ABSTRACT
OBJECTIVE To optimize the molding process of Shuangye pipa granules based on the concept of quality by design （QbD） and analyze its physical fingerprint. METHODS The dry extract of Shuangye pipa granules was used as the main drug. The retention rate of total flavonoid， moisture absorption rate， dissolution rate， angle of repose and molding rate of the granules were selected as evaluation indexes. The single-factor test combined with the entropy weight method and Box-Behnken response surface design was used to optimize the molding process， and validation test was conducted. The physical fingerprints of 10 batches of Shuangye pipa granules prepared by the optimal process were comprehensively analyzed by eight secondary physical indexes （relative homogeneity， moisture， moisture absorption rate， Hausner ratio， angle of repose， bulk density， tap density and porosity）. RESULTS The optimal molding process of Shuangye pipa granules was as follows： soluble starch-maltodextrin-mannitol was 1∶1∶1 （m/m/m）， 95% ethanol was as wetting agent and the amount of it was 37%， the drug-assisted ratio was 1∶0.8 （m/m）， the drying temperature was 59 ℃， drying time was 28 min. The results of 3 validation tests showed that the average comprehensive score was 0.879 6， the RSD of which with prediction value （0.881 9 score） was 1.97%. The similarity between the physical fingerprints of 10 batches of Shuangye pipa granules and the control physical fingerprint was higher than 0.99. CONCLUSIONS The optimized molding process of Shuangye pipa granules is stable and feasible， and the physical property of Shuangye pipa granules is stable and controllable.
ABSTRACT
Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) trims peptide precursors in the ER for presentation by major histocompatibility (MHC)-I molecules to surveying CD8+ T-cells. This function allows ERAAP to regulate the nature and quality of the peptide repertoire and, accordingly, the resulting immune responses. We recently showed that infection with murine cytomegalovirus leads to a dramatic loss of ERAAP levels in infected cells. In mice, this loss is associated with the activation of QFL T-cells, a subset of T-cells that monitor ERAAP integrity and eliminate cells experiencing ERAAP dysfunction. In this study, we aimed to identify host factors that regulate ERAAP expression level and determine whether these could be manipulated during viral infections. We performed a CRISPR knockout screen and identified ERp44 as a factor promoting ERAAP retention in the ER. ERp44s interaction with ERAAP is dependent on the pH gradient between the ER and Golgi. We hypothesized that viruses that disrupt the pH of the secretory pathway interfere with ERAAP retention. Here, we demonstrate that expression of the Envelope (E) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to Golgi pH neutralization and consequently decrease of ERAAP intracellular levels. Furthermore, SARS-CoV-2-induced ERAAP loss correlates with its release into the extracellular environment. ERAAPs reliance on ERp44 and a functioning ER/Golgi pH gradient for proper localization and function led us to propose that ERAAP serves as a sensor of disturbances in the secretory pathway during infection and disease.
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Objective: Fetus-in-fetu (FIF) is an extremely rare disease, and most prior publications are single case reports. Here, we describe the clinical characteristics, imaging manifestations, and the treatment and related complications of FIF from a large tertiary pediatric referral center. Materials: After institutional review board approval, patients with a diagnosis of FIF between January 2010 and November 2019 were further selected and reexamined. We analyzed the general clinical characteristics, imaging manifestations, treatment, and prognosis of the patients. Results: A total of seven (four male and three female) patients with FIF were included in the study. All patients were diagnosed with FIF during the antenatal ultrasound examination along with an abnormal increase in alpha fetoprotein, and it was confirmed by subsequent pathological examination. The median gestation period when FIF was first diagnosed was 25 (range: 22-32) weeks. Ultrasound, computed tomography, and magnetic resonance imaging were the main pre-operative diagnostic techniques used. All patients underwent FIF resection within 1 month after birth: four patients had open surgery and three had laparoscopic surgeries (one case was converted to open surgery); only one patient developed ascites after surgery. All patients are growing up healthy and without tumor recurrence at the last follow-up. The level of alpha fetoprotein decreased to normal within 1 year (range 3-10 months) after surgery performed. Conclusion: As the size of the FIF increases, it can be found and diagnosed in antenatal ultrasound examination. Surgery is an important curative treatment for FIF and generally results in excellent long-term quality of life.
ABSTRACT
IMPORTANCECoronavirus disease 2019 (COVID-19) is a global pandemic associated with high mortality and effective treatment to prevent clinical deterioration to severe pneumonia has not yet been well clarified. OBJECTIVETo investigate the role of several adjuvant treatments in preventing severe pneumonia in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSMulticenter, retrospective cohort study of 564 consecutively hospitalized patients with confirmed COVID-19 at Third Xiangya Hospital of Central South University, Changsha Public Health Treatment Center, First Hospital of Yueyang, Junshan Peoples Hospital of Yueyang, Central Hospital of Shaoyang, Central Hospital of Xiangtan, Second Hospital of Changde, Central Hospital of Loudi, and First Affiliated Hospital of University of South China in Hunan province from January 17, 2020 to February 28, 2020; The final date of follow-up was March 15, 2020. EXPOSURESNonspecific antivirals (arbidol, lopinavir/ritonavir, and interferon ), antihypertensives, and chloroquine. MAIN OUTCOMES AND MEASURESThe development of severe COVID-19 pneumonia; Demographic, epidemiological, clinical, laboratory, radiological, and treatment data were collected and analyzed. RESULTSOf 564 patients, the median age was 47 years (interquartile range, 36-58 years), and 284 (50.4%) patients were men. Sixty-nine patients (12.2%) developed severe pneumonia. Patients who developed severe pneumonia were older (median age of 59 and 45 years, respectively), and more patients had comorbidities including hypertension (30.4% and 12.3%, respectively), diabetes (17.4% and 6.7%, respectively), and cardiovascular disease (8.7% and 3.2%, respectively) and presented with fever (84.1% and 60.4%, respectively) and shortness of breath (10.1% and 3.8%, respectively) compared with those who did not. Nonspecific antiviral therapy did not prevent clinical progression to severe pneumonia, although fewer hypertensive patients on angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARB) therapy developed severe pneumonia in contrast with those on non-ACEI/ARB antihypertensive therapy (1 of 16 [6.3%] patients and 16 of 49 [32.7%] patients, respectively [difference, 26.4%; 95% CI, 1.5% to 41.3%]). Multivariate logistic regression analysis showed that hypertension without receiving ACEI/ARB therapy was an independent risk factor (odds ratio [OR], 2.07; 95% CI, 1.07 to 4.00) for developing severe pneumonia irrespective of age. Besides, none of patients treated with chloroquine developed severe pneumonia, though without significance (difference, 12.0%; 95% CI, -3.5% to 30.0%) by propensity score matching. CONCLUSIONS AND RELEVANCEHypertensive patients on ACEI or ARB may be protective from severe pneumonia in COVID-19 and hence these therapies should not be ceased unless there is a strong indication or further epidemiological evidence. Though none of the current antiviral and immunoregulation therapy showed benefit in preventing COVID-19 progression, chloroquine deserved further investigation. KEYPOINTSO_ST_ABSQuestionC_ST_ABSDoes the use of adjuvant therapy reduce progression to severe pneumonia in patients with coronavirus disease 2019 (COVID-19)? FindingsIn this retrospective, observational cohort study involving 564 patients with confirmed COVID-19, hypertension was an independent risk factor for progression to severe pneumonia irrespective of age and those on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy were less likely to develop severe COVID-19 pneumonia, while nonspecific antivirals or chloroquine did not have significant impact on clinical progression. MeaningHypertensive patients with COVID-19 should not have ACEI or ARB ceased, unless there is a strong indication or further epidemiological evidence, given its potential protective effects.
