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1.
Am J Clin Pathol ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33791753

RESUMO

OBJECTIVES: The present study was conducted to evaluate the usefulness of capillary electrophoresis (CE), cation-exchange high-performance liquid chromatography (HPLC), and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) for the screening of hemoglobin (Hb) variants prevalent in southern China. METHODS: A total of 102 types of Hb variants in 1,083 variant carriers were identified over a 5-year period. These variants were analyzed by a CE method (Capillarys 3 TERA), a cation-exchange HPLC analyzer (Variant II Turbo 2.0), and a MALDI-TOF MS system (QuanTOF). RESULTS: The presence of 85 (83.3%, 85/102), 84 (82.4%, 84/102), and 62 (60.8%, 62/102) Hb variants was detected by Capillarys 3 TERA, Variant II Turbo 2.0, and QuanTOF, respectively. Of the three methods, only Capillarys 3 TERA recognized all 10 of the most frequent Hb variants in southern China. There were six, two, and three Hb variants that can only be detected by Capillarys 3 TERA, Variant II Turbo 2.0, and QuanTOF, respectively. The detection limit of mass difference for QuanTOF was approximately 11 to 20 Da. CONCLUSIONS: MALDI-TOF MS is suitable for use as an auxiliary method rather than a stand-alone method for the screening of Hb variants prevalent in southern China.

2.
JMIR Mhealth Uhealth ; 9(3): e19239, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33646130

RESUMO

BACKGROUND: There has been a significant increase in the trend of using social media as a platform to deliver weight management interventions. This illustrates a need to develop a holistic understanding of doctor-patient communication and peer-to-peer communication in social media interventions and to determine their influences on weight management for people with overweight or obesity. Such studies will highlight how social media can be more effectively integrated into weight management programs to enhance individuals' short-term and long-term weight management behaviors. OBJECTIVE: The aim of this study was to examine patients' experiences with doctor-patient communication and peer interactions in a social media-based (WeChat) weight management program, and to describe the interplay of three social influence factors-social support, social comparison, and surveillance-in their weight control practices. The program, designed and implemented by the research team located in a tertiary referral hospital in a southeastern province in China, included both diet and physical activity components that targeted people with overweight or obesity. METHODS: We conducted in-depth interviews with 32 program participants of different ages (mean 35.6, SD 7.7 years), gender (18 women), duration of program membership (mean 1.4 years), and weight loss outcomes (54% weight loss to 9% weight gain). All interview data were audio-recorded, transcribed, and translated using the translation-backtranslation technique. Nvivo software was used to facilitate the coding process. RESULTS: Results of thematic analysis indicated the distinct functions of professionally led support and peer support. Professional support was presented in the form of knowledge infusion, efficacy enhancement, and provision of timely feedback. Peer support fostered empathy and sense of belonging, and had a mutually reinforcing relationship with peer comparison and peer-based surveillance. Peer comparison enhanced motivation and positive competition. However, it also reinforced negative group norms, and resulted in downturns in reference standards and collective inactivity. Social media surveillance prompted participants' reactions to the gaze from medical professionals and peers that could be encouraging or inhibiting. Surveillance enhanced vigilance with weight control norms; however, its influence weakened when participants chose to fake weight data and turn off notifications. Findings from this study illustrated the interrelated and fluctuating influences of support, comparison, and surveillance. CONCLUSIONS: The interactive traits of social media eased the practices of social support and social comparison, and created new forms of surveillance. This study contributes to an in-depth understanding of social media influences on individuals' weight control behaviors. Practical implications of the study concern improved strategies for maintaining the positive dynamics of social media interactions and preventing negative resistance to surveillance technology. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900025861; http://www.chictr.org.cn/showprojen.aspx?proj=42497.

3.
Bioorg Med Chem Lett ; 40: 127906, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33689873

RESUMO

Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2'-OMe and 2'-H substitutions were also advantageous. We found that the 4'-NO2 substituent can be replaced with a 4'-CN or 4'-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.

4.
Lancet Haematol ; 8(4): e289-e298, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33770484

RESUMO

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.


Assuntos
Dexametasona/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Oseltamivir/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Administração Oral , Adulto , China/epidemiologia , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Hemorragia/epidemiologia , Humanos , Análise de Intenção de Tratamento/métodos , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Oseltamivir/efeitos adversos , Contagem de Plaquetas/estatística & dados numéricos , Contagem de Plaquetas/tendências , Púrpura Trombocitopênica Idiopática/imunologia , Segurança , Resultado do Tratamento
5.
Emerg Microbes Infect ; 10(1): 629-637, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33691606

RESUMO

COVID-19 vaccines emerging from different platforms differ in efficacy, duration of protection, and side effects. To maximize the benefits of vaccination, we explored the utility of employing a heterologous prime-boost strategy in which different combinations of the four types of leading COVID-19 vaccine candidates that are undergoing clinical trials in China were tested in a mouse model. Our results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies. Moreover, a heterologous prime-boost regimen with an adenovirus vector vaccine also improved Th1-biased T cell responses. Our results provide new ideas for the development and application of COVID-19 vaccines to control the SARS-CoV-2 pandemic.


Assuntos
Vacinas contra Adenovirus/imunologia , Anticorpos Antivirais/sangue , Imunização Secundária/métodos , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/imunologia , Vacinas contra Adenovirus/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , /efeitos adversos , Interferon gama/sangue , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação/efeitos adversos , Vacinas de Subunidades/administração & dosagem , Vacinas Sintéticas/administração & dosagem
6.
Int Immunopharmacol ; 95: 107502, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33690000

RESUMO

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease with a low platelet count. CD44 is a pivotal component involved in phagocytosis and inflammation, and monoclonal antibodies (mAbs) against CD44 have been shown to be beneficial in several autoimmune diseases. In the present study, we investigated the correlation between CD44 levels and disease severity in patients with ITP and explored the immunomodulatory mechanisms of the antihuman CD44 mAb BJ18 on platelet phagocytosis mediated by monocytes/macrophages. METHODS: Plasma was collected from 45 participants to measure the circulating concentration of CD44 using ELISA. Peripheral blood mononuclear cells from patients and controls were isolated and induced to differentiate into monocytes/macrophages utilizing cytokines and drugs. CD44 expression on circulating cells and the effects of BJ18 on platelet phagocytosis, Fcɣ receptor (FcɣR) expression and M1/M2 polarization of macrophages were evaluated using flow cytometry and qPCR. RESULTS: CD44 levels of both the soluble form found in plasma and the form expressed on the surface of circulating monocytes/macrophages were significantly elevated in ITP patients. Linear correlations were verified between the CD44 levels and major clinical characteristics. In an in vitro study, BJ18 successfully inhibited platelet phagocytosis by monocytes/macrophages obtained from ITP patients. Further studies indicated that BJ18 corrected abnormal FcγR expression on monocytes/macrophages. Moreover, the polarization of proinflammatory M1 macrophages could also be regulated by BJ18. CONCLUSIONS: Our data indicated that the CD44 level has potential predictive value for disease severity and that the antihuman CD44 mAb BJ18 may be a promising therapy for ITP patients.

7.
Microb Ecol ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743015

RESUMO

Soil microorganisms play an important role in the circulation of materials and nutrients between plants and soil ecosystems, but the drivers of microbial community composition and diversity remain uncertain in different vegetation restoration patterns. We studied soil physicochemical properties (i.e., soil moisture, bulk density, pH, soil nutrients, available nutrients), plant characteristics (i.e., Shannon index [HPlant] and Richness index [SPlant], litter biomass [LB], and fine root biomass [FRB]), and microbial variables (biomass, enzyme activity, diversity, and composition of bacterial and fungal communities) in different plant succession patterns (Robinia pseudoacacia [MF], Caragana korshinskii [SF], and grassland [GL]) on the Loess Plateau. The herb communities, soil microbial biomass, and enzyme activities were strongly affected by vegetation restoration, and soil bacterial and fungal communities were significantly different from each other at the sites. Correlation analysis showed that LB and FRB were significantly positively correlated with the Chao index of soil bacteria, soil microbial biomass, enzyme activities, Proteobacteria, Zygomycota, and Cercozoa, while negatively correlated with Actinobacteria and Basidiomycota. In addition, soil water content (SW), pH, and nutrients have important effects on the bacterial and fungal diversities, as well as Acidobacteria, Proteobacteria, Actinobacteria, Nitrospirae, Zygomycota, and microbial biomass. Furthermore, plant characteristics and soil properties modulated the composition and diversity of soil microorganisms, respectively. Overall, the relative contribution of vegetation and soil to the diversity and composition of soil bacterial and fungal communities illustrated that plant characteristics and soil properties may synergistically modulate soil microbial communities, and the composition and diversity of soil bacterial and fungal communities mainly depend on plant biomass and soil nutrients.

8.
J Virol ; 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658348

RESUMO

Glycoprotein B (gB) is an essential fusion protein for the Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and in the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and ten patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified twelve novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB214-223 and gB840-849, restricted by HLA-B*58:01 and B*38:02, respectively, elicited specific CD8+ T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8+ T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation in vivo stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development.ImportanceT cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Herein, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8+ T cells inhibit B cell transformation ex vivo and that gB-specific CD8+ T cell responses in vivo may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and to the development of a gB subunit vaccine.

9.
Nano Lett ; 21(6): 2476-2486, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33683126

RESUMO

Epstein-Barr virus (EBV) infection is a global health concern infecting over 90% of the population. However, there is no currently available vaccine. EBV primarily infects B cells, where the major glycoprotein 350 (gp350) is the main target of neutralizing antibodies. Given the advancement of nanoparticle vaccines, we describe rationally designed vaccine modalities presenting 60 copies of gp350 on self-assembled nanoparticles in a repetitive array. In a mouse model, gp350s on lumazine synthase (LS) and I3-01 adjuvanted with MF59 or aluminum hydroxide (Alhydrogel) elicited over 65- to 133-fold higher neutralizing antibody titers than the corresponding gp350 monomer to EBV. Furthermore, immunization with gp350D123-LS and gp350D123-I3-01 vaccine induced a Th2-biased response. For the nonhuman primate model, gp350D123-LS in MF59 elicited higher titers of total IgG and neutralizing antibodies than the monomeric gp350D123. Overall, these results support gp350D123-based nanoparticle vaccine design as a promising vaccine candidate for potent protection against EBV infection.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33610792

RESUMO

The zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.

11.
Nat Biotechnol ; 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623157

RESUMO

Computational approaches for drug discovery, such as quantitative structure-activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies.

12.
Lancet Infect Dis ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33548194

RESUMO

BACKGROUND: A vaccine against COVID-19 is urgently needed for older adults, in whom morbidity and mortality due to the disease are increased. We aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in adults aged 60 years and older. METHODS: We did a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial of CoronaVac in healthy adults aged 60 years and older in Renqiu (Hebei, China). Vaccine or placebo was given by intramuscular injection in two doses (days 0 and 28). Phase 1 comprised a dose-escalation study, in which participants were allocated to two blocks: block 1 (3 µg inactivated virus in 0·5 mL of aluminium hydroxide solution per injection) and block 2 (6 µg per injection). Within each block, participants were randomly assigned (2:1) using block randomisation to receive CoronaVac or placebo (aluminium hydroxide solution only). In phase 2, participants were randomly assigned (2:2:2:1) using block randomisation to receive either CoronaVac at 1·5 µg, 3 µg, or 6 µg per dose, or placebo. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection (which was assessed in all participants who had received the two doses of vaccine according to their random assignment, had antibody results available, and did not violate the trial protocol). Seroconversion was defined as a change from seronegative at baseline to seropositive for neutralising antibodies to live SARS-CoV-2 (positive cutoff titre 1/8), or a four-fold titre increase if the participant was seropositive at baseline. This study is ongoing and is registered with ClinicalTrials.gov (NCT04383574). FINDINGS: Between May 22 and June 1, 2020, 72 participants (24 in each intervention group and 24 in the placebo group; mean age 65·8 years [SD 4·8]) were enrolled in phase 1, and between June 12 and June 15, 2020, 350 participants were enrolled in phase 2 (100 in each intervention group and 50 in the placebo group; mean age 66·6 years [SD 4·7] in 349 participants). In the safety populations from both phases, any adverse reaction within 28 days after injection occurred in 20 (20%) of 100 participants in the 1·5 µg group, 25 (20%) of 125 in the 3 µg group, 27 (22%) of 123 in the 6 µg group, and 15 (21%) of 73 in the placebo group. All adverse reactions were mild or moderate in severity and injection site pain (39 [9%] of 421 participants) was the most frequently reported event. As of Aug 28, 2020, eight serious adverse events, considered unrelated to vaccination, have been reported by seven (2%) participants. In phase 1, seroconversion after the second dose was observed in 24 of 24 participants (100·0% [95% CI 85·8-100·0]) in the 3 µg group and 22 of 23 (95·7% [78·1-99·9]) in the 6 µg group. In phase 2, seroconversion was seen in 88 of 97 participants in the 1·5 µg group (90·7% [83·1-95·7]), 96 of 98 in the 3 µg group (98·0% [92·8-99·8]), and 97 of 98 (99·0% [94·5-100·0]) in the 6 µg group. There were no detectable antibody responses in the placebo groups. INTERPRETATION: CoronaVac is safe and well tolerated in older adults. Neutralising antibody titres induced by the 3 µg dose were similar to those of the 6 µg dose, and higher than those of the 1·5 µg dose, supporting the use of the 3 µg dose CoronaVac in phase 3 trials to assess protection against COVID-19. FUNDING: Chinese National Key Research and Development Program and Beijing Science and Technology Program.

13.
Chemosphere ; 274: 129779, 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33540317

RESUMO

The degradation potential of microplastics remains a critical issue for researching marine litter, and it is one of the most important factors that can be used for calculating the persistence time of microplastics in certain conditions. However, there are lack of standard or approved methods for estimating the ageing stage of environmental microplastics. In this study, the potential of spectral-image fusion strategy was investigated to analyze the degradation degree of polyethylene microplastics in natural exposure of coastline. The proposed spectral-image fusion linear model showed a significant ability to classify the degradation degree of environmental microplastics samples with the best accuracy of 97.1% as compared to two single-sensing information-based linear models (with one spectral wavelength of the carbonyl index at 1720 cm-1 or three-channel components from LAB color-space). This is the first attempt to qualitatively measure the degradation degree of the naturally exposed microplastics based on spectral-image fusion model. The proposed fusion model based strategy is an effective tool for predicting the degradation degree of the field exposed microplastics.

14.
Hum Vaccin Immunother ; : 1-8, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33566720

RESUMO

Meningococcal meningitis caused by Neisseria meningitidis is a reportable infectious disease in China, due to the high incidence of meningitis in the era before the availability of vaccines. The disease incidence was markedly reduced after meningococcal vaccination was introduced in the 1980s. Currently, there are polysaccharide, conjugate, and combined vaccine formulations against meningococcal meningitis in the Chinese market, almost all of which are produced by domestic manufacturers. It is necessary to further enhance national meningococcal surveillance to improve the level of prevention and control of meningococcus. However, the immune efficacy and persistence of immunity of vaccines should be monitored. More importantly, additional investments should be made to develop serogroup B meningococcal vaccines.

15.
Clin Chem Lab Med ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33554549

RESUMO

Objectives: Hemoglobin A1c (HbA1c) and glycated albumin (GA) are glycemic control status indicators in patients with diabetes mellitus. Hemoglobin H (HbH) disease is a moderately severe form of α-thalassemia. Here we examine the usefulness of HbA1c and GA in monitoring glycemic control in patients with HbH disease. Methods: HbA1c, GA, and an oral glucose tolerance test were performed in 85 patients with HbH disease and 130 healthy adults. HbA1c was measured using five methods, including two systems based on cation-exchange high-performance liquid chromatography (Variant II Turbo 2.0 and Bio-Rad D100), a capillary zone electrophoresis method (Capillarys 3 TERA), a boronate affinity HPLC method (Premier Hb9210), and an immunoassay (Cobas c501). Results: Significant lower levels of HbA1c were observed in patients with HbH disease than in healthy adults. In contrast, GA showed no statistically significant differences between participants with and without HbH disease. A considerable number of diabetic patients with HbH disease would be missed if using HbA1c as a diagnostic criterion for diabetes mellitus. Conclusions: GA but not HbA1c is suitable for monitoring glycemic control in patients with HbH disease that can modify the discriminative ability of HbA1c for diagnosing diabetes.

16.
ACS Nano ; 15(2): 2738-2752, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33464829

RESUMO

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53-50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 in vitro, further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.


Assuntos
/metabolismo , /prevenção & controle , Nanopartículas/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , /farmacologia , Chlorocebus aethiops , Feminino , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Glicoproteína da Espícula de Coronavírus/química , Células Vero
17.
BMJ Open ; 11(1): e040532, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414143

RESUMO

OBJECTIVES: To determine the prevalence of comorbidities in patients with type 2 diabetes mellitus (T2DM) and identify the factors independently associated with comorbidities in a tertiary care department in Ningbo, China. DESIGN: A computerised medical records database was used to conduct a cross-sectional study. SETTING: The study was conducted in a tertiary care department in Ningbo, China. PARTICIPANTS: The study was conducted on adult patients with T2DM, and it included 8 years of data, from 1 January 2012 to 31 December 2019. THE PRIMARY OUTCOME MEASURE: Comorbidity was defined as the coexistence of at least one other chronic condition, that is, either a physical non-communicable disease (duration ≥3 months), a mental health condition (duration ≥3 months) or an infectious disease (duration ≥3 months). RESULTS: In total, 4777 patients with T2DM satisfied the eligibility criteria. Over 8 years, the prevalence of comorbidities was 93.7%. The odds of comorbidities increased with the age of patients (18 to 39 years: 1; 40 to 59 years: OR 2.80, 95% CI 1.98 to 3.96; 60 to 69 years: OR 4.43, 95% CI 3.04 to 6.44; and ≥70 years: OR 10.97, 95% CI 7.17 to 16.77). The odds were lower in female patients (OR 0.66, 95% CI 0.51 to 0.84), patients residing in rural areas (OR 0.75, 95% CI 0.59 to 0.95) and patients without health insurance (OR 0.62, 95% CI 0.46 to 0.83). The odds were higher in single/divorced/widowed patients compared with those in married patients (OR 1.95, 95% CI 1.21 to 3.12). CONCLUSIONS: A large percentage of patients with T2DM in the tertiary care department in Ningbo, China, had comorbidities, and the factors associated with comorbidities were identified. The findings could be used in developing, evaluating and implementing interventions aimed at improving outcomes in patients with T2DM with comorbidities.

18.
Pharmacotherapy ; 41(3): 277-290, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33316842

RESUMO

OBJECTIVES: The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O-desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug-drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co-administered with the CYP2D6 inhibitors duloxetine and paroxetine. METHODS: Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat ) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra-rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6-mediated DDIs when tramadol was co-administered with paroxetine or duloxetine. RESULTS: The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration-time curve (AUCinf-tDlast ) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co-administered with paroxetine or duloxetine, the magnitude of the inhibitor-substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. CONCLUSION: The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future.

19.
Cell Discov ; 6(1): 80, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33298900

RESUMO

The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-Cov and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, and facilitates the attachment of Spike-bearing viral particles to the cell surface to promote viral entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry and reveals drugs capable of targeting this important step in the viral life cycle.

20.
J Intensive Care ; 8(1): 88, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33292649

RESUMO

BACKGROUND: The clinical significance of cardiac troponin measurement in patients hospitalised for coronavirus disease 2019 (covid-19) is uncertain. We investigated the prevalence of elevated troponins in these patients and its prognostic value for predicting mortality. METHODS: Studies were identified by searching electronic databases and preprint servers. We included studies of hospitalised covid-19 patients that reported the frequency of troponin elevations above the upper reference limit and/or the association between troponins and mortality. Meta-analyses were performed using random-effects models. RESULTS: Fifty-one studies were included. Elevated troponins were found in 20.8% (95% confidence interval [CI] 16.8-25.0 %) of patients who received troponin test on hospital admission. Elevated troponins on admission were associated with a higher risk of subsequent death (risk ratio 2.68, 95% CI 2.08-3.46) after adjusting for confounders in multivariable analysis. The pooled sensitivity of elevated admission troponins for predicting death was 0.60 (95% CI 0.54-0.65), and the specificity was 0.83 (0.77-0.88). The post-test probability of death was about 42% for patients with elevated admission troponins and was about 9% for those with non-elevated troponins on admission. There was significant heterogeneity in the analyses, and many included studies were at risk of bias due to the lack of systematic troponin measurement and inadequate follow-up. CONCLUSION: Elevated troponins were relatively common in patients hospitalised for covid-19. Troponin measurement on admission might help in risk stratification, especially in identifying patients at high risk of death when troponin levels are elevated. High-quality prospective studies are needed to validate these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020176747.

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