Effect of electroacupuncture of "Jiaji" (EX-B2) on NOD-like receptor protein 3 mediated pyroptosis in spinal cord tissue of rats with acute spinal cord injury. / å¤¹è„Šç”µé’ˆå¯¹æ€¥æ€§è„Šé«“æŸä¼¤å¤§é¼ è„Šé«“ç»„ç»‡NODæ ·å—ä½“çƒ­è›‹ç™½ç»“æž„åŸŸç›¸å ³è›‹ç™½3介导的细胞焦亡的影响.

OBJECTIVES: To observe the effect of electroacupuncture (EA) stimulation of "Jiaji"(EX-B2) on motor function, histomorphology, and expression of NOD-like receptor protein 3 (NLRP3) and N-terminal domain of gasdermin D (GSDMD-N) in the spinal cord tissue of rats with spinal cord injury (SCI), so as to explore its mechanism underlying improvement of SCI. METHODS: Forty eight female SD rats were randomly divided into sham surgery (sham), SCI model (model), EA, and NLRP3 agonist (monosodium urate, MSU) combined with Jiaji EA (MSU+EA) groups, with 12 rats in each group which were further divided into 3 d and 7 d subgroups, with 6 rats at each time point. Two EA groups received EA stimulation of EX-B2 with a frequency of 100 Hz, electrical current of 1-2 mA for 30 min, once a day for 3 or 7 days. After 5 min, 6 h, and 24 h of modeling, rats of the MSU+EA group received intraperitoneal injection of MSU (200 µg/kg, 200 µg/mL) . The motor function was evaluated using Basso-Beattie-Bresnahan (BBB) scale, the morphological structure of rat spinal cord tissue was observed by H.E. staining. The expression of pyroptosis related factors NLRP3, cleaved Caspase-1 and GSDMD-N of the spinal cord was observed by using immunohistochemistry and Western blot separately, the expression and localization of Iba-1 and GSDMD-N in the spinal cord tissue were observed using immunofluorescence double staining method. RESULTS: Compared with the sham group, the BBB scores after modeling and on day 3 and 7 were decreased (P<0.05), while the average OD values (immunoactivity) and expression levels of NLRP3, cleaved Caspase-1 and GSDMD-N proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N (co-expression) of the spinal cord tissues on day 3 and 7 were significantly increased in the model group (P<0.05). In comparison with the model group, the BBB scores on day 3 and 7 were obviously increased (P<0.05), while the immunoactivity and expression levels of NLRP3, cleaved Caspase-1 and GSDMD proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N on day 3 and 7 significantly down-regulated in the EA group (P<0.05) but not in the MSU+EA group (P>0.05), suggesting an elimination of the effects of EA after administration of NLRP3 agonist (MSU). H.E. staining showed obvious bleeding area in the spinal cord tissue, loose tissue and inflammatory cell infiltration on day 3 after modeling, and basic absorption of the bleeding, loose tissue, obvious vacuolar changes of the white matter area, loss and contraction of neurons with infiltration of a large number of inflammatory cells, which was milder in the EA group but not in the MSU+EA group. CONCLUSIONS: EA of EX-B2 can improve the motor function of SCI rats, which may be related to its functions in inhibiting pyroptosis of microglia mediated by NLRP3/Caspase-1 signaling pathway.

MOF Template-Derived Carbon Shell-Embedded CoP Hierarchical Nanosheet as Bifunctional Catalyst for Overall Water Splitting.

The design of earth-abundant and highly efficient bifunctional electrocatalysts for hydrogen evolution and oxygen evolution reactions (HER/OER) is crucial for hydrogen production through overall water splitting. Herein, we report a novel nanostructure consisting of vertically oriented CoP hierarchical nanosheet arrays with in situ-assembled carbon skeletons on a Ti foil electrode. The novel Zeolitic Imidazolate Framework-67 (ZIF-67) template-derived hierarchical nanosheet architecture effectively improved electrical conductivity, facilitated electrolyte transport, and increased the exposure of the active sites. The obtained bifunctional hybrid exhibited a low overpotential of 72 mV at 10 mA cm-2 and a small Tafel slope of 65 mV dec-1 for HER, and an improved overpotential of 329 mV and a Tafel slope of 107 mV dec-1 for OER. Furthermore, the assembled C@CoP||C@CoP electrolyzer showed excellent overall water splitting performance (1.63 V) at a current density of 10 mA cm-2 and superior durability. This work provides a structure engineering strategy for metal-organic framework (MOF) template-derived hybrids with outstanding electrocatalytic performance.

The safety and efficacy between remimazolam and propofol in intravenous anesthesia of endoscopy operation: a systematic review and meta-analysis.

BACKGROUND: Propofol is the most widely used intravenous anesthetic in endoscopic surgery, but is associated with several adverse reactions. Public research has shown that remimazolam, a safe general anesthetic, is increasingly being used as a substitute for propofol in clinical operations. Our meta-analysis aimed to analyze whether the adverse reaction rate of remimazolam in endoscopic surgery is acceptable and whether the surgical success rate is not lower than that of propofol. AIM: This meta-analysis examined the adverse events and efficacy of remimazolam vs. propofol during endoscopic surgery. METHOD: MEDLINE, Embase, ClinicalTrials.gov, and Google Scholar were comprehensively searched. Seven studies comparing remimazolam and propofol were included in our meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane manual were used to assess the quality of the results published in all included studies to ensure that our meta-analysis results are reliable and worthwhile. RESULTS: Compared to propofol, the use of remimazolam reduced postoperative injection pain [relative risk (RR)=0.06, 95% confidence interval (CI): 0.03-0.12, P <0.00001], postoperative hypotension (RR=0.45, 95% CI: 0.28-0.73, P =0.001), and postoperative respiratory depression (RR=0.20, 95% CI: 0.08-0.47, P =0.0002); however, it also slightly reduced the success rate of the operation [risk difference (RD)=-0.02, 95% CI: -0.04 to -0.01, P =0.0007]. There were no significant differences in the occurrence of bradycardia symptoms after the operation (RD=-0.01, 95% CI: -0.03 to 0.01, P =0.35), recovery time after the operation [standardized mean difference (SMD)=0.68, 95% CI: -0.43 to 1.80, P =0.23] or discharge time (SMD=0.17, 95% CI: -0.58 to 0.23, P =0.41). We also performed a subgroup analysis of each corresponding outcome. CONCLUSION: Our analysis showed that remimazolam may be a safer shock option than propofol for endoscopic surgery. However, further research is required to determine their utility.

[Research progress of acupuncture-moxibustion in treatment of spinal cord injury through mediating inflammatory reaction].

Inflammatory reaction after spinal cord injury (SCI) is the main obstacle to the recovery of neural function. In the occurrence and development of SCI, the complex regulatory mechanisms are involved in inflammatory reaction, including the activation of inflammatory cells (e.g.macrophages and microglia), and the release of cytokines (e.g. tumor necrosis factor, interleukin and chemokines). Acupuncture-moxibustion is significantly effective in clinical treatment of SCI, and its mechanism is related to adjusting the function of inflammatory cells after SCI, modulating the expression of cytokines and the activation of NLRP3 inflammatory bodies, as well as the expression of high mobility group protein B1 and calcitonin gene related peptide. This article summarizes the research progress of mechanism of inflammatory reaction after SCI and the effects of acupuncture-moxibustion intervention in recent years so that the new ideas can be provided to clarify the pathogenesis of SCI and the effect of acupuncture-moxibustion intervention.

Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury.

Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein, is essential for oligodendrocyte maturation and myelination; however, its role in the kidneys or in SOX9 regulation remains unknown. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.

Risk factors for and delayed recognition of genitourinary fistula following radical hysterectomy for cervical cancer: a population-based analysis / 부인종양

Objective@#This study aimed to identify the risk factors for genitourinary fistulas and delayed fistula recognition after radical hysterectomy for cervical cancer. @*Methods@#This study was a retrospective analysis of data collected in the Major Surgical complications of Cervical Cancer in China (MSCCCC) database from 2004–2016. Data on sociodemographic characteristics, clinical characteristics, and hospital characteristics were extracted. Differences in the odds of genitourinary fistula development were investigated with multivariate logistic regression analyses, and differences in the time to recognition of genitourinary fistula were assessed by Kruskal–Wallis test. @*Results@#In this study, 23,404 patients met the inclusion criteria. Surgery in a cancer center, a women’s and children’s hospital, a facility in a first-tier city, or southwest region, stage IIA, type C1 hysterectomy, laparoscopic surgery and ureteral injury were associated with a higher risk of ureterovaginal fistula (UVF) (p<0.050). Surgery in southwest region, bladder injury and laparoscopic surgery were associated with greater odds of vesicovaginal fistula (VVF) (p<0.050). Surgery at cancer centers and high-volume hospitals was associated with an increase in the median time to UVF recognition (p=0.016; p=0.005). International Federation of Gynecology and Obstetrics (FIGO) stage IIA1-IIB was associated with delayed recognition of VVF (p=0.040). @*Conclusion@#Intraoperative urinary tract injury and surgical approach were associated with differences in the development of UVFs and VVFs. Patients who underwent surgery in cancer centers and high-volume hospitals were more likely to experience delayed recognition of UVF. Patients with FIGO stage IIA1-IIB disease were more likely to experience delayed recognition of VVF.

Alirocumab in the treatment of hypercholesterolemia:a rapid health technology assessment / 药物流行病学杂志

Objective To evaluate the efficacy,safety and cost-effectiveness of alirocumab for the treatment of hypercholesterolemia in a rapid health technology assessment(rHTA).Methods PubMed,Embase,Cochrane Library,CNKI,WanFang Data and health technology assessment(HTA)relative websites were electronically searched to collect HTA reports,systematic reviews/Meta-analyses and pharmacoeconomic literatures on the alirocumab for the treatment of hypercholesterolemia from inception to August 14th,2022.Two reviewers independently screened the literature,extracted the data results and accessed the quality of included studies.Descriptive analysis and summary were then performed.Results A total of 38 documents were included,including 28 systematic reviews/Meta analyses,7 pharmacoeconomic studies and 3 HTA reports.This study showed that,compared with placebo or other lipid lowering therapy,alirocumab lowered the levels of LDL-C,Lp(a),TC,TG,Apo B,non-HDL-C,increased the levels of HDL-C and Apo A1,reduced the risk of major adverse cardiovascular events(MACE),all-cause mortality,cerebrovascular events,and unstable angina,but did not reduce cardiovascular death,myocardial infarction or coronary revascularization.Safety studies showed that,compared with placebo or other lipid lowering therapy,alirocumab did not increase the risk of other adverse reactions but associated with higher injection site reactions.Pharmacoeconomic studies showed that alirocumab was cost-effective in patients with three branch coronary artery disease and acute coronary syndrome with LDL-C≥2.59 mmol·L-1.Conclusion Alirocumab is effective and safe for the treatment of hypercholesterolemia,and cost-effective for the patients of coronary arteriosclerotic heart disease with multi-vessel disease or with high base-line level of LDL-C.

Roles of Oxygen Species in Low-Temperature Catalytic o-Xylene Oxidation on MOF-Derived Bouquetlike CeO2.

To realize efficient low-temperature catalytic o-xylene oxidation, MOF-derived CeO2-X catalysts were prepared via the pyrolysis of MOF precursors with different ratios of cerium nitrate to trimesic acid. Among the synthesized catalysts, the bouquet like CeO2-1 exhibited the best activity with T50 and T90 of 156 and 198 °C and the lowest activation energy of 60.67 kJ·mol-1 (WHSV= 48 000 mL·g-1·h-1, o-xylene concentration = 500 ppm). o-Xylene was completely mineralized, and no change in conversion efficiency or CO2 yield was found at 5 vol % H2O for over 50 h. The rich active oxygen species (XPS: Osur/Olatt = 0.69) and abundant oxygen vacancies (Raman: ID/IF2g = 0.036) of CeO2-1 made crucial contribution to its superior catalytic activity. The O2-TPD and H2-TPR results confirmed that CeO2-1 had more surface active oxygen and better mobility of bulk oxygen. Moreover, the reaction routes under different atmospheres were probed through in situ DRIFTS, in which oxygen vacancy played a key role in promoting the adsorption and activation of molecular oxygen and facilitating the migration of the bulk lattice oxygen.

Combined experimental and theoretical study of o-xylene elimination on Fe-Mn oxides catalysts.

The development of low-cost and easily accessible catalysts to realize the practical applications of catalytic combustion of volatile organic compounds remains a challenge. In this work, a series of Fe-Mn oxides catalysts were prepared via a facile redox-precipitation route for the elimination of o-xylene. Among the synthesized catalysts, Fe3Mn1-RP exhibited excellent activity for o-xylene elimination with a T50 and T90 of 223 °C and 236 °C, respectively (o-xylene concentration = 500 ppm, WHSV = 36,000 mL g-1 h-1). Characterization results demonstrated that superior catalytic activity could be achieved from large specific surface area, good reducibility and high proportion of Mn4+. Besides, high Fe contents proved beneficial in generating additional oxygen vacancies, thereby improving the performance of the catalyst. The stable crystal structures and surface electron density distributions of the catalysts, and adsorption sites of o-xylene on the catalyst surface, were also determined through density functional theory (DFT) calculations to provide an in-depth mechanism on how the o-xylene oxidation occurred. Moreover, analysis of the energy barrier during the oxidation process proved that the ring-opening reaction on the surface of Fe3Mn1-RP with an activation energy as low as 2.46 eV would more likely occur via oxygen vacancies.

Mass transfer and reaction simultaneously enhanced airlift microbial electrolytic cell system with high gaseous o-xylene removal capacity.

To overcome the limitation of mass transfer and reaction rate involved in the biodegradation of gaseous o-xylene, the airlift reactor and microbial electrolysis cell were integrated to construct an airlift microbial electrolysis cell (AL-MEC) system for the first time, in which the bioanode was modified by polypyrrole to further improve biofilm attachment. The developed AL-MEC system achieved 95.4% o-xylene removal efficiency at optimized conditions, and maintained around 75% removal efficiency even while the inlet o-xylene load was as high as 684 g m-3 h-1. The existence of O2 exhibited a competition in electrons with the bioanode but a positive effect on ring-opening process in the o-xylene oxidation. The limitation of mass transfer had been overcome as the empty bed resistance time in the range of 20-80 s did not influence the system performance significantly. The microbial community analysis confirmed the o-xylene degradation microbes and electroactive bacteria were the dominant, which could be further enriched at 0.3 V against standard hydrogen electrode. This work revealed the feasibility of the AL-MEC system for the degradation of o-xylene and similar compounds, and provided insights into bioelectrochemical system design with high gaseous pollution removal capacity.

Myosteatosis predicting risk of transition to severe COVID-19 infection.

BACKGROUND: About 10-20% of patients with Coronavirus disease 2019 (COVID-19) infection progressed to severe illness within a week or so after initially diagnosed as mild infection. Identification of this subgroup of patients was crucial for early aggressive intervention to improve survival. The purpose of this study was to evaluate whether computer tomography (CT) - derived measurements of body composition such as myosteatosis indicating fat deposition inside the muscles could be used to predict the risk of transition to severe illness in patients with initial diagnosis of mild COVID-19 infection. METHODS: Patients with laboratory-confirmed COVID-19 infection presenting initially as having the mild common-subtype illness were retrospectively recruited between January 21, 2020 and February 19, 2020. CT-derived body composition measurements were obtained from the initial chest CT images at the level of the twelfth thoracic vertebra (T12) and were used to build models to predict the risk of transition. A myosteatosis nomogram was constructed using multivariate logistic regression incorporating both clinical variables and myosteatosis measurements. The performance of the prediction models was assessed by receiver operating characteristic (ROC) curve including the area under the curve (AUC). The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. RESULTS: A total of 234 patients were included in this study. Thirty-one of the enrolled patients transitioned to severe illness. Myosteatosis measurements including SM-RA (skeletal muscle radiation attenuation) and SMFI (skeletal muscle fat index) score fitted with SMFI, age and gender, were significantly associated with risk of transition for both the training and validation cohorts (P < 0.01). The nomogram combining the SM-RA, SMFI score and clinical model improved prediction for the transition risk with an AUC of 0.85 [95% CI, 0.75 to 0.95] for the training cohort and 0.84 [95% CI, 0.71 to 0.97] for the validation cohort, as compared to the nomogram of the clinical model with AUC of 0.75 and 0.74 for the training and validation cohorts respectively. Favorable clinical utility was observed using decision curve analysis. CONCLUSION: We found CT-derived measurements of thoracic myosteatosis to be associated with higher risk of transition to severe illness in patients affected by COVID-19 who presented initially as having the mild common-subtype infection. Our study showed the relevance of skeletal muscle examination in the overall assessment of disease progression and prognosis of patients with COVID-19 infection.

Machine learning based on clinical characteristics and chest CT quantitative measurements for prediction of adverse clinical outcomes in hospitalized patients with COVID-19.

OBJECTIVES: To develop and validate a machine learning model for the prediction of adverse outcomes in hospitalized patients with COVID-19. METHODS: We included 424 patients with non-severe COVID-19 on admission from January 17, 2020, to February 17, 2020, in the primary cohort of this retrospective multicenter study. The extent of lung involvement was quantified on chest CT images by a deep learning-based framework. The composite endpoint was the occurrence of severe or critical COVID-19 or death during hospitalization. The optimal machine learning classifier and feature subset were selected for model construction. The performance was further tested in an external validation cohort consisting of 98 patients. RESULTS: There was no significant difference in the prevalence of adverse outcomes (8.7% vs. 8.2%, p = 0.858) between the primary and validation cohorts. The machine learning method extreme gradient boosting (XGBoost) and optimal feature subset including lactic dehydrogenase (LDH), presence of comorbidity, CT lesion ratio (lesion%), and hypersensitive cardiac troponin I (hs-cTnI) were selected for model construction. The XGBoost classifier based on the optimal feature subset performed well for the prediction of developing adverse outcomes in the primary and validation cohorts, with AUCs of 0.959 (95% confidence interval [CI]: 0.936-0.976) and 0.953 (95% CI: 0.891-0.986), respectively. Furthermore, the XGBoost classifier also showed clinical usefulness. CONCLUSIONS: We presented a machine learning model that could be effectively used as a predictor of adverse outcomes in hospitalized patients with COVID-19, opening up the possibility for patient stratification and treatment allocation. KEY POINTS: • Developing an individually prognostic model for COVID-19 has the potential to allow efficient allocation of medical resources. • We proposed a deep learning-based framework for accurate lung involvement quantification on chest CT images. • Machine learning based on clinical and CT variables can facilitate the prediction of adverse outcomes of COVID-19.

Analysis of perioperative complications and influencing factors of complications in 1 000 cases of robotic gynecological surgery / 中华妇产科杂志

Objective:To investigate the occurrence and influencing factors of perioperative complications after robotic gynecologic surgery.Methods:The clinical data and occurrence of perioperative complications in 1 000 cases robotic surgery completed in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed.Results:(1) Clinical data: the average age of the patients was (50.2±10.4) years old, and the average body mass index (BMI) was (24.4±3.6) kg/m 2. Among 1 000 cases, 811 cases of them were malignant tumors, including 405 cases of cervical cancer, 279 cases of endometrial carcinoma, 112 cases of epithelial ovarian cancer (EOC), 15 cases of vulvar cancer; 189 cases of them were benign diseases, including 43 cases of uterine prolapse, 57 cases hysterectomy of uterine leiomyoma and adenomyosis of the uterus ≥12 weeks, 84 cases myomectomy of uterine leiomyoma, and 5 cases of fallopian tubal ligation requiring anastomosis. Surgical methods: in patients with malignant tumors, cervical cancer, hysterectomy plus salpingectomy or salpingo-oophorectomy for stage Ⅰa1, and radical hysterectomy plus pelvic lymphatic dissection plus salpingectomy or salpingo-oophorectomy for stage Ⅰa2-Ⅱb. Endometrial carcinoma, performed by staging surgery. Staging surgery for EOC with early stage and cytoreductive surgery with advanced EOC. Vulvar cancer, extensive vulvar resection plus inguinal lymphadenectomy. In patients with benign diseases, uterine prolapse, hysterectomy plus salpingectomy or salpingo-oophorectomy plus sacrocolpopexy. Uterine leiomyoma or adenomyosis with uterus ≥ 12 weeks, hysterectomy plus salpingectomy or salpingo-oophorectomy. Myomectomy for patients requiring uterine preservation with uterine leiomyoma. Tubal anastomosis for patients with fallopian tubal ligation. (2) Surgical complications: intraoperative complications occurred in 25 patients (2.5%, 25/1 000), including 11 patients with vascular laceration, 11 patients with ureteral injury, 2 patients with bladder injury, and 1 patient with intestinal injury. Postoperative complications occurred in 130 patients (13.0%, 130/1 000), including 66 cases of lower limb venous thrombosis, 20 cases of lymphatic cyst, 8 cases of hydronephrosis, 9 cases of ileus, 16 cases with infection, 6 cases with genital fistula, 4 cases with trocar site herniation and 1 case with subcutaneous emphysema. The incidence of intraoperative complications was 3.1% (25/811) in malignant tumors and no case in benign diseases, the incidence rate in malignant tumors was significantly higher than that in benign diseases ( χ2=4.778, P=0.029). The incidence rate in cervical cancer (4.2%, 17/405) and EOC (3.6%, 4/112) were significantly higher than those in endometrial carcinoma (1.4%, 4/279) and vulvar cancer (0/15; P<0.05). The incidence of postoperative complications was 15.2% (123/811) in malignant tumors and 3.7% (7/189) in benign diseases. The incidence rate in malignant tumors was significantly higher than that in benign diseases ( χ2=17.807, P<0.01), but there were no significant difference among different malignant tumors ( χ2=4.318, P=0.229). (3) The correlative factors affecting the occurrence of surgical complications: patient′s age, BMI, previous pelvic or abdominal surgery history, the nature of disease (malignant or benign), operation time, and comorbidities had a significant impact on the incidence of postoperative complications ( P<0.05). Multivariate logistic regression analysis showed that the patient′s age ≥40 years old, BMI ≥25 kg/m 2, previous pelvic or abdominal surgery history, malignant tumors and comorbidities were independent influential factors of the postoperative complications ( P<0.05). Conclusions:Perioperative complications vary according to the type of the surgery. The age, BMI, previous pelvic or abdominal surgery history, malignant tumors, and comorbidities are influential factors of postoperative complications.

Clinical Factors Associated with Progression and Prolonged Viral Shedding in COVID-19 Patients: A Multicenter Study.

Coronavirus disease 2019 (COVID-19) is a global pandemic associated with a high mortality. Our study aimed to determine the clinical risk factors associated with disease progression and prolonged viral shedding in patients with COVID-19. Consecutive 564 hospitalized patients with confirmed COVID-19 between January 17, 2020 and February 28, 2020 were included in this multicenter, retrospective study. The effects of clinical factors on disease progression and prolonged viral shedding were analyzed using logistic regression and Cox regression analyses. 69 patients (12.2%) developed severe or critical pneumonia, with a higher incidence in the elderly and in individuals with underlying comorbidities, fever, dyspnea, and laboratory and imaging abnormalities at admission. Multivariate logistic regression analysis indicated that older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.06), hypertension without receiving angiotensinogen converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) therapy (OR, 2.29; 95% CI, 1.14-4.59), and chronic obstructive pulmonary disease (OR, 7.55; 95% CI, 2.44-23.39) were independent risk factors for progression to severe or critical pneumonia. Hypertensive patients without receiving ACEI/ARB therapy showed higher lactate dehydrogenase levels and computed tomography (CT) lung scores at about 3 days after admission than those on ACEI/ARB therapy. Multivariate Cox regression analysis revealed that male gender (hazard ratio [HR], 1.22; 95% CI, 1.02-1.46), receiving lopinavir/ritonavir treatment within 7 days from illness onset (HR, 0.75; 95% CI, 0.63-0.90), and receiving systemic glucocorticoid therapy (HR, 1.79; 95% CI, 1.46-2.21) were independent factors associated with prolonged viral shedding. Our findings presented several potential clinical factors associated with developing severe or critical pneumonia and prolonged viral shedding, which may provide a rationale for clinicians in medical resource allocation and early intervention.

The immunodominant and neutralization linear epitopes for SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes a tremendous threat to global health. Although vaccines against the virus are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulated the three-dimensional structures of SARS-CoV-2 proteins with high performance computer, predicted the B cell epitopes on spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches, and then validated the epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induced antibody production, six of which were immunodominant epitopes in patients identified via the binding of epitopes with the sera from domestic and imported COVID-19 patients, and 23 were conserved within SARS-CoV-2, SARS-CoV and bat coronavirus RaTG13. We also found that the immunodominant epitopes of domestic SARS-CoV-2 were different from that of the imported, which may be caused by the mutations on S (G614D) and N proteins. Importantly, we validated that eight epitopes on S protein elicited neutralizing antibodies that blocked the cell entry of both D614 and G614 pseudo-virus of SARS-CoV-2, three and nine epitopes induced D614 or G614 neutralizing antibodies, respectively. Our present study shed light on the immunodominance, neutralization, and conserved epitopes on SARS-CoV-2 which are potently used for the diagnosis, virus classification and the vaccine design tackling inefficiency, virus mutation and different species of coronaviruses.

A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury.

Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.

Artificial Intelligence Augmentation of Radiologist Performance in Distinguishing COVID-19 from Pneumonia of Other Origin at Chest CT.

Background Coronavirus disease 2019 (COVID-19) and pneumonia of other diseases share similar CT characteristics, which contributes to the challenges in differentiating them with high accuracy. Purpose To establish and evaluate an artificial intelligence (AI) system for differentiating COVID-19 and other pneumonia at chest CT and assessing radiologist performance without and with AI assistance. Materials and Methods A total of 521 patients with positive reverse transcription polymerase chain reaction results for COVID-19 and abnormal chest CT findings were retrospectively identified from 10 hospitals from January 2020 to April 2020. A total of 665 patients with non-COVID-19 pneumonia and definite evidence of pneumonia at chest CT were retrospectively selected from three hospitals between 2017 and 2019. To classify COVID-19 versus other pneumonia for each patient, abnormal CT slices were input into the EfficientNet B4 deep neural network architecture after lung segmentation, followed by a two-layer fully connected neural network to pool slices together. The final cohort of 1186 patients (132 583 CT slices) was divided into training, validation, and test sets in a 7:2:1 and equal ratio. Independent testing was performed by evaluating model performance in separate hospitals. Studies were blindly reviewed by six radiologists without and then with AI assistance. Results The final model achieved a test accuracy of 96% (95% confidence interval [CI]: 90%, 98%), a sensitivity of 95% (95% CI: 83%, 100%), and a specificity of 96% (95% CI: 88%, 99%) with area under the receiver operating characteristic curve of 0.95 and area under the precision-recall curve of 0.90. On independent testing, this model achieved an accuracy of 87% (95% CI: 82%, 90%), a sensitivity of 89% (95% CI: 81%, 94%), and a specificity of 86% (95% CI: 80%, 90%) with area under the receiver operating characteristic curve of 0.90 and area under the precision-recall curve of 0.87. Assisted by the probabilities of the model, the radiologists achieved a higher average test accuracy (90% vs 85%, Δ = 5, P < .001), sensitivity (88% vs 79%, Δ = 9, P < .001), and specificity (91% vs 88%, Δ = 3, P = .001). Conclusion Artificial intelligence assistance improved radiologists' performance in distinguishing coronavirus disease 2019 pneumonia from non-coronavirus disease 2019 pneumonia at chest CT. © RSNA, 2020 Online supplemental material is available for this article.

Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms.

Aberrant cell cycle activation is a hallmark of carcinogenesis. Recently three cell cycle targeting cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for the treatment of metastatic breast cancer. CDK4/6 inhibitors suppress proliferation through inhibition of CDK4/6-dependent retinoblastoma-1 (Rb1) phosphorylation and inactivation, a key regulatory step in G1-to-S-phase transition. Importantly, aberrant cell cycle activation is also linked with several non-oncological diseases including acute kidney injury (AKI). AKI is a common disorder caused by toxic, inflammatory, and ischemic damage to renal tubular epithelial cells (RTECs). Interestingly, AKI triggered by the anti-cancer drug cisplatin can be mitigated by ribociclib, a CDK4/6 inhibitor, through mechanisms that remain unclear. Employing in vivo cell cycle analysis and functional Rb1 knock-down, here, we have examined the cellular and pharmacological basis of the renal protective effects of ribociclib during cisplatin nephrotoxicity. Remarkably, siRNA-mediated Rb1 silencing or RTEC-specific Rb1 gene ablation did not alter the severity of cisplatin-associated AKI; however, it completely abrogated the protective effects conferred by ribociclib administration. Furthermore, we find that cisplatin treatment evokes CDK4/6 activation and Rb1 phosphorylation in the normally quiescent RTECs, however, this is not followed by S-phase entry likely due to DNA-damage induced G1 arrest. The cytoprotective effects of ribociclib are thus not a result of suppression of S-phase entry but are likely dependent on the maintenance of Rb1 in a hypo-phosphorylated and functionally active form under stress conditions. These findings delineate the role of Rb1 in AKI and illustrate the pharmacological basis of the renal protective effects of CDK4/6 inhibitors.

Performance of Radiologists in Differentiating COVID-19 from Non-COVID-19 Viral Pneumonia at Chest CT.

Background Despite its high sensitivity in diagnosing coronavirus disease 2019 (COVID-19) in a screening population, the chest CT appearance of COVID-19 pneumonia is thought to be nonspecific. Purpose To assess the performance of radiologists in the United States and China in differentiating COVID-19 from viral pneumonia at chest CT. Materials and Methods In this study, 219 patients with positive COVID-19, as determined with reverse-transcription polymerase chain reaction (RT-PCR) and abnormal chest CT findings, were retrospectively identified from seven Chinese hospitals in Hunan Province, China, from January 6 to February 20, 2020. Two hundred five patients with positive respiratory pathogen panel results for viral pneumonia and CT findings consistent with or highly suspicious for pneumonia, according to original radiologic interpretation within 7 days of each other, were identified from Rhode Island Hospital in Providence, RI. Three radiologists from China reviewed all chest CT scans (n = 424) blinded to RT-PCR findings to differentiate COVID-19 from viral pneumonia. A sample of 58 age-matched patients was randomly selected and evaluated by four radiologists from the United States in a similar fashion. Different CT features were recorded and compared between the two groups. Results For all chest CT scans (n = 424), the accuracy of the three radiologists from China in differentiating COVID-19 from non-COVID-19 viral pneumonia was 83% (350 of 424), 80% (338 of 424), and 60% (255 of 424). In the randomly selected sample (n = 58), the sensitivities of three radiologists from China and four radiologists from the United States were 80%, 67%, 97%, 93%, 83%, 73%, and 70%, respectively. The corresponding specificities of the same readers were 100%, 93%, 7%, 100%, 93%, 93%, and 100%, respectively. Compared with non-COVID-19 pneumonia, COVID-19 pneumonia was more likely to have a peripheral distribution (80% vs 57%, P < .001), ground-glass opacity (91% vs 68%, P < .001), fine reticular opacity (56% vs 22%, P < .001), and vascular thickening (59% vs 22%, P < .001), but it was less likely to have a central and peripheral distribution (14% vs 35%, P < .001), pleural effusion (4% vs 39%, P < .001), or lymphadenopathy (3% vs 10%, P = .002). Conclusion Radiologists in China and in the United States distinguished coronavirus disease 2019 from viral pneumonia at chest CT with moderate to high accuracy. © RSNA, 2020 Online supplemental material is available for this article. A translation of this abstract in Farsi is available in the supplement. ترجمه چکیده این مقاله به فارسی، در ضمیمه موجود است.