Systematic Pharmacological Strategies to Explore the Regulatory Mechanism of Ma Xing Shi Gan Decoction on COVID-19

Objective To use systematic pharmacological strategies to explore the regulatory mechanisms of Ma Xing Shi Gan Decoction(MXSGD)against the coronavirus disease 2019(COVID-19).Methods Data on the compounds and targets of MXSGD were collected from the Traditional Chinese Medicene Systems Parmacology Database and Analysis Platform(TCMSP)and TCM Databases@Taiwan.Data on ACE2-related targets and the protein-protein interaction(PPI)were collected from the String database.The Cytoscape 3.7.2 was used to construct and analyze the networks.The DAVID platform was used for Gene Ontology(GO)and pathway enrichment analyses.Results Data on 272 MXSGD targets and 21 SARS-CoV-2 potential targets were collected.Four networks were constructed and analyzed based on the data:(1)compound-target network of MXSGD;(2)MXSGD-SARS-CoV-2-PPI network;(3)cluster of MXSGD-SARS-CoV-2-PPI network;(4)Herb-Pathway-Target network.The core targets included AKT1,MAPK3,IL-6,TP53,VEGFA,TNF,CASP3,EGFR,EGF and MAPK1.The antiviral biological processes were inflammatory responses(inflammatory cells,inflammatory cytokines and their signaling pathways),immune responses(T cells,monocytes,B cells and other immune cells),immune factors(IFN-γ,TNF-αand so on),virus defense,humoral immunity and mucosal innate immune response.The antivirus-related signaling pathways included TNF,NOD-like receptor,FoxO,PI3K-AKT and Toll-like receptor signaling pathways.Conclusions MXSGD can control disease progression by regulating multiple compounds and targets;it can reduce inflammation and balance immunity by regulating several proteins that interact with ACE2 and signaling pathways closely related to disease development.

Development of septic shock and prognostic assessment in critically ill patients with coronavirus disease outside Wuhan, China

BACKGROUND: The study aims to illustrate the clinical characteristics and development of septic shock in intensive care unit(ICU) patients confirmed with severe acute respiratory syndrome coronavirus 2(SARS-Co V-2) infection, and to perform a comprehensive analysis of the association between septic shock and clinical outcomes in critically ill patients with coronavirus disease(COVID-19).METHODS: Patients confirmed with SARS-Co V-2 infection, who were admitted to the ICU of the Third People's Hospital of Shenzhen from January 1 to February 7, 2020, were enrolled. Clinical characteristics and outcomes were compared between patients with and without septic shock.RESULTS: In this study, 35 critically ill patients with COVID-19 were included. Among them, the median age was 64 years(interquartile range [IQR] 59-67 years), and 10(28.4%) patients were female. The median ICU length of stay was 16 days(IQR 8-23 days). Three(8.6%) patients died during hospitalization. Nine(25.7%) patients developed septic shock in the ICU, and these patients had a significantly higher incidence of organ dysfunction and a worse prognosis than patients without septic shock.CONCLUSIONS: Septic shock is associated with a poor outcome in critically ill COVID-19 patients and is one of the hallmarks of the severity of patients receiving ICU care. A dysregulated immune response, uncontrolled infl ammation, and coagulation disorders are strongly associated with the development and progression of COVID-19-related septic shock.

DNA vaccines targeting amyloid-βoligomer ameliorate cognitive deficits of aged APP/PS1/tau triple-transgenic mouse models of Alzheimer’s disease

The amyloid-β(Aβ)oligomer,rather than the Aβmonomer,is considered to be the primary initiator of Alzheimer’s disease.It was hypothesized that p(Aβ3-10)10-MT,the recombinant Aβ3-10 gene vaccine of the Aβoligomer has the potential to treat Alzheimer’s disease.In this study,we intramuscularly injected the p(Aβ3-10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice,which are a model for Alzheimer’s disease.Our results showed that the p(Aβ3-10)10-MT vaccine effectively reduced Aβoligomer levels and plaque deposition in the cerebral cortex and hippocampus,decreased the levels tau protein variants,reduced synaptic loss,protected synaptic function,reduced neuron loss,and ameliorated memory impairment without causing any cerebral hemorrhaging.Therefore,this novel DNA vaccine,which is safe and highly effective in mouse models of Alzheimer’s disease,holds a lot of promise for the treatment of Alzheimer’s disease in humans.

Long-term results of extended Boari flap technique for management of complete ureteral avulsion:A case report

BACKGROUND Ureteroscopy is well-established as a primary treatment modality for urolithiasis.Ureteral avulsion,particularly complete or full-length avulsion with a resultant long segment of the ureter left attached to the ureteroscope,is a rare but devastating complication of the procedure.Management of this complication is challenging.Moreover,general consensus regarding the optimal management is undetermined.We report our experience of managing a complete ureteral avulsion case via an extended Boari flap technique with long-term results.CASE SUMMARY A 41-year-old female patient subjected to complete ureteral avulsion caused by ureteroscopy was referred to our hospital.A modified,extended Boari flap technique was successfully performed to repair the full-length ureteral defect.Maximal mobilization of the bladder and affected kidney followed by psoas hitch and downward nephropexy maximized the probability of a tension-free anastomosis.Meticulous blood supply preservation to the flap also contributed to the success.During the 4-year study period,no complications except for a mild urinary frequency and a slightly lower maximum urinary flow rate were reported.The patient was satisfied with the surgical outcomes.CONCLUSION The extended Boari flap procedure is a feasible and preferred technique to manage complete ureteral avulsion,particularly in emergencies.

COVID-19 managed with early non-invasive ventilation and a bundle pharmacotherapy: A case report

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has become an immense public health burden,first in China and subsequently worldwide.Developing effective control measures for COVID-19,especially measures that can halt the worsening of severe cases to a critical status is of urgent importance.CASE SUMMARY A 52-year-old woman presented with a high fever(38.8°C),chills,dizziness,and weakness.Epidemiologically,she had not been to Wuhan where COVID-19 emerged and did not have a family history of a disease cluster.A blood test yielded a white blood cell count of 4.41×109/L(60.6±2.67%neutrophils and 30.4±1.34%lymphocytes).Chest imaging revealed bilateral ground-glass lung changes.Based on a positive nasopharyngeal swab nucleic acid test result and clinical characteristics,the patient was diagnosed with COVID-19.Following treatment with early non-invasive ventilation and a bundle pharmacotherapy,she recovered with a good outcome.CONCLUSION Early non-invasive ventilation with a bundle pharmacotherapy may be an effective treatment regimen for the broader population of patients with COVID-19.

Two mechanically ventilated cases of COVID-19 successfully managed with a sequential ventilation weaning protocol: Two case reports

BACKGROUND Patients with critical coronavirus disease 2019(COVID-19),characterized by respiratory failure requiring mechanical ventilation(MV),are at high risk of mortality.An effective and practical MV weaning protocol is needed for these fragile cases.CASE SUMMARY Here,we present two critical COVID-19 patients who presented with fever,cough and fatigue.COVID-19 diagnosis was confirmed based on blood cell counts,chest computed tomography(CT)imaging,and nuclei acid test results.To address the patients’respiratory failure,they first received noninvasive ventilation(NIV).When their condition did not improve after 2 h of NIV,each patient was advanced to MV[tidal volume(Vt),6 mL/kg ideal body weight(IBW);8-10 cmH2 O of positive end-expiratory pressure;respiratory rate,20 breaths/min;and 40%-80%FiO2]with prone positioning for 12 h/day for the first 5 d of MV.Extensive infection control measures were conducted to minimize morbidity,and pharmacotherapy consisting of an antiviral,immune-enhancer,and thrombosis prophylactic was administered in both cases.Upon resolution of lung changes evidenced by CT,the patients were sequentially weaned using a weaning screening test,spontaneous breathing test,and airbag leak test.After withdrawal of MV,the patients were transitioned through NIV and high-flow nasal cannula oxygen support.Both patients recovered well.CONCLUSION A MV protocol attentive to intubation/extubation timing,prone positioning early in MV,infection control,and sequential withdrawal of respiratory support,may be an effective regimen for patients with critical COVID-19.

Evaluation of the safety and efficiency of cytotoxic T cell therapy sensitized by tumor antigens original from T-ALL-iPSC in vivo

Background:Since RNA sequencing has shown that induced pluripotent stem cells(iPSCs)share a common antigen profile with tumor cells,cancer vaccines that focus on iPSCs have made promising progress in recent years.Previously,we showed that iPSCs derived from leukemic cells of patients with primary T cell acute lymphoblastic leukemia(T-ALL)have a gene expression profile similar to that of T-ALL cell lines.Methods:Mice with T-ALL were treated with dendritic and T(DC-T)cells loaded with intact and complete antigens from T-ALL-derived iPSCs(T-ALL-iPSCs).We evaluated the safety and antitumor efficiency of autologous tumor-derived iPSC antigens by flow cytometry,cytokine release assay,acute toxicity experiments,long-term toxicity experiments,and other methods.Results:Our results indicate that complete tumor antigens from T-ALL-iPSCs could inhibit the growth of inoculated tumors in immunocompromised mice without causing acute and long-term toxicity.Conclusion:T-ALL-iPSC-based treatment is safe and can be used as a potential strategy for leukemia immunotherapy.

Adsorptive hemofiltration for sepsis management: expert recommendations based on the Asia Pacific experience

To the Editor:In sepsis,bacterial endotoxins play a central role by inducing a dysregulated and exaggerated release of inflammatory mediators and cytokines,often described as the“cytokine storm”or“cytokinemia.”[1]Both endotoxins and cytokines have been implicated in the development of organ dysfunction,including acute kidney injury(AKI).[2]Removing circulating endotoxins and excess cytokines from the circulation restores chemotactic gradients,localizing the immune response to the principal site of infection and re-establishing a regulated immune response.[1,3]Therefore,using hemofilters with enhanced endotoxin and cytokine adsorptive properties may bring about additional therapeutic benefits compared with conventional continuous renal replacement therapy(CRRT)filters.

Parallel profiling of antigenicity alteration and immune escape of SARS-CoV-2 Omicron and other variants

SARS-CoV-2 variants have evolved a variety of critical mutations,leading to antigenicity changes and immune escape.The recent emerging SARS-CoV-2 Omicron variant attracted global attention due to its significant resistance to current antibody therapies and vaccines.

One-step Construction of Xanthone Scaffold Assisted by Microwave Irradiation to Optimize the Synthesis of DMXAA

An efficient and concise synthesis of 5,6-dimethylxanthenone-4-acetic acid（DMXAA） was developed. The overall yield of this 3-step procedure was 82%. The key reaction is the one-step construction of xanthone scaffold between 2,5-dibromo-3,4-dimethylbenzoic acid and 2-hydroxyphenyl-acetic acid assisted by microwave irradiation.

Successful management of seven cases of critical COVID-19 with early noninvasive-invasive sequential ventilation algorithm and bundle pharmacotherapy

We report the clinical and laboratory findings and successful management of seven patients with critical coronavirus disease 2019(COVID-19)requiring mechanical ventilation(MV).The patients were diagnosed based on epidemiological history,clinical manifestations,and nucleic acid testing.Upon diagnosis with COVID-19 of critical severity,the patients were admitted to the intensive care unit,where they received early noninvasive-invasive sequential ventilation,early prone positioning,and bundle pharmacotherapy regimen,which consists of antiviral,anti-inflammation,immune-enhancing,and complication-prophylaxis medicines.The patients presented fever(n=7,100%),dry cough(n=3,42.9%),weakness(n=2,28.6%),chest tightness(n=1,14.3%),and/or muscle pain(n=1,14.3%).All patients had normal or lower than normal white blood cell count/lymphocyte count,and chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs.Nucleic acid testing confirmed COVID-19 in all seven patients.The median MV duration and intensive care unit stay were 9.9 days(interquartile range,6.5-14.6 days;range,5-17 days)and 12.9 days(interquartile range,9.7-17.6 days;range,7-19 days),respectively.All seven patients were extubated,weaned off MV,transferred to the common ward,and discharged as of the writing of this report.Thus,we concluded that good outcomes for patients with critical COVID-19 can be achieved with early noninvasive-invasive sequential ventilation and bundle pharmacotherapy.

Chronic heart failure:Role of the GP in management

The commonest cause of chronic heat failure in China is ischemic heart disease,followed by hypertension and valvular heart disease.Echocardiography is essential in establishing a diagnosis as well as helping to identify a cause and to monitor progress.Management includes nonpharmacological as well as pharmacological treatment,and self-care with careful monitoring of salt and fluid intake as well as regular weight measurement.Care planning and team-based care are essential in managing patients with chronic heart failure,who often have concurrent multimorbidity and are receiving polypharmacy.

Connexin 36 Mediates Orofacial Pain Hypersensitivity Through GluK2 and TRPA1

Trigeminal neuralgia is a debilitating condition,and the pain easily spreads to other parts of the face.Here,we established a mouse model of partial transection of the infraorbital nerve(pT-ION)and found that the Connexin 36(Cx36)inhibitor mefloquine caused greater alleviation of pT-ION-induced cold allodynia compared to the reduction of mechanical allodynia.Mefloquine reversed the pT-IONinduced upregulation of Cx36,glutamate receptor ionotropic kainate 2(GluK2),transient receptor potential ankyrin 1(TRPA1),and phosphorylated extracellular signal regulated kinase(p-ERK)in the trigeminal ganglion.Cold allodynia but not mechanic al allodynia induced by pT-ION or by virusmediated overexpression of Cx36 in the trigeminal ganglion was reversed by the GluK2 antagonist NS 102,and knocking down Cx36 expression in Nav1.8-expressing nociceptors by injecting virus into the orofacial skin area of Nav1.8-Cre mice attenuated cold allodynia but not mechanic al allodynia.In conclusion,we show that Cx36 contributes greatly to the development of orofacial pain hypersensitivity through GluK2,TRPA1,and p-ERK signaling.

Anxiety symptoms in patients with Mayer-Rokitansky-Küster-Hauser syndrome:a cross-sectional study

Background:As a congenital malformation that results in infertility and an inability to have vaginal intercourse,Mayer-Rokitansky-Küster-Hauser(MRKH)syndrome places a considerable psychological burden on patients,which results in anxiety symptoms.However,only single case studies or a few small to medium-sized cross-sectional studies were identified to focus on anxiety symptoms in MRKH patients.Thus,the aim of this study was to explore the status of anxiety symptoms and the related factors in patients with MRKH syndrome.Methods:This cross-sectional study involving 141 patients with MRKH syndrome and 178 healthy women was conducted from January 2018 to December 2018.All participants were required to complete a demographic questionnaire and the Generalized Anxiety Disorder 7-item scale(GAD-7),Patient Health Questionnaire-9,Eysenck Personality Questionnaire-Revised,Short Scale for Chinese,and Chinese Version of the Female Sexual Function Index.The main outcome was the anxiety symptoms measured by the GAD-7.Main outcome was compared between the MRKH syndrome group and the healthy control group.Then,we explored the related factors by comparing patients with and without anxiety symptoms.Results:Of the respondents,24.1%experienced moderate to severe anxiety symptoms.Patients with MRKH syndrome manifested more severe anxiety symptoms than healthy women.Negative self-evaluation of femininity(odds ratio[OR]2.706,95%confidence interval[CI]1.010-7.247),neurotic personality traits(OR 1.100,95%CI 1.029-1.175),and coexisting depressive symptoms(OR 4.422,95%CI 1.498-13.049)were more prevalent in anxious patients.Conclusion:The findings stress the importance of anxiety symptom screening in MRKH patients and identify patients at risk of anxiety symptoms,providing a possible basis for future intervention.