Duration of viable virus shedding in SARS-CoV-2 omicron variant infection

Clinical features of SARS-CoV-2 Omicron variant infection, including incubation period and transmission rates, distinguish this variant from preceding variants. However, whether the duration of shedding of viable virus differs between omicron and previous variants is not well understood. To characterize how variant and vaccination status impact shedding of viable virus, we serially sampled symptomatic outpatients newly diagnosed with COVID-19. Anterior nasal swabs were tested for viral load, sequencing, and viral culture. Time to PCR conversion was similar between individuals infected with the Delta and the Omicron variant. Time to culture conversion was also similar, with a median time to culture conversion of 6 days (interquartile range 4-8 days) in both groups. There were also no differences in time to PCR or culture conversion by vaccination status.

Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19

ImportanceThe antiviral activity and efficacy of anti-SARS-CoV-2 monoclonal antibody (mAb) therapies to accelerate recovery from COVID-19 is important to define. ObjectiveTo determine safety and efficacy of the mAb bamlanivimab to reduce nasopharyngeal (NP) SARS-CoV-2 RNA levels and symptom duration. DesignACTIV-2/A5401 is a randomized, blinded, placebo-controlled platform trial. Two dose cohorts were enrolled between August 19 and November 17, 2020 for phase 2 evaluation: in the first, participants were randomized 1:1 to bamlanivimab 7000 mg versus placebo, and in the second to bamlanivimab 700 mg versus placebo. Randomization was stratified by time from symptom onset ([≤] or >5 days) and risk of progression to severe COVID-19 ("higher" vs "lower"). SettingMulticenter trial conducted at U.S. sites. ParticipantsNon-hospitalized adults [≥]18 years of age with positive SARS-CoV-2 antigen or nucleic acid test within 7 days, [≤]10 days of COVID-19 symptoms, and with oxygen saturation [≥]92% within 48 hours prior to study entry. InterventionSingle infusion of bamlanivimab (7000 or 700 mg) or placebo. Main Outcomes and MeasuresDetection of NP SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28, time to improvement of all of 13 targeted COVID-19 symptoms by daily self-assessment through day 28, and grade 3 or higher treatment emergent adverse events (TEAEs) through day 28. Secondary measures included quantitative NP SARS-CoV-2 RNA, all-cause hospitalizations and deaths (composite), area under the curve of symptom scores from day 0 through day 28, plasma bamlanivimab concentrations, plasma and serum inflammatory biomarkers, and safety through week 24. ResultsNinety-four participants were enrolled to the 7000 mg cohort and 223 to the 700 mg cohort and initiated study intervention. The proportion meeting protocol criteria for "higher" risk for COVID-19 progression was 42% and 51% for the 7000 and 700 mg cohort, respectively. Median time from symptom onset at study entry for both cohorts was 6 days. There was no difference in the proportion with undetectable NP SARS-CoV-2 RNA at any post-treatment timepoints (risk ratio compared to placebo, 0.82-1.05 for 7000 mg dose [overall p=0.88] and 0.81-1.21 for 700 mg dose [overall p=0.49]), time to symptom improvement (median of 21 vs 18.5 days, p=0.97, for 7000 mg bamlanivimab vs placebo and 24 vs 20.5 days, p=0.08, for 700 mg bamlanivimab vs placebo), or grade 3+ TEAEs with either dose compared to placebo. Median NP SARS-CoV-2 RNA levels were lower at day 3 and C-reactive protein, ferritin, and fibrinogen levels significantly reduced at days 7 and 14 for bamlanivimab 700 mg compared to placebo, with similar trends observed for bamlanivimab 7000 mg. Viral decay modeling supported more rapid decay with bamlanivimab compared to placebo. Conclusions and RelevanceTreatment with bamlanivimab 7000 mg and 700 mg was safe and compared to placebo led to more rapid reductions in NP SARS-CoV-2 RNA and inflammatory biomarkers, but did not decrease time to symptom improvement. The clinical utility of mAbs for outcomes other than hospitalizations and deaths is uncertain. Trial RegistrationClinicalTrials.gov Identifier: NCT04518410 KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat is the safety and efficacy of bamlanivimab monoclonal antibody (mAb) treatment for mild to moderate COVID-19? FindingsIn this randomized, placebo-controlled phase 2 trial of 317 non-hospitalized adults with COVID-19, there was no relationship between symptoms or disease progression risk and nasopharyngeal (NP) virus shedding. Bamlanivimab was safe and reduced NP SARS-CoV-2 RNA levels and inflammatory biomarker levels more than placebo, but did not shorten symptom duration. MeaningNasal virus shedding was not associated with symptoms or baseline risk factors for severe COVID-19. Bamlanivimab, which has been associated with reduced hospitalizations in high-risk individuals, demonstrated antiviral activity with early post-treatment NP sampling but did not accelerate symptom improvement. The clinical utility of bamlanivimab for outcomes other than hospitalizations and deaths, including longer-term outcomes, is uncertain.

SARS-CoV-2 Viremia is Associated with Distinct Proteomic Pathways and Predicts COVID-19 Outcomes

BackgroundSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) plasma viremia has been associated with severe disease and death in coronavirus disease 2019 (COVID-19) in small-scale cohort studies. The mechanisms behind this association remain elusive. MethodsWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using qRT-PCR based platform. Proteomic data were generated with Proximity Extension Assay (PEA) using the Olink platform. ResultsThree hundred participants with nucleic acid test-confirmed COVID-19 were included in this study. Levels of plasma SARS-CoV-2 viremia at the time of presentation predicted adverse disease outcomes, with an adjusted odds ratio (aOR) of 10.6 (95% confidence interval [CI] 4.4, 25.5, P<0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and aOR of 3.9 (95%CI 1.5, 10.1, P=0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, endothelium/vasculature and alterations in coagulation pathways. ConclusionsThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.

Effect of long-chain non-coding RNA GAS5 on insulin secretion of islet cells by targeting miR-29, miR-96, and miR-208 / 中华内分泌代谢杂志

Objective:To investigate the role and mechanism of long non-coding RNA GAS5 in the targeted regulation of miR-29, miR-96, and miR-208 in promoting insulin secretion of pancreatic β-cells.Methods:Q-PCR was used to detect the expression of miR-29, miR-96, and miR-208 in sera of 122 healthy subjects and 88 type 2 diabetic patients; and so of long non-coding RNA GAS5 and miR-208 in the rat islet cell tumor strain ins-1832/13. Effects of silencing and overexpressing GAS5 on insulin secretion of islet β-cells by lentiviral vector construction were observed. Bioinformatics was used to predict that GAS5 had complementary binding sites with miR-29, miR-96, and miR-208, which was further verified by luciferase reporting system. GAS5 siRNA was co-transfected with miR-29, miR-96, and miR-208 inhibitors, and the effect of GAS5 on insulin receptor (INSR), insulin receptor substrate (irs-1) and PI3K levels was detected by the above method, so as to reveal the effect of GAS5 on insulin secretion in islet cells.Results:The expression of GAS5 in serum of T2DM patients was lower than that of healthy control group ( t=4.632, P<0.01), and expression of miR-29, miR-96, and miR-208 were higher than those of healthy control group ( t were 7.832, 9.164, and 12.359, all P<0.01). GAS5 level was negatively correlated with miR-29, miR-96, and miR-208 ( r were -0.50, -0.47, and -0.70, respectively). GAS5 expression was significantly decreased in serum of type 2 diabetic patients compared with that of in healthy subjects. Overexpression of GAS5 by lentivirus resulted in increased glucose-stimulated insulin secretion and increased insulin concentration compared to negative control. In contrast, knockdown of GAS5 led to significant reduction of glucose-stimulated insulin secretion and insulin concentration. GAS5 levels were negatively correlated with miR-29, miR-96, and miR-208 in serum samples of type-2 diabetes patients. GAS5 can negatively regulate the expression of miR-96, miR-29, and miR-208. By bioinformatics tools, we screened miR-29, miR-96 and miR-208 as targets of GAS5, and their interaction was validated with dual luciferase reporter gene assay. shGAS5 significantly decreased the expressions of INSR, IRS-1 and PI3K( P were 0.022, 0.038, and 0.009), while overexpressed GAS5 significantly upregulated the expressions of INSR, IRS-1 and PI3K at both mRNA and protein levels( P were 0.024, 0.045, and 0.016). Conclusion:GAS5 could stimulate insulin secretion of islet cell through its inhibitry regulationor of expressions of miR-29, miR-96, and miR-208, therely up-regulating INSR, IRS-1, and PI3K that may be the potential targets of these miRNAs, and stimulate insulin secretion of islet cells.

SARS-CoV-2 Viral Load is Associated with Increased Disease Severity and Mortality

The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). We quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. SARS-CoV-2 plasma RNA was detected in 27% of hospitalized participants and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, higher prevalence of detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, were associated with increased risk of mortality. SARS-CoV-2 viral load may aid in the risk stratification of patients with COVID-19 and its role in disease pathogenesis should be further explored.

SARS-CoV-2 Detection in Different Respiratory Sites: A Systematic Review and Meta-Analysis

BackgroundThe accurate detection of SARS-CoV-2 through respiratory sampling is critical for the prevention of further transmission and the timely initiation of treatment for COVID-19. There is a diverse range of SARS-CoV-2 detection rates in reported studies, with uncertainty as to the optimal sampling strategy for COVID-19 diagnosis and monitoring. MethodsWe performed a systematic review and meta-analysis of studies comparing respiratory sampling strategies for the detection of SARS-CoV-2 RNA. The inclusion criteria were studies that assessed at least two respiratory sampling sites (oropharyngeal swab, nasopharyngeal swab, and sputum) in participants with COVID-19. The percentage positive tests were compared between sampling modalities by constructing a Z-test assuming independence and using the standard errors obtained from the random effects meta-analysis. FindingsFrom 1039 total studies, we identified 11 studies that met our inclusion criteria, with SARS-CoV-2 testing results from a total of 3442 respiratory tract specimens. Compared to nasopharyngeal swab sampling, sputum testing resulted in significantly higher rates of SARS-CoV-2 RNA detection while oropharyngeal swab testing had lower rates of viral RNA detection. Earlier sampling after symptom onset was associated with improved detection rates, but the differences in SARS-CoV-2 RNA detection by sampling method was consistent regardless of the duration of symptoms. InterpretationThe results support sputum sampling as a primary method of COVID-19 diagnosis and monitoring, and highlight the importance of early testing after symptom onset to increase the rates of COVID-19 diagnosis. FundingThis study was funded in part by the NIH grants U01AI106701 and by the Harvard University for AIDS Research (NIAID 5P30AI060354).

Evaluation of coronary artery hemodynamics and its relationship with atherosclerosis in west diet fed LDL‐R knockout mice by ultrasound bio‐microscopy / 中华超声影像学杂志

To evaluate the relationship between atherosclerosis and hemodynamic of coronary artery in mice detecting by ultrasound bio‐microscopy flow imaging . Methods Double 14 20‐week‐old LDL‐R‐/‐and C57BL/6 male mice were selected ,and randomly divided into two groups in each genotype according to weight . Each two groups were fed to 28 weeks or 36 weeks age respectively with west diet . Coronary artery hemodynamics in these mice were assessed in vivo by Vevo ?2100 ultrasound imaging system ,then the intima‐media thickness( IM T ) of aorta in histopathology were analyzed . T he differences of coronary artery hemodynamic parameters such as maximum velocity ( Vmax ) ,mean velocity ( Vmean) and velocity time integral ( V T I) were compared between mice of different genotypes of the same week and mice of different weeks of the same genotype . And the relationship between coronary artery hemodynamic in ultrasound and aortic IM T in histopathology were analyzed . Results ① All coronary hemodynamic parameters in LDL‐R‐/‐ mice were significantly lower than those of wild‐type mice except the Vmax between two 28‐week‐old genotypes group at the same weeks of age of different genotypes ( all P ＜0 .05) . But there was no significant difference in coronary artery hemodynamic parameters between mice of the same genotype at different weeks of age( P ＞0 .05) . ②T he histopathological measurements of aortic IM T in LDL‐R‐/‐mice were significantly higher than those of wild type mice ( all P ＜ 0 .05 ) ,and those of 36‐week‐old mice were significantly higher than those of 28‐week‐old mice ( all P ＜ 0 .05 ) . ③ All coronary hemodynamic parameters such as Vmax ,Vmean and V TI were negatively correlated with pathological measurements of aortic IM T ( r ＝ －0 .532 , －0 .423 , －0 .524 ; all P ＜ 0 .05 ) . Conclusions The parameters of coronary artery hemodynamics obtained by ultrasound bio‐microscopy are well correlated with the pathological results of atherosclerosis . Ultrasound bio‐microscopic flow imaging can be used as a new method to evaluate the degree of atherosclerosis in mice by detecting the hemodynamic parameters of coronary artery .

Assessment of left ventricular function in HeFH patients with myocardial layer-specific analysis based on two-dimensional echocardiography / 中国医学影像技术

Objective To explore the value of layer-specific strain in assessment of left ventricular function in patients with heterozygous familial hypercholesterolemia (HeFH) with normal left ventricular ejection fraction (LVEF).Methods Thirty-four patients with diagnosed HeFH and underwent transthoracic echocardiography were included as HeFH group,while 29 healthy volunteers were taken as control group.EchoPAC software was used to obtain endocardial longitudinal strain (LSendo),myocardial longitudinal strain (LSmyo) and epicardial longitudinal strain (LSepi) of the epicardial,and then statistical analysis was performed.Results LSendo and LSmyo in HeFH group were significantly lower than those in control group (P＜0.001).LSendo and LSmyo were negatively correlated with total cholesterol and low density lipoprotein cholesterol (all P＜0.05).Conclusion Layer-specific strain of left ventricular is of great value in assessing early myocardial damage in patients with HeFH.

Clinical observation on treatment of coronary heart disease by promoting blood circulation and removing stasis / 中国生化药物杂志

ObjectiveAnalyze the mechanism of traditional Chinese medicine Salvia miltiorrhiza in treating coronary heart disease (CHD).MethodsThe animal experiment using actual research, namely the selection of rat isolated heart perfusion model, rat model of myocardial ischemia and ventricular tachycardia in rabbits model, then the effects of different animal groups in hemodynamics, coronary flow, serum superoxide dismutase (SOD) content, malondialdehyde (MDA) the results of the content.ResultsAfter treatment, the content of SOD was significantly increased and the content of MDA was significantly decreased in the treatment group, and the difference between the two groups was statistically significant (P<0.05).ConclusionTraditional chinese medicine Salvia miltiorrhiza has significant effect on the treatment of coronary heart disease, which is beneficial to the recovery of patients' condition, and is worthy of clinical application.

Purification and cytokine profile of autologous conditioned serum / 中国组织工程研究

BACKGROUND:Autologous conditioned serum (ACS) is a new and safe biological therapy method mainly used for osteoarthritis, rheumatoid arthritis and other similar diseases. OBJECTIVE:To explore the purification method and cytokine profile of ACS. METHODS:Blood obtained equipment (containing 3 mm of glass beads) was used to collect peripheral blood samples that were mixed uniformly and then placed in a 37℃ thermostatic incubator for 24 hours, finally filtered to obtain ACS. The quantitative determination of interleukin (IL)-1Ra, IL-6, IL-8, and IL-1β was conducted, and the 36 kinds of cytokines were semi-quantitatively detected by cytokine antibody array. RESULTS AND CONCLUSION: The levels of various cytokines in ACS were obviously increased, among which, IL-1Ra level (important for alleviating osteoarthritis) was increased from 140.25 ng/L to 1125 ng/L(increased by above 8 times); IL-6 level was increased from 389.5 ng/L to 2802 ng/L; IL-8 level was not detected firstly and finally increased to 2822 ng/L. Cytokine antibody array results showed that at least 10 kinds of cytokines in ACS were changed, and most of cytokines were on a rise, and few in decline. These results indicate that the ACS contains IL-1Ra and a variety of cytokines, and some chemokines in the ACS recruit more immune cells to the inflammation sites and accelerate the inflammatory process, further exerting therapeutic effects.

The inhibitive effects of celastrol on LDL oxidation and HAEC cell oxidative damage / 中国药理学通报

Aim To evaluate the inhibitive effects of celastrol on LDL oxidation and HAEC cell oxidative damage. Methods The Cu2+-induced LDL oxidation model was employed to evaluate celastrol inhibitive effect on LDL oxidation in vitro, the oxidative reaction kinetic curves were determined, and the AUC, lag time,TBARS value were assayed. The AAPH-induced HAEC damaging cellular model was employed to evalu-ate the effect of celastrol on oxidative cellular damage. The safe dose of celastrol on normal cells was deter-mined by MTT method, and the effects of celastrol on HAEC oxidative damage were evaluated at the range of this safe dose. The LDH leakage,ROS level,SOD and GPX enzymatic activity,Nrf2 and HO-1 mRNA expres-sion were determined. Results At the dose range of 100 nmol · L-1 to 1 μmol · L-1 , celastrol effectively extended the lag time of LDL oxidative process induced by Cu2+, reduced the AUC of oxidative reaction kinet-ic curve and reduced the generation of lipid peroxide in the LDL oxidative process. In the cellular experiment, celastrol effectively reduced the LDH leakage induced by AAPH, increased the integrity of cell membrane and nucleus, enhanced the antioxidative enzyme activi-ties of cellular SOD,GPX and increased the expressions of Nrf2,HO-1 mRNA, celastrol also maintained the in-tegrity of cellular structure. Conlusion Celastrol can effectively inhibit LDL oxidation induced by Cu2+, and can inhibit HAEC cell oxidative damage induced by AAPH at the dose range of 100 to 400 nmol·L-1 .

Diagnosis of fetal complete atrioventricular block with echocardiography / 中华医学超声杂志（电子版）

Objective To evaluate the application of M-mode echocardiography and Doppler echocardiography in diagnosing complete atrioventricular block (CAVB) in fetus. Methods M-mode and Doppler echocardiography were used to screen the fetuses and bradycadia was established as CAVB in 10 cases. Atrial and ventricular rhythm was measured by M-mode echocardiography. Flow of mitral valve, left ventricular in-flow and out-flow tract, venous duct was measured by Doppler echocardiography. The characteristics and prognoses of CAVB fetus were compared and analyzed. Results CAVB was established as independence in rhythm of atrium and ventricle. The rhythm of atrium could be in normal range, while the rhythm of ventricle should be slower than normal. Enlarged chambers were observed in 6 cases, cardiac dysfunction in 5 cases, and pericardial effusion in 7 cases. Tricuspid regurgitation and mitral regurgitation existed in 5 and 1 case, respectively. All of the CAVB fetus in this study underwent abortions. Conclusions Fetal echocardiography is proven to be a useful tool to diagnose CAVB, which greatly influenced the cardiac function in fetuses. Clear diagnosis as early as possible is crucial to the treatment of CAVB fetus.

An antiretroviral regimen containing 6 months of stavudine followed by long-term zidovudine for first-line HIV therapy is optimal in resource-limited settings: a prospective, multicenter study in China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>An zidovudine (AZT)-substitution regimen containing 24-week stavudine (d4T) followed by long-term AZT for HIV therapy is potential to trade off short-term AZT-related anemia and long-term risks associated with d4T in resource-limited settings. However, evidence is scarce. This study aims to assess the efficacy and safety of AZT-substitution regimen, aiming to find a regimen with better efficacy, less adverse events, and more affordability in resource-limited settings.</p><p><b>METHODS</b>This prospective, multicenter study enrolled 499 (190 on d4T regimen, 172 on AZT regimen, and 137 on AZT-substitution regimen) HIV-1-infected subjects who initiated combined antiretroviral therapy and attended follow-up visits over 96 weeks from 2009 to 2011. Lamivudine (3TC) and either nevirapine (NVP) or efavirenz (EFV) were the other two drugs in the antiretroviral regimens. Virologic and immunologic responses and adverse events were monitored at baseline and at weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96.</p><p><b>RESULTS</b>In terms of hematological adverse effects, AZT-substitution group had similar safety profiles to d4T group and was superior to AZT group. In comparison with AZT-substitution group, AZT group was associated with higher risk of developing anemia (adjusted hazard ratio (aHR) for anemia ≥ grade II, 8.44, 95% CI 1.81-39.46) and neutropenia (aHR for neutropenia ≥ grade II, 1.86, 95% CI 1.19-2.93). The prevalence of lipodystrophy in d4T group was 19.5%, while that in AZT-substitution group was zero. As to antiretroviral efficacy, these three groups showed no differences.</p><p><b>CONCLUSION</b>AZT-substitution regimen provides a relatively safe and effective first-line antiretroviral strategy in resource-limited settings.</p>

Effect of glucagon-like peptide-1 analogue combined with insulin for treating obese or overweight type 2 diabetes / 中国基层医药

Objective To observe the therapeutic efficacy and safety of the glucagon-like peptide-1 ( GLP-1 )analogue combined with isulin for treating obese or overweight type 2 diabetes.Methods 40 cases with obese or overweight type 2 diabetic patients( body mass index(BMI) ≥24) who have previously used human insulin,and experienced poor glycemic control( ≥7.5％ ) were selected.They were randomly divided into two groups.A group treated by GLP-1 analogue liraglutide plus insulin,and B group by continuous adjustment of insulin.12 weeks later,fasting blood glucose(FBG),2-hour plasma glucose (2hPG),hemoglobin A 1 C (HbA1c),body weight were observed and the incidence of hypoglycemia,insulin dosage were recorded.Results Weight and insulin dosage of group A was significantly lower than those of group B after treatment 12 week( t =2.738,2.865,all P ＜ 0.01 ).Numbers of hypoglycemia events were 6 in group A(30％ ),and 9 in group B(45％ ),but there was no statistical significance between the two groups ( P ＞ 0.05).Conclusion The addition of liraglutide to insulin in patients with obese or overweight type 2 diabetes is associated with reductions in weight and insulin dosage,without increase risk of hypoglycemia.This treatment proved effective and safe.