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BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) and cerebral microbleed (CMB) have distinct effects on intracerebral haemorrhage (ICH). We aim to investigate the combined effect of cSS and CMB on outcomes after ICH. METHODS: Based on a single-centre stroke registry database, patients with spontaneous ICH who had CT scan within 48 hours after ictus and MRI subsequently were identified. Eligible patients were divided into four groups (cSS-CMB-, cSS-CMB+, cSS+CMB-, cSS+CMB+) according to cSS and CMB on susceptibility-weighted image of MRI. Primary outcomes were haematoma volume on admission and unfavourable outcome defined as modified Rankin Scale scores ≥3 at 3 months. Secondary outcomes were all-cause death, recurrence of stroke and ICH during follow-up (median follow-up 2.0 years, IQR 1.0-3.0 years). RESULTS: A total of 673 patients were identified from 1044 patients with spontaneous ICH. 131 (19.5%) had cSS and 468 (69.5%) had CMB. Patients with cSS+CMB+ had the highest rate of poor outcome at 3 months, as well as all-cause death, recurrent stroke and ICH during follow-up. In cSS- patients, CMB was associated with smaller haematoma (ß -0.13; 95% CI -0.22 to -0.03; p=0.009), but it still increased risks of recurrent ICH (OR 4.6; 95% CI 1.3 to 15.6; p=0.015) and stroke (OR 2.0; 95% CI 1.0 to 4.0; p=0.049). These effects of CMB became unremarkable in the context of cSS+. CONCLUSIONS: Patients with different combinations of cSS and CMB have distinct patterns of short-term and long-term outcomes. Although CMB is related to restrained haematoma, it does not improve long-term outcomes. TRIAL REGISTRATION NUMBER: NCT04803292.
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Background: Previous studies have shown that cortical superficial siderosis (cSS) can increase hematoma volume and predict poor outcomes following primary intracerebral hemorrhage (ICH). Objective: We aimed to determine whether a large hematoma volume was the essential factor contributing to worse outcomes of cSS. Methods: Patients with spontaneous ICH underwent a CT scan within 48 h after ictus. Evaluation of cSS was performed using magnetic resonance imaging (MRI) within 7 days. The 90-day outcome was assessed using the modified Rankin Scale (mRS). In addition, we investigated the correlation between cSS, hematoma volume, and 90-day outcomes using multivariate regression and mediation analyses. Results: Among the 673 patients with ICH [mean (SD) age, 61 (13) years; 237 female subjects (35.2%); median (IQR) hematoma volume, 9.0 (3.0-17.6) ml], 131 (19.5%) had cSS. There was an association between cSS and larger hematoma volume (ß = 4.449, 95% CI 1.890-7.009, p < 0.001) independent of hematoma location and was also related to worse 90-day mRS (ß = 0.333, 95% CI 0.008-0.659, p = 0.045) in multivariable regression. In addition, mediation analyses revealed that hematoma volume was an essential factor mediating the effect of cSS on unfavorable 90-day outcomes (proportion mediated:66.04%, p = 0.01). Conclusion: Large hematoma volume was the major charge of directing cSS to worse outcomes in patients with mild to moderate ICH, and cSS was related to a larger hematoma in both lobar and non-lobar areas. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04803292, identifier: NCT04803292.
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OBJECTIVE: Hospital-acquired pneumonia (HAP) is one of the most common diseases in the intensive care unit, where the development of disease is closely related with the host immune response. Monocytes play an important role in both innate and adaptive immune system. We aimed to investigate the changes of circulating monocyte subsets in subjects with HAP to explore its value in monitoring HAP. METHODS: In total, 60 HAP patients and 18 healthy individuals were enrolled in this study. Human monocyte subsets are classified into 3 groups: nonclassical (NC), intermediate (ITM), and classical (CL). Also, programmed death ligand 1 (PD-L1) expression on circulating monocyte subsets was measured by flow cytometry. RESULTS: Data showed that the ratio of NC, ITM, and CL among monocytes was comparable between HAP patients and healthy controls (Pâ >â .05). There was a remarkable imbalance of NC and CL in newly emerged HAP compared to healthy controls (Pâ <â .05), subsequently reaching normalization in recurrent HAP (Pâ >â .05). Furthermore, although PD-L1 was seemly constitutively expressed by NC, ITM, and CL groups regardless of disease status, it was noted that PD-L1 was dominantly expressed in the CL group (Pâ <â .05). CONCLUSION: Given distinct PD-L1 expression, a shift of CL/NC in newly emerged HAP would constitute an inhibitory anti-pathogen immune response. Normalization of circulating monocyte subsets on recurrence of HAP might be the consequence of immune memory of bacterial infection.
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Monócitos , Pneumonia , Humanos , Antígeno B7-H1/metabolismo , HospitaisRESUMO
PURPOSE: Many investigations on prognostic factors in lung cancer have been conducted; however, little is known regarding the outcomes of lung cancer cases complicated by deep vein thrombosis (DVT). This study aimed to determine the risk factors and impact on outcomes of lung cancer patients concurrent with DVT. METHODS: Lung cancer patients who underwent lower-extremity venous ultrasound were enrolled in this study. The patients were divided into a DVT group and a non-DVT group. Demographic information, clinical characteristics, and survival were analyzed by t-test, Wilcoxon test, chi-squared test, and logistic regression analysis. RESULTS: Of the 160 enrolled lung cancer patients, DVT was detected in 30 patients. Among the DVT group, adenocarcinoma was the most common histological type (27/30, 90.00%). Lung cancer complicated with DVT was associated with advanced stage, more severe myocardial injury, and a hypercoagulable state (P < .05). Differences in driver genes between the two groups were not significant. Radiologically, lung cancer patients with DVT were more likely to present with pericardial effusion and pleural effusion than patients without DVT (P < .05). Following multivariable logistic regression analysis, advanced stage (OR 5.368, [95%CI 1.871-18.165], P = .021), NT-proBNP >300 pg/ml (OR 5.575, [95%CI 1.733-3.722], P = .018), D-dimer >5 mg/L (OR 8.449, [95%CI 4.323-18.536], P = .004), CRP >12 mg/L (OR 6.687, [95%CI 1.967-13.617], P = .010), and serum CEA >25 ng/ml (OR 4.755, [95%CI 1.358-3.123], P = .029) were independent risk factors for adenocarcinoma complicated with DVT. Finally, survival analysis revealed that the occurrence of DVT resulted in a poorer prognosis despite anticoagulant therapy (P < .05). CONCLUSION: DVT is a potential complication in patients with lung adenocarcinoma and could represent a prognostic marker for unfavorable outcome. It is essential to screen for DVT in high-risk adenocarcinoma patients.
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Adenocarcinoma , Neoplasias Pulmonares , Trombose Venosa , Humanos , Trombose Venosa/complicações , Trombose Venosa/epidemiologia , Fatores de Risco , Neoplasias Pulmonares/complicações , Anticoagulantes , Adenocarcinoma/complicações , Estudos RetrospectivosRESUMO
Purpose: Recently, the SARS-CoV-2 Omicron variant was identified as responsible for a novel wave of COVID-19 worldwide. We perform a retrospective study to identify potential risk factors contributing to radiological progression in the COVID-19 patients due to the Omicron variant infection. These findings would provide guiding information for making clinical decisions that could improve the Omicron infection prognosis and reduce disease-related death. Methods: This is a retrospective cohort study from a single center in China. According to the radiological change within admissive one week, enrolled cases were divided into two groups: the progressive (1w-PD) and the stable or improved disease (1w-non-PD). Separate analyses were performed on patients stratified into subgroups using the Mann-Whitney U-test, the Fisher exact test, or the Chi-squared test and a multivariable logistic regression analysis. Results: Both the 1w-non-PD and 1w-PD cohorts displayed comparable asymptomatic infection, have similar underlying disease, impairment in respiratory function, coagulation dysfunction, tissue injury, SARS-CoV-2 viral load, and disease severity. However, the 1w-PD cohort was more inclined to cluster in populations presented with age between 41 and 65, higher CURB-65 scores, undetectable SARS-CoV-2 IgG, and lung affection. Based on the multiple logistic regression analysis, complicated bilateral and ground-glass opacities (GGOs) like pneumonia at admission were independent risk factors to radiological progression within admissive one week. Conclusion: This study provided preliminary data regarding disease progression in Omicron-infected patients that indicated the development of pneumonia in the context of Omicron infection was worthy of potential risk factors.
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Objective: To identify the predominant type of cerebral small vessel disease (SVD) and outcomes in patients with simultaneous multiple intracerebral hemorrhages (SMICH). Methods: Consecutive patients with intracerebral hemorrhage (ICH) from a single-center prospective cohort were retrospectively reviewed. Presumed etiology was classified according to the SMASH-U criteria. Demographics, clinical and laboratory variables, and neuroimaging data were compared between patients with primary SMICH and those with single ICH. Functional outcomes were assessed using the modified Rankin scale 90 days after ICH. Results: Of the 598 enrolled patients, 37 (6.2%) met the criteria for SMICH. Risk factors for SMICH included a high burden of deep cerebral microbleeds (CMBs) (odds ratio [OR] 1.06, 95% confidence interval [CI], 1.00-1.12; p = 0.040), white matter hyperintensity scores (OR 1.27, 95% CI 1.04-1.57; p = 0.021), history of ICH (OR 3.38, 95% CI 1.31-8.05; p = 0.008), and low serum magnesium levels (OR 0.01, 95% CI 0.00-0.25; p = 0.007). Based on the SMASH-U classification, 15(40.5%) SMICH were classified as hypertension, whereas 17 (45.9%) as undetermined-etiology. To further explore the potential microangiopathy underlying undetermined-SMICH, these patients with undetermined-etiology were compared to those with cerebral amyloid angiopathy-ICH, and were associated with a higher burden of deep CMBs but less severe centrum semiovale enlarged perivascular spaces. Likewise, compared with hypertension-ICH patients, those with undetermined SMICH were consistently associated with a higher deep CMB counts. Moreover, multivariate analysis revealed that SMICH was independently associated with poor outcomes (OR 2.23, 95%CI 1.03-4.76; p = 0.038). Conclusion: Our results suggest that most patients with primary SMICH harbor hypertensive-SVD as principal angiopathy. Patients with SMICH are at a high risk of poor outcomes. (ClinicalTrials.gov Identifier: NCT04803292).
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Hydrocephalus induced by intraventricular hemorrhage (IVH) is associated with unfavorable prognosis. The increased permeability of choroid plexus and breakdown of the blood-brain barrier (BBB) was reported as a prominent mechanism of IVH-induced hydrocephalus, and vascular endothelial-cadherin (VE-cadherin) was demonstrated to be relevant. Metformin was reported to protect endothelial junction and preserve permeability widely; however, its role in hydrocephalus remains unclear. In this study, the decreased expression of VE-cadherin in the choroid plexus, accompanied with ventricle dilation, was investigated in an IVH rat model induced by intraventricular injection of autologous blood. Metformin treatment ameliorated hydrocephalus and upregulated VE-cadherin expression in choroid plexus meanwhile. We then observed that the internalization of VE-cadherin caused by the activation of vascular endothelial growth factor (VEGF) signaling after IVH was related to the occurrence of hydrocephalus, whereas it can be reversed by metformin treatment. Restraining VEGF signaling by antagonizing VEGFR2 or inhibiting Src phosphorylation increased the expression of VE-cadherin and decreased the severity of hydrocephalus after IVH. Our study demonstrated that the internalization of VE-cadherin via the activation of VEGF signaling may contribute to IVH-induced hydrocephalus, and metformin may be a potential protector via suppressing this pathway.
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Hidrocefalia , Metformina , Animais , Antígenos CD , Caderinas/metabolismo , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Plexo Corióideo/metabolismo , Hidrocefalia/tratamento farmacológico , Hidrocefalia/etiologia , Metformina/farmacologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
In order to study the impact of the "carbon peak and neutrality" mode on future power generation and the environment in China, a Verhulst gray model was established to predict the development of the power generation industry from 2021 to 2060 under the non-"carbon peak and neutrality" mode. In addition, based on the "China 2030 Energy and Power Development Planning Research and 2060 Outlook Report," the development of the power generation industry from 2021 to 2060 under the "carbon peak and neutrality" mode was obtained, and the development scenarios of the future power generation industry in China under two models were compared and studied. The emission factors and emission reduction factors of CO2, SO2, NOx, PM, PM10, and PM2.5 were constructed through the conservation of elements and the generating performance standard, and then four environmental benefits A1-A4 were defined. The results showed that the installed capacity of thermal power will reach the carbon peak in 2026 under the "carbon peak and neutrality" mode. To achieve the carbon neutralization, the installed capacity of thermal power will be reduced by an average of 28 million kilowatts per year after 2026, and the installed capacity of renewable energy generated is required to increase by 154 million kilowatts per year after 2020. Compared with that in the non-"carbon peak and neutrality" mode, the installed capacity of thermal power generation will be greatly reduced, and the installed capacity of renewable energy power generation will be greatly increased under the "carbon peak and neutrality" mode, resulting in huge A1 and A2 environmental benefits. In the next four decades, the cumulative emission reductions in CO2, SO2, NOx, PM, PM10, and PM2.5 thermal power generation A1 are predicted to be 6.64×1010 tons, 1.54×107 tons, 1.55×107 tons, 3.18×106 tons, 1.71×106tons, and 2.23×105 tons, respectively. The cumulative emission reductions of renewable energy power generation A2 will be 5.77×1010 tons, 1.64×107 tons, 1.42×107 tons, 2.86×106 tons, 1.54×106 tons, and 2×105 t tons, respectively. Under the "carbon peak and neutrality" mode, compared with those from coal-fired power generation, the environmental benefits A3 and A4 produced by the relative cleanliness of renewable energy and nuclear power indicated that the cumulative emission reductions (A3+A4) in clean energy power generation of CO2, SO2, NOx, PM, PM10, and PM2.5 in the next four decades will be 3.014×1011 tons, 7.292×107 tons, 7.119×107 tons, 1.454×107 tons, 7.827×106tons, and 1.018×106 tons, respectively.
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Dióxido de Carbono , Centrais Elétricas , Carbono , Dióxido de Carbono/análise , China , Material ParticuladoRESUMO
Conventional immunoprobes have absorption capabilities across the visible to near infrared (NIR-I, 650-900 nm) region. Recently, second near infrared (NIR-II, 1000-1700 nm) window have gained much attention due to their deeper penetration depth and improved visualization. Here, we describe the design and synthesis of a fully human nanobody-based fluorescent immunoprobe (ICGM-n501) for NIR-II bioimaging with strengthened fluorescent emission by antigen for the first time. By site-directed conjugation of an FDA-approved dye analogue, indocyanine green decorated with maleimide (ICGM), into a tumor-specific n501, ICGM-n501 provides real-time monitoring of abdominal transportation pathway of antibody-based bioagents with high resolution (0.21 mm), presents better accuracy and lower dosage (0.21 µmol kg-1) in bioimaging of peritoneal metastatic tumors than bioluminescence agent D-luciferin. In this work, ICGM-n501 demonstrates its potential in clinical surgery guidance, provide an expanded category of available NIR-II fluorophores and a template for next-generation immunoassay bioagents.
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OBJECTIVES: We aimed to investigate the differences in clinical features between pulmonary embolism (PE) patients concomitant with lung cancer and without lung cancer (LC) and gain further understanding of the impact of lung cancer on pulmonary embolism. METHODS: This retrospective study sampled 114 patients diagnosed with pulmonary embolism from January 2017 to April 2021 in the First Affiliated Hospital of Soochow University. The patients were categorized into the LC group (n = 22) or non-LC group (n = 92). Myocardial injury, coagulation and blood cell parameters, along with imaging findings, were analyzed for the two groups. The primary outcome measure was the 90-day mortality. RESULTS: Of the 114 patients with pulmonary embolism in the present study, the 90 intermediate-risk patients were enrolled for further investigations. Compared to the non-LC group, patients in the LC group had milder myocardial injury, more severe coagulation function disorder, a higher incidence of central PE and a smaller change in diameter of the main pulmonary artery. We found that the occurrence of pericardial effusion created the risk of lung cancer in patients with pulmonary embolism, but there was no increase in the 90-day mortality for non-LC group versus LC group. CONCLUSION: Intermediate risk PE patients concomitant with lung cancer seem to be more likely to present specific clinical features, accordingly, clinicians must pay great attention to PE patients concomitant with lung cancer and implement effective treatments to simultaneously manage the two conditions.
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Neoplasias Pulmonares , Embolia Pulmonar , Humanos , Incidência , Estudos Retrospectivos , Fatores de RiscoRESUMO
Malignant pleural effusions (MPE) are a common terminal pathway for many types of cancer, especially non-small cell lung cancer (NSCLC). However, the phenotype and differentiation status of MPE-infiltrating CD8+ T cells have not yet been systematically addressed. In this study, the surface molecules and cytokine secretion of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. We found an increased frequency of CD8+ T cells in MPE compared to PB among lung cancer patients, of which the effector memory subset (Tem, CCR7- CD45RA-) and central memory subset (Tcm, CCR7+ CD45RA-) were upregulated. MPE-derived Tem and Tcm subsets expressed more PD1 or CD39, and there was a greater population of cells in these subsets that co-expressed them. In addition, Tem and Tcm cells from MPE had higher cytokine production than terminally differentiated effector memory cells (TemRA, CCR7- CD45RA+) and naïve cells (Tnaive, CCR7+CD45RA+). Our results demonstrate that the Tem and Tcm cells in MPE may have advantages in both tumor reactivity and immune functionality. Altogether, these findings help to characterize the phenotype of MPE-derived CD8+ T cells in terms of differentiation and tumor reactivity and reveal their potential as a target for immunotherapy.
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Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Derrame Pleural Maligno , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citocinas/metabolismo , Humanos , Memória Imunológica , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Neoplasias Pulmonares/metabolismo , Fenótipo , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologia , Receptores CCR7/genética , Receptores CCR7/metabolismo , Subpopulações de Linfócitos TRESUMO
OBJECTIVE: To systematically review the efficacy of short length of biliopancreatic limb (BPL) in laparoscopic one anastomosis gastric bypass (OAGB). METHODS: By thoroughly investigating in PubMed, Embase, and the Cochrane Library, each research containing the comparison between short BPL and 200-cm BPL was included, inception in July 2021. The research followed the guidance of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) recommendations. RESULT: A total of 1288 patients were included for meta-analysis. Results showed that in the short term, compared with 200-cm BPL, percentage excess weight loss (%EWL) did not show significant reduction (p = 0.91), neither did the incidence of vitamin D deficiency (p = 0.87) nor hypoalbuminemia (p = 0.06), while percentage total weight loss (%TWL) was significantly higher in the 200-cm BPL group (p = 0.0005). At 1, 2, and 8 years postoperatively, patients with short BPL still obtained significantly reduced body mass index (BMI). CONCLUSION: Short BPL shows significant effect of weight loss; however, it seems no significantly lower rates of adverse events in the short term are found. More research with randomized controlled design is encouraged to further address the incidence of adverse events in the long term.
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Derivação Gástrica , Obesidade Mórbida , Humanos , Derivação Gástrica/métodos , Obesidade Mórbida/cirurgia , Redução de PesoRESUMO
Highly coordinated signaling following TCR stimulation triggers activation and subsequent differentiation of T cells. CD38 is a major mammalian nicotinamide adenine dinucleotide (NAD)+ glycohydrolase expressed on T cells, and appears to be an important modulator of T cell response in tumor models. However, the functional involvement of CD38 in T cells remains largely unknown. Therefore, we characterize the presence and function of CD38 in lymphocytes from metastatic pleural effusions (MPE). Of note, a significant accumulation of CD38+CD8+ T cells was observed in MPE compared with matched peripheral blood mononuclear cells (PBMC). Moreover, PD-1 expression was significantly increased within the CD38+CD8+ T cell fraction compared to CD38- counterparts. We further showed decreased amounts of IFNγ and TNFα production together with reduced mitochondrial membrane potential in CD38+CD8+ T cells. Indeed, the impaired capacity of secreting IFNγ and TNFα by CD38+CD8+ T cells was likely due to damaged mitochondrial function. Taken together, we have identified a subset of CD38+CD8+ T cells in MPE, which possessed exhausted phenotype accompanied by altered mitochondrial metabolism.
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Neoplasias , Derrame Pleural , ADP-Ribosil Ciclase 1 , Animais , Linfócitos T CD8-Positivos , Imunidade , Leucócitos Mononucleares/metabolismo , Mamíferos/metabolismo , Neoplasias/patologia , Derrame Pleural/patologia , Fator de Necrose Tumoral alfaRESUMO
AIMS: Calcified aortic valve disease (CAVD) is a cardiovascular disease with increasing morbidity and mortality. The pathogenetic cellular mechanism is the phenotypic transition of aortic valve interstitial cells (VICs). Here, we explored the effect of berberine (BBR) on the phenotypic transition of VICs and elucidated the underlying molecular mechanisms, providing a theoretical basis in finding novel clinical treatments for CAVD. METHODS AND RESULTS: Calcific aortic valves and normal controls were collected for western blot and the results demonstrated that osteogenic and inflammatory markers were significantly up-regulated in calcific aortic valves. BBR inhibited inflammation and osteogenic differentiation of VICs under osteogenic conditions, as well as alkaline phosphatase activity and calcified nodule formation. Mechanistically, BBR could inhibit the activation of Smad1/5/8 and NF-κB pathways under OM conditions. LDN193189 and BAY11-7082, the inhibitor of Smad1/5/8 and NF-κB respectively, were added for further verification. Similarly, the osteogenic and fibrotic markers of VICs induced by osteogenic induction medium were decreased by LDN193189 and BAY11-7082. Western blot was used to examine upstream receptors of Smad1/5/8, the results showed that BBR inhibited the activation of Smad1/5/8 by downregulating ALK2 and ALK3. CONCLUSION: BBR decreased the inflammatory factors and suppressed the osteogenic differentiation of VICs, which might be associated with the inhibition of Smad1/5/8 and NF-κB signaling pathways.
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Valva Aórtica , Berberina , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica , Berberina/farmacologia , Biomarcadores/metabolismo , Calcinose , Células Cultivadas , NF-kappa B/metabolismo , OsteogêneseRESUMO
Phage display technology allows for rapid selection of antibodies from the large repertoire of human antibody fragments displayed on phages. However, antibody fragments should be converted to IgG for biological characterizations and affinity of antibodies obtained from phage display library is frequently not sufficient for efficient use in clinical settings. Here, we describe a new approach that combines phage and mammalian cell display, enabling simultaneous affinity screening of full-length IgG antibodies. Using this strategy, we successfully obtained a novel germline-like anti-TIM-3 monoclonal antibody named m101, which was revealed to be a potent anti-TIM-3 therapeutic monoclonal antibody via in vitro and in vivo experiments, indicating its effectiveness and power. Thus, this platform can help develop new monoclonal antibody therapeutics with high affinity and low immunogenicity.
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Anticorpos Monoclonais , Bacteriófagos , Animais , Técnicas de Visualização da Superfície Celular , Células Germinativas , Humanos , Mamíferos , Biblioteca de PeptídeosRESUMO
The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.
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Enzima de Conversão de Angiotensina 2/química , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , COVID-19 , SARS-CoV-2/química , Anticorpos de Cadeia Única/química , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Humanos , Camundongos , SARS-CoV-2/imunologia , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/uso terapêuticoRESUMO
Background: Abnormal glucose metabolism was shown to be associated with the occurrence of remote diffusion-weighted imaging lesions (R-DWILs) after primary intracerebral hemorrhage (ICH) onset. Insulin resistance is a metabolic disorder that was regarded as an indicator of chronic systemic inflammation. In this study, we aimed to determine the effect of insulin resistance on the occurrence of R-DWILs in ICH. Methods: Patients with primary ICH within 14 days after onset were prospectively enrolled from November 2017 to October 2019. R-DWILs was defined as remote focal hyperintensity from the hematoma in DWI, with corresponding hypointensity in apparent diffusion coefficient. The homeostasis model assessment of insulin resistance (HOMA-IR) was used for insulin resistance estimation and calculated as fasting insulin (µU/ml) × fasting glucose (mmol/L)/22.5. Patients in our cohort were divided into four groups according to HOMA-IR index quartiles. Logistic regression analysis and smoothing plots were used to evaluate the association of HOMA-IR with R-DWIL occurrence. Sensitivity analysis was performed in non-diabetic patients, non-obese patients, hypertensive ICH patients, and patients 60 years and older separately. The association between HOMA-IR and systemic inflammatory immune indices neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte ratio (MLR) was examined with multiple linear regression analysis. Results: Among the 345 patients, 54 (15.7%) had R-DWILs. Both the third and fourth quartiles of HOMA-IR index were robustly associated with an increased risk of R-DWIL occurrence (adjusted OR 3.58, 95% CI 1.33-9.65; adjusted OR 3.91, 95%CI 1.47-10.41) when compared with the first quartile. The association was consistent in non-diabetic, non-obese, hypertensive ICH patients, as well as in patients 60 years and older. Furthermore, both NLR and MLR were independently associated with HOMA-IR. Conclusions: Our study suggested that insulin resistance evaluated with HOMA-IR index was independently associated with the presence of R-DWILs in patients with acute and subacute primary ICH. It may provide new insights into the metabolism-related brain injury after ICH ictus.
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Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/metabolismo , Imagem de Difusão por Ressonância Magnética , Resistência à Insulina , Idoso , Biomarcadores , Glicemia , Hemorragia Cerebral/etiologia , Transtornos Cerebrovasculares/complicações , Imagem de Difusão por Ressonância Magnética/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Mediadores da Inflamação/metabolismo , Insulina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Bariatric surgery has been applied for weight loss and comorbidity control in China since 2000. Recent studies have shown positive results for bariatric surgery in patients with a body mass index (BMI) of less than 35 kg/m2. However, the effect of surgery on Chinese patients with type II diabetes mellitus (T2DM) has not yet been systematically investigated. METHODS: A comprehensive literature search was performed in the Cochrane Library, Embase, PubMed, and Web of Science from January 2014 to March 2020. All studies examined bariatric surgery outcomes on Chinese patients at 12-, 36-, and 60-month follow-up. The research followed the guidance of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) recommendations. RESULTS: Eleven studies containing 611 patients were included in this meta-analysis. Clinical indices at 12-, 36-, and 60-month follow-up were analyzed. Significant decreases were identified in body weight, BMI, waist circumference (WC), blood pressure (BP), fasting plasma glucose (FPG), glycosylated hemoglobin A1c (hemoglobin A1c, or HbA1c), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) postoperatively. An increasing trend in the T2DM remission rate was discovered. The remission group was observed to have significantly lower HbA1c and C-peptide level, a shorter duration of T2DM, and a higher BMI than the nonremission group at 12 months. CONCLUSIONS: Bariatric surgery successfully provided significant BMI control as well as a reduction and normalization of glucose- and lipid-related metabolism at 12, 36, and 60 months postoperatively in Chinese patients with T2DM with a preoperative BMI of less than 35 kg/m2. An increasing trend in the T2DM remission rate suggested promising future applications in this population.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Obesidade Mórbida , Glicemia , Índice de Massa Corporal , China/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/cirurgia , Hemoglobinas Glicadas , Humanos , Obesidade Mórbida/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Early haematoma expansion is determinative in predicting outcome of intracerebral haemorrhage (ICH) patients. The aims of this study are to develop a novel prediction model for haematoma expansion by applying deep learning model and validate its prediction accuracy. METHODS: Data of this study were obtained from a prospectively enrolled cohort of patients with primary supratentorial ICH from our centre. We developed a deep learning model to predict haematoma expansion and compared its performance with conventional non-contrast CT (NCCT) markers. To evaluate the predictability of this model, it was also compared with a logistic regression model based on haematoma volume or the BAT score. RESULTS: A total of 266 patients were finally included for analysis, and 74 (27.8%) of them experienced early haematoma expansion. The deep learning model exhibited highest C statistic as 0.80, compared with 0.64, 0.65, 0.51, 0.58 and 0.55 for hypodensities, black hole sign, blend sign, fluid level and irregular shape, respectively. While the C statistics for swirl sign (0.70; p=0.211) and heterogenous density (0.70; p=0.141) were not significantly higher than that of the deep learning model. Moreover, the predictive value for the deep learning model was significantly superior to that of the logistic model of haematoma volume (0.62; p=0.042) and the BAT score (0.65; p=0.042). CONCLUSIONS: Compared with the conventional NCCT markers and BAT predictive model, the deep learning algorithm showed superiority for predicting early haematoma expansion in ICH patients.
Assuntos
Aprendizado Profundo , Hemorragia Cerebral/diagnóstico por imagem , China , Hematoma/diagnóstico por imagem , Humanos , Tomografia Computadorizada por Raios XRESUMO
Burkholderia thailandensis is a clinically underestimated conditional pathogen in the genus Burkholderia, the pathogenicity of the infection caused by B. thailandensis remains poorly understood. According to previous studies, Type-VI secretion system (T6SS) is a protein secreting device widely existing in Gram-negative bacilli. Valine-glycine repeat protein G (VgrG) is not only an important component of T6SS, but also a virulence factor of many Gram-negative bacilli. In one of our previous studies, a unique T6SS vgrG gene (vgrG2 gene) was present in a virulent B. thailandensis strain BPM (BPM), but not in the relatively avirulent B. thailandensis strain E264 (E264). Meanwhile, transcriptome analysis of BPM and E264 showed that the vgrG2 gene was strongly expressed in BPM, but not in E264. Therefore, we identified the function of the vgrG2 gene by constructing the mutant and complemented strains in this study. In vitro, the vgrG2 gene was observed to be involved in the interactions with host cells. The animal model experiment showed that the deletion of vgrG2 gene significantly led to the decrease in the lethality of BPM and impaired its ability to trigger host immune response. In conclusion, our study provides a new perspective for studying the pathogenicity of B. thailandensis and lays the foundation for discovering the potential T6SS effectors.