Synthesis of Indole-Fused Pyrazino[1,2-a]quinazolinones by Copper(I)-Catalyzed Selective Hydroamination-Cyclization of Alkynyl-tethered Quinazolinones.

We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39% to 99% under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.

Retrospective Cohort Study of Syphilis-Related Stillbirths in Winnipeg, Manitoba From 2017-2020.

OBJECTIVE: Syphilis-related stillbirths (SRSBs) disproportionately affect marginalized women with 11% of all local stillbirths having maternal syphilis as a contributory factor in 2020. This study describes the incidence and perinatal factors associated with SRSB. METHODS: This was a retrospective cohort study of all stillbirths occurring from 1 January 2017 to 31 December 2020, at a single tertiary-level referral hospital in Winnipeg, Manitoba. Cases that met criteria for SRSB were identified from hospital records and included in the final analysis. Maternal demographics, comorbidities, prenatal care attendance, sexually transmitted infection testing, treatment, and diagnostic investigations at time of stillbirth were collected from hospital charts using a standardized data collection form. Descriptive statistics were performed to present the results. RESULTS: The proportion of SRSB increased over the period of study from 0%-11%. Eleven cases were identified as SRSB, with diagnosis occurring intrapartum in 7 cases and antenatally in 4 cases. Of the 4 antenatal cases, only 2 had identifiable treatment responses indicated by microbiological and pathology workup. Commonly identified risk factors for SRSB were homelessness, mental illness, substance use, sexually transmitted co-infections, and lack of prenatal care. CONCLUSIONS: Cases of SRSB are rising in Winnipeg with 11% of all stillbirths having maternal syphilis as a contributory factor by 2020. SRSBs disproportionately affect marginalized women. The dramatic and rapid changes in the epidemiology of syphilis in Winnipeg are likely shared by other Canadian regions and warrant increased prevention strategies to improve outcomes.

Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC-derived small extracellular vesicles (MSC-sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC-sEV on DCs in allergic diseases remain unclear. MSC-sEV were prepared from the induced pluripotent stem cells (iPSC)-MSCs by anion-exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte-derived DCs were generated and cultured in the presence of MSC-sEV to differentiate the so-called sEV-immature DCs (sEV-iDCs) and sEV-mature DCs (sEV-mDCs), respectively. The phenotypes and the phagocytic ability of sEV-iDCs were analyzed by flow cytometry. sEV-mDCs were co-cultured with isolated CD4+ T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated. We demonstrated that MSC-sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA-DR, but had no effects on mDCs with these markers. However, MSC-sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti-IL-10 monoclonal antibody or IL-10Rα blocking antibody, we identified that sEV-mDCs suppressed the Th2 immune response by reducing the production of IL-4, IL-9, and IL-13 via IL-10. Furthermore, sEV-mDCs increased the level of Treg cells. Our study identified that mDCs treated with MSC-sEV inhibited the Th2 responses, providing novel evidence of the potential cell-free therapy acting on DCs in allergic airway diseases.

Highly birefringent one-air-hole panda fiber.

This Letter proposes a highly birefringent one-air-hole panda fiber, which is fabricated by corroding a single stress zone of the traditional panda-type polarization-maintaining fiber (PMF). An additional geometric asymmetry is induced in the fiber to increase the birefringence effect and enhance the light-matter interaction, which improves the performance of the sensor and the device applications of the special fiber. A theoretical and experimental analysis of the one-air-hole panda fiber demonstrates that the birefringence of the fiber can be of the order of 10-3, which is one order of magnitude higher than that of the traditional panda-type fiber. The corroded region provides a microchannel to be filled with a functional material to compose optical fiber sensors; a sample of a salt solution was filled into the microchannel to measure the refractive index with a sensitivity of 3760 nm/RIU (refractive index units).

Insights into genetic assistant practice and the workforce in North America.

Genetic assistant positions are now widely integrated in genetic services to address genetic counselor shortages and ultimately improve efficiency. While over 40% of genetic counselors report working with a genetic assistant ("NSGC Professional Status Survey: Work Environment," 2022), there is limited information about the genetic assistant workforce. The present study surveyed 164 genetic assistants and 139 individuals with experience working with genetic assistants (specifically genetic counselors, residents, geneticists, and administrative staff). Information was collected about genetic assistant demographics, positions, roles and responsibilities, and career paths. The data revealed that the genetic assistant workforce is demographically similar to the genetic counselor workforce and that most genetic assistants intend to pursue a career in genetic counseling. The genetic assistant positions were heterogeneous in terms of the roles and responsibilities assigned, even when separated by work setting. Lastly, participants reported that there were at least 144 genetic assistants across their institutions, a number that has likely grown since the time of the survey. The findings from this study highlight important opportunities for future research and focus, especially development of a scope of practice and competencies for genetic assistants, as well as the potential to use genetic assistant positions as an avenue to improve diversity within the genetic counseling workforce.

[Effect of a novel phosphodiesterase 5 inhibitor, CPD1, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury].

This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor ß1 (TGF-ß1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-ß signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.

Camrelizumab in different PD-L1 expression cohorts of pre-treated advanced or metastatic non-small cell lung cancer: a phase II study.

BACKGROUND: This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). METHODS: Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. RESULTS: A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4-30.8). Objective response rate was 17.8% (95% CI 12.0-25.0) and improved with the increasing PD-L1 TPS (TPS < 1%, 12.2% [95% CI 5.7-21.8]; ≥ 1-< 25%, 19.4% [95% CI 7.5-37.5]; ≥ 25-< 50%, 36.4% [95% CI 10.9-69.2]; ≥ 50%, 23.3% [95% CI 9.9-42.3]). No response was observed in the five patients harboring EGFR mutations. Median progression-free survival was 3.2 months (95% CI 2.0-3.4), and patients with positive PD-L1 TPS had longer progression-free survival. Median overall survival was 14.8 months (95% CI 10.2-18.7). Treatment-related adverse events (TRAEs) of any grade occurred in 87.7% of patients, and 21.2% had grade ≥ 3 TRAEs. CONCLUSION: Camrelizumab showed improved efficacy compared with historical data of the second-line chemotherapy in pre-treated advanced/metastatic NSCLC. Patients with positive PD-L1 expression derived greater benefit from camrelizumab. Camrelizumab has a manageable safety profile.

Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction.

Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing TH 2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin- ) cells. PBMCs and Lin- cells were cocultured with induced pluripotent stem cell-derived MSCs (iPSC-MSCs) under the stimulation of epithelial cytokines IL-25 and IL-33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS-ICOSL pathway. iPSC-MSCs successfully decreased the high levels of IL-13, IL-9, and IL-5 in PBMCs in response to IL-25, IL-33, and the high percentages of IL-13+ ILC2s and IL-9+ ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC-MSCs. However, iPSC-MSCs were found directly to enhance ILC2 levels and functions via ICOS-ICOSL interaction in Lin- cells and pure ILC2s. iPSC-MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS-ICOSL interaction. The MSC-induced Treg cells then suppressed ILC2s by secreting IL-10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS-ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders.

Discovery and structural optimization of 9-O-phenylsulfonyl-berberines as new lipid-lowering agents.

Berberine is a quaternary isoquinoline alkaloid that exhibits potent hypoglycemic and hypolipidemic activity. Many medicinal chemists are currently working on structural modifications around the parent scaffold of berberine, expecting to further enhance its hypolipidemic activity and reducing its cytotoxicity. In this study, a focused berberine-like compound library containing 12,600 molecules was built via the introduction of various "drug-like" fragments at the C8 and C9 positions of berberine. Sixteen comopounds were hit by using the in-house QSAR models previously reported by our group. Considering synthesis feasibility and the cost of building-blocks, only four berberine analogs (library ID: 2028, 3847, 6033, and 12456) were selected and synthesized for investigating their lipid-lowering activities. Preliminary lipid-lowering study showed that compound 12456 with the phenylsulfonyl group at the C9 position had potent cholesterol inhibitory activity in HepG2 cells, superior to that of the parent compound berberine. Subsequently, a total of twenty-five 9-O-phenylsulfonyl-berberines (1a-1y) and twenty-four 9-O-phenylsulfonyl-tetrahydroberberine (2a-2x) were designed, synthesized, and evaluated by lipid-lowering experiments. The results displayed that most compounds exhibited more lipid-lowering activities than berberine. Among them, compound 1m inhibited cholesterol production close to 50% in both cell models when compared with the blank control; the inhibition of triglycerides exceeded 70%. Moreover, 1m also had significant pharmacological effects on the inhibition of LDLC and promotion of HDLC production, especially in the HepG2 cell model, in which the inhibitory rate against LDLC was close to 70% and the increase rate of HDLC was more than 75%. The hypolipidemic experiment of SD rats demonstrated that after 40 days of administration (1m, 15 mg/kg/d), blood cholesterol was reduced by 19.6%, triglycerides reduced by 34.52%, and LDLC reduced by 41.49%, when compared with the high-fat diet model (HFD). In addition, after 80 days of administration, the three indexes of 1m were still better than that of berberine. Oil Red O staining and H&E staining results showed that 1m exhibited potent lipid scavenging activity. All in all, 1m was discovered and identified as a potent lipid-lowering agent and a new berberine-like candidate, being evaluated by subsequent studies.

The Canadian Gynecologic Oncology Peri-operative Management Survey: re-examining Enhanced Recovery After Surgery (ERAS) recommendations.

OBJECTIVE: Enhanced Recovery After Surgery (ERAS) is a global surgery quality improvement program associated with improved clinical outcomes across the spectrum of disciplines, including gynecologic oncology. The objective of this study was to re-survey the practice of ERAS Gynecologic Oncology guidelines across Canada, after the initial guidelines publication (2016), subsequent guidelines update (2019), and Society of Gynecologic Oncology of Canada (GOC) education events. METHODS: A survey was created and developed through the GOC Communities of Practice ERAS section and distributed to all members between March and November 2021. The results of this survey were compared with the survey performed in 2015 RESULTS: The initial GOC survey in 2015 included 77/92 active gynecologic oncologists (84%) representing all provinces in Canada. The current updated survey had responses from 59/118 active gynecologic oncologists (51%) also from every province. Compared with the original survey there was a statistically significant improvement in uptake of 10 ERAS recommendations: smoking/alcohol cessation, modern fasting guidelines (allowance of clear fluids and solid food pre-operatively), carbohydrate loading, pre-operative warming, early feeding, post-operative laxative use, avoidance of nasogastric tubes and abdominal drains, foley catheter removal at 6 hours, and active mobilization (all p<0.003). Only two fields (stopping oral contraceptive medications pre-operatively and foley catheter removal post-operative day 1) showed worsening uptake across the two surveys (p<0.01). The ERAS recommendations that did not change in the examined time frame included routine use of mechanical bowel preparation, venous thromboembolism prophylaxis, pre-operative antibiotics, and additional antibiotic dosing for prolonged surgery. CONCLUSIONS: This survey demonstrates increased uptake of 10 of the ERAS guideline recommendations among Canadian gynecologic oncology providers. These findings may translate to improvements in clinical outcomes and healthcare system-level benefits including increased hospital capacity and cost savings.

Manual Uterine Aspiration in the Emergency Department as a First-Line Therapy for Early Pregnancy Loss: A Single-Centre Retrospective Study.

OBJECTIVES: Manual uterine aspiration (MUA) is a currently underused management option for early pregnancy loss (EPL) in the emergency department (ED). This study addresses the safety and efficiency of MUA in the ED. METHODS: We performed a single-site retrospective observational chart review of pregnant women presenting to the ED with vaginal bleeding and ED pathology submissions for products of conception (POC) between 2012 and 2016. Patients were excluded for gestational age >14 weeks, no evidence of pregnancy loss, uterine cavity anomaly, hemodynamic instability, or hemoglobin <80 g/L. We compared the frequencies of complications (need for blood transfusion, repeat ED visit, failed initial management, admission to hospital) and ED utilization time between 4 management options: expectant, misoprostol, MUA, and electric vacuum aspiration (EVA) outside the ED, as well as time to procedure between MUA and EVA. RESULTS: A total of 162 patients were included with 123 (76%) having a pathology report positive for POC. The mean patient and gestational ages were 30 ± 7 years and 66 ± 17 days, respectively. One hundred nine patients were managed expectantly, 9 were given misoprostol, 23 underwent MUA, and 21 underwent EVA. Composite complication rates were 40%, 33%, 9%, and 10% (P = 0.001), and mean ED times were 5.4, 4.9, 7.3, and 6.0 hours (P = 0.01), for expectant, misoprostol, MUA, and EVA, respectively. The mean time to procedure was 5.1 hours for MUA and 23.1 hours for EVA (p=0.002). CONCLUSIONS: Integrating MUA in the ED has the potential to reduce health care resource utilization while improving patient care.

Clinical Features of Spontaneous Remission in the Classic Fever of Unknown Origin: A Retrospective Study.

Objective To summarize the clinical features of spontaneous remission in classic fever of unknown origin (FUO). Methods Medical records of 121 patients diagnosed with FUO at admission in Peking Union Medical College Hospital between January 2018 and June 2018 were reviewed retrospectively. Patients who were discharged without etiological diagnoses were followed for 2 years. The clinical features and outcomes of these patients were summarized. Multivariate logistic regression was used to analyze related factors of spontaneous remission of FUO. Results After excluding 2 patients who lost to follow-up, the etiology of 119 FUO patients were as follows: infectious diseases in 30 (25.2%) cases, connective tissue diseases in 28 (23.5%) cases, tumor diseases in 8 (6.7%) cases, other diseases in 6 (5.0%) cases, and unknown diagnoses in 47 (39.5%) cases. Totally, 41 patients experienced spontaneous remission of fever (the median time from onset to remission was 9 weeks, ranging from 4 to 39 weeks). In patients with spontaneous remission in FUO, lymphadenopathy was less common clinical manifestation, the levels of inflammatory markers including leukocyte count, neutrophil count, neutrophil ratio, C-reactive protein, and ferritin were lower, and the proportion of CD8 positive T lymphocytes expressing CD38 was lower. Multivariate logistic regression analysis of factors with a P-value < 0.05 in univariate analysis shown that white blood cell count (OR: 0.545, 95%CI: 0.306-0.971, P = 0.039), neutrophil count (OR: 2.074, 95%CI: 1.004-4.284, P = 0.049), and proportion of neutrophils (OR: 0.928, 95%CI: 0.871-0.990, P = 0.022) were independent significant factors associated with spontaneous remission in FUO. Conclusions This study suggested that most patients discharged with undiagnosed classic FUO would remit spontaneously. Thus, for patients with stable clinical conditions, follow-up and observation could be the best choice. Patients with lower level of some inflammatory factors may have a high likelihood of spontaneous remission in classic FUO.

[Clinical Characteristics of 68 Patients with Osteoarticular Tuberculosis].

Objective To analyze the clinical features of patients with osteoarticular tuberculosis. Method This retrospective study included a cohort of 68 osteoarticular tuberculosis patients hospitalized in Peking Union Medical College Hospital from January 2013 to December 2020.Results The patients included 42(61.8%)males and 26(38.2%)females,with a median age of 56 years.Tuberculosis pathogen was detected in 39(57.4%)patients,and 29(42.6%)patients were diagnosed by clinical manifestations.The median time from onset to diagnosis was 4 months.The most common manifestations were pain and dysfunction(86.8%),followed by fever(47.1%),weight loss(36.8%),and night sweats(13.2%).Concomitant active tuberculosis in other organs was observed in 27(39.7%)patients.Unifocal and multifocal osteoarticular tuberculosis occurred in 51(75.0%)patients and 17(25.0%)patients,respectively,which mainly attacked thoracic and lumbar spines.Tuberculosis T cell test was positive in 92.7% patients.All the bone biopsies revealed epithelioid granuloma with/without necrosis,with 75.0% positive for mycobacterial DNA,55.1% positive for mycobacterial culture,and 20% positive for acid-fast staining.The risk of developing multifocal osteoarticular tuberculosis in the patients with weight loss was 5.333 times(P=0.013)that of the patients with stable weight.Conclusions The diagnosis of osteoarticular tuberculosis is difficult and tuberculosis T cell test is an effective means.Bone biopsy is the key to diagnosis,and the PCR of mycobacterial DNA shows the highest positive derection rate.Multifocal osteoarticular tuberculosis is not rare,especially in the patients with weight loss.Thus,a comprehensive imaging evaluation is recommended to avoid missed diagnosis.

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Characteristics and reference ranges of CD4+T cell subpopulations among healthy adult Han Chinese in Shanxi Province, North China.

BACKGROUND: Immunophenotyping of blood lymphocytes is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Predominately identified CD4+T cell subsets, Th1, Th2, Th17, as well as regulatory T (Treg) cells, play crucial roles in several immunological and pathological conditions. Considering the variations in cell counts among populations and ethnicities, specific CD4+T cell subset reference values need to be locally established to enable meaningful comparisons and accurate data interpretation in clinical and research settings. Therefore, the aim of this study was to establish distributions and reference ranges for blood CD4+T cell subpopulations in age- and sex-balanced healthy adults of a Han Chinese population in Shanxi Province, North China. METHODS: Peripheral blood CD4+T cell subsets were examined in 150 healthy volunteers (75 males, 75 females) aged 20-70 years with a four-color FACSCalibur flow cytometer. RESULTS: Reference value percentages (absolute counts, cells/µl) were defined as 95% of the population for cell types as follows: CD4+T, 23.78-51.07 (360-1127); Th1, 0.43-39.62 (2.64-276.21); Th2, 0.27-3.57 (1.80-27.14); Th17, 0.22-2.62 (1.10-19.54); and Treg, 2.17-7.94 (13.47-64.58). The ranges for the Th1:Th2 and Th17:Treg ratios were 0.59-52.37 and 0.04-0.76, respectively. Notably, a significant increase was observed in the values of Treg cells in older individuals, and the numbers of Treg cells in females also tended to decrease when compared to those in males. Therefore, we established the distribution and reference range of CD4+T cell subsets based on age and sex, demonstrating the lowest values of Treg cells in younger females. CONCLUSIONS: Collectively, our data provide population-, age-, and sex-specific distributions and reference ranges of circulating CD4+T cell subpopulations, which can be adopted to guide clinical decisions and interpretation of immunophenotyping data in the Han Chinese population in Taiyuan, Shanxi Province, China. In addition, the low expression of peripheral Treg cells in younger females may be associated with the predisposition of females to autoimmune diseases.

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak is evolving rapidly worldwide. OBJECTIVE: To evaluate the risk of serious adverse outcomes in patients with COVID-19 by stratifying the comorbidity status. METHODS: We analysed data from 1590 laboratory confirmed hospitalised patients from 575 hospitals in 31 provinces/autonomous regions/provincial municipalities across mainland China between 11 December 2019 and 31 January 2020. We analysed the composite end-points, which consisted of admission to an intensive care unit, invasive ventilation or death. The risk of reaching the composite end-points was compared according to the presence and number of comorbidities. RESULTS: The mean age was 48.9 years and 686 (42.7%) patients were female. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached the composite end-points. 399 (25.1%) reported having at least one comorbidity. The most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. After adjusting for age and smoking status, COPD (HR (95% CI) 2.681 (1.424-5.048)), diabetes (1.59 (1.03-2.45)), hypertension (1.58 (1.07-2.32)) and malignancy (3.50 (1.60-7.64)) were risk factors of reaching the composite end-points. The hazard ratio (95% CI) was 1.79 (1.16-2.77) among patients with at least one comorbidity and 2.59 (1.61-4.17) among patients with two or more comorbidities. CONCLUSION: Among laboratory confirmed cases of COVID-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A greater number of comorbidities also correlated with poorer clinical outcomes.

Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicentre) and outside Hubei (non-epicentre): a nationwide analysis of China.

BACKGROUND: During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences. METHODS: Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined. RESULTS: At the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7 versus 44.9 years), had more cases with comorbidity (32.9% versus 19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7 versus 4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0% versus 11.1%, death rate 7.3% versus 0.3%, HR (95% CI) for critical illness 1.59 (1.05-2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4 versus 4.7 days) and prognosis (HR (95%) 0.84 (0.40-1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01-1.08)). CONCLUSION: There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.

Preparation of isoquercitrin by biotransformation of rutin using α-L-rhamnosidase from Aspergillus niger JMU-TS528 and HSCCC purification.

Isoquercitrin is a flavonoid with important applications in the pharmaceutical and nutraceutical industries. However, a low yield and high production cost hinders the industrial preparation of isoquercitrin. In the present study, isoquercitrin was prepared by biotransformation of rutin using α-L-rhamnosidase from Aspergillus niger JMU-TS528 combined with high-speed countercurrent chromatography (HSCCC) purification. As a result, the optimum transformation pH, temperature, and time were pH 4.0, 60 °C, and 60 min, respectively. The Km and Vmax were 0.36 mM and 0.460 mmol/min, respectively. For isoquercitrin production, the optimal rutin concentration and transformation time were approximately 1000 mg/L and 60 min. The rutin transformation rate reached 96.44%. The isoquercitrin was purified to a purity of 97.83% using one-step purification with HSCCC. The isoquercitrin was identified using UPLC-Q-TOF-MS. The comprehensive results indicated that the biotransformation procedure using the α-L-rhamnosidase from A. niger JMU-TS528 combined with HSCCC was a simple and effective process to prepare isoquercitrin, which might facilitate the production of isoquercitrin for industrial use.

[Clinical Features and Risk Factors of Systemic Lupus Erythematosus Complicated with Cytomegalovirus Infection].

Objective To explore the clinical characteristics and risk factors of systemic lupus erythematosus(SLE)complicated with cytomegalovirus infection(CMV). Methods The medical records of patients diagnosed with SLE at discharge in the Department of Immunology at Peking Union Medical College Hospital between July 1,2017 and April 1,2019 were retrospectively reviewed,and the clinical and laboratory data related to CMV infection were analyzed. Results Of the 231 patients with SLE,115(49.8%)had CMV infection.Among them,78(67.8%)were asymptomatic CMV infection and 37(32.2%)were diagnosed with CMV disease.Univariate analysis showed the number of organs involved(P=0.015),presence of other infections(P=0.004),methylprednisolone pulse therapy(P=0.001),cumulative dose of prednisolone within 30 days(P=0.001),average dose of prednisolone within 30 days(P<0.001),intravenous cyclophosphamide(P=0.003),methylprednisolone pulse therapy plus immunosuppressants(P=0.001),Systemic Lupus Erythematosus Disease Activity Index 2000 at admission(P=0.018),and serum albumin(ALB)level≤30 g/L(P<0.001)were associated with CMV infection.Multivariate analysis showed presence of other infections(OR=8.003,95%CI=2.108-30.383,P=0.002),methylprednisolone pulse therapy plus immunosuppressants(OR=10.336,95%CI=2.107-50.711, P=0.004),and serum ALB≤ 30 g/L(OR=3.367,95%CI=1.157-9.796,P=0.026)were independent risk factors for CMV infection. Conclusion Presence of other infections,recent methylprednisolone pulse therapy plus immunosuppressants,and serum ALB≤30 g/L can increase the risk of CMV infection in patients with SLE.

Pace capture and adenosine triphosphate provocation are complementary rather than mutually exclusive methods to ensure durable pulmonary vein isolation.

INTRODUCTION: Adenosine triphosphate (ATP)-provoked dormant conduction (DC) and pacing for unexcitability are used to identify conduction gaps along the ablation lines after circumferential pulmonary vein isolation (CPVI). We aim to determine whether ATP provocation and pacing are interchangeable as endpoints for ablation of paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: A total of 107 patients with PAF were randomly divided into two groups after completion of CPVI. In group I (A-P group, n = 53), ATP was administered first. If DC was uncovered, additional ablation was performed until ATP tests were negative. Bipolar pacing along the ablation line was performed subsequently. In group II (P-A group, n = 54), the same protocol was used, but the pacing and the ATP tests were performed in the opposite sequence. The 12-month ablation outcomes of all patients were compared with those of a historical control group of 107 patients with PAF in whom only ATP test was performed. Regardless of which test was performed first, the other modality still identified conduction gaps. In group I, pacing maneuvers identified gaps in 49% (n = 26) of patients who had negative ATP tests. In group II, ATP tests uncovered DC in 18.5% (n = 10) of patients in whom pacing identified no gaps. After 12 months, a higher proportion of patients (91.6%) were free from atrial tachyarrhythmias compared with the historical control group (81.3%; P = 0.031). CONCLUSION: Pacing along the ablation lines and ATP provocation are complementary tests for evaluating the durability of CPVI and can lead to better long-term outcomes when used in combination.