics, fuel relocation may lead to an increase in the burst temperature and burst strain of the cladding, and it also induces an earlier failure of cladding.
Microvesicles (MVs) released by cells are involved in a multitude of physiological events as important mediators of intercellular communication. MVs derived from mesenchymal stem cells (MSCs) contain ...various paracrine factors from the cells that primarily contribute to their therapeutic efficacy observed in numerous clinical trials. As nano-sized and bi-lipid layered vesicles retaining therapeutic potency equivalent to that of MSCs, MSC-derived MVs have been in focus as ideal medicinal candidates for regenerative medicine, and are preferred over MSC infusion therapy with their improved safety profiles. However, technical challenges in obtaining sufficient amounts of MVs have limited further progress in studies and clinical application. Of the multiple efforts to reinforce the therapeutic capacity of MSCs, few studies have reportedly examined the scale-up of MSC-derived MV production. In this study, we successfully amplified MV secretion from MSCs compared to the conventional culture method using a simple and efficient 3D-bioprocessing method. The MSC-derived MVs produced in our dynamic 3D-culture contained numerous therapeutic factors such as cytokines and micro-RNAs, and showed their therapeutic potency in in vitro efficacy evaluation. Our results may facilitate diverse applications of MSC-derived MVs from the bench to the bedside, which requires the large-scale production of MVs.
PDF
