Simple mathematical model for predicting COVID-19 outbreaks in Japan based on epidemic waves with a cyclical trend.

BACKGROUND: Several models have been used to predict outbreaks during the COVID-19 pandemic, with limited success. We developed a simple mathematical model to accurately predict future epidemic waves. METHODS: We used data from the Ministry of Health, Labour and Welfare of Japan for newly confirmed COVID-19 cases. COVID-19 case data were summarized as weekly data, and epidemic waves were visualized and identified. The periodicity of COVID-19 in each prefecture of Japan was confirmed using time-series analysis and the autocorrelation coefficient, which was used to investigate the longer-term pattern of COVID-19 cases. Outcomes using the autocorrelation coefficient were visualized via a correlogram to capture the periodicity of the data. An algorithm for a simple prediction model of the seventh COVID-19 wave in Japan comprised three steps. Step 1: machine learning techniques were used to depict the regression lines for each epidemic wave, denoting the "rising trend line"; Step 2: an exponential function with good fit was identified from data of rising straight lines up to the sixth wave, and the timing of the rise of the seventh wave and speed of its spread were calculated; Step 3: a logistic function was created using the values calculated in Step 2 as coefficients to predict the seventh wave. The accuracy of the model in predicting the seventh wave was confirmed using data up to the sixth wave. RESULTS: Up to March 31, 2023, the correlation coefficient value was approximately 0.5, indicating significant periodicity. The spread of COVID-19 in Japan was repeated in a cycle of approximately 140 days. Although there was a slight lag in the starting and peak times in our predicted seventh wave compared with the actual epidemic, our developed prediction model had a fairly high degree of accuracy. CONCLUSION: Our newly developed prediction model based on the rising trend line could predict COVID-19 outbreaks up to a few months in advance with high accuracy. The findings of the present study warrant further investigation regarding application to emerging infectious diseases other than COVID-19 in which the epidemic wave has high periodicity.

Clinical characteristics and mortality risk among critically ill patients with COVID-19 owing to the B.1.617.2 (Delta) variant in Vietnam: A retrospective observational study.

BACKGROUND: SARS-CoV-2 Delta variant caused a large number of COVID-19 cases in many countries, including Vietnam. Understanding mortality risk factors is crucial for the clinical management of severe COVID-19. METHODS: We conducted a retrospective study at an intensive care center in Ho Chi Minh City that urgently built by Bach Mai Hospital during the COVID-19 outbreak in Vietnam, when the Delta variant predominated. Participants were laboratory-confirmed patients with SARS-CoV-2 infection, admitted in August 2021. Data on patients' demographic and clinical characteristics, radiographic and laboratory findings, treatment, and clinical time course were compared between survivors and non-survivors. Risk factors to mortality were assessed using logistic regression. RESULTS: Among 504 eligible COVID-19 patients, case fatality was 52.2%. Unvaccinated patients accounted for 61.2% of non-survivors and 43.6% of survivors (p < 0.001). The time from onset to hospital admission was 8 days in non-survivors and 7 days in survivors (p = 0.004). Among non-survivors, 90.2% developed acute respiratory distress syndrome (ARDS). Oxygen therapy was administered for all patients, but antiviral agent was given to 51.7% of non-survivors. 54.2% of non-survivors tested positive for the bacterial infection using blood culture. The risk factors for mortality were diabetes mellitus, respiration rate, oxygen saturation, vaccination status, time from onset to admission, and older age. CONCLUSIONS: Critical patients with COVID-19 owing to the Delta variant in Vietnam had delayed hospital admission, leading to ARDS and death. Early availability of vaccines and preventing bacterial infections are crucial for reducing mortality of COVID-19, especially in low- and middle-income countries.

Glucose Depletion Enhances the Stem Cell Phenotype and Gemcitabine Resistance of Cholangiocarcinoma Organoids through AKT Phosphorylation and Reactive Oxygen Species.

Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.

CV-11974, angiotensin II type I receptor antagonist, protects against ischemia-reperfusion injury of the small intestine in rats.

BACKGROUND: Angiotensin II has been implicated in the pathogenesis of vascular inflammation in various organs. The aim of the present study was to examine the effect of angiotensin II type I receptor antagonist, CV-11974, on reperfusion-induced small intestinal injury in rats. METHODS: Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion for 60 min in male Wistar rats. CV-11974 was given to the rats by intravenous injection 1 h before the vascular clamping. The intestinal mucosal injury and inflammation were evaluated by biochemical markers and histological findings. Thiobarbituric acid reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expressions of pro-inflammatory cytokines (CINC-1) in intestinal mucosa were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-PCR (RT-PCR). In additional experiments with an in vitro flow system, human neutrophils were perfused on human umbilical vein endothelial cells (HUVEC) pretreated with anoxia-reoxygenation with or without CV-11974 and then the adhesive neutrophils were counted. RESULTS: Reperfusion after ischemia resulted in an increase in luminal protein concentrations, hemoglobin concentrations, thiobarbituric acid reactive substances, and MPO activity. Pretreatment with CV-11974 significantly inhibited the increases in these parameters. CV-11974 also inhibited increases in intestinal CINC-1 protein and mRNA expression induced by ischemia-reperfusion. Moreover, in an in vitro study, CV-11974 significantly inhibited the adherence of neutrophils to HUVEC exposed to reoxygenation after anoxia. CONCLUSIONS: These results suggest that the blockade of angiotensin II type I receptor by treatment with CV-11974 remarkably reduced the reperfusion-induced intestinal injury.

Tocotrienols reduce 25-hydroxycholesterol-induced monocyte-endothelial cell interaction by inhibiting the surface expression of adhesion molecules.

The migration of circulating monocytes into the subendothelial space occurs through the expressing of some adhesion molecules on endothelial cells. In the present study, using human aortic endothelial cells (HAECs), we investigated whether a model compound for oxysterols, 25-hydroxycholesterol, can enhance the monocyte adherence to HAECs exposed to 25-hydroxycholesterol via increasing expression of vascular cell adhesion molecule-1 (VCAM-1). We also aimed to determine the in vitro effects of tocotrienols on the enhanced interaction between monocytes and endothelial cells. We found that 25-hydroxycholesterol enhances surface expression determined by ELISA, induces VCAM-1 mRNA expression by real time-PCR, and stimulates adhesiveness of HAECs to U937 monocytic cells in a dose-dependent fashion. The combination treatment with anti-VCAM-1 and anti-CD11b monoclonal antibodies significantly reduced the monocyte adherence to 25-hydroxycholesterol-stimulated HAECs. Compared to alpha-tocopherol, tocotrienols displayed a more profound inhibitory effect on adhesion molecule expression and monocytic cell adherence. We observed that delta-tocotrienol exerted a most profound inhibitory action on monocytic cell adherence when compared to alpha-tocopherol and alpha-, beta-, and gamma-tocotrienols. Tocotrienols accumulated in HAECs to levels approximately 25-95-fold greater than that of alpha-tocopherol. In conclusion, these results indicate that a model compound 25-hydroxycholesterol can enhance the interaction between monocytes and HAECs, and that tocotrienols had a profound inhibitory effect on monocytic cell adherence to HAECs relative to alpha-tocopherol via inhibiting the VCAM-1 expression. These superior inhibitory effects of tocotrienols may be dependent on their intracellular accumulation.

Inhibitory effects of red wine extracts on endothelial-dependent adhesive interactions with monocytes induced by oxysterols.

Red wine polyphenolic compounds have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study is to examine whether red wine extracts (RWE) can ameliorate oxysterol-induced endothelial response, and whether inhibition of adhesion molecule expression is involved in monocyte adhesion to endothelial cells. Surface expression and mRNA levels of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) were determined by ELISA and RT-PCR performed on human aortic endothelial cells (HAEC) monolayers stimulated with 7beta-hydroxycholesterol or 25-hydroxycholesterol. Incubation of HAEC with oxysterols (10 microM) increased expression of adhesion molecules in a time-dependent manner. Pretreatment of HAEC with RWE at final concentrations of 1, 10, and 100 ng/ml significantly inhibited the increase of surface protein expression and mRNA levels. Adherence of monocytes to oxysterol-stimulated HAEC was increased compared to that of unstimulated cells. Treatment of HAEC with RWE significantly inhibited adherence of monocytes. These results suggest that RWE works as an anti-atherogenic agent through the inhibition of endothelial-dependent adhesive interactions with monocytes induced by oxysterols.

The inhibitory effect of alacepril, an angiotensin-converting enzyme inhibitor, on endothelial inflammatory response induced by oxysterol and TNF-alpha.

The objectives were to determine the effects of alacepril, an angiotensin-converting enzyme inhibitor, on the expression of adhesion molecules and monocyte adherence to endothelial cells induced by 7-ketocholesterol (7-KC) and tumor necrosis factor (TNF)-alpha. We used human aortic endothelial cells (HAECs) and U937 monocytic cells. Surface expression and mRNA levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were determined by EIA and RT-PCR. Adherence of U937 to HAECs was assessed by adhesion assay. Incubation of HAEC with 7-KC increased the surface expression of protein and mRNA levels of ICAM-1 and VCAM-1 on HAECs and the production of reactive oxygen species (ROS) in HAECs. Pretreatment with alacepril reduced the enhanced expression of these molecules in a dose-dependent manner. The inhibitory effect of alacepril against 7-KC or TNF-alpha-induced CAMs expression was stronger than that of captopril or enalapril. Alacepril inhibited the production of ROS in HAECs stimulated by 7-KC or TNF-alpha. These results suggest that alacepril works as anti-atherogenic agent through inhibiting endothelial-dependent adhesive interactions with monocytes induced by 7-KC and TNF-alpha.

7-Ketocholesterol enhances the expression of adhesion molecules on human aortic endothelial cells by increasing the production of reactive oxygen species.

The aim of the present study was to assess the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), monocytic adhesion of human aortic endothelial cells (HAECs), and the production of intracellular reactive oxygen species (ROS), when HAECs were stimulated by 7-ketocholesterol. 7-ketocholesterol enhances surface expression of ICAM-1 and VCAM-1 as determined by EIA, induces their mRNA expression by RT-PCR, and stimulates adhesiveness of HAECs to U937 monocytic cells. We confirmed up-regulation of ROS production of HAECs treated with 7-ketocholesterol. Although the surface expression of ICAM-1 and VCAM-1 on HAECs treated with 7-ketocholesterol increased in a time-dependent manner, alpha-tocopherol inhibited this increase of the surface expression of ICAM-1 and VCAM-1. In the monocytic adhesion assay, adhesion of U937 to HAECs treated with 7-ketocholesterol was enhanced, but monoclonal anti-ICAM-1 and VCAM-1 antibodies reduced the endothelial adhesiveness. In conclusion, this study suggests that the endothelial adhesiveness to monocytic cells that was increased by 7-ketocholesterol was associated with enhanced expression of ICAM-1 and VCAM-1 mediated by ROS production.

Inhibitory effects of red wine extracts on endothelial-dependent adhesive interactions with monocytes induced by oxysterols

Red wine polyphenolic compounds have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study is to examine whether red wine extracts (RWE) can ameliorate oxysterol-induced endothelial response, and whether inhibition of adhesion molecule expression is involved in monocyte adhesion to endothelial cells. Surface expression and mRNA levels of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) were determined by ELISA and RT-PCR performed on human aortic endothelial cells (HAEC) monolayers stimulated with 7b-hydroxycholesterol or 25-hydroxycholesterol. Incubation of HAEC with oxysterols (10 µM) increased expression of adhesion molecules in a time-dependent manner. Pretreatment of HAEC with RWE at final concentrations of 1, 10, and 100 ng/ml significantly inhibited the increase of surface protein expression and mRNA levels. Adherence of monocytes to oxysterol-stimulated HAEC was increased compared to that of unstimulated cells. Treatment of HAEC with RWE significantly inhibited adherence of monocytes. These results suggest that RWE works as an anti-atherogenic agent through the inhibition of endothelial-dependent adhesive interactions with monocytes induced by oxysterols.

An AT1-receptor antagonist and an angiotensin-converting enzyme inhibitor protect against hypoxia-induced apoptosis in human aortic endothelial cells through upregulation of endothelial cell nitric oxide synthase activity.

The protective effects and roles of AT1-receptor antagonists (AT1-RA) or angiotensin-converting enzyme inhibitors (ACEI) on vascular endothelial cell (EC) injury during hypoxia are not entirely known. Therefore, we investigated these effects and mechanisms in human aortic (HA) EC. DNA fragmentation, Lactate dehydrogenase (LDH) release, and caspase-3 activity were measured in cultured HAEC after exposure to hypoxia in the presence or absence of an AT1-RA (candesartan, CS) and/or an ACEI (temocaprilat, TC). Next, we investigated endothelial cell nitric oxide synthase (ecNOS) and inducible (i) NOS to determine the role of the bradykinin(BK)-NO pathway in the protective effect on ACEI and AT1-RA in the setting of hypoxia-induced apoptosis. Exposure to hypoxia increased DNA fragmentation in HAEC associated with the activation of caspase-3, but did not affect LDH release. In addition, hypoxia induced ecNOS mRNA but not mRNA iNOS. CS and/or TC reduced apoptosis induced by hypoxia in a dose-dependent manner, and significantly increased BK and ecNOS expression. This effect was attenuated by the kinin B2 receptor antagonist, HOE 140, and the NOS inhibitor, N-nitro-L-arginine methylester (L-NMMA). Hypoxia activates the pathway leading to apoptosis by enhancing caspase-3 activity. Both CS and TC can ameliorate hypoxia-induced apoptosis in HAEC through inhibiting caspase-3 activation by enhancing ecNOS activity, via the accumulation of BK.

Alpha-tocopherol prevents apoptosis of vascular endothelial cells via a mechanism exceeding that of mere antioxidation.

Alpha-tocopherol has been reported to exert an anti-atherogenesis effect. We attempted to clarify the effect of alpha-tocopherol-both as an antioxidant and as a nonantioxidant--on apoptosis induced by oxidized low-density lipoprotein (LDL) or oxysterols. Oxidized LDL and oxysterols induced necrosis and/or apoptosis of vascular endothelial cells. The induction of apoptosis was associated with increased caspase-3 activity and the generation of intracellular reactive oxygen species, both the effects of which were attenuated by alpha-tocopherol. Apoptosis was also decreased by beta-tocopherol or intracellular radical scavengers, but these suppressive effects were less than those of alpha-tocopherol. Neither beta-tocopherol nor the scavengers had pronounced effect on caspase-3 activity, but each of them decreased the generation of reactive oxygen species to the same extent as alpha-tocopherol. Our study suggests that alpha-Toc protects against apoptosis not only by scavenging reactive oxygen species, but also by inhibiting caspase activity, which means that its activity may exceed that of a mere antioxidant.