Using an In Vivo Mouse Model to Determine the Exclusion Criteria of Preexisting Anti-AAV9 Neutralizing Antibody Titer of Pompe Disease Patients in Clinical Trials.

The efficacy of adeno-associated virus (AAV)-based gene therapy is dependent on effective viral transduction, which might be inhibited by preexisting immunity to AAV acquired from infection or maternal delivery. Anti-AAV neutralizing Abs (NAbs) titer is usually measured by in vitro assay and used for patient enroll; however, this assay could not evaluate NAbs' impacts on AAV pharmacology and potential harm in vivo. Here, we infused a mouse anti-AAV9 monoclonal antibody into Balb/C mice 2 h before receiving 1.2 × 1014 or 3 × 1013 vg/kg of rAAV9-coGAA by tail vein, a drug for our ongoing clinical trials for Pompe disease. The pharmacokinetics, pharmacodynamics, and cellular responses combined with in vitro NAb assay validated the different impacts of preexisting NAbs at different levels in vivo. Sustained GAA expression in the heart, liver, diaphragm, and quadriceps were observed. The presence of high-level NAb, a titer about 1:1000, accelerated vector clearance in blood and completely blocked transduction. The AAV-specific T cell responses tended to increase when the titer of NAb exceeded 1:200. A low-level NAbs, near 1:100, had no effect on transduction in the heart and liver as well as cellular responses, but decreased transduction in muscles slightly. Therefore, we propose to preclude patients with NAb titers > 1:100 from rAAV9-coGAA clinical trials.

Single-Dose Intranasal Immunisation with Novel Chimeric H1N1 Expressing the Receptor-Binding Domain of SARS-CoV-2 Induces Robust Mucosal Immunity, Tissue-Resident Memory T Cells, and Heterologous Protection in Mice.

Current COVID-19 vaccines can effectively reduce disease severity and hospitalisation; however, they are not considerably effective in preventing infection and transmission. In this context, mucosal vaccines are pertinent to prevent SARS-CoV-2 infection and spread. In this study, we generated a replication-competent recombinant chimeric influenza A virus (IAV) expressing the receptor-binding domain (RBD) of a SARS-CoV-2 prototype in the C-terminus of the neuraminidase (NA) of A/Puerto Rico/08/1934 H1N1 (PR8). The remaining seven segments from A/WSN/1933 H1N1 (WSN) were named PR8NARBD/WSN. We observed that the recombinant virus with the WSN backbone demonstrated improved expression of NA and RBD. A single intranasal dose of PR8NARBD/WSN(103PFU) in mice generated robust mucosal immunity, neutralising antibodies, cellular immunity, and tissue-resident memory T cells specific to SARS-CoV-2 and IAV. Importantly, immunisation with PR8NARBD/WSN viruses effectively protected mice against lethal challenges with H1N1, H3N2 IAV, and SARS-CoV-2 Beta variant and significantly reduced lung viral loads. Overall, our research demonstrates the promising potential of PR8NARBD/WSN as an attractive vaccine against emerging SARS-CoV-2 variants and influenza A virus infections.

Smart senior care cognition and health among Chinese elderly: A moderated mediation model featuring parent-child relationship and internet use.

In the context of digital transformation, smart senior care (SSC) cognition among elderly individuals has become an important contributor to their health. Using a sample of 345 older adults derived from the cross-sectional data of a questionnaire survey on the application of home-based SSC services and products among elderly individuals, this study explored how the parent‒child relationship mediated the linkage between SSC cognition and elderly health. To examine the moderating role of internet use, we applied the multigroup structural equation modeling (SEM) approach to test whether significant disparities exist between older adults who use the internet and those who do not on the pathways in the mediation model. After controlling for gender, age, hukou (household registration permit), ethnicity, income, marital status, and education level, we found that SSC cognition exerted significant positive effects on elderly health, in which the parent‒child relationship exerted a mediating effect. As for differences between the elderly with internet use and those without, on the three pathways connecting SSC cognition and health, SSC cognition and parent‒child relationship, and parent‒child relationship and health among elderly individuals, older adults who used the internet were more susceptible than those who did not. The findings are helpful for improving the policy-making on elderly health and may serve as a practical guide and theoretical reference for the promotion of active aging.

Ineffective Effort in Patients With Acute Brain Injury Undergoing Invasive Mechanical Ventilation.

BACKGROUND: Ineffective effort (IE) is a frequent patient-ventilator asynchrony in invasive mechanical ventilation. This study aimed to investigate the incidence of IE and to explore its relationship with respiratory drive in subjects with acute brain injury undergoing invasive mechanical ventilation. METHODS: We retrospectively analyzed a clinical database that assessed patient-ventilator asynchrony in subjects with acute brain injury. IE was identified based on airway pressure, flow, and esophageal pressure waveforms collected at 15-min intervals 4 times daily. At the end of each data set recording, airway-occlusion pressure (P0.1) was determined by the airway occlusion test. IE index was calculated to indicate the severity of IE. The incidence of IE in different types of brain injuries as well as its relationship with P0.1 was determined. RESULTS: We analyzed 852 data sets of 71 subjects with P0.1 measured and undergoing mechanical ventilation for at least 3 d after enrollment. IE was detected in 688 (80.8%) data sets, with a median index of 2.2% (interquartile range 0.4-13.1). Severe IE (IE index ≥ 10%) was detected in 246 (28.9%) data sets. The post craniotomy for brain tumor and the stroke groups had higher median IE index and lower P0.1 compared with the traumatic brain injury group (2.6% [0.7-9.7] vs 2.7% [0.3-21] vs 1.2% [0.1-8.5], P = .002; 1.4 [1-2] cm H2O vs 1.5 [1-2.2] cm H2O vs 1.8 [1.1-2.8] cm H2O, P = .001). Low respiratory drive (P0.1 < 1.14 cm H2O) was independently associated with severe IE in the expiratory phase (IEE) even after adjusting for confounding factors by logistic regression analysis (odds ratio 5.18 [95% CI 2.69-10], P < .001). CONCLUSIONS: IE was very common in subjects with acute brain injury. Low respiratory drive was independently associated with severe IEE.

Efficacy and safety of remifentanil dose titration to correct the spontaneous hyperventilation in aneurysmal subarachnoid haemorrhage: protocol and statistical analysis for a prospective physiological study.

INTRODUCTION: Spontaneous hyperventilation (SHV) is common in aneurysmal subarachnoid haemorrhage (aSAH). The reduction in arterial partial pressure of carbon dioxide (PaCO2) may change the brain physiology, such as haemodynamics, oxygenation, metabolism and may lead to secondary brain injury. However, how to correct SHV safely and effectively in patients with aSAH has not been well investigated. The aim of this study is to investigate the efficacy and safety of remifentanil dose titration to correct hyperventilation in aSAH, as well as the effect of changes in PaCO2 on cerebral blood flow (CBF). METHODS AND ANALYSIS: This study is a prospective, single-centre, physiological study in patients with aSAH. The patients who were mechanically ventilated and who meet with SHV (tachypnoea combined with PaCO2 <35 mm Hg and pH >7.45) will be enrolled. The remifentanil will be titrated to correct the SHV. The predetermined initial dose of remifentanil is 0.02 µg/kg/min and will be maintained for 30 min, and PaCO2 and CBF will be measured. After that, the dose of remifentanil will be sequentially increased to 0.04, 0.06, and 0.08 µg/kg/min, and the measurements for PaCO2 and CBF will be repeated 30 min after each dose adjustment and will be compared with their baseline values. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (KY 2021-006-02) and has been registered at ClinicalTrials.gov. The results of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04940273.

Hand Exoskeleton Design and Human-Machine Interaction Strategies for Rehabilitation.

Stroke and related complications such as hemiplegia and disability create huge burdens for human society in the 21st century, which leads to a great need for rehabilitation and daily life assistance. To address this issue, continuous efforts are devoted in human-machine interaction (HMI) technology, which aims to capture and recognize users' intentions and fulfil their needs via physical response. Based on the physiological structure of the human hand, a dimension-adjustable linkage-driven hand exoskeleton with 10 active degrees of freedom (DoFs) and 3 passive DoFs is proposed in this study, which grants high-level synergy with the human hand. Considering the weight of the adopted linkage design, the hand exoskeleton can be mounted on the existing up-limb exoskeleton system, which greatly diminishes the burden for users. Three rehabilitation/daily life assistance modes are developed (namely, robot-in-charge, therapist-in-charge, and patient-in-charge modes) to meet specific personal needs. To realize HMI, a thin-film force sensor matrix and Inertial Measurement Units (IMUs) are installed in both the hand exoskeleton and the corresponding controller. Outstanding sensor-machine synergy is confirmed by trigger rate evaluation, Kernel Density Estimation (KDE), and a confusion matrix. To recognize user intention, a genetic algorithm (GA) is applied to search for the optimal hyperparameters of a 1D Convolutional Neural Network (CNN), and the average intention-recognition accuracy for the eight actions/gestures examined reaches 97.1% (based on K-fold cross-validation). The hand exoskeleton system provides the possibility for people with limited exercise ability to conduct self-rehabilitation and complex daily activities.

The CD8+ and CD4+ T Cell Immunogen Atlas of Zika Virus Reveals E, NS1 and NS4 Proteins as the Vaccine Targets.

Zika virus (ZIKV)-specific T cells are activated by different peptides derived from virus structural and nonstructural proteins, and contributed to the viral clearance or protective immunity. Herein, we have depicted the profile of CD8+ and CD4+ T cell immunogenicity of ZIKV proteins in C57BL/6 (H-2b) and BALB/c (H-2d) mice, and found that featured cellular immunity antigens were variant among different murine alleles. In H-2b mice, the proteins E, NS2, NS3 and NS5 are recognized as immunodominant antigens by CD8+ T cells, while NS4 is dominantly recognized by CD4+ T cells. In contrast, in H-2d mice, NS1 and NS4 are the dominant CD8+ T cell antigen and NS4 as the dominant CD4+ T cell antigen, respectively. Among the synthesized 364 overlapping polypeptides spanning the whole proteome of ZIKV, we mapped 91 and 39 polypeptides which can induce ZIKV-specific T cell responses in H-2b and H-2d mice, respectively. Through the identification of CD8+ T cell epitopes, we found that immunodominant regions E294-302 and NS42351-2360 are hotspots epitopes with a distinct immunodominance hierarchy present in H-2b and H-2d mice, respectively. Our data characterized an overall landscape of the immunogenic spectrum of the ZIKV polyprotein, and provide useful insight into the vaccine development.

Comparison of percutaneous transluminal angioplasty and surgical revision after intraoperative dilatation with biliary tract probes for arteriovenous fistula stenosis at juxta-anastomosis.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) is widely used for stenosis of vascular access (VA) for hemodialysis. We aimed to evaluate the effectiveness of both PTA and surgical revision after intraoperative dilatation with biliary tract probes for juxta-anastomotic stenosis in autogenous radiocephalic arteriovenous fistulas (RCAVFs). METHODS: We performed a retrospective analysis of PTA and surgical revision after intraoperative dilatation with biliary tract probes; these were the first interventions after RCAVF establishment in 112 patients with juxta-anastomotic stenosis. Anatomical (number of stenoses) and clinical variables (age and gender of the patient, time of hemodialysis, AVF age, presence of diabetes mellitus, and cause of end-stage renal disease) were reviewed. Technical success, clinical success, and post-intervention primary patency were evaluated. RESULTS: Our study enrolled 35 patients in the PTA group and 77 patients in the surgical revision group. Clinical and technical success rates of both groups were 100%. There were no complications, such as bleeding or hematomas. Using the Kaplan-Meier method, the post-intervention primary patency rates at 3, 6, 9, 12, 18, and 24 months in the PTA group were 100%, 94.28%, 77.1%, 60%, 54.29%, and 45.71%, respectively, and those in the surgical revision group were 100%, 94.81%, 92.2%, 90.91%, 81.82%, and 76.62%, respectively. The post-intervention primary patency rates at 9-24 months in the surgical revision group were significantly higher than those in the PTA group (χ2 = 19.04, p < 0.0001). CONCLUSION: The post-intervention long-term primary patency rate of surgical revision after intraoperative dilatation with biliary tract probes is higher than that of PTA for the first intervention of patients with juxta-anastomotic stenosis in RCAVFs. The surgical revision method is safe and effective, especially in hospitals that have not yet carried out PTA.

The Effect of the "Triple-Layer Medical Security" Policy on the Vulnerability as Expected Poverty of Rural Households: Evidence from Yunnan Province, China.

China launched the "critical battle against poverty" nationwide in 2012. As its main battlefield, Yunnan province promulgated the "triple medical security" (TMS) policy in 2017. This study, based on the pooled cross-section database of 2015-2020 of registered poor households in Yunnan province, employed the logit model to examine the effect of TMS on the vulnerability as expected poverty (VEP) of these households. It found that increasing the reimbursement rates for overall medical expenses and inpatient expenses and decreasing the proportion of out-of-pocket medical payment to income reduced the VEP; increases in the number of sick people in the family increased its VEP, and although the increase in the reimbursement rate for overall medical expenses or for inpatient expenses partially offset the VEP caused by the increase in the number of chronically ill people in the family, the VEP caused by the increase in the number of critically ill people would increase in the short term with the increase in the reimbursement rate for overall medical expenses or for inpatient expenses. The findings help improve policies concerning the medical security and health of the rural poor population, providing theoretical reference and practical guidance for future research.

Factors Associated With HIV Testing Among MSM in Guilin, China: Results From a Cross-Sectional Study.

Objectives: The objective of this study is to explore factors affecting the HIV testing behaviors among men who have sex with men (MSM) in China. Methods: A cross-sectional study was conducted in Guilin, China from April to June of 2021. Questionnaire data of 300 MSM were analyzed, and binary logistic regression models were used to examine the socio-demographic and sexual behavior characteristics associated with three HIV testing behaviors (self-testing, institutional testing, and regular testing). Results: The results showed that half of the respondents had the habit of regular HIV testing. Only 30.0% of MSM chose to do HIV testing after high-risk sexual behavior, and self-perceived luck was the main reason for not having HIV testing. Moreover, the influencing factors of three HIV testing behaviors after high-risk sexual behavior differ. Interestingly, income was not related to any of the three HIV testing behaviors among those MSM who participated. Conclusion: This research indicates insufficient health education on HIV testing behaviors among MSM in China. Health promotion practices targeting the MSM population to improve HIV-related knowledge, thus contributing to the HIV epidemic, are required.

The predictive value of bioimpedance-derived fluid parameters for cardiovascular events in patients undergoing hemodialysis.

BACKGROUND: It is becoming increasingly evident that the accurate assessment of fluid status is critical to ensure optimal care in patients undergoing hemodialysis (HD). Various fluid parameters, including overhydration (OH) and overhydration/extracellular water (OH/ECW%), which can be obtained using a bioimpedance spectroscopy device have been used to indicate the hydration status in such patients. This study aimed to explore the effect of these fluid parameters on cardiovascular events and determine which parameter was a better predictor of cardiovascular events (CVEs). METHODS: A total of 227 patients who underwent HD at the Hangzhou Hospital of Traditional Chinese Medicine were enrolled in this prospective study between December 2017 and August 2018. Clinical data were collected, and the fluid status of patients was assessed using a body composition monitor. The patients were followed up until December 2020. The primary outcomes were CVEs. The association between fluid parameters and CVEs was analyzed using Cox proportional hazards models. The areas under the curve (AUCs) of receiver operating characteristic analysis and improvement in the global chi-squared value were used to compare the predictive values of fluid parameters for CVEs. RESULTS: During a median follow-up of 31 months, 66 CVEs were recorded. The patients with a higher absolute hydration index (OH) and a relative hydration index (OH/ECW%) exhibited an increased risk of developing CVEs. After adjusting for confounding factors, both OH [hazard ratio (HR) 1.279 per L, 95% confidence interval (CI) 1.047-1.562; p = 0.016] and OH/ECW% (HR 1.061 per %, 95% CI 1.017-1.108; p = 0.006) were independently associated with CVEs. The predictive ability of the absolute hydration index was superior to the relative hydration index based on AUC calculations for CVEs. Furthermore, a greater change in χ2 in predicting CVEs was noted for the absolute hydration index. CONCLUSIONS: Both absolute hydration index and relative hydration index were found to be independent predictors of CVEs in univariate and multivariate analyses. Furthermore, the absolute hydration index had a better additive predictive value than the relative hydration index in predicting CVEs.

Incidence, Risk Factors and Outcomes of Sepsis in Critically Ill Post-craniotomy Patients: A Single-Center Prospective Cohort Study.

Background: Data concerning the epidemiology of sepsis in critically ill post-craniotomy patients are scarce. This study aimed to assess the incidence, risk factors, and outcomes of sepsis in this population. Methods: This was a single-center prospective cohort study. Post-craniotomy patients admitted to the intensive care unit (ICU) were screened daily for the presence of infection and sepsis. Results: Of the 900 included patients, 300 developed sepsis. The cumulative incidence of sepsis was 33.3% [95% confidence interval (CI), 30.2-36.4%]. Advanced age, male, hypertension, trauma, postoperative intracranial complications, and lower Glasgow Coma Scale (GCS) on the first postoperative day were independent risk factors of sepsis. Septic patients had higher hospital mortality (13.7 vs. 8.3%, P = 0.012), longer ICU length of stay (LOS) (14 vs. 4 days, P < 0.001), longer hospital LOS (31 vs. 19 days, P < 0.001), and higher total medical cost (CNY 138,394 vs. 75,918, P < 0.001) than patients without sepsis. Conclusion: Sepsis is a frequent complication in critically ill post-craniotomy patients. Advanced age, male, hypertension, trauma, postoperative intracranial complications, and lower GCS on the first postoperative day were independent risk factors of sepsis.

Social Integration as Mediator and Age as Moderator in Social Capital Affecting Mental Health of Internal Migrant Workers: A Multi-Group Structural Equation Modeling Approach.

The rise of migrant workers has been a unique social phenomenon as China goes through industrialization, urbanization, and modernization. They are a special social group formed during the economic and social transition of the country. Migration of rural labor has pushed China on its new path toward industrialization and urbanization. Because of the urban-rural dual system of the country, however, it is difficult for migrant workers to be fully integrated into host cities, making them susceptible to negative emotions and mental health issues. Therefore, their mental health is an issue of great volume in the domains of social undertakings, people's livelihood, and public health. However, existing studies have paid limited attention to the psychological profile of migrant workers and even less to the interplays among their social capital, social integration, and mental health. Targeting China's internal migrant workers, this article tapped the interactions among their social integration, social capital, and mental health with a sample of the cross-sectional data from the China Labor Dynamics Survey (CLDS) in 2018. Multi-group structural equation modeling (SEM) was employed to test the moderating action of age by analyzing whether the mediation model differed significantly in the paths among young, middle-aged, and older migrant workers. The SEM based on bootstrapping suggested that, after controlling for the influence of gender, education, marital status, personal annual income, employer type, and self-rated health, migrant workers' social capital positively affect their mental health in a significant way, with social integration playing a mediating role. In terms of age difference, middle-aged migrant workers were more subject to the aforementioned mechanism than young ones, and young migrant workers were more affected by the mechanism than older ones. This study revealed different psycho-social interplays among social capital, social integration, and mental health across young, middle-aged, and elderly migrant workers. The findings could serve as an important theoretical reference and as practical guidance for improving policies concerning migrant workers' mental health and social benefits in the context of economic transition.

Primary seminoma of prostate in a patient with Klinefelter syndrome: A case report.

RATIONALE: Klinefelter syndrome (KS) is a sex differentiation syndrome that occurs in men and is characterized by the 47XXY genotype. An association between KS and cancer has also been reported. The occurrence of seminoma of the prostate in KS has not been reported in the literature to date. Primary seminoma should be included in the differential diagnosis of prostate neoplasms in patients with KS. PATIENT CONCERNS: A 39-year-old man presenting with urinary retention was admitted to our hospital. Physical examination revealed sparse pubic hairs, atrophic testes, and an underdeveloped penis. Hormonal examination revealed significantly lowered serum testosterone levels and markedly higher follicle-stimulating hormone levels. A chromosomal examination was performed. Computed tomography and magnetic resonance imaging imaging showed a neoplasm in the left lobe of the prostate, and immunohistochemical examination of a transrectal needle biopsy of the prostate was performed. DIAGNOSES: Chromosomal examination was exhibited a 47 XXY genotype. Histopathology and of Immunohistochemistry of the transrectal needle biopsy specimen confirmed a seminoma. No other neoplasm was found on systemic examination; therefore, the patient was diagnosed with primary prostate seminoma and Klinefelter syndrome. INTERVENTIONS: The patient refused any treatment except catheterization because of religious reason. OUTCOMES: The patient died 2 years later. LESSONS: Primary seminoma should be included in the differential diagnosis of neoplasms of the prostate in patients with KS. Transrectal ultrasound-guided prostate needle biopsy is essential for the diagnosis of prostate neoplasms, and cisplatin-based chemotherapy remains the primary treatment for seminoma.

Application of a three-dimensional visualization model in intraoperative guidance of percutaneous nephrolithotomy.

OBJECTIVES: To establish a three-dimensional visualization model of percutaneous nephrolithotomy, apply it to guiding intraoperative puncture in a mixed reality environment, and evaluate its accuracy and clinical value. METHODS: Patients with percutaneous nephrolithotomy indications were prospectively divided into three-dimensional group and control group with a ratio of 1:2. For patients in three-dimensional group, positioning markers were pasted on the skin and enhanced computed tomography scanning was performed in the prone position. Holographic three-dimensional models were made and puncture routes were planned before operation. During the operation, the three-dimensional model was displayed through HoloLens glass and visually registered with the patient's body. Puncture of the target renal calyx was performed under three-dimensional-image guiding and ultrasonic monitoring. Patients in the control group underwent routine percutaneous nephrolithotomy in the prone position under the monitoring of B-ultrasound. Deviation distance of the kidney, puncture time, puncture attempts, channel coincidence rate, stone clearance rate, and postoperative complications were assessed. RESULTS: Twenty-one and 40 patients were enrolled in three-dimensional and control group, respectively. For three-dimensional group, the average deviation between virtual and real kidney was 3.1 ± 2.9 mm. All punctures were performed according to preoperative planning. Compared with the control group, the three-dimensional group had shorter puncture time (8.9 ± 3.3 vs 14.5 ± 6.1 min, P < 0.001), fewer puncture attempts (1.4 ± 0.6 vs 2.2 ± 1.5, P = 0.009), and might also have a better performance in stone clearance rate (90.5% vs 72.5%, P = 0.19) and postoperative complications (P = 0.074). CONCLUSIONS: The percutaneous nephrolithotomy three-dimensional model manifested acceptable accuracy and good value for guiding puncture in a mixed reality environment.

Quality-of-Life Evaluation among the Oldest-Old in China under the "Active Aging Framework".

China is facing an increasingly contradictory challenge between growing demand for health services for the oldest-old and the unbalanced and inadequate development in the context of rapid population aging. This study sought to evaluate the quality of life of the oldest-old in China under the active aging framework. Health, participation, and security data were sourced from China Statistics/Labor Statistics/Civil Affairs Yearbook 2000-2016 and National 1% Sample Survey Data 2005-2015. Then, we used the current life table, entropy method, coefficient variation, and panel data regression to evaluate the quality of life among the oldest-old and reveal its regional differences and mechanisms. The results show: (1) From 2005 to 2015, the overall quality of life in China steadily improved, and the quality of health, participation, and security of the oldest-old increased by 6.06%, 5.64%, and 47.48%, respectively. (2) Distinct regional disparities exist in the distribution of quality of life for the oldest-old in China; the "east-northeast-middle-west" stepped-declining pattern existed stably. (3) Population and family structure, economic development, and social security were the main reasons for the regional differences in quality of life for the oldest-old. Narrowing the socioeconomic gap between regions, promoting the function of family pension, and improving social old-age service supply will help improve the quality of life of the oldest-old.

The Antibody Response Against Neuraminidase in Human Influenza A (H3N2) Virus Infections During 2018/2019 Flu Season: Focusing on the Epitopes of 329-N-Glycosylation and E344 in N2.

Seasonal influenza A (H3N2) virus has been a concern since its first introduction in humans in 1968. Accumulating antigenic changes in viral hemagglutinin (HA), particularly recent cocirculations of multiple HA genetic clades, allow H3N2 virus evade into humans annually. From 2010, the binding of neuraminidase (NA) to sialic acid made the traditional assay for HA inhibition antibodies (Abs) unsuitable for antigenicity characterization. Here, we investigated the serum anti-NA response in a cohort with a seroconversion of microneutralizing (MN) Abs targeting the circulating strain, A/Singapore/INFIMH-16-0019/2016 (H3N2, 3C.2a1)-like, a virus during 2018/2019 flu seasons. We discovered that MN Ab titers show no difference between children and adults. Nevertheless, higher titers of Abs with NA activity inhibition (NI) activity of 129 and seroconversion rate of 68.42% are presented in children aged 7-17 years (n = 19) and 73.47 and 41.17% in adults aged 21-59 years (n = 17), respectively. The MN Abs generated in children display direct correlations with HA- and NA-binding Abs or NI Abs. The NI activity exhibited cross-reactivity to N2 of H3N2 viruses of 2007 and 2013, commonly with 329-N-glycosylation and E344 in N2, a characteristic of earlier 3C.2a H3N2 virus in 2014. The percentage of such viruses pronouncedly decreased and was even replaced by those dominant H3N2 viruses with E344K and 329 non-glycosylation, which have a significantly low activity to the tested antisera. Our findings suggest that NI assay is a testable assay applied in H3N2 infection in children, and the antigenic drift of current N2 should be considered for vaccine selection.

Homologous PB1 gene promotes the replication efficiency of avian influenza H7N4 candidate vaccine virus.

BACKGROUND: The first and only case of human infection with the avian influenza A (H7N4) virus in China emerged in 2018. The H7N4 virus was distinct from previous H7N9 viruses and raised public concerns. Therefore, developing a suitable H7N4 candidate vaccine virus (CVV) remains crucial for potential pandemic preparedness. METHODS: We constructed a reassortant virus with a (6 + 2) genome composition, then introduced the polymerase basic protein 1 (PB1) from a wild-type virus to develop a (5 + 3) reassortant virus through reverse genetics. We performed whole-genome sequencing to confirm the genome stability, assessed the growth ability in MDCK cells, and analyzed virus antigenicity using hemagglutination inhibition assays. Subsequently, the effect of homologous PB1 on polymerase activity, viral protein yield, and pathogenicity was assessed. RESULTS: The (5 + 3) virus harbouring the homologous PB1 gene exhibited significantly improved growth characteristics, higher viral protein yield, and polymerase activity than the (6 + 2) virus. After successive passage in embryonated eggs, glutamic acid (E) substituted glycine(G) at position 218 (H3 numbering) in the hemagglutinin (HA) gene of both (5 + 3) and (6 + 2) viruses. The substitution improved the growth of the (6 + 2) virus but exhibited no significant effect or alteration on the antigenicity of the (5 + 3) virus. Moreover, the (5 + 3) virus exhibited low pathogenicity in chickens and ferrets. CONCLUSION: Homologous PB1 of the H7N4 virus improves the growth ability while sustaining low pathogenicity. Collectively, the gene composition of the (5 + 3) reassortant virus is a suitable H7N4 CVV for potential pandemic preparedness.

Synaptic changes modulate spontaneous transitions between tonic and bursting neural activities in coupled Hindmarsh-Rose neurons.

Experimentally, certain cells in the brain exhibit a spike-burst activity with burst synchronization at transition to and during sleep (or drowsiness), while they demonstrate a desynchronized tonic activity in the waking state. We herein investigated the neural activities and their transitions by using a model of coupled Hindmarsh-Rose neurons in an Erdos-Rényi random network. By tuning synaptic strength, spontaneous transitions between tonic and bursting neural activities can be realized. With excitatory chemical synapses or electrical synapses, slow-wave activity (SWA) similar to that observed during sleep can appear, as a result of synchronized bursting activities. SWA cannot appear in a network that is dominated by inhibitory chemical synapses, because neurons exhibit desynchronized bursting activities. Moreover, we found that the critical synaptic strength related to the transitions of neural activities depends only on the network average degree (i.e., the average number of signals that all the neurons receive). We demonstrated, both numerically and analytically, that the critical synaptic strength and the network average degree obey a power-law relation with an exponent of -1. Our study provides a possible dynamical network mechanism of the transitions between tonic and bursting neural activities for the wakefulness-sleep cycle, and of the SWA during sleep. Further interesting and challenging investigations are briefly discussed as well.