Design of hepadnavirus core protein-based chimeric virus-like particles carrying epitopes from respiratory syncytial virus.

Respiratory syncytial virus (RSV) is one of the most important pathogens causing respiratory tract infection in humans, especially in infants and the elderly. The identification and structural resolution of the potent neutralizing epitopes on RSV fusion (F) protein enable an "epitope-focused" vaccine design. However, the display of RSV F epitope II on the surface of the widely-used human hepatitis B virus core antigen (HBcAg) has failed to induce neutralizing antibody response in mice. Here, we used the hepadnavirus core protein (HcAg) from different mammalian hosts as scaffolds to construct chimeric virus-like particles (VLPs) presenting the RSV F epitope II. Mouse immunization showed that different HcAg-based chimeric VLPs elicited significantly different neutralizing antibody responses, among which the HcAg derived from roundleaf bat (RBHcAg) is the most immunogenic. Furthermore, RBHcAg was used as the scaffold platform to present multiple RSV F epitopes, and the immunogenicity was further improved in comparison to that displaying a single epitope II. The designed RBHcAg-based multiple-epitope-presenting VLP formulated with MF59-like adjuvant elicited a potent and balanced Th1/Th2 immune response, and offered substantial protection in mice against the challenge of live RSV A2 virus. The designed chimeric VLPs may serve as the potential starting point for developing epitope-focused vaccines against RSV. Our study also demonstrated that RBHcAg is an effective VLP carrier for presenting foreign epitopes, providing a promising platform for epitope-focused vaccine design.

Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Laparoscopic or open liver resection for intrahepatic cholangiocarcinoma: A meta-analysis and systematic review.

Background: Although laparoscopic hepatectomy has been widely used in the treatment of benign and malignant liver diseases, its applicability in intrahepatic cholangiocarcinoma (ICC) is controversial. We conducted a meta-analysis to compare the short-term and long-term outcomes of laparoscopic hepatectomy (Lap-ICC) and open hepatectomy (Open-ICC) in ICC patients. Methods: The PubMed, Web of science, Cochrane Library, China National Knowledge Infrastructure and other databases were searched for the relevant literature. The research data were extracted according to the inclusion and exclusion criteria. Results: Seventeen studies, including 3975 ICC patients, were selected for the meta-analysis. Compared to Open-ICC, Lap-ICC had lower rates of lymph node dissection (OR=0.44, P=0.01) and metastasis (OR=0.58, P=0.03), along with less intraoperative bleeding (MD=-128.43 ml, P<0.01) lower blood transfusion rate (OR=0.43, P<0.01), shorter hospital stay (MD=-2.75 day, P<0.01), higher R0 resection rate (OR=1.60, P<0.01), and lower tumor recurrence rate (OR=0.67, P=0.01). However, there was no difference between the two groups in terms of operation time, number of lymph node dissection, incision margin distance, overall complications rate, severe complications rate, and the 1-, 3- and 5-year DFS and OS rates. Conclusion: Laparoscopic hepatectomy is partially superior to open hepatectomy in terms of less bleeding, shorter hospital stay and higher R0 resection rate, while the long-term efficacy of the two approaches is similar.

Safety and immunogenicity of a mosaic vaccine booster against Omicron and other SARS-CoV-2 variants: a randomized phase 2 trial.

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

Analysis of risk factors for acute pancreatitis complicated with pancreatic sinistral portal hypertension and construction of predictive model.

Objective: Pancreatic sinistral portal hypertension (PSPH) is a common complication of acute pancreatitis (AP) and can cause massive gastrointestinal bleeding, which is one of the causes of AP-related mortality. However, there is currently no predictive model for AP concurrent with PSPH. This study aimed to identify the risk factors for AP concurrent with PSPH and use these factors to build a related predictive model. Materials and methods: We collected clinical data from 282 patients with AP. 192 patients were used as a training group and 90 patients as a validation group. Univariate and multivariate analyses were used to identify independent risk factors for AP complicated with PSPH, and then a nomogram was established. The models are cross verification and Internal verification. The predictive ability and accuracy of the model were evaluated based on the working curve of the subjects and the calibration curve, respectively. The clinical value of the model was evaluated using decision curve analysis (DCA). Results: The univariate analysis revealed significant differences in the occurrence of PSPH with respect to sex, recurrent AP, history of hypertension, smoking history, patency of the splenic vein, pancreatic necrosis or pancreatic pseudocyst formation, the most significant site of pancreatic swelling, presence of a Dmure D polymer, MCTSI, and involvement of lipase and amylase. The logistic multivariate regression analysis showed that male sex, splenic-vein stenosis or occlusion and swelling were located in the body-tail, and MCTSI was an independent risk factor for PSPH. The nomogram and ROC curve were constructed. The area under the working curve of the subjects was 0.91, and the sensitivity and specificity were 82.5% and 89.1%, respectively. In the validation group, the C-index is 0.826. The nomogram was internally validated using 1,000 bootstrap samples, and the c-index was 0.898. The calibration curve demonstrated that the predicted probability was concordant with the observed probability, and the DCA confirmed that the model had robust clinical utility. Conclusion: Male sex, splenic-vein stenosis or occlusion, recurrent AP, and swelling are located in the body-tail, and MCTSI is an independent risk factor for the occurrence of PSPH. The predictive model developed for AP complicated with PSPH may serve toward developing preventive and therapeutic approaches for PSPH.

Efficacy of lenvatinib combined with sequential transarterial chemoembolization for primary hepatocellular carcinoma and the effects on serum basic fibroblast growth factor and vascular endothelial growth factor.

Objective: The aim of this research was to investigate the therapeutic efficacy of lenvatinib combined with sequential transarterial chemoembolization (TACE) on primary hepatocellular carcinoma (HCC) and the effects on serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Method: A total of 104 patients with primary HCC, admitted to People's Hospital of Leshan from April 2018 to January 2021, were selected as the study subjects and were divided into the TACE-LEN group (n = 53) who were treated with lenvatinib combined with sequential TACE and the TACE group (n = 51) who were treated with TACE alone, according to the appropriate treatment modalities. The clinical efficacy 8 weeks after treatment; the serum levels of total bilirubin, conjugated bilirubin, and alanine aminotransferase (ALT); the prothrombin time (PT); the indocyanine green retention rate at 15 min (ICGR15); and the serum bFGF and VEGF levels before treatment and at 8 weeks after treatment were compared between the two groups. The incidence of adverse events and the survival rates at 18 months were also recorded for both groups. COX regression analysis was used to analyze the risk factors affecting the survival of patients. Results: Eight weeks after treatment, the objective response rate was higher in the TACE-LEN group than in the TACE group (77.36% vs. 56.36%, p < 0.05), but there were no statistically significant differences in the bilirubin and ALT levels, the PT, and the ICGR15 between the two groups (p > 0.05). The serum bFGF and VEGF levels post-therapeutic were lower in the TACE-LEN group than in the TACE group (p < 0.05). The differences in the incidence of postoperative adverse events and the survival rate within 6 months were not statistically significant between the two groups (p > 0.05). In addition, the survival rates within 12 and 18 months after treatment were higher in the TACE-LEN group than in the TACE group than in the TACE group (81.1% vs. 64.7%, 69.8% vs. 49.1%, p < 0.05). ICG-R15 and treatment regimen are risk factors for survival. Conclusion: The worse the liver reserve is, the worse the prognosis is. The combination of TACE and lenvatinib showed better efficacy and longer survival than TACE monotherapy for HCC patients and reduced the levels of bFGF and VEGF.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants.

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.

Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients in a randomized phase 2 trial.

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV.

Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2.

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

Exploring the Application of a Multi-Targeted Nursing Group for Enhanced Recovery After Surgery Using the LEER ("Less Pain", "Early Movement", "Early Return to a Normal Diet" and "Reassurance") Model.

OBJECTIVE: To explore the effects and value of establishing a multi-target nursing group (MTNG) for facilitating goal-oriented enhanced recovery after surgery (ERAS) using the LEER ("less pain", "early movement", "early return to a normal diet" and "reassurance") model. METHODS: The clinical data of 198 patients with hepatobiliary and pancreatic malignancies were retrospectively analyzed. The patients were divided into two groups: 91 cases were collected in a traditional group, which adopted traditional perioperative care, and 107 cases were collected in an MTNG group, which adopted MTNG measures. The differences in the clinical data including postoperative recovery, unplanned readmission rate, the implementation rate of nursing measures, the degree of a patient's understanding of the disease, and patient compliance and satisfaction with nursing care during hospitalization were compared and analyzed between the two groups. RESULTS: The MTNG group reflected a lower pain degree and hospitalization expenses (P < 0.05), earlier postoperative flatulence, earlier recommencing of a normal diet, and earlier postoperative ambulation (P < 0.05), together with a shorter postoperative indwelling catheter duration and length of hospital stay (P < 0.05). There were no significant differences in the incidence of postoperative complications and unplanned postoperative readmission rates between the two groups (P > 0.05). The implementation rate of nursing measures and the degree of patients understanding the disease, and patient compliance and satisfaction with nursing care were higher in the MTNG group (P < 0.05). CONCLUSION: The MTNG approach, based on ERAS with the LEER model, was conducive to the safe and rapid postoperative recovery of patients, the precise and efficient implementation of ERAS measures, the improvement of medical treatment satisfaction among patients.