New anti-inflammatory limonoids from the fruits of Melia azedarach.

The phytochemical study of the fruits of Melia azedarach (Meliaceae) led to the isolation and characterisation of two novel natural limonoids1-deoxy- 3, 20-dicinnamoyl-11-methoxy-meliacarpinin (1) and 12ß- O- methyl nimbolinin A (2), along with twelve known limonoids. Its structure was identified by 1D- and 2D-NMR, HR-ESI-MS and comparison with published data. The anti-inflammatory effect of the compounds was measured in vitro in RAW 264.7 cells by evaluating the production of NO stimulated by LPS. Compounds 1, 8 and 14 indicated significant anti-inflammatory effect with inhibition rate of 11.76, 8.45 and 6.59 µM, respectively. Limonoid 1 significantly inhibited the production of NO, TNF-α and IL-1ß in RAW 264.7 cells. Therefore, limonoid derivative may be a promising source of bioactive metabolite for inflammatory diseases.

Phenylspirodrimane with Moderate Reversal Effect of Multidrug Resistance Isolated from the Deep-Sea Fungus Stachybotrys sp. 3A00409.

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3-10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.

The regulatory role and mechanism of mast cells in tumor microenvironment.

Mast cells (MCs) have emerged as pivotal contributors to both the defensive immune response and immunomodulation. They also exhibit regulatory functions in modulating pathological processes across various allergic diseases. The impact of MC presence within tumor tissues has garnered considerable attention, yielding conflicting findings. While some studies propose that MCs within tumor tissues promote tumor initiation and progression, others advocate an opposing perspective. Notably, evidence emphasizes the dual role of MCs in cancer, both as promoters and suppressors, is crucial for optimizing cancer treatment strategies. These conflicting viewpoints have generated substantial controversy, underscoring the need for a comprehensive understanding of MC's role in tumor immune responses.

Mortality Study of Patients with Omicron Infection Before and After the Implementation of the New Crown Standard.

Objective: To investigate the mortality rate of patients with Omicron infection before and after the implementation of the new crown standard, and to evaluate the impact of new treatment protocols on the mortality rate of patients with Omicron infection. Methods: Clinical data of 1419 Omicron-infected patients treated in our hospital from April 10, 2022 to June 3, 2022 were collected(Patients diagnosed with Omicron infection who met the diagnostic criteria in the "Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 9)"15 and whose nasal/pharyngeal swab samples were typed as Omicron variants by laboratory viral genotyping). They were divided into the observation group (April 25 2022 - June 3 2022) and the control group (April 10 2022 - April 24 2022) before and after the implementation criteria. Clinical data of 1419 patients were collected and compared between the two groups on whether to use anticoagulant drugs, whether to use antiplatelet drugs, gender, whether to use new drugs of thymosin/thymus method, age, whether to use herbal medicine, whether to use Fuzheng prescription, blood routine, liver function, kidney function indicators, mortality of patients. Results: A total of 1419 patients were initially selected; 501 patients with incomplete information were excluded, and finally, 918 patients were included. According to the time period before and after the application criteria, they were divided into an observation group (586 cases) and a control group (332 cases). There were no statistically significant differences in gender, age, antiplatelet drug use, and herbal medicine use between the two groups (P < .05). However, there were significant differences in the use of anticoagulant drugs, thymidine/thymidine drugs, and Fu Zhengfang between the two groups. It was statistically significant that the mortality rate in the observation group (2.39)% was significantly lower than that in the control group (5.12)%. P < .05 White blood cell count, red blood cell ratio, lymphocyte count, hemoglobin, neutrophil count, and neutrophil ratio were not significantly different between the two groups (P < .05) .In comparison to the control group (4.92±8.00)10^9/L, the platelet count in the observation group (4.77±3.41)109/L was considerably lower. The difference was statistically significant (P < .05). The comparison of total bilirubin, total protein values and alkaline phosphatase values between the two groups was not significant (P < .05). In the observation group, albumin (38.71±6.39) g/L, glutamate transaminase (23.93±26.03) U/L, glutathione transaminase (26.12±25.53) U/L, gamma-glutamyltransferase (34.28±52.3) U/L, globulin values (28.13±5.55) g/L were significantly lower than those of the control group (36.66±7.08) g/L, (30.36±65.77) U/L, (33.29±49.72) U/L, (43.76±80.23) U/L, (29.85±5.67) g/L, the difference was statistically significant (P < .05). Between the two groups, there were no significant differences in the values of uric acid or creatinine (P > .05). Levels and uric acid readings did not differ significantly, P > .05. The difference between the urea values of the observation group (7.44±6.34 mmol/L) and the control group (8.75±7.51 mmol/L) was statistically significant (P < .05). Conclusion: After the implementation of the treatment protocol for COVID-19 (Trial Version 9), the number of death cases among patients with Omicron variant infection has significantly decreased. The treatment protocol is safe and feasible and can be widely applied in clinical settings..And it will further promote the development and administration of vaccines to prevent and control the spread of the novel coronavirus, reducing the occurrence of patients and death cases.

FSTL3 promotes tumor immune evasion and attenuates response to anti-PD1 therapy by stabilizing c-Myc in colorectal cancer.

Programmed cell death 1 ligand 1 (PDL1)/programmed cell death 1 (PD1) blockade immunotherapy provides a prospective strategy for the treatment of colorectal cancer (CRC), but various constraints on the effectiveness of the treatment are still remaining. As reported in previous studies, follistatin-like 3 (FSTL3) could mediate inflammatory response in macrophages by induction lipid accumulation. Herein, we revealed that FSTL3 were overexpressed in malignant cells in the CRC microenvironment, notably, the expression level of FSTL3 was related to tumor immune evasion and the clinical efficacy of anti-PD1 therapy. Further studies determined that hypoxic tumor microenvironment induced the FSTL3 expression via HIF1α in CRC cells, FSTL3 could bind to the transcription factor c-Myc (354-406 amino acids) to suppress the latter's ubiquitination and increase its stability, thereby to up-regulated the expression of PDL1 and indoleamine 2,3-dioxygenase 1 (IDO1). The results in the immunocompetent tumor models verified that FSLT3 knockout in tumor cells increased the proportion of CD8+ T cells in the tumor microenvironment, reduced the proportion of regulatory T cells (CD25+ Foxp3+) and exhausted T cells (PD1+ CD8+), and synergistically improved the anti-PD1 therapy efficacy. To sum up, FSTL3 enhanced c-Myc-mediated transcriptional regulation to promote immune evasion and attenuates response to anti-PD1 therapy in CRC, suggesting the potential of FSTL3 as a biomarker of immunotherapeutic efficacy as well as a novel immunotherapeutic target in CRC.

Effects of Huzhangoside C on Dextran Sodium Sulfate-Stimulated Colitis in Mice.

Chronic inflammation is a major risk factor for cancer. Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, ultimately leading to a breakdown of intestinal barrier function. Clematis florida var. plena is a folk prescription used to treat inflammation and rheumatism in She pharmacy. The bioactivity of C. florida var. plena is primarily due to triterpene saponins. Huzhangoside C (HZ) is an active component of C. florida var. plena. In this study, the anti-inflammatory effect of HZ on a mouse colitis model induced by dextran sulfate sodium (DSS) was investigated. Result indicated a notable reduction in body weight loss and colon length shortening in HZ-mediated mice compared to DSS-stimulated control mice. Furthermore, inflammatory signaling mechanisms involving interleukin-6 and tumor necrosis factor-α were suppressed in HZ-treated mice. HZ treatment significantly suppressed the expression of nuclear factor kappa B (NF-κB), STAT3, and iNOS in colon tissue. After HZ treatment, malondialdehyde and nitric oxide levels were significantly decreased, while Nrf-2, superoxide dismutase, and glutathione expression levels were notably improved. The result indicated that HZ could activate the Nrf-2 signal cascade, inhibit the expression of NF-κB, eNOS, and STAT3, and enhance the intestinal barrier function of DSS stimulated ulcerative colitis intestinal injury. The results suggest that HZ is potential anti-inflammatory agent for treating IBD.

A Portable Three-Layer Compton Camera for Wide-Energy-Range Gamma-ray Imaging: Design, Simulation and Preliminary Testing.

(1) Background: The imaging energy range of a typical Compton camera is limited due to the fact that scattered gamma photons are seldom fully absorbed when the incident energies are above 3 MeV. Further improving the upper energy limit of gamma-ray imaging has important application significance in the active interrogation of special nuclear materials and chemical warfare agents, as well as range verification of proton therapy. (2) Methods: To realize gamma-ray imaging in a wide energy range of 0.3~7 MeV, a principle prototype, named a portable three-layer Compton camera, is developed using the scintillation detector that consists of an silicon photomultiplier array coupled with a Gd3Al2Ga3O12:Ce pixelated scintillator array. Implemented in a list-mode maximum likelihood expectation maximization algorithm, a far-field energy-domain imaging method based on the two interaction events is applied to estimate the initial energy and spatial distribution of gamma-ray sources. The simulation model of the detectors is established based on the Monte Carlo simulation toolkit Geant4. The reconstructed images of a 133Ba, a 137Cs and a 60Co point-like sources have been successfully obtained with our prototype in laboratory tests and compared with simulation studies. (3) Results: The proportion of effective imaging events accounts for about 2%, which allows our prototype to realize the reconstruction of the distribution of a 0.05 µSv/h 137Cs source in 10 s. The angular resolution for resolving two 137Cs point-like sources is 15°. Additional simulated imaging of the 6.13 MeV gamma-rays from 14.1 MeV neutron scattering with water preliminarily demonstrates the imaging capability for high incident energy. (4) Conclusions: We conclude that the prototype has a good imaging performance in a wide energy range (0.3~7 MeV), which shows potential in several MeV gamma-ray imaging applications.

Small-molecule exhibits anti-tumor activity by targeting the RNA m6A reader IGF2BP3 in ovarian cancer.

Based on its absence in normal tissues and its role in tumorigenesis and tumor progression, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of N6-methyladenosine (M6A) on RNA, represents a putative valuable and specific target for some cancer therapy. In this study, we performed bioinformatic analysis and immunohistochemistry (IHC) to find that IGF2BP3 was highly expressed in tumor epithelial cells and fibroblasts of ovarian cancer (OC), and was associated with poor prognosis, metastasis, and chemosensitivity in OC patients. In particular, we discovered that knockdown IGF2BP3 expression inhibited the malignant phenotype of OC cell lines by decreasing the protein levels of c-MYC, VEGF, CDK2, CDK6, and STAT1. To explore the feasibility of IGF2BP3 as a therapeutic target for OC, a small molecular AE-848 was designed and screened by molecular operating environment (MOE), which not only could duplicate the above results of knockdown assay but also reduced the expression of c-MYC in M2 macrophages and tumor-associated macrophages and promoted the cytokine IFN-γ and TNF-α secretion. The pharmacodynamic models of two kinds of OC bearing animals were suggested that systemic therapy with AE-848 significantly inhibited tumor growth by reducing the expression of tumor-associated antigen (c-MYC/VEGF/Ki67/CDK2) and improving the anti-tumor effect of macrophages. These results suggest that AE-848 can inhibit the growth and progression of OC cells by disrupting the stability of the targeted mRNAs of IGF2BP3 and may be a targeted drug for OC treatment.

Ultraviolet B radiation-induced JPH203-loaded keratinocyte extracellular vesicles exert etiological interventions for psoriasis therapy.

Psoriasis is a multifactorial immuno-inflammatory skin disease, characterized by keratinocyte hyperproliferation and aberrant immune activation. Although the pathogenesis is complex, the interactions among inflammation, Th17-mediated immune activation, and keratinocyte hyperplasia are considered to play a crucial role in the occurrence and development of psoriasis. Therefore, pharmacological interventions on the "inflammation-Th17-keratinocyte" vicious cycle may be a potential strategy for psoriasis treatment. In this study, JPH203 (a specific inhibitor of LAT1, which engulfs leucine to activate mTOR signaling)-loaded, ultraviolet B (UVB) radiation-induced, keratinocyte-derived extracellular vesicles (J@EV) were prepared for psoriasis therapy. The EVs led to increased interleukin 1 receptor antagonist (IL-1RA) content due to UVB irradiation, therefore not only acting as a carrier for JPH203 but also functioning through inhibiting the IL-1-mediated inflammation cascade. J@EV effectively restrained the proliferation of inflamed keratinocytes via suppressing mTOR-signaling and NF-κB pathway in vitro. In an imiquimod-induced psoriatic model, J@EV significantly ameliorated the related symptoms as well as suppressed the over-activated immune reaction, evidenced by the decreased keratinocyte hyperplasia, Th17 expansion, and IL17 release. This study shows that J@EV exerts therapeutic efficacy for psoriasis by suppressing LAT1-mTOR involved keratinocyte hyperproliferation and Th17 expansion, as well as inhibiting IL-1-NF-κB mediated inflammation, representing a novel and promising strategy for psoriasis therapy.

Chukrasia tabularis limonoid plays anti-inflammatory role by regulating NF-κB signaling pathway in lipopolysaccharide-induced macrophages.

Background: Chukrasia tabularisis, a well-known tropical tree native to southeastern China, has anti-inflammatory and antioxidant activities, and contains large amounts of limonoids and triterpenoids. Objective: The aim of this study was to investigate the potential anti-inflammatory activity of limonoids from C. tabularis on lipopolysaccharide (LPS)-mediated RAW264.7 cells. Methods and results: Using a bioassay-guided approach, the chemical fraction with high anti-inflammatory activity was found and its chemical constituents were investigated. Phytochemical studies on active extracts resulted in the separation of three novel phragmalin limonoids (1-3), together with two known limonoids (4-5) and 11 tirucallane triterpenes (6-16). The activity of these isolated compounds in the production of nitric oxide (NO) on LPS-reated macrophages was evaluated. Limonoid 2 indicated significant anti-inflammatory activities with IC50 value of 4.58 µM. Limonoid 2 notably inhibited the production of NO, interleukin- 6 and tumor necrosis factor-α on macrophage. Signal transduction and activation of STAT and NF-κB activators were effectively blocked by limonoid 2. Conclusions: These results indicate that limonoid 2 has an anti-inflammatory effect by the inhibiting JAK2/STAT3, iNOS/eNOS, and NF-κB signaling pathways and regulating inflammatory mediators.

Characterizing distinct profiles of immune and inflammatory response with age to Omicron infection.

Background: Understanding inflammatory and immune responses to Omicron infection based on age is crucial when addressing this global health threat. However, the lacking of comprehensive elucidation hinders the development of distinct treatments tailored to different age populations. Methods: 1299 cases of Omicron infection in Shanghai were enrolled between April 10, 2022 and June 3, 2022, dividing into three groups by ages: Adult group (18-59 years), Old group (60-79 years), and Elder group (≥ 80 years). Laboratory data including inflammatory cytokines, cellular, and humoral immunity were collected and analyzed. Results: The mean age of Adult, Old, and Elder groups were 44.14, 69.98, and 89.35 years, respectively, with 40.9% being men. The Elder group patients exhibited higher white blood cell (WBC) counts and elevated levels of inflammatory cytokines, but their lymphocyte counts were relatively lower. In comparison to the Old group patients, the Elder group patients demonstrated significantly lower CD3+ T-cell counts, CD3+ T-cell proportion, CD4+ T-cell counts, CD8+ T-cell counts, and CD19+ B-cell counts, while the NK-cell counts were higher. Omicron negative patients displayed a higher proportion of CD19+ B-cells and higher levels of Complement-3 and IL-17 compared to the positive patients in the Old group. Omicron negative patients had lower WBC counts, CD3+CD8+ T-cells proportion, and the levels of serum amyloid A and IgA in the Elder group, but the CD4+/CD8+ ratio was higher. Conclusions: Our study identified the distinct profiles of inflammatory and immune responses to Omicron infection varying with age and highlighted the diverse correlations between the levels of various biomarkers and Omicron infected/convalescent patients.

Predictive value of immunoglobulin G, activated partial thromboplastin time, platelet, and indirect bilirubin for delayed viral clearance in patients infected with the Omicron variant.

Background: Omicron is the recently emerged highly transmissible severe acute respiratory syndrome coronavirus 2 variant that has caused a dramatic increase in coronavirus disease-2019 infection cases worldwide. This study was to investigate the association between demographic and laboratory findings, and the duration of Omicron viral clearance. Methods: Approximately 278 Omicron cases at the Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine were retrospectively analyzed between August 11 and August 31, 2022. Demographic and laboratory data were also collected. The association between demographics, laboratory findings, and duration of Omicron viral clearance was analyzed using Pearson correlation analysis and univariate and multivariate logistic regression. Results: Univariate logistic regression analyses showed that a prolonged viral clearance time was significantly associated with older age and lower immunoglobulin (Ig) G and platelet (PLT) levels. Using multinomial logistic regression analyses, direct bilirubin, IgG, activated partial thromboplastin time (APTT), and PLT were independent factors for longer viral shedding duration. The model combining direct bilirubin, IgG, APTT, and PLT identifies patients infected with Omicron whose viral clearance time was ≥7 days with 62.7% sensitivity and 83.4% specificity. Conclusion: These findings suggest that direct bilirubin, IgG, PLT, and APTT are significant risk factors for a longer viral shedding duration in patients infected with Omicron. Measuring levels of direct bilirubin, IgG, PLT, and APTT is advantageous to identify patients infected with Omicron with longer viral shedding duration.

Anti-Inflammatory Activity of Phenylethanoids from Acanthus ilicifolius var. xiamenensis.

Acanthus ilicifolius var. xiamenensis is a traditional herbal medicine in China. In this study, the anti-inflammatory activities of active ingredients of A. ilicifolius var. xiamenensis were investigated in RAW 264.7 cells and Freund's complete adjuvant-induced arthritic rats. Results showed that n-butanol extract exerted antiarthritic potential by reducing paw edema, arthritis score, and altered hematological and biochemical parameters in experimental rats. Phytochemical studies on n-butanol extract resulted in the isolation of five alkaloids (1-5) and five phenylethanoids (6-10). The anti-inflammatory assay of compounds 1-10 on lipopolysaccharide (LPS)-treated RAW 264.7 cells indicated that phenylethanoids 9 and 10 exhibited notable inhibitory activities. The result indicated that compounds 9 and 10 attenuated inflammation by decreasing the production of nuclear factor kappa-B (NF-κB) p65, inhibitory subunit of NF kappa B alpha, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and inducible nitric oxide synthase in LPS-mediated RAW 264.7 macrophages. Phenylethanoids 9 and 10 increased the expression of interleukin-10 and endothelial nitric oxide synthase. Therefore, compounds 9 and 10 showed anti-inflammatory activity by regulation of NF-κB and JAK/STAT signaling pathways.

Sedation and analgesia requirements during venovenous extracorporeal membrane oxygenation in acute respiratory distress syndrome patients.

INTRODUCTION: The purpose of this study is to describe sedation and analgesia management, and identify the factors associated with increased demand for medication in acute respiratory distress syndrome (ARDS) patients receiving venovenous extracorporeal membrane oxygenation (VV-ECMO). METHODS: This retrospective, single-center study included consecutive adult ARDS patients who received VV-ECMO for at least 24 hours from January 2018 to December 2020 in a comprehensive intensive care unit. The electronic medical records were retrospectively reviewed to collect data. RESULTS: Forty-two adult patients meeting the inclusion criteria were included in the study. Midazolam, sufentanil, and remifentanil were main sedatives and analgesics used in the patient population. The morphine equivalents, representative of the demand for opioids, was 512.9 (IQR, 294.5, 798.2) mg/day. The midazolam equivalents, representative of benzodiazepine requirement, was 279.6 (IQR, 208.8, 384.5) mg/day. The levels of serum creatinine, total bilirubin, lactic acid, SOFA score, and APACHE Ⅱ score at cannulation were found to be associated with opiate or benzodiazepine requirements. Multiple linear regression analysis revealed a linear correlation between midazolam equivalents and morphine equivalents (p < 0.001). In addition, there was a negative linear correlation between Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score and midazolam equivalents (p = 0.024). CONCLUSIONS: The sedation and analgesia requirements of ARDS patients receiving VV-ECMO often increase simultaneously. More large-scale studies are needed to confirm the risk factors for increased sedation and analgesia needs in patients supported on VV-ECMO.

Bioactivity-guided isolation of anti-inflammatory limonins from Chukrasia tabularis.

Chukrasia tabularis is an economically important tree and widely cultured in the southeast of China. Its barks, leaves, and fruits are consumed as a traditional medicine and perceived as a valuable source for bioactive limonin compounds. The extracts from root barks of C. tabularis showed significant anti-inflammatory effect. The aim of this research was to explore the material basis of C. tabularis anti-inflammatory activity, and to purify and identify anti-inflammatory active ingredients. By a bioassay-guided isolation of dichloromethane fraction obtained two novel phragmalin limonins, Chukrasitin D and E (1 and 2), together with 12 known limonins (3-14). The chemical structure of these compounds is determined on the basis of extensive spectral analysis and chemical reactivity. In addition, the activities of these isolated limonins on the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and nuclear factor kappa B (NF-κB) in RAW264.7 cells induced by lipopolysaccharide (LPS) were evaluated. Limonins 1 and 2 indicated significant anti-inflammatory activity with IC50 values of 6.24 and 6.13 µM. Compound 1 notably inhibited the production of NF-κB, TNF-α and interleukin 6 (IL-6) in macrophages. The present results suggest that the root barks of C. tabularis exhibited anti-inflammatory effect and the limonins may be responsible for this activity.

Anti-inflammatory and anti-oxidant properties of Melianodiol on DSS-induced ulcerative colitis in mice.

Background: Ulcerative colitis is a unique inflammatory bowel disease with ulcerative lesions of the colonic mucosa. Melianodiol (MN), a triterpenoid, isolated from the fruits of the Chinese medicinal plant Melia azedarach, possesses significant anti-inflammatory properties. Objective: The present study investigated the protective effects of MN on lipopolysaccharide (LPS)-induced macrophages and DSS-mediated ulcerative colitis in mice. Methods: In the study, mice were given MN (50, 100, and 200 mg/kg) and 5-ASA (500 mg/kg) daily for 9 days after induction by DSS for 1 week. The progress of the disease was monitored daily by observation of changes in clinical signs and body weight. Results: The results showed that MN effectively improved the overproduction of inflammatory factors (IL-6, NO, and TNF-α) and suppressed the activation of the NF-κB signalling cascade in LPS-mediated RAW264.7 cells. For DSS-mediated colitis in mice, MN can reduce weight loss and the disease activity index (DAI) score in UC mice, suppress colon shortening, and alleviate pathological colon injury. Moreover, MN treatment notably up regulated the levels of IL-10 and down regulated those of IL-1ß and TNF-α, and inhibited the protein expression of p-JAK2, p-STAT3, iNOS, NF-κB P65, p-P65, p-IKKα/ß, and p-IκBα in the colon. After MN treatment, the levels of MDA and NO in colonic tissue were remarkably decreased, whereas the levels of GSH, SOD, Nrf-2, Keap-1, HO-1, IκBα, and eNOS protein expression levels were significantly increased. Conclusion: These results indicate that MN can activate the Nrf-2 signalling pathway and inhibit the JAK/STAT, iNOS/eNOS, and NF-κB signalling cascades, enhance intestinal barrier function, and effectively reduce the LPS-mediated inflammatory response in mouse macrophages and DSS-induced intestinal injury in UC.

Early Prediction Model for Critical Illness of Hospitalized COVID-19 Patients Based on Machine Learning Techniques.

Motivation: Patients with novel coronavirus disease 2019 (COVID-19) worsen into critical illness suddenly is a matter of great concern. Early identification and effective triaging of patients with a high risk of developing critical illness COVID-19 upon admission can aid in improving patient care, increasing the cure rate, and mitigating the burden on the medical care system. This study proposed and extended classical least absolute shrinkage and selection operator (LASSO) logistic regression to objectively identify clinical determination and risk factors for the early identification of patients at high risk of progression to critical illness at the time of hospital admission. Methods: In this retrospective multicenter study, data of 1,929 patients with COVID-19 were assessed. The association between laboratory characteristics measured at admission and critical illness was screened with logistic regression. LASSO logistic regression was utilized to construct predictive models for estimating the risk that a patient with COVID-19 will develop a critical illness. Results: The development cohort consisted of 1,363 patients with COVID-19 with 133 (9.7%) patients developing the critical illness. Univariate logistic regression analysis revealed 28 variables were prognosis factors for critical illness COVID-19 (p < 0.05). Elevated CK-MB, neutrophils, PCT, α-HBDH, D-dimer, LDH, glucose, PT, APTT, RDW (SD and CV), fibrinogen, and AST were predictors for the early identification of patients at high risk of progression to critical illness. Lymphopenia, a low rate of basophils, eosinophils, thrombopenia, red blood cell, hematocrit, hemoglobin concentration, blood platelet count, and decreased levels of K, Na, albumin, albumin to globulin ratio, and uric acid were clinical determinations associated with the development of critical illness at the time of hospital admission. The risk score accurately predicted critical illness in the development cohort [area under the curve (AUC) = 0.83, 95% CI: 0.78-0.86], also in the external validation cohort (n = 566, AUC = 0.84). Conclusion: A risk prediction model based on laboratory findings of patients with COVID-19 was developed for the early identification of patients at high risk of progression to critical illness. This cohort study identified 28 indicators associated with critical illness of patients with COVID-19. The risk model might contribute to the treatment of critical illness disease as early as possible and allow for optimized use of medical resources.

Transient Interporosity Flow in Shale/Tight Oil Reservoirs: Model and Application.

The dual-porosity model has been used widely to describe the fracture network in well test or numerical simulation due to the high computational efficiency. The shape factor, which can be used to determine the capability of mass transfer between the matrix and fracture, is the core of the dual-porosity model. However, the conventional shape factor, which is usually obtained under pseudo-steady state assumption, has certain limitation in characterization of the mass transfer efficiency in a shale/tight reservoir. In this study, a new transient interporosity flow model has been established by considering the influence of nonlinear flow, stress sensitivity, and fracture pressure depletion. To solve this new model, a finite difference and Newton iteration method was applied. According to the Duhamel principle, the solution for time-dependent fracture pressure boundary condition has been obtained. The solution has been verified by using the fine-grid finite element method. Then, the influence of nonlinear flow, stress sensitivity, and fracture pressure depletion on shape factor and interporosity flow rate has been studied. The study results show that constant shape factors are not suitable for unconventional reservoirs, and the interporosity flow in the shale/tight reservoir is controlled by multiple factors. The new model can be used in test interpretation and numerical simulation, and also provides a new approach for the optimization of the perforation cluster number.

Non-metal-mediated N-oxyl radical (TEMPO)-induced acceptorless dehydrogenation of N-heterocycles via electrocatalysis.

The development of protocols for direct catalytic acceptorless dehydrogenation of N-heterocycles with metal-free catalysts holds the key to difficulties in green and sustainable chemistry. Herein, an N-oxyl radical (TEMPO) acting as an oxidant in combination with electrochemistry is used as a synthesis system under neutral conditions to produce N-heterocycles such as benzimidazole and quinazolinone. The key feature of this protocol is the utilization of the TEMPO system as an inexpensive and easy to handle radical surrogate that can effectively promote the dehydrogenation reaction. Mechanistic studies also suggest that oxidative TEMPOs redox catalytic cycle participates in the dehydrogenation of 2,3-dihydro heteroarenes.

A new cyclopeptide alkaloid from Clematis Florida.

One new 14-membered ring cyclopeptide alkaloid, plenane A (1), along with six known compounds (2-7), was isolated from the roots of Clematis florida. Their structures were elucidated by means of NMR spectroscopic analysis and mass spectrometry. In addition, their anti- inflammatory effects on lipopolysaccharide-induced RAW264.7 macrophages were evaluated in vitro. The compounds 1, 2 and 6 exhibited potent indirect inhibitory effects, with IC50 values of 40.92, 22.88 and 6.32 µM, respectively.