Comparison of antibody persistency through one year between one-dose and two-dose regimens of Ad5-nCoV vaccine for COVID-19.

This post-hoc analysis compared the receptor-binding domain (RBD)-specific and pseudovirus neutralizing antibodies against the wild-type SARS-CoV-2 strain elicited by one or two doses (56-d interval) of Ad5-nCoV vaccine regimen (NCT04341389 and NCT04566770). Both trials had low-dose and high-dose groups. Propensity score matching was used to adjust the baseline between one- and two-dose regimens. To predict the decrease in antibody titers 1 y after vaccination, half-lives of RBD-binding antibodies and pseudovirus neutralizing antibodies were computed. We obtained 34 and 29 pairs of participants in the low- and high-dose groups based on the propensity score matching. The two-dose regimen of Ad5-nCoV increased the peaking level of neutralizing antibodies compared to the one-dose regimen at day 28, but the responses of the neutralizing antibodies were not consistent with those of the RBD antibodies. Half-lives of the RBD-binding antibodies in the two-dose Ad5-nCoV regimen (202-209 days) were longer than those in the one-dose regimen (136-137 d); half-lives of the pseudovirus neutralizing antibody in the one-dose Ad5-nCoV regimen (177 d) were longer than those in the two-dose regimen (116-131 d). The predicted positive rates of RBD-binding antibodies in the one-dose regimen (34.1%-38.3%) would be lower than those in the two-dose Ad5-nCoV regimen (67.0%-84.0%), while the positive rates of pseudovirus neutralizing antibodies in the one-dose regimen (65.4%-66.7%) would be higher than those in the two-dose regimen (48.3%-58.0%). The two-dose Ad5-nCoV regimen with a 56-d interval had no effect on the persistence of neutralizing antibodies but slowed decay trend of RBD-binding antibodies.

Correlation between Elbow Flexor Muscle Strength and Needle Electromyography Parameters after Musculocutaneous Nerve Injury.

OBJECTIVES: To explore the changes of elbow flexor muscle strength after musculocutaneous nerve injury and its correlation with needle electromyography (nEMG) parameters. METHODS: Thirty cases of elbow flexor weakness caused by unilateral brachial plexus injury (involving musculocutaneous nerve) were collected. The elbow flexor muscle strength was evaluated by manual muscle test (MMT) based on Lovett Scale. All subjects were divided into Group A (grade 1 and grade 2, 16 cases) and Group B (grade 3 and grade 4, 14 cases) according to their elbow flexor muscle strength of injured side. The biceps brachii of the injured side and the healthy side were examined by nEMG. The latency and amplitude of the compound muscle action potential (CMAP) were recorded. The type of recruitment response, the mean number of turns and the mean amplitude of recruitment potential were recorded when the subjects performed maximal voluntary contraction. The quantitative elbow flexor muscle strength was measured by portable microFET 2 Manual Muscle Tester. The percentage of residual elbow flexor muscle strength (the ratio of quantitative muscle strength of the injured side to the healthy side) was calculated. The differences of nEMG parameters, quantitative muscle strength and residual elbow flexor muscle strength between the two groups and between the injured side and the healthy side were compared. The correlation between elbow flexor manual muscle strength classification, quantitative muscle strength and nEMG parameters was analyzed. RESULTS: After musculocutaneous nerve injury, the percentage of residual elbow flexor muscle strength in Group B was 23.43% and that in Group A was 4.13%. Elbow flexor manual muscle strength classification was significantly correlated with the type of recruitment response, and the correlation coefficient was 0.886 (P<0.05). The quantitative elbow flexor muscle strength was correlated with the latency and amplitude of CMAP, the mean number of turns and the mean amplitude of recruitment potential, and the correlation coefficients were -0.528, 0.588, 0.465 and 0.426 (P<0.05), respectively. CONCLUSIONS: The percentage of residual elbow flexor muscle strength can be used as the basis of muscle strength classification, and the comprehensive application of nEMG parameters can be used to infer quantitative elbow flexor muscle strength.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial.

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

Batch-to-batch consistency trial of an adenovirus type-5 vector-based COVID-19 vaccine in adults aged 18 years and above.

BACKGROUND: The demonstration of batch-to-batch consistency is indispensable for quality control of vaccines. METHODS: We conducted a randomized, double-blind, parallel-controlled trial to evaluate the immunogenicity consistency of a single shot of Ad5-nCoV in healthy adults who had not previously received any COVID-19 vaccine. All eligible participants were randomly assigned equally to receive one of the three consecutive batches of Ad5-nCoV (5 × 1010 viral particles/vial, 0.5 mL). The primary endpoint was geometric mean titers (GMTs) of serum SARS-CoV-2 receptor-binding domain (RBD)-specific IgG on day 28 post-vaccination. RESULTS: One thousand fifty participants were enrolled, with 350 (33%) participants per group. On day 28 post-vaccination, GMTs in three groups were 78.3 binding antibody units (BAU)/mL (95% CI 70.3-87.3), 82.9 BAU/mL (73.9-92.9), and 78.8 BAU/mL (70.2-88.4), respectively. The two-sided 95% CIs for the GMT ratios between each pair of batches were all between 0.67 and 1.5. The highest incidence of solicited adverse reactions within 7 days post-vaccination was reported by batch 3 recipients (23.1% versus 15.1% in batch 1 recipients and 14.6% in bath 2 recipients; p = 0.0039). None of the serious adverse events were related to vaccination. CONCLUSIONS: Immunogenicity consistency between consecutive batches of Ad5-nCoV was well established in adults. CLINICAL TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05313646).

Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial.

BACKGROUND: Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine. METHODS: We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine-Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0 × 1011 viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0 × 1011 viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259. FINDINGS: Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (p<0·0001). The low dose group had a serum NAb GMT of 744·4 (95% CI 520·1-1065·6) and the high dose group had a GMT of 714·1 (479·4-1063·7) 14 days after booster dose, significantly higher than the GMT in the CoronaVac group (78·5 [60·5-101·7]; p<0·0001). INTERPRETATION: We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination. FUNDING: National Natural Science Foundation of China and Jiangsu Provincial Key Research and Development Program.

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 variants

SARS-CoV-2 and its variants are raging worldwide. Unfortunately, the global vaccination is not efficient enough to attain a vaccine-based herd-immunity and yet no special and effective drug is developed to contain the spread of the disease. Previously we have identified CD147 as a novel receptor for SARS-CoV-2 infection. Here, we demonstrated that CD147 antibody effectively inhibits infection and cytokine storm caused by SARS-CoV-2 variants. In CD147KO VeroE6 cells, infections of SARS-CoV-2, its variants (B.1.1.7, B.1.351) and pseudovirus mutants (B.1.1.7, B.1.351, B.1.525, B.1.526 (S477N), B.1.526 (E484K), P.1, P.2, B.1.617.1, B.1.617.2) were decreased. Meanwhile, CD147 antibody effectively blocked the entry of variants and pseudomutants in VeroE6 cells, and inhibited the expression of cytokines. A model of SARS-CoV-2-infected hCD147 transgenic mice was constructed, which recapitulated the features of exudative diffuse alveolar damage and dynamic immune responses of COVID-19. CD147 antibody could effectively clear the virus and alveolar exudation, resolving the pneumonia. We found the elevated level of cyclophilin A (CyPA) in plasma of severe/critical cases, and identified CyPA as the most important proinflammatory intermediate causing cytokine storm. Mechanistically, spike protein of SARS-CoV-2 bound to CD147 and initiated the JAK-STAT pathway, which induced expression of CyPA. CyPA reciprocally bound to CD147, triggered MAPK pathway and consequently mediated the expression of cytokine and chemokine. In conclusion, CD147 is a critical target for SARS-CoV-2 variants and CD147 antibody is a promising drug to control the new wave of COVID-19 epidemic.

Sensorimotor and pain-related alterations of the gray matter and white matter in Type 2 diabetic patients with peripheral neuropathy.

Although diabetic peripheral neuropathy (DPN) has long been considered a disease of the peripheral nervous system, recent neuroimaging studies have shown that alterations in the central nervous system may play a crucial role in its pathogenesis. Here, we used surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) to investigate gray matter (GM) and white matter (WM) differences between patients with DPN (n = 67, 44 painless and 23 painful) and healthy controls (HCs; n = 88). Compared with HCs, patients with DPN exhibited GM abnormalities in the pre- and postcentral gyrus and in several deep GM nuclei (caudate, putamen, medial pallidum, thalamus, and ventral nuclear). They also exhibited altered WM tracts (corticospinal tract, spinothalamic tract, and thalamocortical projecting fibers). These findings suggest impaired motor and somatosensory pathways in DPN. Further, patients with DPN (particularly painful DPN) exhibited morphological differences in the cingulate, insula, prefrontal cortex, and thalamus, as well as impaired WM integrity in periaqueductal WM and internal and external capsules. This suggests pain-perception/modulation pathways are altered in painful DPN. Intermodal correlation analyses found that the morphological indices of the brain regions identified by the SBM analysis were significantly correlated with the fractional anisotropy of brain regions identified by the TBSS analysis, suggesting that the GM and WM alterations were tightly coupled. Overall, our study showed sensorimotor and pain-related GM and WM alterations in patients with DPN, which might be involved in the development of DPN.

Optimization system of mesenchymal stem cells for tissue engineering chondrogenic differentiation / 中华骨科杂志

Articular cartilage defect is a common joint damage, however, due to the particularity of cartilage tissue, its repair ability is limited. Thus, articular cartilage damage often changes to more severe osteoarthritis which brings huge pain and economic burden to patients. The development of cartilage tissue engineering brings good news to these patients, but also faces great challenges. Because of the characteristics of mesenchymal stem cells(MSCs) including autologous source, amplification and cartilage differentiation potential, MSCs are often used as the seed cells of cartilage tissue engineering and got widely attention. In the commonly used treatment strategy of articular cartilage differentiated from mesenchymal cells, in vitro pre culture and differentiation showed good therapeutic effects.The mesenchymal stem cells collected from the patient were concentrated, cultured and induced differentiation in vitro, a certain number of differentiated chondrocytes were obtained, and then the cells and culture matrix were transplanted to the patient together. However, the tissue engineering cartilage obtained from mesenchymal stem cells cannot fully meet the requirements of clinical treatment. Moreover, due to the differences of disease type, degree and individuality, there are various optimized factors for the treatment of MSCs derived tissue-engineered cartilage transplantation. For the same type of disease treatment, the optimization system still has no unified recognized standard. In order to obtain better adapt to the human body and meet the clinical requirements of articular cartilage, this review focus onoptimized factors of MSCs in the treatment of orthopedic diseases, summarize and analysis the research status, and discuss the induced factorsfrom three aspects: environmental factors, scaffold selection and seed cells.It provides an idea for using mesenchymal stem cells to obtain better tissue-engineered cartilage and to establish a better optimization system.

Prognostic significance of lymphatic vessel invasion diagnosed by D2-40 in Chinese invasive breast cancers.

Lymphatic vessel invasion (LVI) is promising in determining prognosis and treatment strategies, but the application of LVI as a histopathological criterion in breast cancer patients especially those of different subgroups is controversial. This research aims to evaluate the prognostic value of LVI assessed by D2-40 not only in patients with early invasive breast cancer but also in lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative subgroups.The study cohort included 255 patients with a median follow-up of 101 months. Immunohistochemical staining for D2-40 was performed to identify LVI.LVI was present in 64 (25.1%), 15 (12.1%), 49 (37.4%), 19 (20.9%), 23 (27.7%), 13 (31.7%), and 9 (22.5%), respectively, in the whole cohort, lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative patients. LVI was associated with large tumor size (P = .04), high histological grade (P = .004), involved lymph node (P < .001), and high expression of Ki-67 (P = .003). No significant difference was found among patients with different subtypes and LVI status. The presence of LVI was significantly associated with adverse disease-free survival in the whole cohort (P < .001), lymph node-negative (P < .001), lymph node-positive (P < .001), luminal A-like (P < .001), and luminal B-like patients (P < .001) in both of the univariate and multivariate survival analysis.This study indicated that the presence of LVI stained by D2-40 provided independent prognostic information not only in the whole cohort but also in the subgroup of patients with lymph node-negative, lymph node-positive, luminal A-like, and luminal B-like diseases, which may make a case for routine clinical assessment of LVI using D2-40.

Primary or metastatic hepatic carcinoma? A breast cancer patient after adjuvant chemotherapy and radiotherapy postoperatively with intrahepatic cholangiocarcinoma and review of the literature.

BACKGROUND: The liver is a common site of metastases, followed by the bone and lung in breast cancer. The symptoms of hepatic metastases are similar to intrahepatic cholangiocarcinoma (ICC). ICC is rare, with an overall incidence rate of 0.95 cases per 100,000 adults. The incidence of ICC for patients with breast cancer is very uncommon. Breast cancer patient with ICC is easily misdiagnosed as hepatic metastases. CASE PRESENTATION: We report a breast cancer patient postoperatively who was hospitalized because of having continuous irregular fever for 1 month. Antibiotics were given for 1 week without any significant effect. Her admission bloods revealed elevated levels of carcino-embryonic antigen. Magnetic resonance imaging diagnosis showed multiple liver metastases. We believed that the woman had hepatic metastases until biopsy guided by computed tomography. The liver biopsy pathology analysis considered the possibility of primary intrahepatic cholangiocarcinoma. CONCLUSIONS: Breast cancer patient with space-occupying lesions in the liver is easily considered to be progressed hepatic metastases. Image-guided biopsy is the best diagnostic method for breast cancer with liver mass to avoid misdiagnosis and classify the molecular subtypes to make appropriate treatment.

[Flow cytometry-pathology combined study of breast cancer].

OBJECTIVE: To study the relation between histopathologic grading and some of the cytogenetic and molecular biology characteristics of breast cancer. METHODS: On the basis of estrogen receptor (ER) expression, DNA content, S-phase fraction (SPF), bcl-2 and mutant p53 protein (mtp53) expression were examined by FCM in 121 breast cancer patients. In 66 patients with invasive ductal breast cancer, histopathologic grading was also examined. RESULTS: The aneuploidy rate and DNA index (DI) were significantly different in grade I, II and III breast cancer. SPF and mtp53 expression significantly increased with increase in histopathologic grading (P < 0.05), but bcl-2 did not show this trend. SPF and mtp53 expression were significantly more in breast cancer with negative ER than in those with positive ER (P < 0.05). Again, no such differences in bcl-2 regardless of ER expression. Correlations existed between DI vs SPF, DI vs mtp53, and SPF vs mtp53 expressions (P < 0.01) but bcl-2 did not correlate with any one of them. CONCLUSION: Cytogenetic and molecular biology studies on the basis of histopathologic grading may provide more information in prognostic prediction of breast cancer.