Cross-reactive immune responses to monkeypox virus induced by MVA vaccination in mice.

Mpox (monkeypox) infection cases increased recently in non-Mpox outbreak areas, potentially causing an international threat. The desire to defend against a potential outbreak has led to renewed efforts to develop Mpox vaccines. In this report, mice were immunized with various doses of modified vaccinia virus Ankara (MVA) to evaluate the cross-reactive immune response of MVA immunization against protective antigens of the current monkeypox virus. We demonstrated that MVA induced specific antibodies against protective antigens (A29, A35, B6, M1, H3, and I1), mediating the neutralization abilities against the MVA and the monkeypox virus (MPXV). Moreover, recombinant protective antigens of the MPXV elicited cross-binding and cross-neutralizing activities for MVA. Hence, the MVA induced cross-reactive immune responses, which may guide future efforts to develop vaccines against the recent MPXV. Notably, compared to the other protective antigens, the predominant A29 and M1 antigens mediated higher cross-neutralizing immune responses against the MVA, which could serve as antigen targets for novel orthologous orthopoxvirus vaccine.

Increased difficulty and complications of delayed laparoscopic cholecystectomy following percutaneous transhepatic gallbladder drainage in acute cholecystitis: a retrospective study.

BACKGROUND: Percutaneous transhepatic gallbladder drainage (PTGBD) is a relatively less invasive alternative treatment to cholecystostomy. However, the influence of the difficulty of delayed laparoscopic cholecystectomy (DLC) after PTGBD on clinical outcomes remains unknown. This study aimed to evaluate the clinical effects of DLC following PTGBD. METHODS: The clinical data of 113 patients diagnosed with moderate (grade II) acute cholecystitis according to the 2018 Tokyo Guidelines in the acute phase and who underwent DLC in our hospital from January 2018 to February 2022 were retrospectively collected and separated into two groups according to whether they received PTGBD treatment in the acute stage. The PTGBD group comprised 27 cases, and the no-PTGBD group included 86 cases. The TG18 difficulty score was used to evaluate every surgical procedure in the cases by reviewing the surgical videos. The clinical baseline characteristics and post-treatment outcomes were also evaluated. RESULTS: Both groups showed significant differences in length of postoperative stay, blood loss, operation time, and difficulty score. The PTGBD group showed a significantly longer postoperative stay and operation time, more blood loss, and a much higher difficulty score than the no-PTGBD group. Conversion rates did not differ. The morbidity rate in the PTGBD group was statistically higher. CONCLUSIONS: PTGBD is an efficient way to relieve the symptoms of acute cholecystitis. However, it may increase the difficulty and complications of DLC.

Nomogram to predict dermatomyositis prognosis: a population-based study of 457 cases.

OBJECTIVES: Dermatomyositis (DM) is a systemic autoimmune disease, which typically affects the striated muscle with a variable involvement of the skin and other organs. Clinically amyopathic DM (CADM) is a combination of hypomyopathic DM (HDM) and amyopathic DM (ADM), with a characteristic of skin-predominant lesions. To date, large-scale studies on the prognostic factors of DM/CADM have been limited. The aim of this study is to evaluate the prognostic values of clinical manifestations in DM/CADM and to develop a prognostic nomogram for DM/CADM. METHODS: A development cohort (n=239), an internal validation cohort (n=128) and an external validation cohort (n=90) were included in this study. Overall survival (OS) was estimated by the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses were performed. Cox proportional hazards model and forward stepwise selection with the Akaike information criterion were used for multivariate analysis of prognostic factors. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the proposed nomogram. RESULTS: Rapidly progressive interstitial lung disease (RP-ILD) and erythrocyte sedimentation rate (ESR) were identified as risk independent prognostic factors, with antinuclear antibodies (ANA) was identified as protective independent prognostic factors, for DM/CADM. A prognostic nomogram was formulated based on these three predictors. The C-index of the proposed nomogram in the development cohort was 0.874 (95%CI, 0.819-0.929). The predictive accuracy of the proposed nomogram was further validated in the internal validation cohort, with a C-index of 0.799 (95%CI, 0.681-0.917). Furthermore, the C-index was 0.864 (95%CI, 0.699-1.000) in the external validation cohort, indicating a good calibration ability. This proposed nomogram showed a promising predictive accuracy on the prognosis of DM/CADM. CONCLUSIONS: RP-ILD, ANA and ESR are prognostic factors for DM/CADM. The proposed nomogram based on these three factors could accurately predict the 10-year OS probabilities of patients with DM/CADM.

Effects of BBIBP-CorV vaccine on gut microbiota and short-chain fatty acids in mice exposed to bis (2-ethylhexyl) phthalate and dioctyl terephthalate.

As the COVID-19 pandemic has progressed, increasing evidences suggest that the gut microbiota may play a crucial role in the effectiveness of SARS-CoV-2 vaccine. Thus, this study was aimed at investigating the influence of SARS-CoV-2 vaccine on the gut microbiota and short-chain fatty acids (SCFAs) of organisms exposed to environmental contaminants, i.e., plasticizers: phthalate esters. We found that in mice, exposure to dioctyl terephthalate (DOTP) and bis -2-ethylhexyl phthalate (DEHP) decreased the blood glucose level and white fat weight, induced inflammatory responses, caused damage to liver and intestinal tissues, and disrupted the gut microbiota composition and SCFAs metabolism. Specifically, the Bacteroidetes phylum was positively correlated with BBIBP-CorV vaccine, while acetic acid was negatively associated with the vaccine. Interestingly, the BBIBP-CorV vaccine somewhat alleviated tissue inflammation and reduced the contents of acetic acid and propionic acid in mice exposed to DEHP and DOTP. These findings were confirmed by a fecal microbiota transplantation assay. Overall, this study revealed that exposure to DEHP and DOTP adversely affects the gut microbiota and SCFAs, while the BBIBP-CorV vaccine can protect mice against these effects. This work highlighted the relationship between BBIBP-CorV vaccination, gut microbiome composition, and responses to plasticizers, which may facilitate the development and risk assessment of SARS-CoV-2 vaccines and environmental contaminants on microbiota health.

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine.

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants. In naïve animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccine's targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection against Delta and Omicron BA.1variants. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine-primed populations.

A Clinical Risk Model to Predict Rapidly Progressive Interstitial Lung Disease Incidence in Dermatomyositis.

Background: Rapidly progressive interstitial lung disease (RP-ILD) is a fatal complication of dermatomyositis (DM) and clinically amyopathic DM (CADM). The objective of this study was to evaluate risk markers associated with RP-ILD incidence in patients with DM/CADM and to develop a RP-ILD risk prediction (RRP) model. Methods: The clinical records of 229 patients with DM/CADM from Peking University People's Hospital, and 97 patients from four other independent clinical centers were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with later RP-ILD incidence to build a risk score model. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the RRP model. Results: A multiparametric RRP model was established based on weighted clinical features, including fever (yes, 5; no, 0), periungual erythema (yes, 6; no, 0), elevated CRP (yes, 5; no, 0), anti-MDA5 antibody (positive, 8; negative, 0), and anti-Ro-52 antibody (positive, 6; negative, 0). Patients were divided into three risk groups according to the RRP total score: low, 0-9; medium, 10-19; high, 20-30. The C-index and calibration curve of the RRP model showed a promising predictive accuracy on the incidence of RP-ILD. Conclusion: The RRP model might promisingly predict the incidence of RP-ILD in DM/CADM patients to guide early individual treatment and further improve the prognosis of DM/CADM patients.

[Measurement of brain extracellular space and its physiological and pathophysiological significance].

The extracellular space (ECS) of brain is defined as an irregular channel which is located in the interstitial tissue outside the plasma membranes of neurons, and occupied by interstitial fluid (ISF). Diffusion in ECS is described by a modified diffusion equation from which several parameters can be calculated, such as the diffusion coefficient (D), the tortuosity (Lambda), the volume fraction (alpha) and the clearance of molecules. Radiolabeled tracers were used for early diffusion measurements. Presently, the real-time iontophoresis (RTI) method is employed for small ions, whereas the integrative optical imaging (IOI) and the magnetic resonance diffusion weighted imaging (DWI) are developed for macromolecules tracers. Extensive experimental studies with such methods show that in normal brain tissue, the volume fraction of ECS typically is about 20% and the tortuosity is 1.6, although there are regional variations. These parameters change with the brain development and in various pathophysiological states. Knowledge of ECS diffusion properties help us to understand extrasynaptic volume transmission to the development of paradigms for drug delivery in brain.

[Imaging and quantitative measurement of brain extracellular space using MRI Gd-DTPA tracer method].

OBJECTIVE: To observe the diffusion of Gd-DTPA in brain extracellular space (ECS) by magnetic resonance imaging(MRI) and investigate the feasibility of ECS measurement by using MRI tracer method in vivo. METHODS: 2 microL Gd-DTPA was introduced into ECS by caudate nucleus according to stereotaxic atlas in 8 Sprague Dawley(SD) rats (male, 280-320 g). The MRI scans were performed at 1 h, 3 h, 6 h, 9 h and 12 h respectively after administration. MRI appearances of Gd-DTPA diffusion and distribution was observed and compared. The MRI signal enhancement was measured at each time point. The neuroethology assessment was performed after MRI scanning at 12 h. RESULTS: The injection was accurate at the center of the caudate nucleus in 6 rats, while, at the capsula externa in other 2 rats. Gd-DTPA diffused isotropically after it was introduced into caudate nucleus, which spread into lateral cortex at 3 h. The MRI signal enhancement distributed mainly in the middle cerebral artery territory. A significant difference was found between the signal enhancement ratio at 1 h and that at 3 h in the original point of caudate nucleus (t=95.63, P<0.01), and the signal enhancement attenuated following the exponential power function y=1.7886x(-0.1776) (R2=0.94). In 2 rats with the injection point at capsula externa, Gd-DTPA diffused anisotropically along the fiber track of white matter during 1 h to 3 h, and spread into the lateral cortex at 6 h. CONCLUSION: The diffusion and clearance of Gd-DTPA in brain ECS could be monitored and measured quantitatively in vivo by MRI tracer method.

Quantification of Gd-DTPA concentration in neuroimaging using T13D MP-RAGE sequence at 3.0 T.

PURPOSE: To propose a simple and accurate quantitative method based on the linear relationship between magnetic resonance (MR) signal enhancement (ΔSI=SI(postcontrast)-SI(precontrast)) and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) concentration (C) by using T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (T13D MP-RAGE) sequence for the in vivo measurement of Gd-DTPA concentration in real-time neuroimaging at 3.0 T. METHODS: Phantom experiment was carried out to study the linear fitting of signal intensity change vs. Gd-DTPA concentration (ΔSI-C) curve. A goodness-of-fit test was performed to compare the accuracy between the proposed method and the conventional method based on longitudinal relaxation rate (R1=1/T1) measurement. The influences on the goodness of fit (R²) and the signal-to-noise ratio (SNR) by sequence parameters were explored. Six human subjects with different brain tumors, who underwent a Gd-DTPA-enhanced MRI, were enrolled for in vivo application of the novel method. RESULTS: A good linear relationship between ΔSI and Gd-DTPA concentration existed over the concentration range of 0-1 mM (R²=0.985). The linearity of the ΔSI-C curve was as good as that of the 1/T1-C curve (R²=0.988). Concentrations calculated by both methods had a strong correlation (R²=0.920). An improved linearity of the ΔSI-C curve and an increased SNR can be achieved using sequences with a shorter inversion time (TI) and a higher flip angle. The concentration range of Gd-DTPA in human brain tumors was within the quantitative scope of 0-1 mM. CONCLUSIONS: The proposed quantitative method based on ΔSI measurement is accurate and applicable for real-time neuroimaging at 3.0 T.

Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury.

Limited penetration of neuroprotective drug citicoline into the central nervous system (CNS) by systemic administration led to poor efficiency. A novel method of stereotactic drug delivery was explored to make citicoline bypass the blood brain barrier (BBB) and take effect by direct contact with ischemic neurons. A permanent middle cerebral artery occlusion (pMCAO) model of rats was prepared. To get the optimal conditions for citicoline administration by the novel stereotactic delivery pathway, magnetic resonance imaging (MRI) tracer method was used, and a dose-dependent effect was given. Examinations of MRI, behavior evaluation, infarct volume assessment and histological staining were performed to evaluate the outcome. This MRI-guided stereotactic delivery of citicoline resulted in a notable reduction (>80%) in infarct size and a delayed ischemic injury in cortex 12 hours after onset of acute ischemia when compared with the systematic delivery. The improved neuroprotective efficiency was realized by a full distribution of citicoline in most of middle cerebral artery (MCA) territory and an adequate drug reaction in the involved areas of the brain. Brain lesions of treated rats by stereotactic delivery of citicoline were well predicted in the lateral ventricle and thalamus due to a limited drug deposition by MRI tracer method. Our study realized an improved neuroprotective efficiency of citicoline by stereotactic delivery, and an optimal therapeutic effect of this administration pathway can be achieved under MRI guidance.