The Role of Nrf2 in Exercise Improving of NAFLD / 生物化学与生物物理进展

In cardiovascular disorders, neurological diseases, and chronic metabolic diseases, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is essential for maintaining cell homeostasis. According to studies, boosting Nrf2 expression can be used to cure or prevent chronic diseases that are characterized by oxidative stress, inflammation, and mitochondrial dysfunction. Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease characterized by hepatic steatosis brought on by a number of causes other than alcohol. In recent years, its incidence has gradually risen across the globe. According to relevant studies, NAFLD and the Nrf2 signaling pathway are tightly connected. Inhibiting lipid production and metabolism-related enzymes, repairing impaired liver metabolism, and lowering hepatic lipid storage are all possible with Nrf2 activation. Exercise is a powerful tool for treating and preventing NAFLD. However, exercise type, exercise intensity, environment, and exhaustion all have an impact on the Nrf2 signaling pathway. By activating Nrf2, exercise can lessen liver inflammation, oxidative stress, endoplasmic reticulum stress, and insulin resistance, and ameliorate liver damage to improve NAFLD. The activation of Nrf2 signaling pathway, its associated mechanism of controlling antioxidation, and the impact of exercise on the Nrf2 signaling pathway are all explained in this work. Based on the pathogenesis of NAFLD, this article examines the connection between exercise, Nrf2, and NAFLD, and the current state of knowledge regarding Nrf2’s role in the amelioration of NAFLD through exercise. It offers a theoretical frame of reference for future research into how Nrf2 might be used to improve NAFLD.

Discussion on the Medication Rules of ZHONG Guang-Ling in Treating Lumbar Disc Herniation / 广州中医药大学学报

Objective To explore the medication rules of Professor ZHONG Guang-Ling's prescriptions for the treatment of lumbar disc herniation(LDH)based on data mining method,so as to provide reference for the treatment of LDH with Chinese medicine.Methods The prescriptions for the effective cases of outpatients of LDH treated by Professor ZHONG Guang-Ling in the recent 5 years were collected.The medication frequency of Chinese medicines in the included prescriptions and the distribution of their properties,flavors and meridian tropism were investigated.Moreover,the association rule analysis and cluster analysis of the high-frequency drugs were carried out.Results A total of 164 prescriptions were included and 168 Chinese medicines were used.The top 10 high-frequency drugs in descending order were Achyranthis Bidentatae Radix,Chuanxiong Rhizoma,Pheretima,Glycyrrhizae Radix et Rhizoma Praeparata cum Melle,Gentianae Macrophyllae Radix,Angelicae Sinensis Radix,Rehmanniae Radix Praeparata,Persicae Semen,Cyperi Rhizoma,and Carthami Flos.The properties of the prescribed drug were mainly warm and mild in nature,and bitter and pungent in flavor,and mainly had the meridian tropism of the liver,kidney and spleen meridians.According to the therapeutic actions,the drugs were mainly categorized as deficiency-supplementing drugs,dampness-removing and collateral-unblocking drugs,and blood-activating and stasis-removing drugs.The results of association rule analysis yielded 10 drug pairs,and cluster analysis yielded 6 core drug combinations.Conclusion For the treatment of LDH,Professor ZHONG Guang-Ling usually adopts the Chinese medicine for supplementing the deficiency and supporting healthy-qi,together with the medicines for nourishing the liver and kidney and regulating the spleen and stomach from the perspective of liver,kidney and spleen.Moreover,therapy of activating blood and removing stasis is also stressed,pathogen-eliminating medicines for removing dampness,unblocking collaterals and clearing heat are used based on syndrome differentiation,and then simultaneous application of purging and nourishing therapeutics is achieved through the utilization of purging method after supplementing method.

Effectiveness of narrative exposure therapy for post-traumatic stress disorder in children and adolescents： a Meta-analysis / 四川精神卫生

BackgroundNarrative exposure therapy （NET）， an integration of narrative therapy and exposure therapy， has been shown to be effective in relieving the symptoms of post-traumatic stress disorder （PTSD）， which can help patients gain a deeper understanding of their trauma and is also considered to be quite safe. PTSD is highly prevalent in children and adolescents， while the effectiveness of NET intervention varies among the subjects. ObjectiveTo systematically evaluate the effectiveness of NET for PTSD in children and adolescents， so as to provide references for the clinical application of NET. MethodsOn August 1， 2022， the Cochrane Library， PubMed， Web of Science， CINAHL， China National Knowledge Infrastructure （CNKI）， SinoMed， VIP and Wanfang database were searched from their inception to June 2022. Search was conducted with the use of a combination of medical subject heading and free text terms， and randomized controlled trials relevant to NET for PTSD in children and adolescents were collected. Then the quality of the controlled trials was evaluated according to the Cochrane Collaboration's tool for assessing risk of bias （2011）， and Meta-analysis was performed using RevMan 5.4 software. ResultsNine randomized controlled trials involving 394 children and adolescents with PTSD were included. Meta-analysis showed that NET and relaxation therapy reported comparable symptom relief in PTSD patients within 1 to 3 months after intervention （SMD=0.22， 95% CI： -0.84~1.28） and at 6 months after intervention （SMD=0.21， 95% CI： -0.75~1.17）， while NET provided greater PTSD symptom relief than routine therapy both within 1 to 3 months after intervention （SMD=-0.66， 95% CI： -1.04~-0.27） and at 6 months after intervention （SMD=-0.77， 95% CI： -1.36~-0.19）， with statistically significant differences. Regarding the alleviation of depressive symptoms， the effect was similar between NET and routine therapy within 1 to 3 months after intervention （SMD=-0.39， 95% CI： -0.98~0.21） and at 6 months after intervention （SMD=-0.74， 95% CI： -2.23~0.75）. No statistical difference was demonstrated between NET and routine therapy in relieving psychological distress （SMD=-0.54， 95% CI： -2.14~1.07） and suppressing hyperorexia （SMD=-0.17， 95% CI： -0.54~0.19） 1 to 3 months after intervention. ConclusionNET yields a better outcome and a medium- and long-term effectiveness in alleviating symptoms of PTSD in children and adolescents compared with routine therapy， while it does not offer any significant advantages in improving depression symptoms， psychological distress and hyperorexia.

Coupling-Spirocyclization Cascade of Tryptamine-Derived Isocyanides with Iodonium Ylides and Despirocyclization Reactions.

A cobalt(II)-catalyzed coupling-cyclization cascade reaction between tryptamine-derived isocyanides and iodonium ylides is investigated, which allowed for the synthesis of different types of spiroindoline compounds by variation of substituents at the N1- and C2-positions in the indole skeleton. More interesting is that the spiroindoline products could undergo despirocyclization in the presence of amines, enabling efficient construction of enamine compounds.

The relationship between fall and loneliness among older people in China: the mediating role of personality trait.

Aims: We aimed to explore the role of personality traits between fall and loneliness. Methods: A questionnaire survey was used to investigate falls, the big five personality traits, and loneliness among older people (≥ 60 years old) in China mainland. Results: A total of 4,289 older people participated in the survey. There are significant differences in age, marital status, education level, residence, solitariness, and fall in relation to loneliness among older people. Falls, especially when they occurred one time increase the loneliness of older people. Agreeableness, conscientiousness, and neuroticism were significant mediating effects between falls and loneliness. Conclusion: This study implied that agreeableness, conscientiousness, and neuroticism were meditating factors between falls and loneliness. In the future, we should consider the big five personality traits more to understand loneliness and offer older people interventions for reducing their loneliness. The study design was cross-sectional, so the temporal precedence of mediators and causality could not be tested. Because the data were collected retrospectively, current loneliness is likely to have confounding effects on retrospective recall.

Short-term outcome of patients after transcatheter aortic valve replacement receiving different anticoagulants / 中华心血管病杂志

Objective: To compare the safety and efficacy of different anticoagulants in patients with indications for anticoagulation after transcatheter aortic valve replacement (TAVR). Methods: This is a retrospective study. Patients who underwent TAVR from April 2016 to February 2022 in Guangdong Provincial People's Hospital and had indications for anticoagulation were included and divided into two groups according to the type of anticoagulants, i.e. non-vitamin K antagonist oral anticoagulant (NOAC) and warfarin, and patients were followed up for 30 days. The primary endpoint was the combination of death, stroke, myocardial infarction, valve thrombosis, intracardiac thrombosis and major bleeding. The incidence of endpoints was compared between two groups, and multivariate logistic regression analysis was applied to adjust the bias of potential confounders. Results: A total of 80 patients were included. Mean age was (74.4±7.1) years, 43 (53.8%) were male. Forty-nine (61.3%) patients used NOAC, 31 used warfarin, and major indication for anticoagulants was atrial fibrillation (76/80, 95.0%). The adjusted risks of the primary endpoint (OR=0.23, 95%CI 0.06-0.94, P=0.040) of NOAC were lower than that of warfarin, mainly driven by a lower risk of major bleeding (OR=0.19, 95%CI 0.04-0.92, P=0.039). Conclusions: The short-term outcome of NOAC is better than that of warfarin in patients with indications for anticoagulation after TAVR. Randomized controlled trials of large sample size with long-term follow-up are needed to further testify this finding.

Clinical analysis of five cases of neonate brain abscess / 中国小儿急救医学

Objective:To summarize the clinical characteristics of neonatal brain abscess and improve the understanding of diagnosis and treatment of this disease.Methods:Clinical data of five cases of neonatal brain abscess admitted to the First Affiliated Hospital of Zhengzhou University from December 2018 to March 2021 were retrospectively analyzed and followed-up.Results:Among five cases, four cases were premature and one was term infant, three were girls and two were boys. The age of onset was 10, 5, 2, 28 and 11 days after birth, and all had fever as the first manifestation. Three cases had positive blood or cerebrospinal fluid cultures, and the diagnosis of brain abscess was confirmed by head imaging, with the most common lesion being in the frontal lobe. One case was treated conservatively, and four cases underwent abscess aspiration and drainage. After treatment, the range of lesions in five cases was reduced and the clinical symptoms were improved. The neurodevelopmental assessment after discharge did not reveal any intelligence or motor retardation in three cases, and were developing as the same age, while the other two cases had various degrees of neurological sequelae.Conclusion:The clinical characteristics of neonatal brain abscess are not specific, so it is necessary to conduct head imaging examination as early as possible for neonates with septicemia and meningitis with poor therapeutic effect or recurrent disease, so as to improve the early diagnosis rate and long-term prognosis.

Short-term outcome of patients after transcatheter aortic valve replacement receiving different anticoagulants / 中华心血管病杂志

Objective: To compare the safety and efficacy of different anticoagulants in patients with indications for anticoagulation after transcatheter aortic valve replacement (TAVR). Methods: This is a retrospective study. Patients who underwent TAVR from April 2016 to February 2022 in Guangdong Provincial People's Hospital and had indications for anticoagulation were included and divided into two groups according to the type of anticoagulants, i.e. non-vitamin K antagonist oral anticoagulant (NOAC) and warfarin, and patients were followed up for 30 days. The primary endpoint was the combination of death, stroke, myocardial infarction, valve thrombosis, intracardiac thrombosis and major bleeding. The incidence of endpoints was compared between two groups, and multivariate logistic regression analysis was applied to adjust the bias of potential confounders. Results: A total of 80 patients were included. Mean age was (74.4±7.1) years, 43 (53.8%) were male. Forty-nine (61.3%) patients used NOAC, 31 used warfarin, and major indication for anticoagulants was atrial fibrillation (76/80, 95.0%). The adjusted risks of the primary endpoint (OR=0.23, 95%CI 0.06-0.94, P=0.040) of NOAC were lower than that of warfarin, mainly driven by a lower risk of major bleeding (OR=0.19, 95%CI 0.04-0.92, P=0.039). Conclusions: The short-term outcome of NOAC is better than that of warfarin in patients with indications for anticoagulation after TAVR. Randomized controlled trials of large sample size with long-term follow-up are needed to further testify this finding.

Application of traditional Chinese medicine theory in modern traditional Chinese medicine nano-preparation: taking tumor treatment as an example / 中国中药杂志

With Zang-Fu organs, meridians, Qi and blood, and body fluid as the physiological and pathological basis, traditional Chinese medicine(TCM) theory is guided by the holistic concept and characterized by syndrome differentiation. It has made significant contributions to human health maintenance and disease prevention. Modern TCM preparation is developed on the basis of inheriting and developing TCM preparations using modern science and technology under the guidance of TCM theory. At present, the incidence and mortality of common tumors are increasing. TCM has rich clinical experience in the treatment of tumors. However, in the current stage, some TCM preparations have a tendency to deviate from the guidance of TCM theory. With the modernization of TCM, it is worth considering how TCM theory guides modern TCM preparations. Taking tumor treatment as an example, this paper introduced the development of TCM nano-preparation under the influence of modern nanotechnology, summarized the research on the development of modern TCM nano-preparation from the aspects of TCM holistic concept, TCM treatment principles, and TCM theory application, and discussed the application prospect of TCM nano-preparation in overall therapy, drug pairing, carrier selection, and targeted substance selection under the guidance of TCM theory. This paper provides new references for further developing the combination of tradition and modernization of TCM nano-preparation.

Quality control mechanism of mitochondria by 3,4-dihydroxybenzaldehyde through OGT-PINK1 pathway / 中国中药杂志

Based on the O-GlcNAc transferase(OGT)-PTEN-induced putative kinase 1(PINK1) pathway, the mechanism of 3,4-dihydroxybenzaldehyde(DBD) on mitochondrial quality control was investigated. Middle cerebral artery occlusion/reperfusion(MCAO/R) rats were established. SD rats were randomized into sham operation group(sham), model group(MCAO/R), DBD-L group(5 mg·kg~(-1)), and DBD-H group(10 mg·kg~(-1)). After 7 days of administration(ig), MCAO/R was induced in rats except the sham group with the suture method. Twenty-four h after reperfusion, the neurological function and the percentage of cerebral infarct area were measured. Based on hematoxylin and eosin(HE) staining and Nissl staining, the pathological damage of cerebral neurons was examined. Then the ultrastructure of mitochondria was observed under the electron microscope, and the co-localization of light chain-3(LC3), sequestosome-1(SQSTM1/P62), and Beclin1 was further detected by immunofluorescence staining. It has been reported that the quality of mitochondria can be ensured by inducing mitochondrial autophagy through the OGT-PINK1 pathway. Therefore, Western blot was employed to detect the expression of OGT, mitophagy-related proteins PINK1 and E3 ubiquitin ligase(Parkin), and mitochondrial kinetic proteins dynamin-like protein 1(Drp1) and optic atrophy 1(Opa1). The results showed that MCAO/R group had neurological dysfunction, large cerebral infarct area(P<0.01), damaged morphological structure of neurons, decreased number of Nissl bodies, mitochondrial swelling, disappearance of mitochondrial cristae, decrease of cells with LC3 and Beclin1, rise of cells with P62(P<0.01), inhibited expression of OGT, PINK1, and Parkin, up-regulated expression of Drp1, and down-regulated expression of Opa1 compared with the sham group(P<0.01). However, DBD improved the behavioral deficits and mitochondrial health of MCAO/R rats, as manifested by the improved morphology and structure of neurons and mitochondria and the increased Nissl bodies. Moreover, DBD increased cells with LC3 and Beclin1 and decreased cells with P62(P<0.01). In addition, DBD promoted the expression of OGT, PINK1, Parkin, and Opa1 and inhibited the expression of Drp1, enhancing mitophagy(P<0.05, P<0.01). In conclusion, DBD can trigger PINK1/Parkin-mediated brain mitophagy through the OGT-PINK1 pathway, which plays a positive role in maintaining the health of the mitochondrial network. This may be a mitochondrial therapeutic mechanism to promote nerve cell survival and improve cerebral ischemia/reperfusion injury.

Correlation Analysis of Hemolytic Transfusion Reaction Induced by Low Titer Antibody / 中国实验血液学杂志

OBJECTIVE@#To establish the diagnostic process of low titer blood group antibody in the occurrence of adverse reactions of hemolytic transfusion.@*METHODS@#Acid elusion test, enzyme method and PEG method were used for antibody identification. Combined with the patient's clinical symptoms and relevant inspection indexes, the irregular antibodies leading to hemolysis were detected.@*RESULTS@#The patient's irregular antibody screening was positive, and it was determined that there was anti-Lea antibody in the serum. After the transfusion reaction, the low titer anti-E antibody was detected by enhanced test. The patient's Rh typing was Ccee, while the transfused red blood cells were ccEE. The new and old samples of the patient were matched with the transfused red blood cells by PEG method, and the major were incompatible. The evidence of hemolytic transfusion reaction was found.@*CONCLUSION@#Antibodies with low titer in serum are not easy to be detected, which often lead to severe hemolytic transfusion reaction.

A machine learning approach identifies unresolving secondary pneumonia as a contributor to mortality in patients with severe pneumonia, including COVID-19

BackgroundPatients with severe SARS-CoV-2 pneumonia experience longer durations of critical illness yet similar mortality rates compared to patients with severe pneumonia secondary to other etiologies. As secondary bacterial infection is common in SARS-CoV-2 pneumonia, we hypothesized that unresolving ventilator-associated pneumonia (VAP) drives the apparent disconnect between length-of-stay and mortality rate among these patients. MethodsWe analyzed VAP in a prospective single-center observational study of 585 mechanically ventilated patients with suspected pneumonia, including 190 patients with severe SARS-CoV-2 pneumonia. We developed CarpeDiem, a novel machine learning approach based on the practice of daily ICU team rounds to identify clinical states for each of the 12,495 ICU patient-days in the cohort. We used the CarpeDiem approach to evaluate the effect of VAP and its resolution on clinical trajectories. FindingsPatients underwent a median [IQR] of 4 [2,7] transitions between 14 clinical states during their ICU stays. Clinical states were associated with differential hospital mortality. The long length-of-stay among patients with severe SARS-CoV-2 pneumonia was associated with prolonged stays in clinical states defined by severe respiratory failure and with a lower frequency of transitions between clinical states. In all patients, including those with COVID-19, unresolving VAP episodes were associated with transitions to unfavorable states and hospital mortality. InterpretationCarpeDiem offers a machine learning approach to examine the effect of VAP on clinical outcomes. Our findings suggest an underappreciated contribution of unresolving secondary bacterial pneumonia to outcomes in mechanically ventilated patients with pneumonia, including due to SARS-CoV-2. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/22280118v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@27a00eorg.highwire.dtl.DTLVardef@17d2a80org.highwire.dtl.DTLVardef@716d8dorg.highwire.dtl.DTLVardef@cf83ce_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Disentangling the contributions of ICU complications and interventions to ICU outcomes. (A) Traditional approaches evaluate the ICU stay as a black box with severity of illness measured on presentation and dichotomized survival at an arbitrary time point (e.g., day 28) or on ICU or hospital discharge. Hence, the effect of intercurrent complications and interventions cannot be easily measured, a problem that is compounded when ICU stays are long or significantly differ between groups. (B) Defining the ICU course by clinical features during each day in the ICU permits the association of a complication or intervention with transitions toward clinical states associated with favorable or unfavorable outcomes. C_FIG

Glutathione peroxidase 8 expression on cancer cells and cancer-associated fibroblasts facilitates lung cancer metastasis.

Lung cancer is the leading cause of cancer death worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Metastasis is the major cause of poor prognosis and mortality for lung cancer patients, which urgently needs great efforts to be further explored. Herein, glutathione peroxidase 8 (GPX8) was identified as a novel potential pro-metastatic gene in LUAD metastatic mice models from GEO database. GPX8 was highly expressed in tumor tissues, predicting poor prognosis in LUAD patients. Knockdown of GPX8 inhibited LUAD metastasis in vitro and in vivo, while it did not obviously affect tumor growth. Knockdown of GPX8 decreased the levels of p-FAK and p-Paxillin and disturbed the distribution of focal adhesion. Furthermore, GPX8 was overexpressed in cancer-associated fibroblast (CAF) and associated with CAF infiltration in tumor microenvironment of lung cancer. GPX8 silence on fibroblasts suppressed lung cancer cell migration in the coculture system. BRD2 and RRD4 were the potential transcriptionally regulators for GPX8. Bromodomain extra-terminal inhibitor JQ1 downregulated GPX8 expression and suppressed lung cancer cell migration. Our findings indicate that highly expressed GPX8 in lung cancer cells and fibroblasts functions as a pro-metastatic factor in lung cancer. JQ1 is identified as a potential inhibitor against GPX8-mediated lung cancer metastasis.

Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients.

Yes-associated protein 1 (YAP1) is involved in the development of a variety of malignancies. However, the prognosis of malignant digestive tumors with YAP1 expression is still controversial. This study searched 31 articles with 36 data sets of 4023 patients to explore the role of YAP1 expression on the prognosis of digestive malignant tumors by searching the PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library databases. Specifically, relevant cancer expression matrix data were downloaded from The Cancer Genome Atlas (TCGA) database. In this meta-analysis, quantitative analysis showed that the overexpression of YAP1 was not conducive to OS (1.62, 95% CI (1.38, 1.90), P=0.001) and DFS (1.59, 95% CI (1.31, 1.93), P=0.001) in patients with digestive malignant tumors. In addition, TCGA database analysis showed that YAP1 was overexpressed in gastric cancer, cholangiocarcinoma, and colorectal cancer. Survival analysis showed that the patients with high expression of YAP1 in pancreatic cancer have a poor OS (MST: 394 vs. 691 days, P < 0.0001) and DFS (MST: 371 vs. 542 days, P=0.026) prognosis. YAP1 may be a molecular marker that effectively predicts the survival of malignant digestive tumors, especially pancreatic cancer, and is a potential therapeutic target for malignant digestive tumors.

Integrative analysis of viral entry networks and clinical outcomes identifies a protective role for spironolactone in severe COVID-19

Treatment strategies that target host entry factors have proven an effective means of impeding viral entry in HIV and may be more robust to viral evolution than drugs targeting viral proteins directly. High-throughput functional screens provide an unbiased means of identifying genes that influence the infection of host cells, while retrospective cohort analysis can measure the real-world, clinical potential of repurposing existing therapeutics as antiviral treatments. Here, we combine these two powerful methods to identify drugs that alter the clinical course of COVID-19 by targeting host entry factors. We demonstrate that integrative analysis of genome-wide CRISPR screening datasets enables network-based prioritization of drugs modulating viral entry, and we identify three common medications (spironolactone, quetiapine, and carvedilol) based on their network proximity to putative host factors. To understand the drugs real-world impact, we perform a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients and show that spironolactone use is associated with improved clinical prognosis, measured by both ICU admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in a human lung epithelial cell line. Our results suggest that spironolactone may improve clinical outcomes in COVID-19 through tissue-dependent inhibition of viral entry. Our work further provides a potential approach to integrate functional genomics with real-world evidence for drug repurposing.

c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2.

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Acute respiratory distress syndrome after SARS-CoV-2 infection on young adult population: international observational federated study based on electronic health records through the 4CE consortium ARDS after SARS-CoV-2 infection on young adult

PurposeIn young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population. MethodsA retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS. ResultsAmong the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS ( 7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%-although not significantly associated with ARDS), and diabetes (32%). ConclusionTrough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.

Unique molecular signatures sustained in circulating monocytes and regulatory T cells in Convalescent COVID-19 patients

Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized multi-omic single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including covenlesent COVID-19 and sero-negative controls. The reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells are significantly associated with the patients recovered from severe COVID-19. Consistently, sc-RNA seq analysis reveals seven heterogeneous clusters of monocytes (M0-M6) and ten Treg clusters (T0-T9) featuring distinct molecular signatures and associated with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocyte and Treg expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters with S100 family genes: S100A8 & A9 with high HLA-I whereas S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, and a unique TGF-{beta} high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-ived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (>= 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

Myricetin inhibits interferon-γ-induced PD-L1 and IDO1 expression in lung cancer cells.

Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints induced by interferon-γ (IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. In this study, MY was identified to inhibit IFN-γ-induced PD-L1 expression in human lung cancer cells. It also reduced the expression of IDO1 and the production of kynurenine which is the product catalyzed by IDO1, while didn't show obvious effect on the expression of major histocompatibility complex-I (MHC-I), a crucial molecule for antigen presentation. In addition, the function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line overexpressing PD-1. MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. Together, our research revealed a new mechanism of MY mediated anti-tumor activity and highlighted the potential implications of MY in tumor immunotherapy.

Distinguishing Admissions Specifically for COVID-19 from Incidental SARS-CoV-2 Admissions: A National EHR Research Consortium Study

BackgroundAdmissions are generally classified as COVID-19 hospitalizations if the patient has a positive SARS-CoV-2 polymerase chain reaction (PCR) test. However, because 35% of SARS-CoV-2 infections are asymptomatic, patients admitted for unrelated indications with an incidentally positive test could be misclassified as a COVID-19 hospitalization. EHR-based studies have been unable to distinguish between a hospitalization specifically for COVID-19 versus an incidental SARS-CoV-2 hospitalization. Although the need to improve classification of COVID-19 disease vs. incidental SARS-CoV-2 is well understood, the magnitude of the problems has only been characterized in small, single-center studies. Furthermore, there have been no peer-reviewed studies evaluating methods for improving classification. ObjectiveThe aims of this study were to: first, quantify the frequency of incidental hospitalizations over the first fifteen months of the pandemic in multiple hospital systems in the United States; and second, to apply electronic phenotyping techniques to automatically improve COVID-19 hospitalization classification. MethodsFrom a retrospective EHR-based cohort in four US healthcare systems in Massachusetts, Pennsylvania, and Illinois, a random sample of 1,123 SARS-CoV-2 PCR-positive patients hospitalized between 3/2020-8/2021 was manually chart-reviewed and classified as admitted-with-COVID-19 (incidental) vs. specifically admitted for COVID-19 (for-COVID-19). EHR-based phenotyping was used to find feature sets to filter out incidental admissions. ResultsEHR-based phenotyped feature sets filtered out incidental admissions, which occurred in an average of 26% of hospitalizations (although this varied widely over time, from 0%-75%). The top site-specific feature sets had 79-99% specificity with 62-75% sensitivity, while the best performing across-site feature set had 71-94% specificity with 69-81% sensitivity. ConclusionsA large proportion of SARS-CoV-2 PCR-positive admissions were incidental. Straightforward EHR-based phenotypes differentiated admissions, which is important to assure accurate public health reporting and research.