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BackgroundMulti-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. MethodsWe conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. FindingsWe identified 1186 children hospitalized with MIS-C. The highest proportion of children (44{middle dot}4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40{middle dot}2%). Most (67{middle dot}8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72{middle dot}5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51{middle dot}1% of children early in the pandemic, which decreased to 33{middle dot}9% from the pre-delta period to the omicron period. InterpretationMIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms "multi-system inflammatory syndrome in children" or "pediatric inflammatory multisystem syndrome" and "phenotypes". Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this studyPEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidenceThese results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment.
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ObjectivesIntegrating electronic health records (EHR) data from several clinical sites offers great opportunities to improve estimation with a more general population compared to analyses based on a single clinical site. However, sharing patient-level data across sites is practically challenging due to concerns about maintaining patient privacy. The objective of this study is to develop a novel distributed algorithm to integrate heterogeneous EHR data from multiple clinical sites without sharing patient-level data. Materials and MethodsThe proposed distributed algorithm for binary regression can effectively account for between-site heterogeneity and is communication-efficient. Our method is built on a pairwise likelihood function in the extended Mantel-Haenszel regression, which is known to be statistically highly efficient. We construct a surrogate pairwise likelihood function through approximating the target pairwise likelihood by its surrogate. We show that the proposed surrogate pairwise likelihood leads to a consistent and asymptotically normal estimator by effective communication without sharing individual patient-level data. We study the empirical performance of the proposed method through a systematic simulation study and an application with data of 14,215 COVID-19 patients from 230 clinical sites at UnitedHealth Group Clinical Research Database. ResultsThe proposed method was shown to perform close to the gold standard approach under extensive simulation settings. When the event rate is <5%, the relative bias of the proposed estimator is 30% smaller than that of the meta-analysis estimator. The proposed method retained high accuracy across different sample sizes and event rates compared with meta-analysis. In the data evaluation, the proposed estimate has a relative bias <9% when the event rate is <1%, whereas the meta-analysis estimate has a relative bias at least 10% higher than that of the proposed method. ConclusionsOur simulation study and data application demonstrate that the proposed distributed algorithm provides an estimator that is robust to heterogeneity in event rates when effectively integrating data from multiple clinical sites. Our algorithm is therefore an effective alternative to both meta-analysis and existing distributed algorithms for modeling heterogeneous multi-site binary outcomes.
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Objective To investigate the hemodynamic changes in a tortuous coronary to elucidate the effects of tortuosity on coronary perfusion and wall shear stress (WSS). Methods A single tortuous and non-tortuous patient-specific left anterior descending (LAD) coronary artery cases were selected. Two LAD models with and without coronary tortuosity were reconstructed in Mimics software and then transferred to the ANSYS Fluent software for performing computational fluid dynamics (CFD) simulation. The hemodynamic characteristics of both the LAD models were compared. Results The vessel WSS of the tortuous coronary artery clearly decreased in the bend section where the maximum curvature was larger than 1 mm-1.Such a scenario could led to an inadequate blood supply in the downstream vessels. A low WSS (0-26 Pa) acted on the outer wall of the bend, whereas the inner wall of the bend had a high WSS (>100 Pa). The mean WSS of the non-tortuous and tortuous models was 10.79 Pa and 36.12 Pa, respectively. The overall WSS of the tortuous model was larger compared with that of the non-tortuous model. Conclusions Coronary tortuosity increased the overall WSS, which could delay the progress of coronary atherosclerosis.
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OBJECTIVE:To investigate the effects of olmesartan medoxomil on cardiac function,plasma N-terminal pro-brain natriuretic peptide(NT-proBNP)and serum interleukin-23(IL-23)in patients with chronic heart failure(CHF),and to evaluation its safety. METHODS:A total of 40 CHF patients selected from Lianshui County People's Hospital of Jiangsu Province during Dec. 2014-May 2016 were divided into control group and observation group according to random number table,with 20 cases in each group. Control group was given Enalapril maleate tablets with initial dose of 5 mg,po,qd(increasing gradually after one week,limiting dose of 20 mg/d)+Metoprolol tartrate tablets 25 mg,po,bid+Isosorbide mononitrate tablets 40 mg,po,qd+Furose-mide tablets 20 mg,po,bid. Observation group was additionally given Olmesartan medoxomil tablets 20 mg,po,qd,on the basis of control group. Both groups received treatment for consecutive 8 weeks. Cardiac function indexes [LVEDD,LAD,IVST,LVP-WT,LVEF,early diastolic peak E filling velocity/late diastolic peak A filling velocity(E/A)],plasma NT-proBNP and serum IL-23 levels were observed in 2 groups before and after treatment. The incidence of ADR was recorded. RESULTS:Before treat-ment,there was no statistical significance in cardiac function indexes,plasma NT-proBNP or serum IL-23 levels between 2 groups (P>0.05).After treatment,LVEDD,LAD,plasma NT-proBNP and serum IL-23 levels of 2 groups were decreased significantly, while LVEF and E/A levels were increased significantly;the observation group was significantly better than control group,with sta-tistical significance(P<0.05). There was no statistical significance in IVST or LVPWT levels between 2 groups before and after treatment,and there was no statistical significance in the incidence of ADR between observation group(25.00%)and control group(20.00%)(P>0.05). CONCLUSIONS:Olmesartan medoxomil can decrease the levels of plasma NT-proBNP and serum IL-23 in CHF patients,and improve cardiac function with good safety.
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OBJECTIVE:To investigate the effects of olmesartan medoxomil on cardiac function,plasma N-terminal pro-brain natriuretic peptide(NT-proBNP)and serum interleukin-23(IL-23)in patients with chronic heart failure(CHF),and to evaluation its safety. METHODS:A total of 40 CHF patients selected from Lianshui County People's Hospital of Jiangsu Province during Dec. 2014-May 2016 were divided into control group and observation group according to random number table,with 20 cases in each group. Control group was given Enalapril maleate tablets with initial dose of 5 mg,po,qd(increasing gradually after one week,limiting dose of 20 mg/d)+Metoprolol tartrate tablets 25 mg,po,bid+Isosorbide mononitrate tablets 40 mg,po,qd+Furose-mide tablets 20 mg,po,bid. Observation group was additionally given Olmesartan medoxomil tablets 20 mg,po,qd,on the basis of control group. Both groups received treatment for consecutive 8 weeks. Cardiac function indexes [LVEDD,LAD,IVST,LVP-WT,LVEF,early diastolic peak E filling velocity/late diastolic peak A filling velocity(E/A)],plasma NT-proBNP and serum IL-23 levels were observed in 2 groups before and after treatment. The incidence of ADR was recorded. RESULTS:Before treat-ment,there was no statistical significance in cardiac function indexes,plasma NT-proBNP or serum IL-23 levels between 2 groups (P>0.05).After treatment,LVEDD,LAD,plasma NT-proBNP and serum IL-23 levels of 2 groups were decreased significantly, while LVEF and E/A levels were increased significantly;the observation group was significantly better than control group,with sta-tistical significance(P<0.05). There was no statistical significance in IVST or LVPWT levels between 2 groups before and after treatment,and there was no statistical significance in the incidence of ADR between observation group(25.00%)and control group(20.00%)(P>0.05). CONCLUSIONS:Olmesartan medoxomil can decrease the levels of plasma NT-proBNP and serum IL-23 in CHF patients,and improve cardiac function with good safety.
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BACKGROUND: Recent experimental studies have found ultrasound mediated microbubbles potentiate stem cell therapy in myocardial infarction (MI)-induced heart failure, indicating a good application prospect. But whether ultrasound mediated nitric oxide (NO) microbubbles also have the same effect in the intracoronary transplantation of bone marrow mesenchymal stem cells (BMSCs) for treatment of large animals with MI is still unknown. OBJECTIVE: To investigate the effectiveness and possible mechanism of ultrasound mediated NO microbubbles in potentiating intracoronally transplanted BMSCs homing to the infarcted area in a MI pig model.METHODS: Density gradient centrifugation culture method was used in the isolation and cultivation of BMSCs. CM-Dil was used to label BMSCs in vitro. Twenty-four pigs were used to make MI models by blocking the left anterior descending coronary artery, and then were divided into PBS group, BMSCs group, ultrasound+microbubbles+BMSCs(MB) group, ultrasound+NO microbubbles+BMSCs (NO-MB) group(n=6 per group). In the PBS group, 10 mL of PBS was intracoronally injected. In the BMSCs group, about 1×107 BMSCs were diluted in 10 mL of PBS and then intracoronally infused. In the MB group, 0.1 mL/kg sulphur hexafluoride microbubbles (Sono Vue) was intracoronally injected together with ultrasound treatment (1 MHz, 2 W/cm2, 2 minutes), followed by intracoronary infusion of about 1×107 BMSCs that were diluted in 10 mL of PBS. In the NO-MB group, all methods and conditions were identical to those in the MB group except only 0.1 mL/kg of Sono Vue was replaced by 0.1 mL/kg NO microbubbles. Three pigs were sacrificed in each group 48 hours after CM-Dil positive BMSCs transplantation. The labeled BMSCs were observed and counted by fluorescent microscope after frozen sectioning of the infarct area. We assessed and compared left ventricular systolic function with M-mode ultrasound among groups at 4 weeks after intervention. After cardiac function test, the rest pigs were sacrificed and capillary density in the myocardial ischemic area was counted and compared after hematoxylin-eosin staining. RESULTS AND CONCLUSION: (1) The number of CM-Dil positive cells in the area of MI in the NO-MB group was much more than that in the MB group and BMSCs group with statistical significance (P < 0.05). (2) The left ventricle systolic function was significantly improved in the NO-MB group as compared with the MB group (P < 0.05). The same trend was observed between NO-MB group and BMSCs group as well as between NO-MB group and PBS group (P < 0.05). (3) The density of capillaries increased significantly in the NO-MB group compared with the MB group, BMSCs group and PBS group, respectively. To conclude, ultrasound mediated NO microbubble combined with intracoronary BMSCs transplantation can improve the left ventricular systolic function. The possible mechanism could be that ultrasoundmediated NO mocrobubbles promote the homing of transplanted BMSCs to the myocardial ischemia area as well as improve local angiogenesis.
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Objective To explore the effects of ultrasound-exposed microbubbles (UM) on the expression of CXC chemokine receptor 4 (CXCR4) in bone marrow mesenchymal stem cells (BMSCs) and the mechanisms involved.Methods Mesenchymal stem cells were isolated from bone marrow taken from male Sprague-Dawley rats.They were divided into a control group,an ultrasound (US) group,an ultrasound-exposed microbubbles (UM) group,a UM plus catalase (UMC) group,a UM plus AMD3100 (UMA) group,and a UM plus anti-CXCR4 antibody (UMCX) group.The control group was not given any treatment.The US group was treated with 1 MHz ultrasound at 1 Watt per square centimetre for 30 seconds.The UM group was treated with ultrasound plus microbubbles.The UMC group was treated with catalase,microbubbles and ultrasound.The UMA group was treated with AMD3100,microbubbles and ultrasound.The UMCX group was treated with anti-CXCR4 antibody,microbubbles and ultrasound.Quantitative polymerase chain reaction (qPCR) and Western blotting were performed to determine the levels of CXCR4 mRNA transcription and the expression of BMSCs in the control,US,UM and UMC groups.Immediately,5 minutes and 15 minutes after the intervention,fluorescence intensities were observed in the cells labeled with Fluo-4/AM of the control group,US group and UM group under a fluorescence microscope.Migration assays were conducted to determine the chemotactic ability of the BMSCs with respect to stromal-derived factor-1α (SDF-1α) in all six groups.Results No significant differences were found in the levels of CXCR4 mRNA transcription and protein expression between the US and control groups(P＞0.05),but the levels in those groups and the UMC group were lower than those observed in the UM group.Fluorescence intensity in the cells of the US group was not significantly different from that in the control group (P＞0.05),but those levels were both significantly lower than that in the UM group (P＜0.05).There was no significant difference in the number of cells migrating to the SDF-1α between the US (22.4±2.2) and control group (20.5±2.3).However,the number of cells migrating to SDF-1α in the UM group (53.1±3.8) was significantly larger than that in the US group,the control group,the UMC group (35.2+3.1),the UMA group (32.5±2.8) and the UMCX group (30.7+2.9) (P＜ 0.05).Conclusion UM can increase mRNA transcription and the expression of CXCR4 protein in BMSCs,and promote BMSCs migration to SDF-lα.This may in part be mediated by an increase in calcium influx.
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Objective To explore the effects of pretreatment of bone marrow mesenchymal stem cells (BMSCs) by ultrasound-exposed microbubbles (UM) on both homing to ischemic myocardium and cardiac function after acute myocardial infarction (AMI).Methods Rats of AMI model established by ligation of left anterior descending coronary artery were divided into four groups randomized:phospho-buffered saline (PBS) group,stem cells treatment (SCT) group,ultrasound and stem cells treatment (USCT) group,and UM stem cells treatment (UMSCT) group,and each group was injected with PBS,stem cells,US-pretreated stem cells and UM-pretreated stem cells through the caudal veins after AMI respectively.Homing of BMSCs to the ischemic myocardium was examined by confocal microscopy at 48 h after implantation,and cardiac function was examined by ultrasonic cardiogram (UCG) after 4 weeks.Masson staining was used to examine the changes of local ischemic cardiac tissues,and immunohistochemistry was used to detect the density of local neo-capillaries (CD31).Results 1) The numbers of CM-Dil-positive cells counted under confocal microscopy in the ischemic myocardial tissues of each groups 48 hours after implantation were not the same:there was no significant difference of the numbers of positive cells between USCT group (19.67 ±2.08) and SCT group (18.67 ± 2.08).However,the number of positive cells in the UMSCT group (39.33 ±3.06) was larger than that in USCT group and SCT group (P ＜0.05).2) UCG examinations showed that there was no significant difference of left ventricular systole function between the USCT group [LVEF (44.92 ± 2.77)％,LVFS (22.83 ± 1.79)％] and SCT group [LVEF (42.28 ± 2.82)％,LVFS (21.52 ±1.88) ％,P ＞0.05],but both were better than that in PBS group [LVEF (20.52 ± 1.88)％,LVFS (9.55 ±0.85) ％,P ＜0.05].The left ventricular systolic function in UMSCT group [LVEF (61.85 ± 3.15)％,LVFS (32.74± 2.45)％] was significantly higher than that in USCT group and SCT group (P ＜0.05),while which was still significantly lower than that in pseudo-surgery group [LVEF (75.88± 4.52)％,LVFS (42.76 ± 2.88)％,P ＜0.05].3) Pathological examinations showed the percentages of AMI areas in the USCT group (35.9 ± 1.1％) were not different compared with that in SCT group [(36.5 ± 1.3)％,P ＞0.05],while both were significantly smaller than that in PBS group [(45.2± 1.4)％,P ＜0.05].The percentages of AMI areas in the UMSCT group [(25.8 ± 1.0)％] were significantly smaller than that in USCT group and SCT group (P ＜0.05).The density of neo-capillaries (25.9 ± 1.3) in USCT groups had no difference compared with that in SCT group (25.2 ± 1.3),while both were significantly higher than that in PBS group (17.6 ± 1.1,P ＜0.05);the density of neo-capillaries (33.2 ± 1.6) was significantly higher in UMSCT group than that in both USCT group and SCT group (P ＜0.05),which were examined by immunohistochemistry.Conclusions Homing to ischemic myocardium of BMSCs transplanted intravenously could be promoted by UM pretreatment,which stimulates development of capillaries,reduces AMI areas,and improves the cardiac function after AMI.
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Objective To study the characteristics of clustering of cardiovascular risk factors in patients less than 50 years-old of premature stable coronary heart disease(PSCHD)complicated with nonalcoholic fatty liver(NAFL).Methods One hundred and six patients with documented PSCHD were recruited into this study and their clinical data,including biochemical parameters,high-sensitivity C-reactive protein(hsCRP),white blood cell(WBC)count,ete.,were analyzed based on whether they had NAFL by B-type ultrasound scanning and their homeostasis model assessment ratio(Homa-IR)by the criteria for metabolic syndrome formulated by the International Diabetes Federation.Results Thirty-two (30.1percent)of 106 patients of PSCHD complicated with NAFL,and 74(69.9 percent)without NAFL. As compared to patients without NAFL,patients with NAFL had higher fasting blood glucose(FBS),serum level of insulin(INS),total cholesterol(TC),triglyceride(TG),serum activity of alanine aminotransferase(ALT),hsCRP,WBC count,body mass index(BMI),Homa-IR,and higher proportion of those with abnormal blood glucose,hypertension.metabolic syndrome(MS)and carotid atherosclerosis (CA)(P＜0.05),respectively.Bi-variate correlation analysis revealed that hsCRP positively correlated to BMI,TG,ALT and Homa IR(r=0.420,P=0.000;r=0.200,P=0.040;r=0.218,P=0.048:and r=0.546,P=0.000,respectively)and inversely correlated with serum level of high-density lipoprotein cholesterol(HDL-C)(r=-0.220,P=0.023).WBC count positively correlated with FBS(r=0.211,P=0.030).BMI,hsCRP,ALT,and proportions of hypertension,diabetes,MS,NAFL and CA in patients with Homa-IR above median were significantly higher than those in patients with that below median ( P＜0.05,respectively).Conclusions More risk faetors for chronic inflammatory reaction,cardiovascular disease and insulin resistance were clustered more obviously in patients of PSCHD complicated with NAFL.
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AIM and METHODS:To investigate the effect of L-arginine -nitric oxide pathway on patients with essential hypertension via hemodynamics and neuroendocrinology. 24 essential hypertension patients were randomly divided into two groups, group I was given L-Arg, and groups Ⅱ was given normal saline as control. Blood pressure, heart rate, heart funtion, nitric oxide, angiotensinⅡ, endothelin, thromboxane A 2 and prostacyline were measure in all patients. RESULTS: In group Ⅰ arterial pressure decreased, heart rate increased, cardial output, systolic volume and eject fraction increased, total peripheral resistance decreased. NO and PGI 2 levels were inceased. But at 80 min , with NO concentration decreased, SBP,DBP were increased, TPR, FT and AngⅡ were also increased. While HR, CO, SV and EF were decreased. However TXA 2 and PGI 2 showed not much change. CONCLUSION: Exogenous L-arginine produced a vasodilatory effect by increasing NO production ,caused the change of other hemodynamic function . It also indirectly changed plasma ET, AngⅡlevels by negative feed-back and suppressed the accumulation of platelet.